The dermatoscope revealed a fine reticular network around a central scar, which confirmed a diagnosis of dermatofibroma. A dermatofibroma is a benign fibrohistiocytic tumor found in the mid dermis, composed of a mixture of fibroblastic and histiocytic cells. It represents a fibrous reaction triggered by trauma, a viral infection, or an insect bite. Many dermatofibromas have a hyperpigmented halo around a central hypopigmented fibrous scar.

Dermoscopy is a very useful diagnostic technique for dermatofibroma. The most common pattern found is a peripheral reticular pigment network with a central hypopigmented stellate area.

No treatment is necessary unless the diagnosis is uncertain or symptoms warrant it. Dermatofibromas can be removed using punch excision for small lesions or an elliptical (fusiform) excision down to the subcutaneous fat for larger lesions. Cryotherapy is one option to shrink the lesion, but the cure rate is low and lesions may regrow.

The patient was relieved that the lesion was not cancer and opted to leave it be, as it was not bothering him.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Usatine R. Dermatofibroma. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 935-939.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The dermatoscope revealed a fine reticular network around a central scar, which confirmed a diagnosis of dermatofibroma. A dermatofibroma is a benign fibrohistiocytic tumor found in the mid dermis, composed of a mixture of fibroblastic and histiocytic cells. It represents a fibrous reaction triggered by trauma, a viral infection, or an insect bite. Many dermatofibromas have a hyperpigmented halo around a central hypopigmented fibrous scar.

Dermoscopy is a very useful diagnostic technique for dermatofibroma. The most common pattern found is a peripheral reticular pigment network with a central hypopigmented stellate area.

No treatment is necessary unless the diagnosis is uncertain or symptoms warrant it. Dermatofibromas can be removed using punch excision for small lesions or an elliptical (fusiform) excision down to the subcutaneous fat for larger lesions. Cryotherapy is one option to shrink the lesion, but the cure rate is low and lesions may regrow.

The patient was relieved that the lesion was not cancer and opted to leave it be, as it was not bothering him.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Usatine R. Dermatofibroma. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 935-939.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

The dermatoscope revealed a fine reticular network around a central scar, which confirmed a diagnosis of dermatofibroma. A dermatofibroma is a benign fibrohistiocytic tumor found in the mid dermis, composed of a mixture of fibroblastic and histiocytic cells. It represents a fibrous reaction triggered by trauma, a viral infection, or an insect bite. Many dermatofibromas have a hyperpigmented halo around a central hypopigmented fibrous scar.

Dermoscopy is a very useful diagnostic technique for dermatofibroma. The most common pattern found is a peripheral reticular pigment network with a central hypopigmented stellate area.

No treatment is necessary unless the diagnosis is uncertain or symptoms warrant it. Dermatofibromas can be removed using punch excision for small lesions or an elliptical (fusiform) excision down to the subcutaneous fat for larger lesions. Cryotherapy is one option to shrink the lesion, but the cure rate is low and lesions may regrow.

The patient was relieved that the lesion was not cancer and opted to leave it be, as it was not bothering him.

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Smith M. Usatine R. Dermatofibroma. In: Usatine R, Smith M, Mayeaux EJ, et al, eds. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013: 935-939.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/

You can now get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com

Many patients present to their primary care physicians, urgent care centers, and emergency rooms because of neurologic symptoms lasting seconds to hours. Their problems can be a cause for concern and a challenge to diagnose, as in many cases their symptoms have returned to baseline by the time of evaluation. Referral to a neurologist may not be practical for all of them, particularly given that a consultation may take a long time to obtain.

Understanding the causes of transient neurologic syndromes and their phenomenology may help the clinician diagnose, triage, and treat such conditions effectively.

Here, we outline several transient neurologic syndromes—transient ischemic attack (TIA), migraine with aura, partial seizures, hypoglycemic encephalopathy, hyperventilation syndrome, transient global amnesia, narcolepsy, parasomnias, and some rarer conditions— focusing on their diagnostic elements. Others, such as drug-induced transient neurologic syndromes, vertigo, and dizziness, have been well discussed elsewhere.^1–3

THE BIG 3: TIA, MIGRAINE, SEIZURES

A 45-year-old woman with a history of tobacco use and headaches presents to the emergency department with a 4-month history of episodic numbness and tingling of her right arm and face. She reports a prodromal state of anxiety and irritability 24 to 48 hours before symptom onset.

The sensory symptoms begin on her face and gradually progress down the arm and eventually to her fingers. They fully resolve within 2 hours without sequelae. Family members have noted some “slurred speech” during the episodes, and the episodes are occasionally preceded by a unilateral, throbbing headache that improves with rest.

What are the possible causes of her symptoms?

Transient ischemic attack

If a patient reports transient neurologic symptoms and has vascular risk factors, TIA is often the default diagnostic consideration. The risk of stroke is 9.9% in the 2 days after a TIA, 13.4% at 30 days, and 17.3% at 90 days.⁴ Rapid recognition offers a crucial period to minimize the possibility of permanent impairment. Interventions include modifying risk factors (hypertension, diabetes, and smoking) and starting an antiplatelet drug, an anticoagulant drug, or both, and possibly a statin.

It can be difficult to determine if this workup needs to be completed in the inpatient or outpatient setting. There is no clear consensus, but the ultimate goal is timely evaluation (within 24 to 48 hours). The ABCD2 (Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) risk factor calculator was developed to help triage patients, though it has limitations.^5,6

One should assess a patient’s history of a possible TIA in a stepwise fashion. First, analyze the patient’s age and demographics for known vascular risk factors or central embolic sources (eg, atrial fibrillation). Then consider the symptoms. TIA symptoms have rapid onset, usually within seconds⁷; symptoms with a more gradual crescendo suggest a nonvascular cause.⁸ TIA manifestations should resolve within 1 hour, and most studies suggest symptom resolution within 10 minutes is specific for a TIA.^9–11 TIA symptoms are negative neurologic phenomena that denote a loss of function, such as loss of vision, motor weakness, or sensory numbness.

Symptoms should also correlate with a defined vascular territory:

• The middle cerebral artery is commonly involved; its blockage is associated with aphasia, weakness of the face and arm, and homonymous visual field impairment (loss of one-half of the visual fields in both eyes)
• Blockage in the posterior circulation generally causes symptoms localized to the brainstem, cerebellum, and occipital cortex. The symptoms are usually grouped together as the “5Ds”: dizziness, diplopia, dysarthria, dysphagia, and dystaxia/ataxia. Brainstem involvement classically produces “crossed” findings, with ipsilateral cranial findings and contralateral motor or sensory findings.
• Lacunar strokes involve the subcortical white matter and produce typical patterns including pure motor or sensory syndromes.

Loss of consciousness is rarely a symptom of TIA and should suggest another etiology.

The definition of TIA has evolved from an operational one, ie, symptoms lasting less than 24 hours, to a tissue-based one, ie, focal cerebral ischemia not associated with permanent cerebral infarction.¹² Though imperfect, this pathophysiology should help reinforce the most common features of TIA, including a sudden onset of negative symptoms that are localized to a defined vascular territory.^13,14

Migraine with aura

Migraine with aura is common in patients ages 25 to 55 who have a long-standing history of headache. The pathophysiologic mechanism of an aura is believed to be a disseminating wave of cortical depression, which is a self-propagating wave of neural depression and then activation. Ultimately, this leads to a cascade of inflammatory and pain signals, resulting in a headache.

This background helps explain the positive (superimposed) symptoms associated with the aura. Positive symptoms are produced by excessive neuronal discharges stimulating the visual (flashing lights, zigzag lines), sensory (paresthesias), or motor (limb movements) pathways.

Common symptoms associated with aura include visual disturbances such as scintillating scotoma (a blind spot), sensory changes such as tingling, or auditory disruption with tinnitus. Symptoms may evolve over the course of 5 to 20 minutes, first affecting vision and then other senses. In contrast, in a TIA, symptoms usually begin simultaneously and are confined to a vascular territory.^7,15 Symptoms of an aura usually resolve within an hour, but there is evidence showing a substantial number of patients have an aura lasting much longer.¹⁶ Focal weakness is uncommon during an aura but is reported in specific migraine conditions such as hemiplegic migraine and migraine with unilateral motor symptoms. The vast majority of patients experience other neurologic symptoms during this prodrome.^17,18

The prodromal period (2 to 48 hours leading up to the onset of migraine) is a commonly overlooked feature of migraine.¹⁹ Common symptoms during this time include fatigue, mood change, and gastrointestinal symptoms.²⁰ One study demonstrated that patients generally had good intuition concerning these nonspecific prodromal symptoms and could predict the onset of migraine 72% of the time.²¹

In addition, a myriad of possible triggers and exacerbating factors can be identified (and sometimes avoided) such as visual stimuli, weather changes, nitrates, sleep disturbances, menstruation, foods, and stressors.²²

Although headache is often the cardinal manifestation of migraine, some patients experience aura without headache—acephalgic migraine.²³ This can be a diagnostic challenge, especially in an older population with multiple vascular risk factors. New-onset acephalgic migraine may be a cause for concern but is not uncommon and is not associated with a significantly increased risk of stroke.²⁴ Focusing on the character of the neurologic symptoms in regard to timing, progression, and resolution will help differentiate this disease from other transient neurologic syndromes.²⁵

Partial seizure produces a diverse range of stereotypical symptoms due to focal abnormal neuronal activation. The aberrant electrical firing generates positive symptoms involving the motor, sensory, or visual pathway. A history of trauma, neurosurgical intervention, central nervous system infection, stroke, or other seizure foci can suggest this diagnosis. Other prodromal clues include abdominal discomfort, sense of detachment, déjà vu, or jamais vu.²⁶

During a seizure, there may be a progression of positive symptoms similar to what happens in migraine aura, because both represent cortical spread and depression.

Involvement of the motor pathway may produce tonic (stiffening) or clonic (twitching) movement. Other common motor abnormalities include automatisms such as lip smacking, chewing, and hand gestures (picking, fidgeting, fumbling).²⁷

Epileptic discharges in the sensory cortex commonly cause paresthesias or distortion of a sensory input. Visual symptoms may be more complex. In occipital epilepsy, circular phenomena with a colored pattern are common, which contrasts with the photopsia (flashes of light) or fortification (a bright zigzag of lines resembling a fort) seen in migraines.²⁸

Autonomic or somatosensory symptoms can also occur.

Todd paralysis, also called transient postictal paralysis, occurs in only 13% of seizures but can linger for 0.5 to 36 hours.^29,30 This weakness is most pronounced within the affected region after a partial seizure.

In general, focal seizures are often stereotyped with positive neurologic features, usually last a few minutes, and resolve fully. These episodes may cause an arrest in activity but not usually loss of consciousness unless the epileptic discharge secondarily generalizes into the adjacent hemisphere.

A common differential diagnosis encountered during an epilepsy workup is psychogenic nonepileptic seizures. Nonepileptic seizures consist of transient, abnormal movements, sensation, or cognition but lack ictal electroencephalographic changes. This is a specifically challenging patient population, with high healthcare utilization and high risk for iatrogenic harm. In addition, on average, diagnosis can take years to establish and usually requires referral to a tertiary care facility.^31,32

The big 3: Back to our patient

Our patient’s vascular risk factors, transient symptoms, and language involvement support the diagnosis of TIA. A feature that points away from the diagnosis of TIA is the gradual onset of positive neurologic symptoms. This pattern is not consistent with neuronal ischemia.

Also, our patient had a repetitive, stereotypical pattern of symptoms, which supports including partial seizures in the differential diagnosis. On the other hand, her lack of risk factors for seizure (a history of febrile seizures, developmental delay, trauma, or infection) would make this diagnosis less likely. Also pointing away from the diagnosis of seizures are her lack of typical prodromal symptoms, the length of the events, and the postevent headache.

Table 1 summarizes the clinical findings associated with TIA, migraine, and partial seizure.

EPISODES OF CONFUSION

A 35-year-old woman with a history of depression, anxiety, and poorly controlled type 1 diabetes presents to the clinic after several weeks of episodes of confusion, usually accompanied by paresthesias in both hands, dizziness, and palpitations. In each episode, soon after the symptoms began, she had painful cramps in her hand. The symptoms fully resolved within 10 minutes without sequelae.

Questioned further, the patient describes the confusion as a “mental haze” but denies frank disorientation. She has not kept a log of her blood sugar levels but has not noticed a temporal relationship with regard to her meals or insulin injections.

What are the possible causes of these episodes?

Hypoglycemic encephalopathy

Hypoglycemia is common in most people with diabetes, who have been reported to suffer from 62 to 320 severe hypoglycemic episodes in their lifetime.^33,34 The neurologic consequences can be devastating in these severe cases.

During mild to moderate drops in the glucose level, generalized symptoms stem from sympathetic activation. These include generalized anxiety, tremor, palpitations, and sweating. Focal symptoms such as unilateral weakness have also been reported.^35,36

Unfortunately, people with long-standing diabetes have a blunted response to epinephrine that reduces their sensitivity to hypoglycemia, placing them at high risk of permanent neurologic damage. This can lead to seizures and coma, as the hypoglycemia has a greater effect on cortical and subcortical structures (highly metabolic areas) than on the brainstem. Thus, respiratory and cardiovascular function is maintained but cerebral function is abnormal. If this state is prolonged, brain death can occur.^37,38

Hyperventilation syndrome

Hyperventilation syndrome is not well characterized. Most think of it as synonymous with an underlying psychopathology, but there is evidence to suggest it can occur without underlying anxiety.

There is no clear mechanism, but it is hypothesized that diminished carbon dioxide levels lead to cerebral vasoconstriction. This may lead to reduced cerebral blood flow, causing dizziness, lightheadedness, or vertigo.³⁹ Appendicular symptoms including paresthesias, carpopedal spasm, or tetany have been core features since the syndrome was first described in the early 1900s.⁴⁰

Though the disorder has rather nonspecific features, it can be easily reproduced in the clinical setting by asking the patient to breathe deeply and rapidly. This can help confirm the underlying diagnosis and also reassure the patient that the underlying pathology is not life-threatening and that he or she has some control over the disease.

Transient global amnesia usually strikes older patients (50 to 70 years old) in the setting of an acute physical or emotional stressor. There is also a correlation between transient global amnesia and migraine, with studies showing migraineurs are at higher risk than the general population.⁴¹ Despite common clinical concerns, there is no relationship between transient global amnesia and stroke.⁴²

Transient global amnesia is defined by acute transient anterograde amnesia (coding of new memories). To try to reorient themselves, patients will repeatedly ask questions such as “What day is it?” or “Why are we here?” Retrograde memories, especially long-standing ones, are usually well preserved. The patient’s cognition is otherwise intact, and there are no other focal neurologic symptoms. The event usually lasts 2 to 24 hours and resolves without sequelae.^43,44 Afterward, patients remember the event only poorly, which supports the notion that they cannot code new memories.

Confusional episodes: Discussion

Evaluating confusional episodes can be time-consuming and vexing. The subjective nature of the symptoms and the vast differential diagnosis can be overwhelming. Subtle clinical details can help formulate an appropriate evaluation.

Hypoglycemia can produce bizarre neurologic symptoms. Most cases of hypoglycemia produce an exaggerated sympathetic response, though this is blunted in people with longstanding diabetes. In addition, there should be a temporal association with meals, insulin doses, or both.

Transient global amnesia usually occurs with acute stressors and produces a confusional state. These episodes rarely recur, and the patient cannot provide much history regarding the episode secondary to the anterograde amnesia.

Table 2 summarizes the clinical findings associated with hypoglycemic encephalopathy, hyperventilation syndrome, and transient global amnesia.

Back to our patient

In our patient, the likely diagnosis is hyperventilation syndrome, even though we don’t know if her respiratory rate is increased during attacks. Some patients lack awareness of their breathing or are too distracted by the vague symptoms to have insight into the true cause. The cramps and contractions in the hands are a specific feature of the disease and can be accompanied by confusion.

SLEEP DISORDERS

A 17-year-old boy with a history of depression and anxiety presents to his pediatrician because he has had difficulty staying awake in school over the past year. His sleepiness has gradually worsened over the last few months and has taken a toll on his grades, leading to discord in his family. Over the past month he has had some difficulty holding his head up during arguments with friends. He does not lose consciousness during these events but is described as “unresponsive.” He describes vivid dreams when going to sleep that have startled him awake at times. His family history is positive for somnambulism on his father’s side.

Does this patient have a sleep disorder, and if so, which one?

Narcolepsy

Narcolepsy is defined by excessive daytime sleepiness, cataplexy, hypnagogic hallucination, and sleep paralysis. It is more common in men but its prevalence varies widely by geographic region, supporting an underlying interplay between genetics and environment.⁴⁵

Sleep attacks or excessive daytime sleepiness are the cardinal features of narcolepsy. The dissociation between the sleep-wake cycle is evident with rapid transition into rapid-eye-movement (REM) sleep during these sleep attacks. This results in a “refreshing nap” that commonly involves vivid dreams. These episodes occur about 3 to 5 times per day, varying in duration from a few minutes to hours.⁴⁶

Cataplexy is very specific feature of narcolepsy. Triggered by strong emotion, the body loses skeletal muscle tone except for the diaphragm and ocular muscles. The patient does not lose consciousness and remains aware of his or her environment. Of note, the loss of tone does not need to be dramatic. The hypotonia can manifest as jaw-dropping or head-nodding. The paralysis is related to prolonged REM atonia and impaired transition from sleep to wakefulness.⁴⁷ Hypnagogic hallucination and sleep paralysis can occur, together with vivid visual hallucinations.

Parasomnias: Somnambulism and night terrors

Most non-REM parasomnias occur in childhood and diminish in adulthood. Two of the most common disorders are sleepwalking (somnambulism) and night terrors. Both are characterized by arousal from slow-wave sleep and are commonly associated with sedating medication, sleep deprivation, or psychopathology.

In somnambulism, patients exhibit complex motor behavior without interaction with their environment. Most have little recollection of the event.⁴⁸ Sleep terrors produce a more intense reaction. The patient erupts out of sleep with profound terror, confusion, and autonomic changes. Interestingly, the patient can normally fall right back into sleep after the event.^49–51

Back to our patient

Excessive daytime sleepiness and generalized fatigue are commonly encountered in outpatients. They can be frustrating because in many cases, no clear etiology can be discovered.⁵²

This patient has several risk factors for parasomnias. His history of anxiety and depression in the setting of recent stressors sets the stage for night terrors. In addition, like many patients with parasomnias, he has a family history of sleep disorders. His vivid dreams make night terrors possible, but without the stark sympathetic activation it is a less likely diagnosis. It also does not account for the other symptoms he describes.

Our patient’s excessive daytime sleepiness interfering with daily activities, cataplexy, and hypnagogic hallucinations support the diagnosis of narcolepsy. This case highlights the variable weakness experienced during a cataplexy attack. It can range from a simple head droop to complete paralysis. Subtle findings require specific probing by the clinician. Patients with narcolepsy typically present in their late teens to early adulthood, but the cataplexy attacks may develop later in the disease course.

Table 3 summarizes the clinical findings associated with night terrors, somnambulism, and narcolepsy.

Transient (paroxysmal) neurologic events in multiple sclerosis

A less well-known phenomenon in multiple sclerosis is termed “transient” (paroxysmal) neurologic events. These are typically stereotyped episodes lasting seconds, occurring sometimes hundreds of times a day. They are thought to arise from spontaneous electrical activity in an area of demyelination (ephaptic transmission), creating a wide range of symptoms. Some common events include positive sensory symptoms, alteration of the motor system such as spasms, or brainstem symptoms.⁵³

Channelopathy

Two prototypical channelopathies are hyperkalemic and hypokalemic periodic paralysis. They are rare conditions, usually inherited in an autosomal dominant pattern.⁵⁴ Both produce episodic, flaccid weakness in the setting of activity or other stressors (fasting, pregnancy, an emotionally charged episode). The attacks last a few minutes to hours and affect proximal skeletal muscles, with very little respiratory or bulbar involvement.

Hyperkalemic periodic paralysis is also associated with myotonia, which is the inability to voluntarily relax after stimulation. This can be evident after shaking a patient’s hand, as he or she would be unable to release because of the sustained activation. The myotonia is evident between attacks and may help cue a physician to the diagnosis even if the weakness has abated.⁵⁵

As the name implies, potassium levels can vary during the attack, though hyperkalemic periodic paralysis can be seen with normal levels of serum potassium. The underlying pathology is tied to a voltage-gated sodium channel or calcium channel necessary for action potential generation.⁵⁶

Paroxysmal dyskinesias

Paroxysmal dyskinesias encompass a rare group of movement disorders characterized by attacks without alterations in consciousness. Patients have reported dystonic, choreoathetotic, or ballistic movements. The attacks can be triggered by stress, eating, or even other types of movements. Most reported cases have a strong family history and are inherited in an autosomal dominant pattern. The exact pathophysiology is unclear. When paroxysmal dyskinesia was initially discovered, many thought it was a form of epilepsy, but the lack of electroencephalographic changes and postictal events argues against this etiology.

Transient focal neurologic episodes in cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a degenerative condition in which amyloid is deposited in cerebral vessels, making them friable and at risk of bleeding. Most patients have no symptoms whatsoever, and the diagnosis is made by magnetic resonance imaging. Small microbleeds are common, but lobar intraparenchymal hemorrhage is the most feared complication.

Transient focal neurologic episodes, sometimes termed “amyloid spells,” are recurrent, stereotyped neurologic events that are spurred by cortical superficial siderosis (deposition of iron). Unfortunately, these events are difficult to characterize by their clinical morphology. The events can involve the visual, motor, and sensory pathways with both positive and negative symptoms, making the diagnosis difficult without imaging. These events may precede a symptomatic intraparenchymal hemorrhage, offering a unique window to reconsider the decision to continue an antiplatelet or anticoagulant drug.^57,58

Many patients present to their primary care physicians, urgent care centers, and emergency rooms because of neurologic symptoms lasting seconds to hours. Their problems can be a cause for concern and a challenge to diagnose, as in many cases their symptoms have returned to baseline by the time of evaluation. Referral to a neurologist may not be practical for all of them, particularly given that a consultation may take a long time to obtain.

Understanding the causes of transient neurologic syndromes and their phenomenology may help the clinician diagnose, triage, and treat such conditions effectively.

Here, we outline several transient neurologic syndromes—transient ischemic attack (TIA), migraine with aura, partial seizures, hypoglycemic encephalopathy, hyperventilation syndrome, transient global amnesia, narcolepsy, parasomnias, and some rarer conditions— focusing on their diagnostic elements. Others, such as drug-induced transient neurologic syndromes, vertigo, and dizziness, have been well discussed elsewhere.^1–3

THE BIG 3: TIA, MIGRAINE, SEIZURES

A 45-year-old woman with a history of tobacco use and headaches presents to the emergency department with a 4-month history of episodic numbness and tingling of her right arm and face. She reports a prodromal state of anxiety and irritability 24 to 48 hours before symptom onset.

The sensory symptoms begin on her face and gradually progress down the arm and eventually to her fingers. They fully resolve within 2 hours without sequelae. Family members have noted some “slurred speech” during the episodes, and the episodes are occasionally preceded by a unilateral, throbbing headache that improves with rest.

What are the possible causes of her symptoms?

Transient ischemic attack

If a patient reports transient neurologic symptoms and has vascular risk factors, TIA is often the default diagnostic consideration. The risk of stroke is 9.9% in the 2 days after a TIA, 13.4% at 30 days, and 17.3% at 90 days.⁴ Rapid recognition offers a crucial period to minimize the possibility of permanent impairment. Interventions include modifying risk factors (hypertension, diabetes, and smoking) and starting an antiplatelet drug, an anticoagulant drug, or both, and possibly a statin.

It can be difficult to determine if this workup needs to be completed in the inpatient or outpatient setting. There is no clear consensus, but the ultimate goal is timely evaluation (within 24 to 48 hours). The ABCD2 (Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) risk factor calculator was developed to help triage patients, though it has limitations.^5,6

One should assess a patient’s history of a possible TIA in a stepwise fashion. First, analyze the patient’s age and demographics for known vascular risk factors or central embolic sources (eg, atrial fibrillation). Then consider the symptoms. TIA symptoms have rapid onset, usually within seconds⁷; symptoms with a more gradual crescendo suggest a nonvascular cause.⁸ TIA manifestations should resolve within 1 hour, and most studies suggest symptom resolution within 10 minutes is specific for a TIA.^9–11 TIA symptoms are negative neurologic phenomena that denote a loss of function, such as loss of vision, motor weakness, or sensory numbness.

Symptoms should also correlate with a defined vascular territory:

• The middle cerebral artery is commonly involved; its blockage is associated with aphasia, weakness of the face and arm, and homonymous visual field impairment (loss of one-half of the visual fields in both eyes)
• Blockage in the posterior circulation generally causes symptoms localized to the brainstem, cerebellum, and occipital cortex. The symptoms are usually grouped together as the “5Ds”: dizziness, diplopia, dysarthria, dysphagia, and dystaxia/ataxia. Brainstem involvement classically produces “crossed” findings, with ipsilateral cranial findings and contralateral motor or sensory findings.
• Lacunar strokes involve the subcortical white matter and produce typical patterns including pure motor or sensory syndromes.

Loss of consciousness is rarely a symptom of TIA and should suggest another etiology.

The definition of TIA has evolved from an operational one, ie, symptoms lasting less than 24 hours, to a tissue-based one, ie, focal cerebral ischemia not associated with permanent cerebral infarction.¹² Though imperfect, this pathophysiology should help reinforce the most common features of TIA, including a sudden onset of negative symptoms that are localized to a defined vascular territory.^13,14

Migraine with aura

Migraine with aura is common in patients ages 25 to 55 who have a long-standing history of headache. The pathophysiologic mechanism of an aura is believed to be a disseminating wave of cortical depression, which is a self-propagating wave of neural depression and then activation. Ultimately, this leads to a cascade of inflammatory and pain signals, resulting in a headache.

This background helps explain the positive (superimposed) symptoms associated with the aura. Positive symptoms are produced by excessive neuronal discharges stimulating the visual (flashing lights, zigzag lines), sensory (paresthesias), or motor (limb movements) pathways.

Common symptoms associated with aura include visual disturbances such as scintillating scotoma (a blind spot), sensory changes such as tingling, or auditory disruption with tinnitus. Symptoms may evolve over the course of 5 to 20 minutes, first affecting vision and then other senses. In contrast, in a TIA, symptoms usually begin simultaneously and are confined to a vascular territory.^7,15 Symptoms of an aura usually resolve within an hour, but there is evidence showing a substantial number of patients have an aura lasting much longer.¹⁶ Focal weakness is uncommon during an aura but is reported in specific migraine conditions such as hemiplegic migraine and migraine with unilateral motor symptoms. The vast majority of patients experience other neurologic symptoms during this prodrome.^17,18

The prodromal period (2 to 48 hours leading up to the onset of migraine) is a commonly overlooked feature of migraine.¹⁹ Common symptoms during this time include fatigue, mood change, and gastrointestinal symptoms.²⁰ One study demonstrated that patients generally had good intuition concerning these nonspecific prodromal symptoms and could predict the onset of migraine 72% of the time.²¹

In addition, a myriad of possible triggers and exacerbating factors can be identified (and sometimes avoided) such as visual stimuli, weather changes, nitrates, sleep disturbances, menstruation, foods, and stressors.²²

Although headache is often the cardinal manifestation of migraine, some patients experience aura without headache—acephalgic migraine.²³ This can be a diagnostic challenge, especially in an older population with multiple vascular risk factors. New-onset acephalgic migraine may be a cause for concern but is not uncommon and is not associated with a significantly increased risk of stroke.²⁴ Focusing on the character of the neurologic symptoms in regard to timing, progression, and resolution will help differentiate this disease from other transient neurologic syndromes.²⁵

Partial seizure produces a diverse range of stereotypical symptoms due to focal abnormal neuronal activation. The aberrant electrical firing generates positive symptoms involving the motor, sensory, or visual pathway. A history of trauma, neurosurgical intervention, central nervous system infection, stroke, or other seizure foci can suggest this diagnosis. Other prodromal clues include abdominal discomfort, sense of detachment, déjà vu, or jamais vu.²⁶

During a seizure, there may be a progression of positive symptoms similar to what happens in migraine aura, because both represent cortical spread and depression.

Involvement of the motor pathway may produce tonic (stiffening) or clonic (twitching) movement. Other common motor abnormalities include automatisms such as lip smacking, chewing, and hand gestures (picking, fidgeting, fumbling).²⁷

Epileptic discharges in the sensory cortex commonly cause paresthesias or distortion of a sensory input. Visual symptoms may be more complex. In occipital epilepsy, circular phenomena with a colored pattern are common, which contrasts with the photopsia (flashes of light) or fortification (a bright zigzag of lines resembling a fort) seen in migraines.²⁸

Autonomic or somatosensory symptoms can also occur.

Todd paralysis, also called transient postictal paralysis, occurs in only 13% of seizures but can linger for 0.5 to 36 hours.^29,30 This weakness is most pronounced within the affected region after a partial seizure.

In general, focal seizures are often stereotyped with positive neurologic features, usually last a few minutes, and resolve fully. These episodes may cause an arrest in activity but not usually loss of consciousness unless the epileptic discharge secondarily generalizes into the adjacent hemisphere.

A common differential diagnosis encountered during an epilepsy workup is psychogenic nonepileptic seizures. Nonepileptic seizures consist of transient, abnormal movements, sensation, or cognition but lack ictal electroencephalographic changes. This is a specifically challenging patient population, with high healthcare utilization and high risk for iatrogenic harm. In addition, on average, diagnosis can take years to establish and usually requires referral to a tertiary care facility.^31,32

The big 3: Back to our patient

Our patient’s vascular risk factors, transient symptoms, and language involvement support the diagnosis of TIA. A feature that points away from the diagnosis of TIA is the gradual onset of positive neurologic symptoms. This pattern is not consistent with neuronal ischemia.

Also, our patient had a repetitive, stereotypical pattern of symptoms, which supports including partial seizures in the differential diagnosis. On the other hand, her lack of risk factors for seizure (a history of febrile seizures, developmental delay, trauma, or infection) would make this diagnosis less likely. Also pointing away from the diagnosis of seizures are her lack of typical prodromal symptoms, the length of the events, and the postevent headache.

Table 1 summarizes the clinical findings associated with TIA, migraine, and partial seizure.

EPISODES OF CONFUSION

A 35-year-old woman with a history of depression, anxiety, and poorly controlled type 1 diabetes presents to the clinic after several weeks of episodes of confusion, usually accompanied by paresthesias in both hands, dizziness, and palpitations. In each episode, soon after the symptoms began, she had painful cramps in her hand. The symptoms fully resolved within 10 minutes without sequelae.

Questioned further, the patient describes the confusion as a “mental haze” but denies frank disorientation. She has not kept a log of her blood sugar levels but has not noticed a temporal relationship with regard to her meals or insulin injections.

What are the possible causes of these episodes?

Hypoglycemic encephalopathy

Hypoglycemia is common in most people with diabetes, who have been reported to suffer from 62 to 320 severe hypoglycemic episodes in their lifetime.^33,34 The neurologic consequences can be devastating in these severe cases.

During mild to moderate drops in the glucose level, generalized symptoms stem from sympathetic activation. These include generalized anxiety, tremor, palpitations, and sweating. Focal symptoms such as unilateral weakness have also been reported.^35,36

Unfortunately, people with long-standing diabetes have a blunted response to epinephrine that reduces their sensitivity to hypoglycemia, placing them at high risk of permanent neurologic damage. This can lead to seizures and coma, as the hypoglycemia has a greater effect on cortical and subcortical structures (highly metabolic areas) than on the brainstem. Thus, respiratory and cardiovascular function is maintained but cerebral function is abnormal. If this state is prolonged, brain death can occur.^37,38

Hyperventilation syndrome

Hyperventilation syndrome is not well characterized. Most think of it as synonymous with an underlying psychopathology, but there is evidence to suggest it can occur without underlying anxiety.

There is no clear mechanism, but it is hypothesized that diminished carbon dioxide levels lead to cerebral vasoconstriction. This may lead to reduced cerebral blood flow, causing dizziness, lightheadedness, or vertigo.³⁹ Appendicular symptoms including paresthesias, carpopedal spasm, or tetany have been core features since the syndrome was first described in the early 1900s.⁴⁰

Though the disorder has rather nonspecific features, it can be easily reproduced in the clinical setting by asking the patient to breathe deeply and rapidly. This can help confirm the underlying diagnosis and also reassure the patient that the underlying pathology is not life-threatening and that he or she has some control over the disease.

Transient global amnesia usually strikes older patients (50 to 70 years old) in the setting of an acute physical or emotional stressor. There is also a correlation between transient global amnesia and migraine, with studies showing migraineurs are at higher risk than the general population.⁴¹ Despite common clinical concerns, there is no relationship between transient global amnesia and stroke.⁴²

Transient global amnesia is defined by acute transient anterograde amnesia (coding of new memories). To try to reorient themselves, patients will repeatedly ask questions such as “What day is it?” or “Why are we here?” Retrograde memories, especially long-standing ones, are usually well preserved. The patient’s cognition is otherwise intact, and there are no other focal neurologic symptoms. The event usually lasts 2 to 24 hours and resolves without sequelae.^43,44 Afterward, patients remember the event only poorly, which supports the notion that they cannot code new memories.

Confusional episodes: Discussion

Evaluating confusional episodes can be time-consuming and vexing. The subjective nature of the symptoms and the vast differential diagnosis can be overwhelming. Subtle clinical details can help formulate an appropriate evaluation.

Hypoglycemia can produce bizarre neurologic symptoms. Most cases of hypoglycemia produce an exaggerated sympathetic response, though this is blunted in people with longstanding diabetes. In addition, there should be a temporal association with meals, insulin doses, or both.

Transient global amnesia usually occurs with acute stressors and produces a confusional state. These episodes rarely recur, and the patient cannot provide much history regarding the episode secondary to the anterograde amnesia.

Table 2 summarizes the clinical findings associated with hypoglycemic encephalopathy, hyperventilation syndrome, and transient global amnesia.

Back to our patient

In our patient, the likely diagnosis is hyperventilation syndrome, even though we don’t know if her respiratory rate is increased during attacks. Some patients lack awareness of their breathing or are too distracted by the vague symptoms to have insight into the true cause. The cramps and contractions in the hands are a specific feature of the disease and can be accompanied by confusion.

SLEEP DISORDERS

A 17-year-old boy with a history of depression and anxiety presents to his pediatrician because he has had difficulty staying awake in school over the past year. His sleepiness has gradually worsened over the last few months and has taken a toll on his grades, leading to discord in his family. Over the past month he has had some difficulty holding his head up during arguments with friends. He does not lose consciousness during these events but is described as “unresponsive.” He describes vivid dreams when going to sleep that have startled him awake at times. His family history is positive for somnambulism on his father’s side.

Does this patient have a sleep disorder, and if so, which one?

Narcolepsy

Narcolepsy is defined by excessive daytime sleepiness, cataplexy, hypnagogic hallucination, and sleep paralysis. It is more common in men but its prevalence varies widely by geographic region, supporting an underlying interplay between genetics and environment.⁴⁵

Sleep attacks or excessive daytime sleepiness are the cardinal features of narcolepsy. The dissociation between the sleep-wake cycle is evident with rapid transition into rapid-eye-movement (REM) sleep during these sleep attacks. This results in a “refreshing nap” that commonly involves vivid dreams. These episodes occur about 3 to 5 times per day, varying in duration from a few minutes to hours.⁴⁶

Cataplexy is very specific feature of narcolepsy. Triggered by strong emotion, the body loses skeletal muscle tone except for the diaphragm and ocular muscles. The patient does not lose consciousness and remains aware of his or her environment. Of note, the loss of tone does not need to be dramatic. The hypotonia can manifest as jaw-dropping or head-nodding. The paralysis is related to prolonged REM atonia and impaired transition from sleep to wakefulness.⁴⁷ Hypnagogic hallucination and sleep paralysis can occur, together with vivid visual hallucinations.

Parasomnias: Somnambulism and night terrors

Most non-REM parasomnias occur in childhood and diminish in adulthood. Two of the most common disorders are sleepwalking (somnambulism) and night terrors. Both are characterized by arousal from slow-wave sleep and are commonly associated with sedating medication, sleep deprivation, or psychopathology.

In somnambulism, patients exhibit complex motor behavior without interaction with their environment. Most have little recollection of the event.⁴⁸ Sleep terrors produce a more intense reaction. The patient erupts out of sleep with profound terror, confusion, and autonomic changes. Interestingly, the patient can normally fall right back into sleep after the event.^49–51

Back to our patient

Excessive daytime sleepiness and generalized fatigue are commonly encountered in outpatients. They can be frustrating because in many cases, no clear etiology can be discovered.⁵²

This patient has several risk factors for parasomnias. His history of anxiety and depression in the setting of recent stressors sets the stage for night terrors. In addition, like many patients with parasomnias, he has a family history of sleep disorders. His vivid dreams make night terrors possible, but without the stark sympathetic activation it is a less likely diagnosis. It also does not account for the other symptoms he describes.

Our patient’s excessive daytime sleepiness interfering with daily activities, cataplexy, and hypnagogic hallucinations support the diagnosis of narcolepsy. This case highlights the variable weakness experienced during a cataplexy attack. It can range from a simple head droop to complete paralysis. Subtle findings require specific probing by the clinician. Patients with narcolepsy typically present in their late teens to early adulthood, but the cataplexy attacks may develop later in the disease course.

Table 3 summarizes the clinical findings associated with night terrors, somnambulism, and narcolepsy.

Transient (paroxysmal) neurologic events in multiple sclerosis

A less well-known phenomenon in multiple sclerosis is termed “transient” (paroxysmal) neurologic events. These are typically stereotyped episodes lasting seconds, occurring sometimes hundreds of times a day. They are thought to arise from spontaneous electrical activity in an area of demyelination (ephaptic transmission), creating a wide range of symptoms. Some common events include positive sensory symptoms, alteration of the motor system such as spasms, or brainstem symptoms.⁵³

Channelopathy

Two prototypical channelopathies are hyperkalemic and hypokalemic periodic paralysis. They are rare conditions, usually inherited in an autosomal dominant pattern.⁵⁴ Both produce episodic, flaccid weakness in the setting of activity or other stressors (fasting, pregnancy, an emotionally charged episode). The attacks last a few minutes to hours and affect proximal skeletal muscles, with very little respiratory or bulbar involvement.

Hyperkalemic periodic paralysis is also associated with myotonia, which is the inability to voluntarily relax after stimulation. This can be evident after shaking a patient’s hand, as he or she would be unable to release because of the sustained activation. The myotonia is evident between attacks and may help cue a physician to the diagnosis even if the weakness has abated.⁵⁵

As the name implies, potassium levels can vary during the attack, though hyperkalemic periodic paralysis can be seen with normal levels of serum potassium. The underlying pathology is tied to a voltage-gated sodium channel or calcium channel necessary for action potential generation.⁵⁶

Paroxysmal dyskinesias

Paroxysmal dyskinesias encompass a rare group of movement disorders characterized by attacks without alterations in consciousness. Patients have reported dystonic, choreoathetotic, or ballistic movements. The attacks can be triggered by stress, eating, or even other types of movements. Most reported cases have a strong family history and are inherited in an autosomal dominant pattern. The exact pathophysiology is unclear. When paroxysmal dyskinesia was initially discovered, many thought it was a form of epilepsy, but the lack of electroencephalographic changes and postictal events argues against this etiology.

Transient focal neurologic episodes in cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a degenerative condition in which amyloid is deposited in cerebral vessels, making them friable and at risk of bleeding. Most patients have no symptoms whatsoever, and the diagnosis is made by magnetic resonance imaging. Small microbleeds are common, but lobar intraparenchymal hemorrhage is the most feared complication.

Transient focal neurologic episodes, sometimes termed “amyloid spells,” are recurrent, stereotyped neurologic events that are spurred by cortical superficial siderosis (deposition of iron). Unfortunately, these events are difficult to characterize by their clinical morphology. The events can involve the visual, motor, and sensory pathways with both positive and negative symptoms, making the diagnosis difficult without imaging. These events may precede a symptomatic intraparenchymal hemorrhage, offering a unique window to reconsider the decision to continue an antiplatelet or anticoagulant drug.^57,58

Many patients present to their primary care physicians, urgent care centers, and emergency rooms because of neurologic symptoms lasting seconds to hours. Their problems can be a cause for concern and a challenge to diagnose, as in many cases their symptoms have returned to baseline by the time of evaluation. Referral to a neurologist may not be practical for all of them, particularly given that a consultation may take a long time to obtain.

Understanding the causes of transient neurologic syndromes and their phenomenology may help the clinician diagnose, triage, and treat such conditions effectively.

Here, we outline several transient neurologic syndromes—transient ischemic attack (TIA), migraine with aura, partial seizures, hypoglycemic encephalopathy, hyperventilation syndrome, transient global amnesia, narcolepsy, parasomnias, and some rarer conditions— focusing on their diagnostic elements. Others, such as drug-induced transient neurologic syndromes, vertigo, and dizziness, have been well discussed elsewhere.^1–3

THE BIG 3: TIA, MIGRAINE, SEIZURES

A 45-year-old woman with a history of tobacco use and headaches presents to the emergency department with a 4-month history of episodic numbness and tingling of her right arm and face. She reports a prodromal state of anxiety and irritability 24 to 48 hours before symptom onset.

The sensory symptoms begin on her face and gradually progress down the arm and eventually to her fingers. They fully resolve within 2 hours without sequelae. Family members have noted some “slurred speech” during the episodes, and the episodes are occasionally preceded by a unilateral, throbbing headache that improves with rest.

What are the possible causes of her symptoms?

Transient ischemic attack

If a patient reports transient neurologic symptoms and has vascular risk factors, TIA is often the default diagnostic consideration. The risk of stroke is 9.9% in the 2 days after a TIA, 13.4% at 30 days, and 17.3% at 90 days.⁴ Rapid recognition offers a crucial period to minimize the possibility of permanent impairment. Interventions include modifying risk factors (hypertension, diabetes, and smoking) and starting an antiplatelet drug, an anticoagulant drug, or both, and possibly a statin.

It can be difficult to determine if this workup needs to be completed in the inpatient or outpatient setting. There is no clear consensus, but the ultimate goal is timely evaluation (within 24 to 48 hours). The ABCD2 (Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) risk factor calculator was developed to help triage patients, though it has limitations.^5,6

One should assess a patient’s history of a possible TIA in a stepwise fashion. First, analyze the patient’s age and demographics for known vascular risk factors or central embolic sources (eg, atrial fibrillation). Then consider the symptoms. TIA symptoms have rapid onset, usually within seconds⁷; symptoms with a more gradual crescendo suggest a nonvascular cause.⁸ TIA manifestations should resolve within 1 hour, and most studies suggest symptom resolution within 10 minutes is specific for a TIA.^9–11 TIA symptoms are negative neurologic phenomena that denote a loss of function, such as loss of vision, motor weakness, or sensory numbness.

Symptoms should also correlate with a defined vascular territory:

• The middle cerebral artery is commonly involved; its blockage is associated with aphasia, weakness of the face and arm, and homonymous visual field impairment (loss of one-half of the visual fields in both eyes)
• Blockage in the posterior circulation generally causes symptoms localized to the brainstem, cerebellum, and occipital cortex. The symptoms are usually grouped together as the “5Ds”: dizziness, diplopia, dysarthria, dysphagia, and dystaxia/ataxia. Brainstem involvement classically produces “crossed” findings, with ipsilateral cranial findings and contralateral motor or sensory findings.
• Lacunar strokes involve the subcortical white matter and produce typical patterns including pure motor or sensory syndromes.

Loss of consciousness is rarely a symptom of TIA and should suggest another etiology.

The definition of TIA has evolved from an operational one, ie, symptoms lasting less than 24 hours, to a tissue-based one, ie, focal cerebral ischemia not associated with permanent cerebral infarction.¹² Though imperfect, this pathophysiology should help reinforce the most common features of TIA, including a sudden onset of negative symptoms that are localized to a defined vascular territory.^13,14

Migraine with aura

Migraine with aura is common in patients ages 25 to 55 who have a long-standing history of headache. The pathophysiologic mechanism of an aura is believed to be a disseminating wave of cortical depression, which is a self-propagating wave of neural depression and then activation. Ultimately, this leads to a cascade of inflammatory and pain signals, resulting in a headache.

This background helps explain the positive (superimposed) symptoms associated with the aura. Positive symptoms are produced by excessive neuronal discharges stimulating the visual (flashing lights, zigzag lines), sensory (paresthesias), or motor (limb movements) pathways.

Common symptoms associated with aura include visual disturbances such as scintillating scotoma (a blind spot), sensory changes such as tingling, or auditory disruption with tinnitus. Symptoms may evolve over the course of 5 to 20 minutes, first affecting vision and then other senses. In contrast, in a TIA, symptoms usually begin simultaneously and are confined to a vascular territory.^7,15 Symptoms of an aura usually resolve within an hour, but there is evidence showing a substantial number of patients have an aura lasting much longer.¹⁶ Focal weakness is uncommon during an aura but is reported in specific migraine conditions such as hemiplegic migraine and migraine with unilateral motor symptoms. The vast majority of patients experience other neurologic symptoms during this prodrome.^17,18

The prodromal period (2 to 48 hours leading up to the onset of migraine) is a commonly overlooked feature of migraine.¹⁹ Common symptoms during this time include fatigue, mood change, and gastrointestinal symptoms.²⁰ One study demonstrated that patients generally had good intuition concerning these nonspecific prodromal symptoms and could predict the onset of migraine 72% of the time.²¹

In addition, a myriad of possible triggers and exacerbating factors can be identified (and sometimes avoided) such as visual stimuli, weather changes, nitrates, sleep disturbances, menstruation, foods, and stressors.²²

Although headache is often the cardinal manifestation of migraine, some patients experience aura without headache—acephalgic migraine.²³ This can be a diagnostic challenge, especially in an older population with multiple vascular risk factors. New-onset acephalgic migraine may be a cause for concern but is not uncommon and is not associated with a significantly increased risk of stroke.²⁴ Focusing on the character of the neurologic symptoms in regard to timing, progression, and resolution will help differentiate this disease from other transient neurologic syndromes.²⁵

Partial seizure produces a diverse range of stereotypical symptoms due to focal abnormal neuronal activation. The aberrant electrical firing generates positive symptoms involving the motor, sensory, or visual pathway. A history of trauma, neurosurgical intervention, central nervous system infection, stroke, or other seizure foci can suggest this diagnosis. Other prodromal clues include abdominal discomfort, sense of detachment, déjà vu, or jamais vu.²⁶

During a seizure, there may be a progression of positive symptoms similar to what happens in migraine aura, because both represent cortical spread and depression.

Involvement of the motor pathway may produce tonic (stiffening) or clonic (twitching) movement. Other common motor abnormalities include automatisms such as lip smacking, chewing, and hand gestures (picking, fidgeting, fumbling).²⁷

Epileptic discharges in the sensory cortex commonly cause paresthesias or distortion of a sensory input. Visual symptoms may be more complex. In occipital epilepsy, circular phenomena with a colored pattern are common, which contrasts with the photopsia (flashes of light) or fortification (a bright zigzag of lines resembling a fort) seen in migraines.²⁸

Autonomic or somatosensory symptoms can also occur.

Todd paralysis, also called transient postictal paralysis, occurs in only 13% of seizures but can linger for 0.5 to 36 hours.^29,30 This weakness is most pronounced within the affected region after a partial seizure.

In general, focal seizures are often stereotyped with positive neurologic features, usually last a few minutes, and resolve fully. These episodes may cause an arrest in activity but not usually loss of consciousness unless the epileptic discharge secondarily generalizes into the adjacent hemisphere.

A common differential diagnosis encountered during an epilepsy workup is psychogenic nonepileptic seizures. Nonepileptic seizures consist of transient, abnormal movements, sensation, or cognition but lack ictal electroencephalographic changes. This is a specifically challenging patient population, with high healthcare utilization and high risk for iatrogenic harm. In addition, on average, diagnosis can take years to establish and usually requires referral to a tertiary care facility.^31,32

The big 3: Back to our patient

Our patient’s vascular risk factors, transient symptoms, and language involvement support the diagnosis of TIA. A feature that points away from the diagnosis of TIA is the gradual onset of positive neurologic symptoms. This pattern is not consistent with neuronal ischemia.

Also, our patient had a repetitive, stereotypical pattern of symptoms, which supports including partial seizures in the differential diagnosis. On the other hand, her lack of risk factors for seizure (a history of febrile seizures, developmental delay, trauma, or infection) would make this diagnosis less likely. Also pointing away from the diagnosis of seizures are her lack of typical prodromal symptoms, the length of the events, and the postevent headache.

Table 1 summarizes the clinical findings associated with TIA, migraine, and partial seizure.

EPISODES OF CONFUSION

A 35-year-old woman with a history of depression, anxiety, and poorly controlled type 1 diabetes presents to the clinic after several weeks of episodes of confusion, usually accompanied by paresthesias in both hands, dizziness, and palpitations. In each episode, soon after the symptoms began, she had painful cramps in her hand. The symptoms fully resolved within 10 minutes without sequelae.

Questioned further, the patient describes the confusion as a “mental haze” but denies frank disorientation. She has not kept a log of her blood sugar levels but has not noticed a temporal relationship with regard to her meals or insulin injections.

What are the possible causes of these episodes?

Hypoglycemic encephalopathy

Hypoglycemia is common in most people with diabetes, who have been reported to suffer from 62 to 320 severe hypoglycemic episodes in their lifetime.^33,34 The neurologic consequences can be devastating in these severe cases.

During mild to moderate drops in the glucose level, generalized symptoms stem from sympathetic activation. These include generalized anxiety, tremor, palpitations, and sweating. Focal symptoms such as unilateral weakness have also been reported.^35,36

Unfortunately, people with long-standing diabetes have a blunted response to epinephrine that reduces their sensitivity to hypoglycemia, placing them at high risk of permanent neurologic damage. This can lead to seizures and coma, as the hypoglycemia has a greater effect on cortical and subcortical structures (highly metabolic areas) than on the brainstem. Thus, respiratory and cardiovascular function is maintained but cerebral function is abnormal. If this state is prolonged, brain death can occur.^37,38

Hyperventilation syndrome

Hyperventilation syndrome is not well characterized. Most think of it as synonymous with an underlying psychopathology, but there is evidence to suggest it can occur without underlying anxiety.

There is no clear mechanism, but it is hypothesized that diminished carbon dioxide levels lead to cerebral vasoconstriction. This may lead to reduced cerebral blood flow, causing dizziness, lightheadedness, or vertigo.³⁹ Appendicular symptoms including paresthesias, carpopedal spasm, or tetany have been core features since the syndrome was first described in the early 1900s.⁴⁰

Though the disorder has rather nonspecific features, it can be easily reproduced in the clinical setting by asking the patient to breathe deeply and rapidly. This can help confirm the underlying diagnosis and also reassure the patient that the underlying pathology is not life-threatening and that he or she has some control over the disease.

Transient global amnesia usually strikes older patients (50 to 70 years old) in the setting of an acute physical or emotional stressor. There is also a correlation between transient global amnesia and migraine, with studies showing migraineurs are at higher risk than the general population.⁴¹ Despite common clinical concerns, there is no relationship between transient global amnesia and stroke.⁴²

Transient global amnesia is defined by acute transient anterograde amnesia (coding of new memories). To try to reorient themselves, patients will repeatedly ask questions such as “What day is it?” or “Why are we here?” Retrograde memories, especially long-standing ones, are usually well preserved. The patient’s cognition is otherwise intact, and there are no other focal neurologic symptoms. The event usually lasts 2 to 24 hours and resolves without sequelae.^43,44 Afterward, patients remember the event only poorly, which supports the notion that they cannot code new memories.

Confusional episodes: Discussion

Evaluating confusional episodes can be time-consuming and vexing. The subjective nature of the symptoms and the vast differential diagnosis can be overwhelming. Subtle clinical details can help formulate an appropriate evaluation.

Hypoglycemia can produce bizarre neurologic symptoms. Most cases of hypoglycemia produce an exaggerated sympathetic response, though this is blunted in people with longstanding diabetes. In addition, there should be a temporal association with meals, insulin doses, or both.

Transient global amnesia usually occurs with acute stressors and produces a confusional state. These episodes rarely recur, and the patient cannot provide much history regarding the episode secondary to the anterograde amnesia.

Table 2 summarizes the clinical findings associated with hypoglycemic encephalopathy, hyperventilation syndrome, and transient global amnesia.

Back to our patient

In our patient, the likely diagnosis is hyperventilation syndrome, even though we don’t know if her respiratory rate is increased during attacks. Some patients lack awareness of their breathing or are too distracted by the vague symptoms to have insight into the true cause. The cramps and contractions in the hands are a specific feature of the disease and can be accompanied by confusion.

SLEEP DISORDERS

A 17-year-old boy with a history of depression and anxiety presents to his pediatrician because he has had difficulty staying awake in school over the past year. His sleepiness has gradually worsened over the last few months and has taken a toll on his grades, leading to discord in his family. Over the past month he has had some difficulty holding his head up during arguments with friends. He does not lose consciousness during these events but is described as “unresponsive.” He describes vivid dreams when going to sleep that have startled him awake at times. His family history is positive for somnambulism on his father’s side.

Does this patient have a sleep disorder, and if so, which one?

Narcolepsy

Narcolepsy is defined by excessive daytime sleepiness, cataplexy, hypnagogic hallucination, and sleep paralysis. It is more common in men but its prevalence varies widely by geographic region, supporting an underlying interplay between genetics and environment.⁴⁵

Sleep attacks or excessive daytime sleepiness are the cardinal features of narcolepsy. The dissociation between the sleep-wake cycle is evident with rapid transition into rapid-eye-movement (REM) sleep during these sleep attacks. This results in a “refreshing nap” that commonly involves vivid dreams. These episodes occur about 3 to 5 times per day, varying in duration from a few minutes to hours.⁴⁶

Cataplexy is very specific feature of narcolepsy. Triggered by strong emotion, the body loses skeletal muscle tone except for the diaphragm and ocular muscles. The patient does not lose consciousness and remains aware of his or her environment. Of note, the loss of tone does not need to be dramatic. The hypotonia can manifest as jaw-dropping or head-nodding. The paralysis is related to prolonged REM atonia and impaired transition from sleep to wakefulness.⁴⁷ Hypnagogic hallucination and sleep paralysis can occur, together with vivid visual hallucinations.

Parasomnias: Somnambulism and night terrors

Most non-REM parasomnias occur in childhood and diminish in adulthood. Two of the most common disorders are sleepwalking (somnambulism) and night terrors. Both are characterized by arousal from slow-wave sleep and are commonly associated with sedating medication, sleep deprivation, or psychopathology.

In somnambulism, patients exhibit complex motor behavior without interaction with their environment. Most have little recollection of the event.⁴⁸ Sleep terrors produce a more intense reaction. The patient erupts out of sleep with profound terror, confusion, and autonomic changes. Interestingly, the patient can normally fall right back into sleep after the event.^49–51

Back to our patient

Excessive daytime sleepiness and generalized fatigue are commonly encountered in outpatients. They can be frustrating because in many cases, no clear etiology can be discovered.⁵²

This patient has several risk factors for parasomnias. His history of anxiety and depression in the setting of recent stressors sets the stage for night terrors. In addition, like many patients with parasomnias, he has a family history of sleep disorders. His vivid dreams make night terrors possible, but without the stark sympathetic activation it is a less likely diagnosis. It also does not account for the other symptoms he describes.

Our patient’s excessive daytime sleepiness interfering with daily activities, cataplexy, and hypnagogic hallucinations support the diagnosis of narcolepsy. This case highlights the variable weakness experienced during a cataplexy attack. It can range from a simple head droop to complete paralysis. Subtle findings require specific probing by the clinician. Patients with narcolepsy typically present in their late teens to early adulthood, but the cataplexy attacks may develop later in the disease course.

Table 3 summarizes the clinical findings associated with night terrors, somnambulism, and narcolepsy.

Transient (paroxysmal) neurologic events in multiple sclerosis

A less well-known phenomenon in multiple sclerosis is termed “transient” (paroxysmal) neurologic events. These are typically stereotyped episodes lasting seconds, occurring sometimes hundreds of times a day. They are thought to arise from spontaneous electrical activity in an area of demyelination (ephaptic transmission), creating a wide range of symptoms. Some common events include positive sensory symptoms, alteration of the motor system such as spasms, or brainstem symptoms.⁵³

Channelopathy

Two prototypical channelopathies are hyperkalemic and hypokalemic periodic paralysis. They are rare conditions, usually inherited in an autosomal dominant pattern.⁵⁴ Both produce episodic, flaccid weakness in the setting of activity or other stressors (fasting, pregnancy, an emotionally charged episode). The attacks last a few minutes to hours and affect proximal skeletal muscles, with very little respiratory or bulbar involvement.

Hyperkalemic periodic paralysis is also associated with myotonia, which is the inability to voluntarily relax after stimulation. This can be evident after shaking a patient’s hand, as he or she would be unable to release because of the sustained activation. The myotonia is evident between attacks and may help cue a physician to the diagnosis even if the weakness has abated.⁵⁵

As the name implies, potassium levels can vary during the attack, though hyperkalemic periodic paralysis can be seen with normal levels of serum potassium. The underlying pathology is tied to a voltage-gated sodium channel or calcium channel necessary for action potential generation.⁵⁶

Paroxysmal dyskinesias

Paroxysmal dyskinesias encompass a rare group of movement disorders characterized by attacks without alterations in consciousness. Patients have reported dystonic, choreoathetotic, or ballistic movements. The attacks can be triggered by stress, eating, or even other types of movements. Most reported cases have a strong family history and are inherited in an autosomal dominant pattern. The exact pathophysiology is unclear. When paroxysmal dyskinesia was initially discovered, many thought it was a form of epilepsy, but the lack of electroencephalographic changes and postictal events argues against this etiology.

Transient focal neurologic episodes in cerebral amyloid angiopathy

Cerebral amyloid angiopathy is a degenerative condition in which amyloid is deposited in cerebral vessels, making them friable and at risk of bleeding. Most patients have no symptoms whatsoever, and the diagnosis is made by magnetic resonance imaging. Small microbleeds are common, but lobar intraparenchymal hemorrhage is the most feared complication.

Transient focal neurologic episodes, sometimes termed “amyloid spells,” are recurrent, stereotyped neurologic events that are spurred by cortical superficial siderosis (deposition of iron). Unfortunately, these events are difficult to characterize by their clinical morphology. The events can involve the visual, motor, and sensory pathways with both positive and negative symptoms, making the diagnosis difficult without imaging. These events may precede a symptomatic intraparenchymal hemorrhage, offering a unique window to reconsider the decision to continue an antiplatelet or anticoagulant drug.^57,58

Much has improved in renal transplantation over the past 20 years. The focus has shifted to using stronger immunotherapy rather than trying to minimize it. There has been increasing recognition of infection and ways to prevent and treat it. Induction therapy now has greater emphasis so that maintenance therapy can be eased, with the aim of reducing long-term toxicity. Perhaps the biggest change is the practice of screening for donor-specific antibodies at the time of transplant so that predictable problems can be prevented or better handled if they occur. Such advances have helped patients directly and by extending the life of their transplanted organs.

LONGER SURVIVAL

As early as the 1990s, it was recognized that kidney transplant offers a survival advantage for patients with end-stage renal disease over maintenance on dialysis.¹ Although the risk of death is higher immediately after transplant, within a few months it becomes much lower than for patients on dialysis. Survival varies according to the health of the patient and the quality of the transplanted organ.

In general, patients who obtain the greatest benefit from transplants in terms of years of life gained are those with diabetes, especially those who are younger. Those ages 20 to 39 live about 8 years on dialysis vs 25 years after transplant.

CONTRAINDICATIONS TO TRANSPLANT

There are multiple contraindications to a solitary kidney transplant (Table 1), including smoking. Most transplant centers require that smokers quit before transplant. Long-standing smokers almost double their risk of a cardiac event after transplant and double their rate of malignancy. Active smoking at the time of transplant is associated with twice the risk of death by 10 years after transplant compared with that of nonsmokers.² Cotinine testing can detect whether a patient is an active smoker.

WAITING-LIST CONSIDERATIONS

Organs are scarce

The number of patients on the kidney waiting list has increased rapidly in the last few decades, while the number of transplants performed each year has remained about the same. In 2016, about 100,000 patients were on the list, but only about 19,000 transplants were performed.³ Wait times, especially for deceased-donor organs, have increased to about 6 years, varying by blood type and geographic region.

Waiting-list placement

Placement on the waiting list for a deceased-donor kidney transplant occurs when a patient has an estimated glomerular filtration rate (GFR) of 20 mL/min/1.73 m² or less, although referral to the list can be made earlier. Early listing remains advantageous, as total time on the list will be counted before starting dialysis. “Preemptive transplant” means the patient had no dialysis before transplant; this applies to about 10% of transplant recipients. These patients tend to fare the best and are usually recipients of a living-donor organ.

Most patients do not receive a transplant until the GFR is less than 15 mL/min/1.73 m².

Since 2014, wait time has been measured from the beginning of dialysis rather than the date of waiting-list placement in patients who are listed after starting dialysis therapy. This approach is more fair but sometimes introduces problems. A patient who did not previously know about the list may suddenly jump to the head of the line after 10 years of dialysis, by which time comorbidities associated with long-term dialysis make the patient less likely to gain as much benefit from a transplant as people lower on the list. Time on dialysis, or “dialysis vintage,” predicts patient and kidney survival after transplant, with reduced survival associated with increasing time on dialysis.⁴

Shorter wait for a suboptimal kidney

The aging population has increased the number of older patients being listed for transplant, presenting multiple challenges. Patients age 65 or older have a 50% chance of dying before they receive a transplant during a 5-year wait.

A patient may shorten the wait by joining the list for a suboptimal organ. All deceased-donor organs are given a Kidney Donor Profile Index score, which predicts the longevity of an organ after transplant. The score is determined by donor age, kidney function based on the serum creatinine at the time of death, and other donor factors.

A kidney with a score higher than 85% is likely to function longer than only 15% of available kidneys. Patients who receive a kidney with that score have a longer period of risk of death soon after transplant and a slightly higher risk of death in the long term than patients who receive a healthier kidney, although on average they still do better than patients on dialysis.⁵

Older patients should be encouraged to sign up for both the regular waiting list and the suboptimal kidney waiting list to reduce the risk of dying before they get a kidney.

Many advantages

Living-donor organ transplant is associated with a better survival rate than deceased-donor organ transplant, and the advantage becomes greater over time. At 1 year, patient survival is more than 90% in both groups, but by 5 years about 80% of patients with a living-donor organ are still alive vs only about 65% of patients with a deceased-donor organ.

The waiting time for a living-donor transplant may be only weeks to months, rather than years. Because increasing time on dialysis predicts worse patient and graft survival after transplant, the shorter wait time is a big advantage. In addition, because the donor and recipient are typically in adjacent operating rooms, the organ sustains less ischemic damage. In general, the kidney quality is better from healthy donors, resulting in superior function early on and longer graft survival by an average of 4 years. If the living donor is related to the recipient, human leukocyte antigen matching also tends to be better and predicts better outcomes.

Special challenges

Opting for a living-donor organ also entails special challenges. In addition to the ethical issues surrounding living-donor organ donation, an appropriate donor must be found. Donors must be highly motivated and pass physical, laboratory, and psychological evaluations.

For older patients, if the donor is a spouse or close friend, he or she is also likely to be older, making the organ less viable than one from a younger person. Even an adult child may not be an ideal donor if there is a family propensity to kidney disease, such as diabetic nephropathy. No test is available to determine the risk for future diabetes, but it is known to run in families.

POTENT IMMUNOSUPPRESSION

Induction therapy

Induction therapy with antithymocyte globulin or basiliximab provides intense immunosuppression to prevent acute rejection during the early posttransplant period.

Antithymocyte globulin is a potent agent that contains antibodies directed at T cells, B cells, neutrophils, platelets, adhesion molecules, and complement. It binds T cells and removes them from circulation by opsonization in splenic and lymphoid tissue. The immunosuppressive effect is sustained for at least 2 to 3 months after a series of injections (dosage 1.5 mg/kg/day, usually for 4 to 10 doses). Antithymocyte globulin is also used to treat acute rejection, especially high-grade rejection for which steroid therapy is likely to be insufficient.

Basiliximab consists of antibodies to the interleukin 2 (IL-2) receptor of T cells. Binding to T cells prevents their activation rather than removing them from circulation. The drug prevents rejection, with 30% relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day 0 and day 4, which provides receptor saturation for 30 to 45 days.

Basiliximab is also sometimes used off-label for patients who need to discontinue a calcineurin inhibitor (ie, tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for 1 or 2 doses. Case series have been reported for this use, particularly for patients with a heart and liver transplant who develop acute kidney injury while hospitalized.^6,7

Antithymocyte globulin is more effective but also more risky. Brennan et al⁸ randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16% rejection rate vs 26% in the basiliximab group.

Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and long-standing immunosuppressive effects such as increased risk of lymphoma and cytomegalovirus (CMV) infection. Basiliximab side-effect profiles are similar to those of placebo.

Maintenance therapy

The calcineurin inhibitors cyclosporine and tacrolimus remain the standard of care in kidney transplant despite multiple drug interactions and side effects that include renal toxicity and fibrosis. Cyclosporine and tacrolimus both bind intracellular immunophilins and thereby prevent transcription of IL-2 and production of T cells. The drugs work similarly but have different binding sites. Cyclosporine has largely been replaced by tacrolimus because its reliability of dosing and higher potency are associated with lower rejection rates.

Tacrolimus is typically given twice daily (1–6 mg/dose). Twelve-hour trough levels are followed (target: 8–12 ng/mL early on, then 5–8 ng/mL after 3 months posttransplant). Side effects include hypertension and hypercholesterolemia, but less so than with cyclosporine. On the other hand, hyperglycemia tends to be worse with tacrolimus than with cyclosporine, and combining tacrolimus with steroids frequently leads to diabetes. Tacrolimus can also cause acute and chronic renal failure, especially at high drug levels, as well as neurotoxicity, tremors, and hair loss.

Cyclosporine, tacrolimus, and sirolimus (not a calcineurin inhibitor) are metabolized through the same cytochrome P450 pathway (CYP3A4), so they have common drug interactions (Table 2).

Mycophenolate mofetil is typically used as an adjunct therapy (500–1,000 mg twice daily). It is also used for other kidney diseases before transplant, including lupus nephritis. Transplanted kidney rejection rates with mycophenolate mofetil with steroids are about 40%, so the drug is not potent enough to be used without a calcineurin inhibitor.

Side effects include gastrointestinal toxicity in up to 20% of patients, and leukopenia, which is associated with viral infections.

CORONARY ARTERY DISEASE IS COMMON WITH DIALYSIS

Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85% of older patients with diabetes on dialysis. Although patients with end-stage kidney disease tend to have more numerous and severe atherosclerotic lesions compared with the general population, justifying aggressive management, cardiac care tends to be conservative in patients on dialysis.⁹

Death from acute myocardial infarction occurs in about 20% to 30% of patients on dialysis vs about 2% of patients with normal renal function. Five years after myocardial infarction, survival is only about 30% in patients on dialysis.⁹

There are many explanations for excess coronary artery disease in patients on dialysis. In addition to the traditional cardiovascular risk factors of diabetes, hypertension, and preexisting coronary artery disease, patients are in a proinflammatory uremic state and have high levels of phosphorus and fibroblast growth factor 23 that contribute to vascular calcification. Almost all patients have high homocysteine levels and hemodynamic instability, particularly if they are on hemodialysis.

Pretransplant evaluation for heart disease

Patients on the kidney transplant waiting list are screened aggressively for heart disease. A history of myocardial infarction usually results in removal from the list. All patients have an initial electrocardiogram and echocardiogram. Thallium or echocardiographic stress testing is used for patients who are age 50 and older, have diabetes, or have had dialysis for many years. Patients with evidence of ischemia undergo catheterization.

Patients are also screened with computed tomography before transplant. Because the kidney is typically anastomosed to the iliac artery and vein, heavy calcification of the iliac artery can make the procedure too difficult to perform.

Kasiske et al¹⁰ analyzed data from more than 50,000 patients from the US Renal Data System and found that, for about the first year after transplant, patients who underwent kidney transplant were more likely to have a myocardial infarction than those on dialysis. After that, they fared better than patients who remained on dialysis. Those with a living-donor transplant were less likely at all times to have a myocardial infarction than those with a deceased-donor transplant. By 3 years after transplant, the relative risk of having a myocardial infarction was 0.89 for deceased-donor organ recipients and 0.69 for living-donor recipients compared with patients on the waiting list.¹⁰

INFECTIOUS COMPLICATIONS IN KIDNEY RECIPIENTS

Kidney recipients are prone to many common and uncommon infections (Table 3). All potential recipients are tested pretransplant for hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, and tuberculosis. A positive result does not necessarily rule out transplant.

The following viral serology tests are also done before transplant:

Epstein-Barr virus (antibodies are positive in about 90% of adults)

CMV (about 70% of adults are seropositive)

Varicella zoster (seronegative patients should be given live-attenuated varicella vaccine).

Risk of transmission of these viruses relates to the serostatus of the donor and recipient before transplant. If a donor is positive for viral antibodies but the recipient is not (a so-called “mismatch”), risk is higher after transplant.

Hepatitis C

Patients with hepatitis C fare better if they get a transplant than if they remain on dialysis, although their posttransplant course is worse compared with transplant patients who do not have hepatitis. Some patients develop accelerated liver disease after kidney transplant. Hepatitis C-related kidney disease—membranous proliferative glomerulonephritis—also occurs, as do comorbidities such as diabetes.

Careful evaluation is warranted before transplant, including liver imaging, alpha-fetoprotein testing, and liver biopsy to evaluate for hepatocellular carcinoma. A patient with advanced fibrosis or cirrhosis may not be a candidate for kidney transplant alone but could possibly receive a combined kidney and liver transplant.

There is a need to determine the best time to treat hepatitis C infection. Patients with advanced liver disease or hepatitis C-related kidney disease would likely benefit from early treatment. However, delaying treatment could shorten the wait time for a deceased-donor organ positive for hepatitis C.  Transplant candidates with active hepatitis C are uniquely considered to accept hepatitis C-positive kidneys, which are often discarded, and may only wait weeks for such a transplant. The shortened kidney survival associated with a hepatitis C-positive kidney may no longer be true with the new antiviral hepatitis C therapy, which has been shown to be effective post-transplant.

Hepatitis B

No cure is available for hepatitis B infection, but it can be well controlled with antiviral therapy. Patients with hepatitis B infection may be candidates for transplant, but they should be stable on antiviral therapy (lamivudine, entecavir, or tenofovir) to eliminate the viral load before transplant, and therapy should be continued afterward. Liver imaging, alpha-fetoprotein levels, and biopsy are recommended for evaluation. All hepatitis B- negative patients should be vaccinated before transplant.

Organs from living or deceased donors that test positive for hepatitis B core antibody, indicating prior exposure, can be considered for transplant in a patient who tests positive for hepatitis B surface antibody, indicating successful vaccination or prior exposure in the recipient. But donors must have negative surface antigen and polymerase chain reaction (PCR) tests that indicate no active hepatitis B infection.

Cytomegalovirus

CMV typically does not appear until prophylactic therapy is stopped. Classic symptoms are fever, leukopenia, and diarrhea. Infection can involve any organ, and patients may present with hepatitis, pancreatitis or, less commonly, pneumonitis.

Patients who are negative for CMV before transplant and receive a donor-positive organ are at the highest risk. Patients who are CMV IgG-positive are considered to be at intermediate risk, regardless of the donor status. Patients who are negative for CMV and receive a donor-negative organ are at the lowest risk and do not need prophylaxis with valganciclovir.

CMV infection is diagnosed by PCR testing of the blood or immunostaining in tissue biopsy. Occasionally, blood testing is negative in the face of tissue-based disease.

BK virus

BK is a polyoma virus and a common virus associated with kidney transplant. Viremia is seen in about 18% of patients, whereas actual kidney disease associated with a higher level of virus is seen in fewer than 10% of patients. Most people are exposed to BK virus, often in childhood, and it can remain indolent in the bladder and uroepithelium.

Patients can develop BK nephropathy after exposure to transplant immunosuppression.¹¹ Posttransplant monitoring protocols typically include PCR testing for BK virus at 1, 3, 6, and 12 months. No agent has been identified to specifically treat BK virus. The general strategy is to minimize immunosuppressive therapy by reducing or eliminating mycophenolate mofetil. Fortunately, BK virus does not tend to recur, and patients can have a low-level viremia (< 10,000 copies/mL) persisting over months or even years but often without clinical consequences.

The appearance of BK virus on biopsy can mimic acute rejection. Before BK viral nephropathy was a recognized entity, patients would have been diagnosed with acute rejection and may have been put on high-dose steroids, which would have worsened the BK infection.

Posttransplant lymphoproliferative disorder

Posttransplant lymphoproliferative disorder is most often associated with Epstein-Barr virus and usually involves a large, diffuse B-cell lymphoma. Burkitt lymphoma and plasma cell neoplasms also can occur less commonly.

The condition is about 30 times more common in patients after transplant than in the general population, and it is the third most common malignancy in transplant patients after skin and cervical cancers. About 80% of the cases occur early after transplant, within the first year.

Patients typically have a marked elevation in viral load of Epstein-Barr virus, although a negative viral load does not rule it out. A patient who is serologically negative for Epstein-Barr virus receiving a donor-positive kidney is at highest risk; this situation is most often seen in the pediatric population. Potent induction therapies (eg, antilymphocyte antibody therapy) are also associated with posttransplant lymphoproliferative disorder.

Patients typically present with fever of unknown origin with no localizing signs or symptoms. Mass lesions can be challenging to find; positron emission tomography may be helpful. The culprit is usually a focal mass, ulcer (especially in the gastrointestinal tract), or infiltrate (commonly localized to the allograft). Multifocal or disseminated disease can also occur, including lymphoma or with central nervous system, gastrointestinal, or pulmonary involvement.

Biopsy of the affected site is required for histopathology and Epstein-Barr virus markers. PCR blood testing is often positive for Epstein-Barr virus.

Typical antiviral therapy does not eliminate Epstein-Barr virus. In early polyclonal viral proliferation, the first goal is to reduce immunosuppressive therapy. Rituximab alone may also help in polymorphic cases. With disease that is clearly monomorphic and has transformed to a true malignancy, cytotoxic chemotherapy is also required. “R-CHOP,” a combination therapy consisting of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, is usually used. Radiation therapy may help in some cases.

Cryptococcal infection

Previously seen in patients with acquired immune deficiency syndrome, cryptococcal infection is now most commonly encountered in patients with solid-organ transplants. Vilchez et al¹² found a 1% incidence in a series of more than 5,000 patients who had received an organ transplant.

Immunosuppression likely conveys risk, but because cryptococcal infection is acquired, environmental exposure also plays a role. It tends to appear more than 6 months after transplant, indicating that its cause is a primary infection by spore inhalation rather than by reactivation or transmission from the donor organ.¹³ Bird exposure is a risk factor for cryptococcal infection. One case identified the same strain of Cryptococcus in a kidney transplant recipient and the family’s pet cockatoo.¹⁴

Cryptococcal infection typically starts as pneumonia, which may be subclinical. The infection can then disseminate, with meningitis presenting with headache and mental status changes being the most concerning complication. The death rate is about 50% in most series of patients with meningitis. Skin and soft-tissue manifestations may also occur in 10% to 15% of cases and can be nodular, ulcerative, or cellulitic.

More than 75% of fungal infections requiring hospitalization in US patients who have undergone transplant are attributed to either Candida, Aspergillus, or Cryptococcus species.¹⁵ Risk of fungal infection is increased with diabetes, duration of pretransplant dialysis, tacrolimus therapy, or rejection treatment.

Much has improved in renal transplantation over the past 20 years. The focus has shifted to using stronger immunotherapy rather than trying to minimize it. There has been increasing recognition of infection and ways to prevent and treat it. Induction therapy now has greater emphasis so that maintenance therapy can be eased, with the aim of reducing long-term toxicity. Perhaps the biggest change is the practice of screening for donor-specific antibodies at the time of transplant so that predictable problems can be prevented or better handled if they occur. Such advances have helped patients directly and by extending the life of their transplanted organs.

LONGER SURVIVAL

As early as the 1990s, it was recognized that kidney transplant offers a survival advantage for patients with end-stage renal disease over maintenance on dialysis.¹ Although the risk of death is higher immediately after transplant, within a few months it becomes much lower than for patients on dialysis. Survival varies according to the health of the patient and the quality of the transplanted organ.

In general, patients who obtain the greatest benefit from transplants in terms of years of life gained are those with diabetes, especially those who are younger. Those ages 20 to 39 live about 8 years on dialysis vs 25 years after transplant.

CONTRAINDICATIONS TO TRANSPLANT

There are multiple contraindications to a solitary kidney transplant (Table 1), including smoking. Most transplant centers require that smokers quit before transplant. Long-standing smokers almost double their risk of a cardiac event after transplant and double their rate of malignancy. Active smoking at the time of transplant is associated with twice the risk of death by 10 years after transplant compared with that of nonsmokers.² Cotinine testing can detect whether a patient is an active smoker.

WAITING-LIST CONSIDERATIONS

Organs are scarce

The number of patients on the kidney waiting list has increased rapidly in the last few decades, while the number of transplants performed each year has remained about the same. In 2016, about 100,000 patients were on the list, but only about 19,000 transplants were performed.³ Wait times, especially for deceased-donor organs, have increased to about 6 years, varying by blood type and geographic region.

Waiting-list placement

Placement on the waiting list for a deceased-donor kidney transplant occurs when a patient has an estimated glomerular filtration rate (GFR) of 20 mL/min/1.73 m² or less, although referral to the list can be made earlier. Early listing remains advantageous, as total time on the list will be counted before starting dialysis. “Preemptive transplant” means the patient had no dialysis before transplant; this applies to about 10% of transplant recipients. These patients tend to fare the best and are usually recipients of a living-donor organ.

Most patients do not receive a transplant until the GFR is less than 15 mL/min/1.73 m².

Since 2014, wait time has been measured from the beginning of dialysis rather than the date of waiting-list placement in patients who are listed after starting dialysis therapy. This approach is more fair but sometimes introduces problems. A patient who did not previously know about the list may suddenly jump to the head of the line after 10 years of dialysis, by which time comorbidities associated with long-term dialysis make the patient less likely to gain as much benefit from a transplant as people lower on the list. Time on dialysis, or “dialysis vintage,” predicts patient and kidney survival after transplant, with reduced survival associated with increasing time on dialysis.⁴

Shorter wait for a suboptimal kidney

The aging population has increased the number of older patients being listed for transplant, presenting multiple challenges. Patients age 65 or older have a 50% chance of dying before they receive a transplant during a 5-year wait.

A patient may shorten the wait by joining the list for a suboptimal organ. All deceased-donor organs are given a Kidney Donor Profile Index score, which predicts the longevity of an organ after transplant. The score is determined by donor age, kidney function based on the serum creatinine at the time of death, and other donor factors.

A kidney with a score higher than 85% is likely to function longer than only 15% of available kidneys. Patients who receive a kidney with that score have a longer period of risk of death soon after transplant and a slightly higher risk of death in the long term than patients who receive a healthier kidney, although on average they still do better than patients on dialysis.⁵

Older patients should be encouraged to sign up for both the regular waiting list and the suboptimal kidney waiting list to reduce the risk of dying before they get a kidney.

Many advantages

Living-donor organ transplant is associated with a better survival rate than deceased-donor organ transplant, and the advantage becomes greater over time. At 1 year, patient survival is more than 90% in both groups, but by 5 years about 80% of patients with a living-donor organ are still alive vs only about 65% of patients with a deceased-donor organ.

The waiting time for a living-donor transplant may be only weeks to months, rather than years. Because increasing time on dialysis predicts worse patient and graft survival after transplant, the shorter wait time is a big advantage. In addition, because the donor and recipient are typically in adjacent operating rooms, the organ sustains less ischemic damage. In general, the kidney quality is better from healthy donors, resulting in superior function early on and longer graft survival by an average of 4 years. If the living donor is related to the recipient, human leukocyte antigen matching also tends to be better and predicts better outcomes.

Special challenges

Opting for a living-donor organ also entails special challenges. In addition to the ethical issues surrounding living-donor organ donation, an appropriate donor must be found. Donors must be highly motivated and pass physical, laboratory, and psychological evaluations.

For older patients, if the donor is a spouse or close friend, he or she is also likely to be older, making the organ less viable than one from a younger person. Even an adult child may not be an ideal donor if there is a family propensity to kidney disease, such as diabetic nephropathy. No test is available to determine the risk for future diabetes, but it is known to run in families.

POTENT IMMUNOSUPPRESSION

Induction therapy

Induction therapy with antithymocyte globulin or basiliximab provides intense immunosuppression to prevent acute rejection during the early posttransplant period.

Antithymocyte globulin is a potent agent that contains antibodies directed at T cells, B cells, neutrophils, platelets, adhesion molecules, and complement. It binds T cells and removes them from circulation by opsonization in splenic and lymphoid tissue. The immunosuppressive effect is sustained for at least 2 to 3 months after a series of injections (dosage 1.5 mg/kg/day, usually for 4 to 10 doses). Antithymocyte globulin is also used to treat acute rejection, especially high-grade rejection for which steroid therapy is likely to be insufficient.

Basiliximab consists of antibodies to the interleukin 2 (IL-2) receptor of T cells. Binding to T cells prevents their activation rather than removing them from circulation. The drug prevents rejection, with 30% relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day 0 and day 4, which provides receptor saturation for 30 to 45 days.

Basiliximab is also sometimes used off-label for patients who need to discontinue a calcineurin inhibitor (ie, tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for 1 or 2 doses. Case series have been reported for this use, particularly for patients with a heart and liver transplant who develop acute kidney injury while hospitalized.^6,7

Antithymocyte globulin is more effective but also more risky. Brennan et al⁸ randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16% rejection rate vs 26% in the basiliximab group.

Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and long-standing immunosuppressive effects such as increased risk of lymphoma and cytomegalovirus (CMV) infection. Basiliximab side-effect profiles are similar to those of placebo.

Maintenance therapy

The calcineurin inhibitors cyclosporine and tacrolimus remain the standard of care in kidney transplant despite multiple drug interactions and side effects that include renal toxicity and fibrosis. Cyclosporine and tacrolimus both bind intracellular immunophilins and thereby prevent transcription of IL-2 and production of T cells. The drugs work similarly but have different binding sites. Cyclosporine has largely been replaced by tacrolimus because its reliability of dosing and higher potency are associated with lower rejection rates.

Tacrolimus is typically given twice daily (1–6 mg/dose). Twelve-hour trough levels are followed (target: 8–12 ng/mL early on, then 5–8 ng/mL after 3 months posttransplant). Side effects include hypertension and hypercholesterolemia, but less so than with cyclosporine. On the other hand, hyperglycemia tends to be worse with tacrolimus than with cyclosporine, and combining tacrolimus with steroids frequently leads to diabetes. Tacrolimus can also cause acute and chronic renal failure, especially at high drug levels, as well as neurotoxicity, tremors, and hair loss.

Cyclosporine, tacrolimus, and sirolimus (not a calcineurin inhibitor) are metabolized through the same cytochrome P450 pathway (CYP3A4), so they have common drug interactions (Table 2).

Mycophenolate mofetil is typically used as an adjunct therapy (500–1,000 mg twice daily). It is also used for other kidney diseases before transplant, including lupus nephritis. Transplanted kidney rejection rates with mycophenolate mofetil with steroids are about 40%, so the drug is not potent enough to be used without a calcineurin inhibitor.

Side effects include gastrointestinal toxicity in up to 20% of patients, and leukopenia, which is associated with viral infections.

CORONARY ARTERY DISEASE IS COMMON WITH DIALYSIS

Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85% of older patients with diabetes on dialysis. Although patients with end-stage kidney disease tend to have more numerous and severe atherosclerotic lesions compared with the general population, justifying aggressive management, cardiac care tends to be conservative in patients on dialysis.⁹

Death from acute myocardial infarction occurs in about 20% to 30% of patients on dialysis vs about 2% of patients with normal renal function. Five years after myocardial infarction, survival is only about 30% in patients on dialysis.⁹

There are many explanations for excess coronary artery disease in patients on dialysis. In addition to the traditional cardiovascular risk factors of diabetes, hypertension, and preexisting coronary artery disease, patients are in a proinflammatory uremic state and have high levels of phosphorus and fibroblast growth factor 23 that contribute to vascular calcification. Almost all patients have high homocysteine levels and hemodynamic instability, particularly if they are on hemodialysis.

Pretransplant evaluation for heart disease

Patients on the kidney transplant waiting list are screened aggressively for heart disease. A history of myocardial infarction usually results in removal from the list. All patients have an initial electrocardiogram and echocardiogram. Thallium or echocardiographic stress testing is used for patients who are age 50 and older, have diabetes, or have had dialysis for many years. Patients with evidence of ischemia undergo catheterization.

Patients are also screened with computed tomography before transplant. Because the kidney is typically anastomosed to the iliac artery and vein, heavy calcification of the iliac artery can make the procedure too difficult to perform.

Kasiske et al¹⁰ analyzed data from more than 50,000 patients from the US Renal Data System and found that, for about the first year after transplant, patients who underwent kidney transplant were more likely to have a myocardial infarction than those on dialysis. After that, they fared better than patients who remained on dialysis. Those with a living-donor transplant were less likely at all times to have a myocardial infarction than those with a deceased-donor transplant. By 3 years after transplant, the relative risk of having a myocardial infarction was 0.89 for deceased-donor organ recipients and 0.69 for living-donor recipients compared with patients on the waiting list.¹⁰

INFECTIOUS COMPLICATIONS IN KIDNEY RECIPIENTS

Kidney recipients are prone to many common and uncommon infections (Table 3). All potential recipients are tested pretransplant for hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, and tuberculosis. A positive result does not necessarily rule out transplant.

The following viral serology tests are also done before transplant:

Epstein-Barr virus (antibodies are positive in about 90% of adults)

CMV (about 70% of adults are seropositive)

Varicella zoster (seronegative patients should be given live-attenuated varicella vaccine).

Risk of transmission of these viruses relates to the serostatus of the donor and recipient before transplant. If a donor is positive for viral antibodies but the recipient is not (a so-called “mismatch”), risk is higher after transplant.

Hepatitis C

Patients with hepatitis C fare better if they get a transplant than if they remain on dialysis, although their posttransplant course is worse compared with transplant patients who do not have hepatitis. Some patients develop accelerated liver disease after kidney transplant. Hepatitis C-related kidney disease—membranous proliferative glomerulonephritis—also occurs, as do comorbidities such as diabetes.

Careful evaluation is warranted before transplant, including liver imaging, alpha-fetoprotein testing, and liver biopsy to evaluate for hepatocellular carcinoma. A patient with advanced fibrosis or cirrhosis may not be a candidate for kidney transplant alone but could possibly receive a combined kidney and liver transplant.

There is a need to determine the best time to treat hepatitis C infection. Patients with advanced liver disease or hepatitis C-related kidney disease would likely benefit from early treatment. However, delaying treatment could shorten the wait time for a deceased-donor organ positive for hepatitis C.  Transplant candidates with active hepatitis C are uniquely considered to accept hepatitis C-positive kidneys, which are often discarded, and may only wait weeks for such a transplant. The shortened kidney survival associated with a hepatitis C-positive kidney may no longer be true with the new antiviral hepatitis C therapy, which has been shown to be effective post-transplant.

Hepatitis B

No cure is available for hepatitis B infection, but it can be well controlled with antiviral therapy. Patients with hepatitis B infection may be candidates for transplant, but they should be stable on antiviral therapy (lamivudine, entecavir, or tenofovir) to eliminate the viral load before transplant, and therapy should be continued afterward. Liver imaging, alpha-fetoprotein levels, and biopsy are recommended for evaluation. All hepatitis B- negative patients should be vaccinated before transplant.

Organs from living or deceased donors that test positive for hepatitis B core antibody, indicating prior exposure, can be considered for transplant in a patient who tests positive for hepatitis B surface antibody, indicating successful vaccination or prior exposure in the recipient. But donors must have negative surface antigen and polymerase chain reaction (PCR) tests that indicate no active hepatitis B infection.

Cytomegalovirus

CMV typically does not appear until prophylactic therapy is stopped. Classic symptoms are fever, leukopenia, and diarrhea. Infection can involve any organ, and patients may present with hepatitis, pancreatitis or, less commonly, pneumonitis.

Patients who are negative for CMV before transplant and receive a donor-positive organ are at the highest risk. Patients who are CMV IgG-positive are considered to be at intermediate risk, regardless of the donor status. Patients who are negative for CMV and receive a donor-negative organ are at the lowest risk and do not need prophylaxis with valganciclovir.

CMV infection is diagnosed by PCR testing of the blood or immunostaining in tissue biopsy. Occasionally, blood testing is negative in the face of tissue-based disease.

BK virus

BK is a polyoma virus and a common virus associated with kidney transplant. Viremia is seen in about 18% of patients, whereas actual kidney disease associated with a higher level of virus is seen in fewer than 10% of patients. Most people are exposed to BK virus, often in childhood, and it can remain indolent in the bladder and uroepithelium.

Patients can develop BK nephropathy after exposure to transplant immunosuppression.¹¹ Posttransplant monitoring protocols typically include PCR testing for BK virus at 1, 3, 6, and 12 months. No agent has been identified to specifically treat BK virus. The general strategy is to minimize immunosuppressive therapy by reducing or eliminating mycophenolate mofetil. Fortunately, BK virus does not tend to recur, and patients can have a low-level viremia (< 10,000 copies/mL) persisting over months or even years but often without clinical consequences.

The appearance of BK virus on biopsy can mimic acute rejection. Before BK viral nephropathy was a recognized entity, patients would have been diagnosed with acute rejection and may have been put on high-dose steroids, which would have worsened the BK infection.

Posttransplant lymphoproliferative disorder

Posttransplant lymphoproliferative disorder is most often associated with Epstein-Barr virus and usually involves a large, diffuse B-cell lymphoma. Burkitt lymphoma and plasma cell neoplasms also can occur less commonly.

The condition is about 30 times more common in patients after transplant than in the general population, and it is the third most common malignancy in transplant patients after skin and cervical cancers. About 80% of the cases occur early after transplant, within the first year.

Patients typically have a marked elevation in viral load of Epstein-Barr virus, although a negative viral load does not rule it out. A patient who is serologically negative for Epstein-Barr virus receiving a donor-positive kidney is at highest risk; this situation is most often seen in the pediatric population. Potent induction therapies (eg, antilymphocyte antibody therapy) are also associated with posttransplant lymphoproliferative disorder.

Patients typically present with fever of unknown origin with no localizing signs or symptoms. Mass lesions can be challenging to find; positron emission tomography may be helpful. The culprit is usually a focal mass, ulcer (especially in the gastrointestinal tract), or infiltrate (commonly localized to the allograft). Multifocal or disseminated disease can also occur, including lymphoma or with central nervous system, gastrointestinal, or pulmonary involvement.

Biopsy of the affected site is required for histopathology and Epstein-Barr virus markers. PCR blood testing is often positive for Epstein-Barr virus.

Typical antiviral therapy does not eliminate Epstein-Barr virus. In early polyclonal viral proliferation, the first goal is to reduce immunosuppressive therapy. Rituximab alone may also help in polymorphic cases. With disease that is clearly monomorphic and has transformed to a true malignancy, cytotoxic chemotherapy is also required. “R-CHOP,” a combination therapy consisting of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, is usually used. Radiation therapy may help in some cases.

Cryptococcal infection

Previously seen in patients with acquired immune deficiency syndrome, cryptococcal infection is now most commonly encountered in patients with solid-organ transplants. Vilchez et al¹² found a 1% incidence in a series of more than 5,000 patients who had received an organ transplant.

Immunosuppression likely conveys risk, but because cryptococcal infection is acquired, environmental exposure also plays a role. It tends to appear more than 6 months after transplant, indicating that its cause is a primary infection by spore inhalation rather than by reactivation or transmission from the donor organ.¹³ Bird exposure is a risk factor for cryptococcal infection. One case identified the same strain of Cryptococcus in a kidney transplant recipient and the family’s pet cockatoo.¹⁴

Cryptococcal infection typically starts as pneumonia, which may be subclinical. The infection can then disseminate, with meningitis presenting with headache and mental status changes being the most concerning complication. The death rate is about 50% in most series of patients with meningitis. Skin and soft-tissue manifestations may also occur in 10% to 15% of cases and can be nodular, ulcerative, or cellulitic.

More than 75% of fungal infections requiring hospitalization in US patients who have undergone transplant are attributed to either Candida, Aspergillus, or Cryptococcus species.¹⁵ Risk of fungal infection is increased with diabetes, duration of pretransplant dialysis, tacrolimus therapy, or rejection treatment.

Much has improved in renal transplantation over the past 20 years. The focus has shifted to using stronger immunotherapy rather than trying to minimize it. There has been increasing recognition of infection and ways to prevent and treat it. Induction therapy now has greater emphasis so that maintenance therapy can be eased, with the aim of reducing long-term toxicity. Perhaps the biggest change is the practice of screening for donor-specific antibodies at the time of transplant so that predictable problems can be prevented or better handled if they occur. Such advances have helped patients directly and by extending the life of their transplanted organs.

LONGER SURVIVAL

As early as the 1990s, it was recognized that kidney transplant offers a survival advantage for patients with end-stage renal disease over maintenance on dialysis.¹ Although the risk of death is higher immediately after transplant, within a few months it becomes much lower than for patients on dialysis. Survival varies according to the health of the patient and the quality of the transplanted organ.

In general, patients who obtain the greatest benefit from transplants in terms of years of life gained are those with diabetes, especially those who are younger. Those ages 20 to 39 live about 8 years on dialysis vs 25 years after transplant.

CONTRAINDICATIONS TO TRANSPLANT

There are multiple contraindications to a solitary kidney transplant (Table 1), including smoking. Most transplant centers require that smokers quit before transplant. Long-standing smokers almost double their risk of a cardiac event after transplant and double their rate of malignancy. Active smoking at the time of transplant is associated with twice the risk of death by 10 years after transplant compared with that of nonsmokers.² Cotinine testing can detect whether a patient is an active smoker.

WAITING-LIST CONSIDERATIONS

Organs are scarce

The number of patients on the kidney waiting list has increased rapidly in the last few decades, while the number of transplants performed each year has remained about the same. In 2016, about 100,000 patients were on the list, but only about 19,000 transplants were performed.³ Wait times, especially for deceased-donor organs, have increased to about 6 years, varying by blood type and geographic region.

Waiting-list placement

Placement on the waiting list for a deceased-donor kidney transplant occurs when a patient has an estimated glomerular filtration rate (GFR) of 20 mL/min/1.73 m² or less, although referral to the list can be made earlier. Early listing remains advantageous, as total time on the list will be counted before starting dialysis. “Preemptive transplant” means the patient had no dialysis before transplant; this applies to about 10% of transplant recipients. These patients tend to fare the best and are usually recipients of a living-donor organ.

Most patients do not receive a transplant until the GFR is less than 15 mL/min/1.73 m².

Since 2014, wait time has been measured from the beginning of dialysis rather than the date of waiting-list placement in patients who are listed after starting dialysis therapy. This approach is more fair but sometimes introduces problems. A patient who did not previously know about the list may suddenly jump to the head of the line after 10 years of dialysis, by which time comorbidities associated with long-term dialysis make the patient less likely to gain as much benefit from a transplant as people lower on the list. Time on dialysis, or “dialysis vintage,” predicts patient and kidney survival after transplant, with reduced survival associated with increasing time on dialysis.⁴

Shorter wait for a suboptimal kidney

The aging population has increased the number of older patients being listed for transplant, presenting multiple challenges. Patients age 65 or older have a 50% chance of dying before they receive a transplant during a 5-year wait.

A patient may shorten the wait by joining the list for a suboptimal organ. All deceased-donor organs are given a Kidney Donor Profile Index score, which predicts the longevity of an organ after transplant. The score is determined by donor age, kidney function based on the serum creatinine at the time of death, and other donor factors.

A kidney with a score higher than 85% is likely to function longer than only 15% of available kidneys. Patients who receive a kidney with that score have a longer period of risk of death soon after transplant and a slightly higher risk of death in the long term than patients who receive a healthier kidney, although on average they still do better than patients on dialysis.⁵

Older patients should be encouraged to sign up for both the regular waiting list and the suboptimal kidney waiting list to reduce the risk of dying before they get a kidney.

Many advantages

Living-donor organ transplant is associated with a better survival rate than deceased-donor organ transplant, and the advantage becomes greater over time. At 1 year, patient survival is more than 90% in both groups, but by 5 years about 80% of patients with a living-donor organ are still alive vs only about 65% of patients with a deceased-donor organ.

The waiting time for a living-donor transplant may be only weeks to months, rather than years. Because increasing time on dialysis predicts worse patient and graft survival after transplant, the shorter wait time is a big advantage. In addition, because the donor and recipient are typically in adjacent operating rooms, the organ sustains less ischemic damage. In general, the kidney quality is better from healthy donors, resulting in superior function early on and longer graft survival by an average of 4 years. If the living donor is related to the recipient, human leukocyte antigen matching also tends to be better and predicts better outcomes.

Special challenges

Opting for a living-donor organ also entails special challenges. In addition to the ethical issues surrounding living-donor organ donation, an appropriate donor must be found. Donors must be highly motivated and pass physical, laboratory, and psychological evaluations.

For older patients, if the donor is a spouse or close friend, he or she is also likely to be older, making the organ less viable than one from a younger person. Even an adult child may not be an ideal donor if there is a family propensity to kidney disease, such as diabetic nephropathy. No test is available to determine the risk for future diabetes, but it is known to run in families.

POTENT IMMUNOSUPPRESSION

Induction therapy

Induction therapy with antithymocyte globulin or basiliximab provides intense immunosuppression to prevent acute rejection during the early posttransplant period.

Antithymocyte globulin is a potent agent that contains antibodies directed at T cells, B cells, neutrophils, platelets, adhesion molecules, and complement. It binds T cells and removes them from circulation by opsonization in splenic and lymphoid tissue. The immunosuppressive effect is sustained for at least 2 to 3 months after a series of injections (dosage 1.5 mg/kg/day, usually for 4 to 10 doses). Antithymocyte globulin is also used to treat acute rejection, especially high-grade rejection for which steroid therapy is likely to be insufficient.

Basiliximab consists of antibodies to the interleukin 2 (IL-2) receptor of T cells. Binding to T cells prevents their activation rather than removing them from circulation. The drug prevents rejection, with 30% relative reduction in early studies compared with placebo. However, it is ineffective in reversing established rejection. Dosage is 20 mg at day 0 and day 4, which provides receptor saturation for 30 to 45 days.

Basiliximab is also sometimes used off-label for patients who need to discontinue a calcineurin inhibitor (ie, tacrolimus or cyclosporine). In such cases, normal therapy is put on hold while basiliximab is given for 1 or 2 doses. Case series have been reported for this use, particularly for patients with a heart and liver transplant who develop acute kidney injury while hospitalized.^6,7

Antithymocyte globulin is more effective but also more risky. Brennan et al⁸ randomized 278 transplant recipients to either antithymocyte globulin or basiliximab. Patients in the antithymocyte globulin group had a 16% rejection rate vs 26% in the basiliximab group.

Antithymocyte globulin therapy is associated with multiple adverse effects, including fever and chills, pulmonary edema, and long-standing immunosuppressive effects such as increased risk of lymphoma and cytomegalovirus (CMV) infection. Basiliximab side-effect profiles are similar to those of placebo.

Maintenance therapy

The calcineurin inhibitors cyclosporine and tacrolimus remain the standard of care in kidney transplant despite multiple drug interactions and side effects that include renal toxicity and fibrosis. Cyclosporine and tacrolimus both bind intracellular immunophilins and thereby prevent transcription of IL-2 and production of T cells. The drugs work similarly but have different binding sites. Cyclosporine has largely been replaced by tacrolimus because its reliability of dosing and higher potency are associated with lower rejection rates.

Tacrolimus is typically given twice daily (1–6 mg/dose). Twelve-hour trough levels are followed (target: 8–12 ng/mL early on, then 5–8 ng/mL after 3 months posttransplant). Side effects include hypertension and hypercholesterolemia, but less so than with cyclosporine. On the other hand, hyperglycemia tends to be worse with tacrolimus than with cyclosporine, and combining tacrolimus with steroids frequently leads to diabetes. Tacrolimus can also cause acute and chronic renal failure, especially at high drug levels, as well as neurotoxicity, tremors, and hair loss.

Cyclosporine, tacrolimus, and sirolimus (not a calcineurin inhibitor) are metabolized through the same cytochrome P450 pathway (CYP3A4), so they have common drug interactions (Table 2).

Mycophenolate mofetil is typically used as an adjunct therapy (500–1,000 mg twice daily). It is also used for other kidney diseases before transplant, including lupus nephritis. Transplanted kidney rejection rates with mycophenolate mofetil with steroids are about 40%, so the drug is not potent enough to be used without a calcineurin inhibitor.

Side effects include gastrointestinal toxicity in up to 20% of patients, and leukopenia, which is associated with viral infections.

CORONARY ARTERY DISEASE IS COMMON WITH DIALYSIS

Coronary artery disease is highly associated with end-stage kidney disease and occurs in as many as 85% of older patients with diabetes on dialysis. Although patients with end-stage kidney disease tend to have more numerous and severe atherosclerotic lesions compared with the general population, justifying aggressive management, cardiac care tends to be conservative in patients on dialysis.⁹

Death from acute myocardial infarction occurs in about 20% to 30% of patients on dialysis vs about 2% of patients with normal renal function. Five years after myocardial infarction, survival is only about 30% in patients on dialysis.⁹

There are many explanations for excess coronary artery disease in patients on dialysis. In addition to the traditional cardiovascular risk factors of diabetes, hypertension, and preexisting coronary artery disease, patients are in a proinflammatory uremic state and have high levels of phosphorus and fibroblast growth factor 23 that contribute to vascular calcification. Almost all patients have high homocysteine levels and hemodynamic instability, particularly if they are on hemodialysis.

Pretransplant evaluation for heart disease

Patients on the kidney transplant waiting list are screened aggressively for heart disease. A history of myocardial infarction usually results in removal from the list. All patients have an initial electrocardiogram and echocardiogram. Thallium or echocardiographic stress testing is used for patients who are age 50 and older, have diabetes, or have had dialysis for many years. Patients with evidence of ischemia undergo catheterization.

Patients are also screened with computed tomography before transplant. Because the kidney is typically anastomosed to the iliac artery and vein, heavy calcification of the iliac artery can make the procedure too difficult to perform.

Kasiske et al¹⁰ analyzed data from more than 50,000 patients from the US Renal Data System and found that, for about the first year after transplant, patients who underwent kidney transplant were more likely to have a myocardial infarction than those on dialysis. After that, they fared better than patients who remained on dialysis. Those with a living-donor transplant were less likely at all times to have a myocardial infarction than those with a deceased-donor transplant. By 3 years after transplant, the relative risk of having a myocardial infarction was 0.89 for deceased-donor organ recipients and 0.69 for living-donor recipients compared with patients on the waiting list.¹⁰

INFECTIOUS COMPLICATIONS IN KIDNEY RECIPIENTS

Kidney recipients are prone to many common and uncommon infections (Table 3). All potential recipients are tested pretransplant for hepatitis B, hepatitis C, human immunodeficiency virus, syphilis, and tuberculosis. A positive result does not necessarily rule out transplant.

The following viral serology tests are also done before transplant:

Epstein-Barr virus (antibodies are positive in about 90% of adults)

CMV (about 70% of adults are seropositive)

Varicella zoster (seronegative patients should be given live-attenuated varicella vaccine).

Risk of transmission of these viruses relates to the serostatus of the donor and recipient before transplant. If a donor is positive for viral antibodies but the recipient is not (a so-called “mismatch”), risk is higher after transplant.

Hepatitis C

Patients with hepatitis C fare better if they get a transplant than if they remain on dialysis, although their posttransplant course is worse compared with transplant patients who do not have hepatitis. Some patients develop accelerated liver disease after kidney transplant. Hepatitis C-related kidney disease—membranous proliferative glomerulonephritis—also occurs, as do comorbidities such as diabetes.

Careful evaluation is warranted before transplant, including liver imaging, alpha-fetoprotein testing, and liver biopsy to evaluate for hepatocellular carcinoma. A patient with advanced fibrosis or cirrhosis may not be a candidate for kidney transplant alone but could possibly receive a combined kidney and liver transplant.

There is a need to determine the best time to treat hepatitis C infection. Patients with advanced liver disease or hepatitis C-related kidney disease would likely benefit from early treatment. However, delaying treatment could shorten the wait time for a deceased-donor organ positive for hepatitis C.  Transplant candidates with active hepatitis C are uniquely considered to accept hepatitis C-positive kidneys, which are often discarded, and may only wait weeks for such a transplant. The shortened kidney survival associated with a hepatitis C-positive kidney may no longer be true with the new antiviral hepatitis C therapy, which has been shown to be effective post-transplant.

Hepatitis B

No cure is available for hepatitis B infection, but it can be well controlled with antiviral therapy. Patients with hepatitis B infection may be candidates for transplant, but they should be stable on antiviral therapy (lamivudine, entecavir, or tenofovir) to eliminate the viral load before transplant, and therapy should be continued afterward. Liver imaging, alpha-fetoprotein levels, and biopsy are recommended for evaluation. All hepatitis B- negative patients should be vaccinated before transplant.

Organs from living or deceased donors that test positive for hepatitis B core antibody, indicating prior exposure, can be considered for transplant in a patient who tests positive for hepatitis B surface antibody, indicating successful vaccination or prior exposure in the recipient. But donors must have negative surface antigen and polymerase chain reaction (PCR) tests that indicate no active hepatitis B infection.

Cytomegalovirus

CMV typically does not appear until prophylactic therapy is stopped. Classic symptoms are fever, leukopenia, and diarrhea. Infection can involve any organ, and patients may present with hepatitis, pancreatitis or, less commonly, pneumonitis.

Patients who are negative for CMV before transplant and receive a donor-positive organ are at the highest risk. Patients who are CMV IgG-positive are considered to be at intermediate risk, regardless of the donor status. Patients who are negative for CMV and receive a donor-negative organ are at the lowest risk and do not need prophylaxis with valganciclovir.

CMV infection is diagnosed by PCR testing of the blood or immunostaining in tissue biopsy. Occasionally, blood testing is negative in the face of tissue-based disease.

BK virus

BK is a polyoma virus and a common virus associated with kidney transplant. Viremia is seen in about 18% of patients, whereas actual kidney disease associated with a higher level of virus is seen in fewer than 10% of patients. Most people are exposed to BK virus, often in childhood, and it can remain indolent in the bladder and uroepithelium.

Patients can develop BK nephropathy after exposure to transplant immunosuppression.¹¹ Posttransplant monitoring protocols typically include PCR testing for BK virus at 1, 3, 6, and 12 months. No agent has been identified to specifically treat BK virus. The general strategy is to minimize immunosuppressive therapy by reducing or eliminating mycophenolate mofetil. Fortunately, BK virus does not tend to recur, and patients can have a low-level viremia (< 10,000 copies/mL) persisting over months or even years but often without clinical consequences.

The appearance of BK virus on biopsy can mimic acute rejection. Before BK viral nephropathy was a recognized entity, patients would have been diagnosed with acute rejection and may have been put on high-dose steroids, which would have worsened the BK infection.

Posttransplant lymphoproliferative disorder

Posttransplant lymphoproliferative disorder is most often associated with Epstein-Barr virus and usually involves a large, diffuse B-cell lymphoma. Burkitt lymphoma and plasma cell neoplasms also can occur less commonly.

The condition is about 30 times more common in patients after transplant than in the general population, and it is the third most common malignancy in transplant patients after skin and cervical cancers. About 80% of the cases occur early after transplant, within the first year.

Patients typically have a marked elevation in viral load of Epstein-Barr virus, although a negative viral load does not rule it out. A patient who is serologically negative for Epstein-Barr virus receiving a donor-positive kidney is at highest risk; this situation is most often seen in the pediatric population. Potent induction therapies (eg, antilymphocyte antibody therapy) are also associated with posttransplant lymphoproliferative disorder.

Patients typically present with fever of unknown origin with no localizing signs or symptoms. Mass lesions can be challenging to find; positron emission tomography may be helpful. The culprit is usually a focal mass, ulcer (especially in the gastrointestinal tract), or infiltrate (commonly localized to the allograft). Multifocal or disseminated disease can also occur, including lymphoma or with central nervous system, gastrointestinal, or pulmonary involvement.

Biopsy of the affected site is required for histopathology and Epstein-Barr virus markers. PCR blood testing is often positive for Epstein-Barr virus.

Typical antiviral therapy does not eliminate Epstein-Barr virus. In early polyclonal viral proliferation, the first goal is to reduce immunosuppressive therapy. Rituximab alone may also help in polymorphic cases. With disease that is clearly monomorphic and has transformed to a true malignancy, cytotoxic chemotherapy is also required. “R-CHOP,” a combination therapy consisting of rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone, is usually used. Radiation therapy may help in some cases.

Cryptococcal infection

Previously seen in patients with acquired immune deficiency syndrome, cryptococcal infection is now most commonly encountered in patients with solid-organ transplants. Vilchez et al¹² found a 1% incidence in a series of more than 5,000 patients who had received an organ transplant.

Immunosuppression likely conveys risk, but because cryptococcal infection is acquired, environmental exposure also plays a role. It tends to appear more than 6 months after transplant, indicating that its cause is a primary infection by spore inhalation rather than by reactivation or transmission from the donor organ.¹³ Bird exposure is a risk factor for cryptococcal infection. One case identified the same strain of Cryptococcus in a kidney transplant recipient and the family’s pet cockatoo.¹⁴

Cryptococcal infection typically starts as pneumonia, which may be subclinical. The infection can then disseminate, with meningitis presenting with headache and mental status changes being the most concerning complication. The death rate is about 50% in most series of patients with meningitis. Skin and soft-tissue manifestations may also occur in 10% to 15% of cases and can be nodular, ulcerative, or cellulitic.

More than 75% of fungal infections requiring hospitalization in US patients who have undergone transplant are attributed to either Candida, Aspergillus, or Cryptococcus species.¹⁵ Risk of fungal infection is increased with diabetes, duration of pretransplant dialysis, tacrolimus therapy, or rejection treatment.

Multiple randomized controlled trials have compared percutaneous coronary intervention (PCI) vs optimal medical therapy for patients with chronic stable angina. All have consistently shown that PCI does not reduce the risk of death or even myocardial infarction (MI) but that it may relieve angina temporarily. Nevertheless, PCI is still commonly performed for patients with stable coronary disease, often in the absence of angina, and patients mistakenly believe the procedure is life-saving. Cardiologists may not be aware of patients’ misperceptions, or worse, may encourage them. In either case, if patients do not understand the benefits of the procedure, they cannot give informed consent.

See related editorial

This article reviews the pathophysiology of coronary artery disease, evidence from clinical trials of the value of PCI for chronic stable angina, patient and physician perceptions of PCI, and ways to promote patient-centered, shared decision-making.

CLINICAL CASE: EXERTIONAL ANGINA

While climbing 4 flights of stairs, a 55-year-old man noticed tightness in his chest, which lasted for 5 minutes and resolved spontaneously. Several weeks later, when visiting his primary care physician, he mentioned the episode. He had had no symptoms in the interim, but the physician ordered an exercise stress test.

Six minutes into a standard Bruce protocol, the patient experienced the same chest tightness, accompanied by 1-mm ST-segment depressions in leads II, III, and aVF. He was then referred to a cardiologist, who recommended catheterization.

Catheterization demonstrated a 95% stenosis of the right coronary artery with nonsignificant stenoses of the left anterior descending and circumflex arteries. A drug-eluting stent was placed in the right coronary artery, with no residual stenosis.

Did this intervention likely prevent an MI and perhaps save the man’s life?

HOW MYOCARDIAL INFARCTION HAPPENS

Understanding the pathogenesis of MI is critical to having realistic expectations of the benefits of stent placement.

Doctors often describe coronary atherosclerosis as a plumbing problem, where deposits of cholesterol and fat build up in arterial walls, clogging the pipes and eventually causing a heart attack. This analogy, which has been around since the 1950s, is easy to for patients to grasp and has been popularized in the press and internalized by the public—as one patient with a 95% stenosis put it, “I was 95% dead.” In that model, angioplasty and stenting can resolve the blockage and “fix” the problem, much as a plumber can clear your pipes with a Roto-Rooter.

Despite the visual appeal of this model,¹ it doesn’t accurately convey what we know about the pathophysiology of coronary artery disease. Instead of a gradual buildup of fatty deposits, low-density lipoprotein cholesterol particles infiltrate arterial walls and trigger an inflammatory reaction as they are engulfed by macrophages, leading to a cascade of cytokines and recruitment of more inflammatory cells.² This immune response can eventually cause the rupture of the plaque’s fibrous cap, triggering thrombosis and infarction, often at a site of insignificant stenosis.

In this new model, coronary artery disease is primarily a problem of inflammation distributed throughout the vasculature, rather than a mechanical problem localized to the site of a significant stenosis.

Significant stenosis does not equal unstable plaque

Not all plaques are equally likely to rupture. Stable plaques tend to be long-standing and calcified, with a thick fibrous cap. A stable plaque causing a 95% stenosis may cause symptoms with exertion, but it is unlikely to cause infarction.³ Conversely, rupture-prone plaques may cause little stenosis, but a large and dangerous plaque may be lurking beneath the thin fibrous cap.

Relying on angiography can be misleading. Treating all significant stenoses improves blood flow, but does not reduce the risk of infarction, because infarction most often occurs in areas where the lumen is not obstructed. A plaque causing only 30% stenosis can suddenly rupture, causing thrombosis and complete occlusion.

The current model explains why PCI is no better than optimal medical therapy (ie, risk factor modification, antiplatelet therapy with aspirin, and a statin). Diet, exercise, smoking cessation, and statins target inflammatory processes and lower low-density lipoprotein cholesterol levels, while aspirin prevents platelet aggregation, among other likely actions.

The model also explains why coronary artery bypass grafting reduces the risk of MI and death in patients with left main or 3-vessel disease. A patient with generalized coronary artery disease has multiple lesions, many of which do not cause significant stenoses. PCI corrects only a single stenosis, whereas coronary artery bypass grafting circumvents all the vulnerable plaques in a vessel.

THE LANDMARK COURAGE TRIAL

Published in 2007, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial⁴ randomized more than 2,000 patients to receive either optimal medical therapy plus PCI or optimal medical therapy alone. The primary outcome was a composite of death from any cause and nonfatal MI. Patients were followed for at least 3 years, and some for as long as 7 years.

There was an initial small upward spike in the primary outcome in the PCI arm due to periprocedural events. By 5 years, the outcomes of the 2 arms converged and then stayed the same for up to 15 years.⁵ The authors concluded that PCI conferred no benefit over optimal medical therapy in the risk of death or MI.

Some doctors dismiss the study because of its stringent entry criteria—of 35,539 patients assessed, only 3,071 met the eligibility criteria. However, the entry criteria were meant to identify patients most likely to benefit from PCI. Many patients who undergo PCI today would not have qualified for the study because they lack objective evidence of ischemia.⁶ To enroll, patients needed a proximal stenosis of at least 70% and objective evidence of ischemia or a coronary stenosis of more than 80% and classic angina. Exclusion criteria disqualified few patients: Canadian Cardiovascular Society class IV angina (ie, angina evoked from minimal activity or at rest); a markedly positive stress test (substantial ST-segment depression or hypotension during stage I of the Bruce protocol); refractory heart failure or cardiogenic shock; an ejection fraction of less than 30%; revascularization within the past 6 months; and coronary anatomy unsuitable for PCI.

Although COURAGE was hailed as a landmark trial, it largely supported the results of previous studies. A meta-analysis of PCI vs optimal medical therapy published in 2005 found no significant differences in death, cardiac death, MI, or nonfatal MI.⁷ MI was actually slightly more common in the PCI group due to the increased risk of MI during the periprocedural period.

Nor has the evidence from COURAGE discouraged additional studies of the same topic. Despite consistent findings that fit with our understanding of coronary disease as inflammation, we continue to conduct studies aimed at addressing significant stenosis, as if that was the problem. Thus, there have been studies of angioplasty alone, followed by studies of bare-metal stents and then drug-eluting stents.

In 2009, Trikalinos et al published a review of 61 randomized controlled trials comprising more than 25,000 patients with stable coronary disease and comparing medical therapy and angioplasty in its various forms over the previous 20 years.⁸ In all direct and indirect comparisons of PCI and medical therapy, there were no improvements in rates of death or MI.

Even so, the studies continue. The most recent “improvement” was the addition of fractional flow reserve, which served as the inclusion criterion for the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial.⁹ In that study, patients with at least 1 stenosis with a fractional flow reserve less than 0.80 were randomized to PCI plus medical therapy or to medical therapy alone. The primary end point was a composite of death from any cause, MI, and urgent revascularization. Unfortunately, the study was stopped early when the primary end point was met due to a reduction in the need for urgent revascularization. There was no reduction in the rate of MI (hazard ratio 1.05, 95% confidence interval 0.51–2.19).

The reduction in urgent revascularization has also been shown consistently in past studies, but this is the weakest outcome measure because it does not equate to a reduction in the rate of MI. There is no demonstrable harm to putting off stent placement, even in functionally significant arteries, and most patients do not require a stent, even in the future.

In summary, the primary benefit of getting a stent now is a reduced likelihood of needing one later.

PCI MAY IMPROVE ANGINA FASTER

Another important finding of the COURAGE trial was that PCI improved symptoms more than optimal medical therapy.¹⁰ This is not surprising, because angina is often a direct result of a significant stenosis. What was unexpected was that even after PCI, most patients were not symptom-free. At 1 month, significantly more PCI patients were angina-free (42%) than were medical patients (33%). This translates into an absolute risk reduction of 9% or a number needed to treat of 11 to prevent 1 case of angina.

Patients in both groups improved over time, and after 3 years, the difference between the 2 groups was no longer significant: 59% in the PCI group vs 56% in the medical therapy group were angina-free.

A more recent study has raised the possibility that the improvement in angina with PCI is primarily a placebo effect. Researchers in the United Kingdom randomized patients with stable angina and at least a 70% stenosis of one vessel to either PCI or sham PCI, in which they threaded the catheter but did not deploy the stent.¹¹ All patients received aggressive antianginal therapy before the procedure. At 6 weeks, there was improvement in angina in both groups, but no statistically significant difference between them in either exercise time or angina. Approximately half the patients in each group improved by at least 1 grade on the Canadian Cardiovascular Society angina classification, and more than 20% improved 2 grades.

This finding is not without precedent. Ligation of the internal mammary arteries, a popular treatment for angina in the 1950s, often provided dramatic relief of symptoms, until it was proven to be no better than a sham operation.^12,13 More recently, a placebo-controlled trial of percutaneous laser myocardial revascularization also failed to show improvement over a sham treatment, despite promising results from a phase 1 trial.¹⁴ Together, these studies emphasize the subjective nature of angina as an outcome and call into question the routine use of PCI to relieve it.

PCI ENTAILS RISK

PCI entails a small but not inconsequential risk. During the procedure, 2% of patients develop bleeding or blood vessel damage, and another 1% die or have an MI or a stroke. In the first year after stent placement, 3% of patients have a bleeding event from the antiplatelet therapy needed for the stent, and an additional 2% develop a clot in the stent that leads to MI.¹⁵

INFORMED CONSENT IS CRITICAL

As demonstrated above, for patients with stable angina, the only evidence-based benefit of PCI over optimal medical therapy is that symptoms may respond faster. At the same time, there are costs and risks associated with the procedure. Because symptoms are subjective, patients should play a key role in deciding whether PCI is appropriate for them.

The American Medical Association states that a physician providing any treatment or procedure should disclose and discuss with patients the risks and benefits. Unfortunately, a substantial body of evidence demonstrates that this is not occurring in practice.

Patients and cardiologists have conflicting beliefs about PCI

Studies over the past 20 years demonstrate that patients with chronic stable angina consistently overestimate the benefits of PCI, with 71% to 88% believing that it will reduce their chance of death.^16–19 Patients also understand that PCI can relieve their symptoms, though no study seems to have assessed the perceived magnitude of this benefit.

In contrast, when cardiologists were asked about the benefits their patients could expect from PCI, only 20% said that it would reduce mortality and 25% said it would prevent MI.¹⁸ These are still surprisingly high percentages, since the study was conducted after the COURAGE trial.

Nevertheless, these differences in perception show that cardiologists fail to successfully communicate the benefits of the procedure to their patients. Without complete information, patients cannot make informed decisions.

If PCI cannot improve hard outcomes like MI or death in stable coronary disease, why do cardiologists continue to perform it so frequently?

Soon after the COURAGE trial, Lin et al conducted focus groups with cardiologists to find out.²⁰ Some said that they doubted the clinical trial evidence, given the reduction in the cardiac mortality rate over the past 30 years. Others remarked that their overriding goal is to stamp out ischemia, and that once a lesion is found by catheterization, one must proceed with PCI. This has been termed the “oculostenotic reflex,” ie, the interventionist sees coronary artery disease and immediately places a stent.

Atreya et al found objective evidence of this practice.²¹ In a 2016 study of 207 patients with obstructive lesions amenable to PCI, the only factors associated with medical management were those that increased the risk of the procedure: age, chronic kidney disease, distal location of the lesion, and type C lesions (the most difficult ones to treat by PCI). More important, evidence of ischemia, presence of angina, and being on optimal medical therapy or maximal antianginal therapy were not associated with PCI.

When surveyed, cardiologists offered reasons similar to those identified by Lin et al, including a positive stress test (70%) and significant myocardium at risk (50%).¹⁸ Optimal medical therapy failure was cited less often (40%). Over 30% identified relief of chest pain for patients who were not prescribed optimal medical therapy. Another 30% said that patient anxiety contributed to their decision, but patients who reported anxiety were not more likely to get PCI than those who did not.

True informed consent rarely occurs

Surveys of patients and recordings of doctor visits suggest that doctors often discuss the risks of the procedure but rarely accurately describe the benefits or mention alternative treatments, including optimal medical therapy.

Fowler et al²² surveyed 472 Medicare patients who had undergone PCI in the past year about their consent discussion, particularly regarding alternative options. Only 6% of patients recalled discussing medication as a serious option with their doctor.

In 2 published studies,^23,24 we analyzed recorded conversations between doctors and patients in which angiography and PCI were discussed.

In a qualitative assessment of how cardiologists presented the rationale for PCI to patients,²³ we observed that cardiologists gave an accurate presentation of the benefits in only 5% of cases. In 13% of the conversations the benefits were explicitly overstated (eg, “If you don’t do it [angiogram/PCI], what could happen? Well, you could…have a heart attack involving that area which can lead to a sudden death”). In another 35% of cases, physicians offered an implicit overstatement of the benefit by saying they could “fix” the problem (eg, “So that’s where we start thinking, Well maybe we better try to fix that [blockage]”), without specifically stating that fixing the problem would offer any benefit. Patients were left to fill in the blanks. Conversations frequently focused on the rationale for performing PCI (eg, ischemia on a stress test) and a description of the procedure, rather than on the risks and benefits.

In a quantitative study of the same data set, we assessed how often physicians addressed the 7 elements of informed decision-making as defined by Braddock et al.²⁴

• Explaining the patient’s role in decision-making (ie, that the patient has a choice to make) was present in half of the conversations. Sometimes a doctor would simply say, “The next step is to perform catheterization.”
• Discussion of clinical issues (eg, having a blockage, stress test results) was performed in almost every case, demonstrating physicians’ comfort with that element.
• Discussing treatment alternatives occurred in only 1 in 4 conversations. This was more frequent than previously reported, and appeared most often when patients expressed hesitancy about proceeding to PCI.
• Discussing pros and cons of the alternatives was done in 42%.
• Uncertainty about the procedure (eg, that it might not relieve the angina) was expressed in only 10% of conversations.
• Assessment of patient understanding was done in 65% of cases. This included even minimal efforts (eg, “Do you have any questions?”). More advanced methods such as teach-back were never used.
• Exploration of patient preferences (eg, asking patients which treatment they prefer, or attempting to understand how angina affects a patient’s life) the final element, occurred in 73% of conversations.

Only 3% of the conversations contained all 7 elements. Even using a more relaxed definition of 3 critical elements (ie, discussing clinical issues, treatment alternatives, and pros and cons), only 13% of conversations included them all.

Discussion affects decisions

Informed decision-making is not only important because of its ethical implications. Offering patients more information was associated with their choosing not to have PCI. The probability of a patient undergoing PCI was negatively associated with 3 specific elements of informed decision-making. Patients were less likely to choose PCI if the patient’s role in decision-making was discussed (61% vs 86% chose PCI, P < .03); if alternatives were discussed (31% vs 89% chose PCI, P < .01); and if uncertainties were discussed (17% vs 80% chose PCI, P < .01).

There was also a linear relationship between the total number of elements discussed and the probability of choosing PCI: it ranged from 100% of patients choosing PCI when just 1 element was present to 3% of patients choosing PCI when all 7 elements were present. The relationship is not entirely causal, since doctors were more likely to talk about alternatives and risks if patients hesitated and raised questions. Cautious patients received more information.

From these observational studies, we know that physicians do not generally communicate the benefits of PCI, and patients make incorrect assumptions about the benefits they can expect. We know that those who receive more information are less likely to choose PCI, but what would happen if patients were randomly assigned to receive complete information?

We conducted an online survey of more than 1,000 participants over age 50 who had never undergone PCI, asking them to imagine visiting a cardiologist after having a positive stress test for stable chest pain.²⁵ Three intervention groups read different scenarios couched as information provided by their cardiologist:

• The “standard care” group received no specific information about the effects of PCI on the risk of myocardial infarction
• The “specific information” group was specifically told that PCI does not reduce the risk of myocardial infarction
• The “explanatory information” group was told how medications work and why PCI does not reduce the risk of myocardial infarction.

All 3 groups received information about the risks of PCI, its role in reducing angina, and the risks and benefits of optimal medical therapy.

After reading their scenario, all participants completed an identical questionnaire, which asked if they would opt for PCI, medical therapy, or both. Overall, 55% chose PCI, ranging from 70% in the standard care group to 46% in the group given explanatory information. Rates in the specific-information and explanatory-information groups were not statistically different from each other, but both were significantly different from that in the standard-care group. Interestingly, the more information patients were given about PCI, the more likely they were to choose optimal medical therapy.

After reading the scenario, participants were also asked if PCI would “prevent a heart attack.” Of those who received standard care, 71% endorsed that belief, which is remarkably similar to studies of real patients who have received standard care. In contrast, only 39% of those given specific information and 31% given explanatory information held that belief. Moreover, the belief that PCI prevented MI was the strongest predictor of choosing PCI (odds ratio 5.82, 95% confidence interval 4.13–8.26).²⁵

Interestingly, 52% of the standard care group falsely remembered that the doctor had told them that PCI would prevent an MI, even though the doctor said nothing about it one way or the other. It appears that participants were projecting their own beliefs onto the encounter. This highlights the importance of providing full information to patients who are considering this procedure.

TOWARD SHARED DECISION-MAKING

Shared decision-making is a process in which physicians enter into a partnership with a patient, offer information, elicit the patient’s preferences, and then come to a decision in concert with the patient.

Although many decisions can and should involve elements of shared decision-making, the decision to proceed with PCI for stable angina is particularly well-suited to shared decision-making. This is because the benefit of PCI depends on the value a patient attaches to being free of angina sooner. Since there is no difference in the risk of MI or death, the patient must decide if the risks of the procedure and the inconvenience of taking dual antiplatelet therapy are worth the benefit of improving symptoms faster. Presumably, patients who have more severe symptoms or experienced side effects from antianginal therapy would be more likely to choose PCI.

Despite having substantial experience educating patients, most physicians are unfamiliar with the process of shared decision-making. In particular, the process of eliciting preferences is often overlooked.

To address this issue, researchers at the Mayo Clinic developed a decision aid that compares PCI plus optimal medical therapy vs optimal medical therapy alone in an easily understandable information card.¹⁵ On one side, the 2 options are clearly stated, with the magnitude of symptom improvement over time graphically illustrated and the statement, “NO DIFFERENCE in heart attack or death,” prominently displayed. The back of the card discusses the risks of each option in easily understood tables.

The decision aid was compared with standard care in a randomized trial involving patients who were referred for catheterization and possible PCI.²⁶ The decision aid improved patients’ overall knowledge about PCI. In particular, 60% of those who used the decision aid knew that PCI did not prevent death or MI vs 40% of usual-care patients—results similar to those of the online experiment.

Interestingly, the decision about whether to undergo PCI did not differ significantly between the 2 groups, although there was a trend toward more patients in the decision-aid group choosing medical therapy alone (53%) vs the standard-care patients (39%).

To understand why the decision aid did not make more of a difference, the investigators performed qualitative interviews of the cardiologists in the study.²⁷ One theme was the timing of the intervention. Patients using the decision aid had already been referred for catheterization, and some felt the process should have occurred earlier. Engaging in shared decision-making with a general cardiologist before referral could help to improve the quality of patient decisions.

Cardiologists also noted the difficulty in changing their work flow to incorporate the decision aid. Although some embraced the idea of shared decision-making, others were concerned that many patients could not participate, and there was confusion about the difference between an educational tool, which could be used by a patient alone, and a decision aid, which is meant to generate discussion between the doctor and patient. Some expressed interest in using the tool in the future.

These findings serve to emphasize that providing information alone is not enough. If the physician does not “buy in” to the idea of shared decision-making, it will not occur.

PRACTICE IMPLICATIONS

Based on the pathophysiology of coronary artery disease and the results of multiple randomized controlled trials, it is evident that PCI does not prevent heart attacks in patients with chronic stable angina. However, most patients who undergo PCI are unaware of this and therefore do not truly give informed consent. In the absence of explicit information to the contrary, most patients with stable angina assume that PCI prevents MI and thus are biased toward choosing PCI.

Even minimal amounts of explicit information can partially overcome that bias and influence decision-making. In particular, explaining why PCI does not prevent MI was the most effective means of overcoming the bias.

To this end, shared decision aids may help physicians to engage in shared decision-making. Shared decision-making is most likely to occur if physicians are trained in the concept of shared decision-making, are committed to practicing it, and can fit it into their work flow. Ideally, this would occur in the office of a general cardiologist before referral for PCI.

For those practicing in accountable-care organizations, Medicare has recently introduced the shared decision-making model for 6 preference-sensitive conditions, including stable ischemic heart disease. Participants in this program will have the opportunity to receive payments for shared decision-making services and to share in any savings that result from reduced use of resources. Use of these tools holds the promise for providing more patient-centered care at lower cost.

Multiple randomized controlled trials have compared percutaneous coronary intervention (PCI) vs optimal medical therapy for patients with chronic stable angina. All have consistently shown that PCI does not reduce the risk of death or even myocardial infarction (MI) but that it may relieve angina temporarily. Nevertheless, PCI is still commonly performed for patients with stable coronary disease, often in the absence of angina, and patients mistakenly believe the procedure is life-saving. Cardiologists may not be aware of patients’ misperceptions, or worse, may encourage them. In either case, if patients do not understand the benefits of the procedure, they cannot give informed consent.

See related editorial

This article reviews the pathophysiology of coronary artery disease, evidence from clinical trials of the value of PCI for chronic stable angina, patient and physician perceptions of PCI, and ways to promote patient-centered, shared decision-making.

CLINICAL CASE: EXERTIONAL ANGINA

While climbing 4 flights of stairs, a 55-year-old man noticed tightness in his chest, which lasted for 5 minutes and resolved spontaneously. Several weeks later, when visiting his primary care physician, he mentioned the episode. He had had no symptoms in the interim, but the physician ordered an exercise stress test.

Six minutes into a standard Bruce protocol, the patient experienced the same chest tightness, accompanied by 1-mm ST-segment depressions in leads II, III, and aVF. He was then referred to a cardiologist, who recommended catheterization.

Catheterization demonstrated a 95% stenosis of the right coronary artery with nonsignificant stenoses of the left anterior descending and circumflex arteries. A drug-eluting stent was placed in the right coronary artery, with no residual stenosis.

Did this intervention likely prevent an MI and perhaps save the man’s life?

HOW MYOCARDIAL INFARCTION HAPPENS

Understanding the pathogenesis of MI is critical to having realistic expectations of the benefits of stent placement.

Doctors often describe coronary atherosclerosis as a plumbing problem, where deposits of cholesterol and fat build up in arterial walls, clogging the pipes and eventually causing a heart attack. This analogy, which has been around since the 1950s, is easy to for patients to grasp and has been popularized in the press and internalized by the public—as one patient with a 95% stenosis put it, “I was 95% dead.” In that model, angioplasty and stenting can resolve the blockage and “fix” the problem, much as a plumber can clear your pipes with a Roto-Rooter.

Despite the visual appeal of this model,¹ it doesn’t accurately convey what we know about the pathophysiology of coronary artery disease. Instead of a gradual buildup of fatty deposits, low-density lipoprotein cholesterol particles infiltrate arterial walls and trigger an inflammatory reaction as they are engulfed by macrophages, leading to a cascade of cytokines and recruitment of more inflammatory cells.² This immune response can eventually cause the rupture of the plaque’s fibrous cap, triggering thrombosis and infarction, often at a site of insignificant stenosis.

In this new model, coronary artery disease is primarily a problem of inflammation distributed throughout the vasculature, rather than a mechanical problem localized to the site of a significant stenosis.

Significant stenosis does not equal unstable plaque

Not all plaques are equally likely to rupture. Stable plaques tend to be long-standing and calcified, with a thick fibrous cap. A stable plaque causing a 95% stenosis may cause symptoms with exertion, but it is unlikely to cause infarction.³ Conversely, rupture-prone plaques may cause little stenosis, but a large and dangerous plaque may be lurking beneath the thin fibrous cap.

Relying on angiography can be misleading. Treating all significant stenoses improves blood flow, but does not reduce the risk of infarction, because infarction most often occurs in areas where the lumen is not obstructed. A plaque causing only 30% stenosis can suddenly rupture, causing thrombosis and complete occlusion.

The current model explains why PCI is no better than optimal medical therapy (ie, risk factor modification, antiplatelet therapy with aspirin, and a statin). Diet, exercise, smoking cessation, and statins target inflammatory processes and lower low-density lipoprotein cholesterol levels, while aspirin prevents platelet aggregation, among other likely actions.

The model also explains why coronary artery bypass grafting reduces the risk of MI and death in patients with left main or 3-vessel disease. A patient with generalized coronary artery disease has multiple lesions, many of which do not cause significant stenoses. PCI corrects only a single stenosis, whereas coronary artery bypass grafting circumvents all the vulnerable plaques in a vessel.

THE LANDMARK COURAGE TRIAL

Published in 2007, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial⁴ randomized more than 2,000 patients to receive either optimal medical therapy plus PCI or optimal medical therapy alone. The primary outcome was a composite of death from any cause and nonfatal MI. Patients were followed for at least 3 years, and some for as long as 7 years.

There was an initial small upward spike in the primary outcome in the PCI arm due to periprocedural events. By 5 years, the outcomes of the 2 arms converged and then stayed the same for up to 15 years.⁵ The authors concluded that PCI conferred no benefit over optimal medical therapy in the risk of death or MI.

Some doctors dismiss the study because of its stringent entry criteria—of 35,539 patients assessed, only 3,071 met the eligibility criteria. However, the entry criteria were meant to identify patients most likely to benefit from PCI. Many patients who undergo PCI today would not have qualified for the study because they lack objective evidence of ischemia.⁶ To enroll, patients needed a proximal stenosis of at least 70% and objective evidence of ischemia or a coronary stenosis of more than 80% and classic angina. Exclusion criteria disqualified few patients: Canadian Cardiovascular Society class IV angina (ie, angina evoked from minimal activity or at rest); a markedly positive stress test (substantial ST-segment depression or hypotension during stage I of the Bruce protocol); refractory heart failure or cardiogenic shock; an ejection fraction of less than 30%; revascularization within the past 6 months; and coronary anatomy unsuitable for PCI.

Although COURAGE was hailed as a landmark trial, it largely supported the results of previous studies. A meta-analysis of PCI vs optimal medical therapy published in 2005 found no significant differences in death, cardiac death, MI, or nonfatal MI.⁷ MI was actually slightly more common in the PCI group due to the increased risk of MI during the periprocedural period.

Nor has the evidence from COURAGE discouraged additional studies of the same topic. Despite consistent findings that fit with our understanding of coronary disease as inflammation, we continue to conduct studies aimed at addressing significant stenosis, as if that was the problem. Thus, there have been studies of angioplasty alone, followed by studies of bare-metal stents and then drug-eluting stents.

In 2009, Trikalinos et al published a review of 61 randomized controlled trials comprising more than 25,000 patients with stable coronary disease and comparing medical therapy and angioplasty in its various forms over the previous 20 years.⁸ In all direct and indirect comparisons of PCI and medical therapy, there were no improvements in rates of death or MI.

Even so, the studies continue. The most recent “improvement” was the addition of fractional flow reserve, which served as the inclusion criterion for the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial.⁹ In that study, patients with at least 1 stenosis with a fractional flow reserve less than 0.80 were randomized to PCI plus medical therapy or to medical therapy alone. The primary end point was a composite of death from any cause, MI, and urgent revascularization. Unfortunately, the study was stopped early when the primary end point was met due to a reduction in the need for urgent revascularization. There was no reduction in the rate of MI (hazard ratio 1.05, 95% confidence interval 0.51–2.19).

The reduction in urgent revascularization has also been shown consistently in past studies, but this is the weakest outcome measure because it does not equate to a reduction in the rate of MI. There is no demonstrable harm to putting off stent placement, even in functionally significant arteries, and most patients do not require a stent, even in the future.

In summary, the primary benefit of getting a stent now is a reduced likelihood of needing one later.

PCI MAY IMPROVE ANGINA FASTER

Another important finding of the COURAGE trial was that PCI improved symptoms more than optimal medical therapy.¹⁰ This is not surprising, because angina is often a direct result of a significant stenosis. What was unexpected was that even after PCI, most patients were not symptom-free. At 1 month, significantly more PCI patients were angina-free (42%) than were medical patients (33%). This translates into an absolute risk reduction of 9% or a number needed to treat of 11 to prevent 1 case of angina.

Patients in both groups improved over time, and after 3 years, the difference between the 2 groups was no longer significant: 59% in the PCI group vs 56% in the medical therapy group were angina-free.

A more recent study has raised the possibility that the improvement in angina with PCI is primarily a placebo effect. Researchers in the United Kingdom randomized patients with stable angina and at least a 70% stenosis of one vessel to either PCI or sham PCI, in which they threaded the catheter but did not deploy the stent.¹¹ All patients received aggressive antianginal therapy before the procedure. At 6 weeks, there was improvement in angina in both groups, but no statistically significant difference between them in either exercise time or angina. Approximately half the patients in each group improved by at least 1 grade on the Canadian Cardiovascular Society angina classification, and more than 20% improved 2 grades.

This finding is not without precedent. Ligation of the internal mammary arteries, a popular treatment for angina in the 1950s, often provided dramatic relief of symptoms, until it was proven to be no better than a sham operation.^12,13 More recently, a placebo-controlled trial of percutaneous laser myocardial revascularization also failed to show improvement over a sham treatment, despite promising results from a phase 1 trial.¹⁴ Together, these studies emphasize the subjective nature of angina as an outcome and call into question the routine use of PCI to relieve it.

PCI ENTAILS RISK

PCI entails a small but not inconsequential risk. During the procedure, 2% of patients develop bleeding or blood vessel damage, and another 1% die or have an MI or a stroke. In the first year after stent placement, 3% of patients have a bleeding event from the antiplatelet therapy needed for the stent, and an additional 2% develop a clot in the stent that leads to MI.¹⁵

INFORMED CONSENT IS CRITICAL

As demonstrated above, for patients with stable angina, the only evidence-based benefit of PCI over optimal medical therapy is that symptoms may respond faster. At the same time, there are costs and risks associated with the procedure. Because symptoms are subjective, patients should play a key role in deciding whether PCI is appropriate for them.

The American Medical Association states that a physician providing any treatment or procedure should disclose and discuss with patients the risks and benefits. Unfortunately, a substantial body of evidence demonstrates that this is not occurring in practice.

Patients and cardiologists have conflicting beliefs about PCI

Studies over the past 20 years demonstrate that patients with chronic stable angina consistently overestimate the benefits of PCI, with 71% to 88% believing that it will reduce their chance of death.^16–19 Patients also understand that PCI can relieve their symptoms, though no study seems to have assessed the perceived magnitude of this benefit.

In contrast, when cardiologists were asked about the benefits their patients could expect from PCI, only 20% said that it would reduce mortality and 25% said it would prevent MI.¹⁸ These are still surprisingly high percentages, since the study was conducted after the COURAGE trial.

Nevertheless, these differences in perception show that cardiologists fail to successfully communicate the benefits of the procedure to their patients. Without complete information, patients cannot make informed decisions.

If PCI cannot improve hard outcomes like MI or death in stable coronary disease, why do cardiologists continue to perform it so frequently?

Soon after the COURAGE trial, Lin et al conducted focus groups with cardiologists to find out.²⁰ Some said that they doubted the clinical trial evidence, given the reduction in the cardiac mortality rate over the past 30 years. Others remarked that their overriding goal is to stamp out ischemia, and that once a lesion is found by catheterization, one must proceed with PCI. This has been termed the “oculostenotic reflex,” ie, the interventionist sees coronary artery disease and immediately places a stent.

Atreya et al found objective evidence of this practice.²¹ In a 2016 study of 207 patients with obstructive lesions amenable to PCI, the only factors associated with medical management were those that increased the risk of the procedure: age, chronic kidney disease, distal location of the lesion, and type C lesions (the most difficult ones to treat by PCI). More important, evidence of ischemia, presence of angina, and being on optimal medical therapy or maximal antianginal therapy were not associated with PCI.

When surveyed, cardiologists offered reasons similar to those identified by Lin et al, including a positive stress test (70%) and significant myocardium at risk (50%).¹⁸ Optimal medical therapy failure was cited less often (40%). Over 30% identified relief of chest pain for patients who were not prescribed optimal medical therapy. Another 30% said that patient anxiety contributed to their decision, but patients who reported anxiety were not more likely to get PCI than those who did not.

True informed consent rarely occurs

Surveys of patients and recordings of doctor visits suggest that doctors often discuss the risks of the procedure but rarely accurately describe the benefits or mention alternative treatments, including optimal medical therapy.

Fowler et al²² surveyed 472 Medicare patients who had undergone PCI in the past year about their consent discussion, particularly regarding alternative options. Only 6% of patients recalled discussing medication as a serious option with their doctor.

In 2 published studies,^23,24 we analyzed recorded conversations between doctors and patients in which angiography and PCI were discussed.

In a qualitative assessment of how cardiologists presented the rationale for PCI to patients,²³ we observed that cardiologists gave an accurate presentation of the benefits in only 5% of cases. In 13% of the conversations the benefits were explicitly overstated (eg, “If you don’t do it [angiogram/PCI], what could happen? Well, you could…have a heart attack involving that area which can lead to a sudden death”). In another 35% of cases, physicians offered an implicit overstatement of the benefit by saying they could “fix” the problem (eg, “So that’s where we start thinking, Well maybe we better try to fix that [blockage]”), without specifically stating that fixing the problem would offer any benefit. Patients were left to fill in the blanks. Conversations frequently focused on the rationale for performing PCI (eg, ischemia on a stress test) and a description of the procedure, rather than on the risks and benefits.

In a quantitative study of the same data set, we assessed how often physicians addressed the 7 elements of informed decision-making as defined by Braddock et al.²⁴

• Explaining the patient’s role in decision-making (ie, that the patient has a choice to make) was present in half of the conversations. Sometimes a doctor would simply say, “The next step is to perform catheterization.”
• Discussion of clinical issues (eg, having a blockage, stress test results) was performed in almost every case, demonstrating physicians’ comfort with that element.
• Discussing treatment alternatives occurred in only 1 in 4 conversations. This was more frequent than previously reported, and appeared most often when patients expressed hesitancy about proceeding to PCI.
• Discussing pros and cons of the alternatives was done in 42%.
• Uncertainty about the procedure (eg, that it might not relieve the angina) was expressed in only 10% of conversations.
• Assessment of patient understanding was done in 65% of cases. This included even minimal efforts (eg, “Do you have any questions?”). More advanced methods such as teach-back were never used.
• Exploration of patient preferences (eg, asking patients which treatment they prefer, or attempting to understand how angina affects a patient’s life) the final element, occurred in 73% of conversations.

Only 3% of the conversations contained all 7 elements. Even using a more relaxed definition of 3 critical elements (ie, discussing clinical issues, treatment alternatives, and pros and cons), only 13% of conversations included them all.

Discussion affects decisions

Informed decision-making is not only important because of its ethical implications. Offering patients more information was associated with their choosing not to have PCI. The probability of a patient undergoing PCI was negatively associated with 3 specific elements of informed decision-making. Patients were less likely to choose PCI if the patient’s role in decision-making was discussed (61% vs 86% chose PCI, P < .03); if alternatives were discussed (31% vs 89% chose PCI, P < .01); and if uncertainties were discussed (17% vs 80% chose PCI, P < .01).

There was also a linear relationship between the total number of elements discussed and the probability of choosing PCI: it ranged from 100% of patients choosing PCI when just 1 element was present to 3% of patients choosing PCI when all 7 elements were present. The relationship is not entirely causal, since doctors were more likely to talk about alternatives and risks if patients hesitated and raised questions. Cautious patients received more information.

From these observational studies, we know that physicians do not generally communicate the benefits of PCI, and patients make incorrect assumptions about the benefits they can expect. We know that those who receive more information are less likely to choose PCI, but what would happen if patients were randomly assigned to receive complete information?

We conducted an online survey of more than 1,000 participants over age 50 who had never undergone PCI, asking them to imagine visiting a cardiologist after having a positive stress test for stable chest pain.²⁵ Three intervention groups read different scenarios couched as information provided by their cardiologist:

• The “standard care” group received no specific information about the effects of PCI on the risk of myocardial infarction
• The “specific information” group was specifically told that PCI does not reduce the risk of myocardial infarction
• The “explanatory information” group was told how medications work and why PCI does not reduce the risk of myocardial infarction.

All 3 groups received information about the risks of PCI, its role in reducing angina, and the risks and benefits of optimal medical therapy.

After reading their scenario, all participants completed an identical questionnaire, which asked if they would opt for PCI, medical therapy, or both. Overall, 55% chose PCI, ranging from 70% in the standard care group to 46% in the group given explanatory information. Rates in the specific-information and explanatory-information groups were not statistically different from each other, but both were significantly different from that in the standard-care group. Interestingly, the more information patients were given about PCI, the more likely they were to choose optimal medical therapy.

After reading the scenario, participants were also asked if PCI would “prevent a heart attack.” Of those who received standard care, 71% endorsed that belief, which is remarkably similar to studies of real patients who have received standard care. In contrast, only 39% of those given specific information and 31% given explanatory information held that belief. Moreover, the belief that PCI prevented MI was the strongest predictor of choosing PCI (odds ratio 5.82, 95% confidence interval 4.13–8.26).²⁵

Interestingly, 52% of the standard care group falsely remembered that the doctor had told them that PCI would prevent an MI, even though the doctor said nothing about it one way or the other. It appears that participants were projecting their own beliefs onto the encounter. This highlights the importance of providing full information to patients who are considering this procedure.

TOWARD SHARED DECISION-MAKING

Shared decision-making is a process in which physicians enter into a partnership with a patient, offer information, elicit the patient’s preferences, and then come to a decision in concert with the patient.

Although many decisions can and should involve elements of shared decision-making, the decision to proceed with PCI for stable angina is particularly well-suited to shared decision-making. This is because the benefit of PCI depends on the value a patient attaches to being free of angina sooner. Since there is no difference in the risk of MI or death, the patient must decide if the risks of the procedure and the inconvenience of taking dual antiplatelet therapy are worth the benefit of improving symptoms faster. Presumably, patients who have more severe symptoms or experienced side effects from antianginal therapy would be more likely to choose PCI.

Despite having substantial experience educating patients, most physicians are unfamiliar with the process of shared decision-making. In particular, the process of eliciting preferences is often overlooked.

To address this issue, researchers at the Mayo Clinic developed a decision aid that compares PCI plus optimal medical therapy vs optimal medical therapy alone in an easily understandable information card.¹⁵ On one side, the 2 options are clearly stated, with the magnitude of symptom improvement over time graphically illustrated and the statement, “NO DIFFERENCE in heart attack or death,” prominently displayed. The back of the card discusses the risks of each option in easily understood tables.

The decision aid was compared with standard care in a randomized trial involving patients who were referred for catheterization and possible PCI.²⁶ The decision aid improved patients’ overall knowledge about PCI. In particular, 60% of those who used the decision aid knew that PCI did not prevent death or MI vs 40% of usual-care patients—results similar to those of the online experiment.

Interestingly, the decision about whether to undergo PCI did not differ significantly between the 2 groups, although there was a trend toward more patients in the decision-aid group choosing medical therapy alone (53%) vs the standard-care patients (39%).

To understand why the decision aid did not make more of a difference, the investigators performed qualitative interviews of the cardiologists in the study.²⁷ One theme was the timing of the intervention. Patients using the decision aid had already been referred for catheterization, and some felt the process should have occurred earlier. Engaging in shared decision-making with a general cardiologist before referral could help to improve the quality of patient decisions.

Cardiologists also noted the difficulty in changing their work flow to incorporate the decision aid. Although some embraced the idea of shared decision-making, others were concerned that many patients could not participate, and there was confusion about the difference between an educational tool, which could be used by a patient alone, and a decision aid, which is meant to generate discussion between the doctor and patient. Some expressed interest in using the tool in the future.

These findings serve to emphasize that providing information alone is not enough. If the physician does not “buy in” to the idea of shared decision-making, it will not occur.

PRACTICE IMPLICATIONS

Based on the pathophysiology of coronary artery disease and the results of multiple randomized controlled trials, it is evident that PCI does not prevent heart attacks in patients with chronic stable angina. However, most patients who undergo PCI are unaware of this and therefore do not truly give informed consent. In the absence of explicit information to the contrary, most patients with stable angina assume that PCI prevents MI and thus are biased toward choosing PCI.

Even minimal amounts of explicit information can partially overcome that bias and influence decision-making. In particular, explaining why PCI does not prevent MI was the most effective means of overcoming the bias.

To this end, shared decision aids may help physicians to engage in shared decision-making. Shared decision-making is most likely to occur if physicians are trained in the concept of shared decision-making, are committed to practicing it, and can fit it into their work flow. Ideally, this would occur in the office of a general cardiologist before referral for PCI.

For those practicing in accountable-care organizations, Medicare has recently introduced the shared decision-making model for 6 preference-sensitive conditions, including stable ischemic heart disease. Participants in this program will have the opportunity to receive payments for shared decision-making services and to share in any savings that result from reduced use of resources. Use of these tools holds the promise for providing more patient-centered care at lower cost.

Multiple randomized controlled trials have compared percutaneous coronary intervention (PCI) vs optimal medical therapy for patients with chronic stable angina. All have consistently shown that PCI does not reduce the risk of death or even myocardial infarction (MI) but that it may relieve angina temporarily. Nevertheless, PCI is still commonly performed for patients with stable coronary disease, often in the absence of angina, and patients mistakenly believe the procedure is life-saving. Cardiologists may not be aware of patients’ misperceptions, or worse, may encourage them. In either case, if patients do not understand the benefits of the procedure, they cannot give informed consent.

See related editorial

This article reviews the pathophysiology of coronary artery disease, evidence from clinical trials of the value of PCI for chronic stable angina, patient and physician perceptions of PCI, and ways to promote patient-centered, shared decision-making.

CLINICAL CASE: EXERTIONAL ANGINA

While climbing 4 flights of stairs, a 55-year-old man noticed tightness in his chest, which lasted for 5 minutes and resolved spontaneously. Several weeks later, when visiting his primary care physician, he mentioned the episode. He had had no symptoms in the interim, but the physician ordered an exercise stress test.

Six minutes into a standard Bruce protocol, the patient experienced the same chest tightness, accompanied by 1-mm ST-segment depressions in leads II, III, and aVF. He was then referred to a cardiologist, who recommended catheterization.

Catheterization demonstrated a 95% stenosis of the right coronary artery with nonsignificant stenoses of the left anterior descending and circumflex arteries. A drug-eluting stent was placed in the right coronary artery, with no residual stenosis.

Did this intervention likely prevent an MI and perhaps save the man’s life?

HOW MYOCARDIAL INFARCTION HAPPENS

Understanding the pathogenesis of MI is critical to having realistic expectations of the benefits of stent placement.

Doctors often describe coronary atherosclerosis as a plumbing problem, where deposits of cholesterol and fat build up in arterial walls, clogging the pipes and eventually causing a heart attack. This analogy, which has been around since the 1950s, is easy to for patients to grasp and has been popularized in the press and internalized by the public—as one patient with a 95% stenosis put it, “I was 95% dead.” In that model, angioplasty and stenting can resolve the blockage and “fix” the problem, much as a plumber can clear your pipes with a Roto-Rooter.

Despite the visual appeal of this model,¹ it doesn’t accurately convey what we know about the pathophysiology of coronary artery disease. Instead of a gradual buildup of fatty deposits, low-density lipoprotein cholesterol particles infiltrate arterial walls and trigger an inflammatory reaction as they are engulfed by macrophages, leading to a cascade of cytokines and recruitment of more inflammatory cells.² This immune response can eventually cause the rupture of the plaque’s fibrous cap, triggering thrombosis and infarction, often at a site of insignificant stenosis.

In this new model, coronary artery disease is primarily a problem of inflammation distributed throughout the vasculature, rather than a mechanical problem localized to the site of a significant stenosis.

Significant stenosis does not equal unstable plaque

Not all plaques are equally likely to rupture. Stable plaques tend to be long-standing and calcified, with a thick fibrous cap. A stable plaque causing a 95% stenosis may cause symptoms with exertion, but it is unlikely to cause infarction.³ Conversely, rupture-prone plaques may cause little stenosis, but a large and dangerous plaque may be lurking beneath the thin fibrous cap.

Relying on angiography can be misleading. Treating all significant stenoses improves blood flow, but does not reduce the risk of infarction, because infarction most often occurs in areas where the lumen is not obstructed. A plaque causing only 30% stenosis can suddenly rupture, causing thrombosis and complete occlusion.

The current model explains why PCI is no better than optimal medical therapy (ie, risk factor modification, antiplatelet therapy with aspirin, and a statin). Diet, exercise, smoking cessation, and statins target inflammatory processes and lower low-density lipoprotein cholesterol levels, while aspirin prevents platelet aggregation, among other likely actions.

The model also explains why coronary artery bypass grafting reduces the risk of MI and death in patients with left main or 3-vessel disease. A patient with generalized coronary artery disease has multiple lesions, many of which do not cause significant stenoses. PCI corrects only a single stenosis, whereas coronary artery bypass grafting circumvents all the vulnerable plaques in a vessel.

THE LANDMARK COURAGE TRIAL

Published in 2007, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial⁴ randomized more than 2,000 patients to receive either optimal medical therapy plus PCI or optimal medical therapy alone. The primary outcome was a composite of death from any cause and nonfatal MI. Patients were followed for at least 3 years, and some for as long as 7 years.

There was an initial small upward spike in the primary outcome in the PCI arm due to periprocedural events. By 5 years, the outcomes of the 2 arms converged and then stayed the same for up to 15 years.⁵ The authors concluded that PCI conferred no benefit over optimal medical therapy in the risk of death or MI.

Some doctors dismiss the study because of its stringent entry criteria—of 35,539 patients assessed, only 3,071 met the eligibility criteria. However, the entry criteria were meant to identify patients most likely to benefit from PCI. Many patients who undergo PCI today would not have qualified for the study because they lack objective evidence of ischemia.⁶ To enroll, patients needed a proximal stenosis of at least 70% and objective evidence of ischemia or a coronary stenosis of more than 80% and classic angina. Exclusion criteria disqualified few patients: Canadian Cardiovascular Society class IV angina (ie, angina evoked from minimal activity or at rest); a markedly positive stress test (substantial ST-segment depression or hypotension during stage I of the Bruce protocol); refractory heart failure or cardiogenic shock; an ejection fraction of less than 30%; revascularization within the past 6 months; and coronary anatomy unsuitable for PCI.

Although COURAGE was hailed as a landmark trial, it largely supported the results of previous studies. A meta-analysis of PCI vs optimal medical therapy published in 2005 found no significant differences in death, cardiac death, MI, or nonfatal MI.⁷ MI was actually slightly more common in the PCI group due to the increased risk of MI during the periprocedural period.

Nor has the evidence from COURAGE discouraged additional studies of the same topic. Despite consistent findings that fit with our understanding of coronary disease as inflammation, we continue to conduct studies aimed at addressing significant stenosis, as if that was the problem. Thus, there have been studies of angioplasty alone, followed by studies of bare-metal stents and then drug-eluting stents.

In 2009, Trikalinos et al published a review of 61 randomized controlled trials comprising more than 25,000 patients with stable coronary disease and comparing medical therapy and angioplasty in its various forms over the previous 20 years.⁸ In all direct and indirect comparisons of PCI and medical therapy, there were no improvements in rates of death or MI.

Even so, the studies continue. The most recent “improvement” was the addition of fractional flow reserve, which served as the inclusion criterion for the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial.⁹ In that study, patients with at least 1 stenosis with a fractional flow reserve less than 0.80 were randomized to PCI plus medical therapy or to medical therapy alone. The primary end point was a composite of death from any cause, MI, and urgent revascularization. Unfortunately, the study was stopped early when the primary end point was met due to a reduction in the need for urgent revascularization. There was no reduction in the rate of MI (hazard ratio 1.05, 95% confidence interval 0.51–2.19).

The reduction in urgent revascularization has also been shown consistently in past studies, but this is the weakest outcome measure because it does not equate to a reduction in the rate of MI. There is no demonstrable harm to putting off stent placement, even in functionally significant arteries, and most patients do not require a stent, even in the future.

In summary, the primary benefit of getting a stent now is a reduced likelihood of needing one later.

PCI MAY IMPROVE ANGINA FASTER

Another important finding of the COURAGE trial was that PCI improved symptoms more than optimal medical therapy.¹⁰ This is not surprising, because angina is often a direct result of a significant stenosis. What was unexpected was that even after PCI, most patients were not symptom-free. At 1 month, significantly more PCI patients were angina-free (42%) than were medical patients (33%). This translates into an absolute risk reduction of 9% or a number needed to treat of 11 to prevent 1 case of angina.

Patients in both groups improved over time, and after 3 years, the difference between the 2 groups was no longer significant: 59% in the PCI group vs 56% in the medical therapy group were angina-free.

A more recent study has raised the possibility that the improvement in angina with PCI is primarily a placebo effect. Researchers in the United Kingdom randomized patients with stable angina and at least a 70% stenosis of one vessel to either PCI or sham PCI, in which they threaded the catheter but did not deploy the stent.¹¹ All patients received aggressive antianginal therapy before the procedure. At 6 weeks, there was improvement in angina in both groups, but no statistically significant difference between them in either exercise time or angina. Approximately half the patients in each group improved by at least 1 grade on the Canadian Cardiovascular Society angina classification, and more than 20% improved 2 grades.

This finding is not without precedent. Ligation of the internal mammary arteries, a popular treatment for angina in the 1950s, often provided dramatic relief of symptoms, until it was proven to be no better than a sham operation.^12,13 More recently, a placebo-controlled trial of percutaneous laser myocardial revascularization also failed to show improvement over a sham treatment, despite promising results from a phase 1 trial.¹⁴ Together, these studies emphasize the subjective nature of angina as an outcome and call into question the routine use of PCI to relieve it.

PCI ENTAILS RISK

PCI entails a small but not inconsequential risk. During the procedure, 2% of patients develop bleeding or blood vessel damage, and another 1% die or have an MI or a stroke. In the first year after stent placement, 3% of patients have a bleeding event from the antiplatelet therapy needed for the stent, and an additional 2% develop a clot in the stent that leads to MI.¹⁵

INFORMED CONSENT IS CRITICAL

As demonstrated above, for patients with stable angina, the only evidence-based benefit of PCI over optimal medical therapy is that symptoms may respond faster. At the same time, there are costs and risks associated with the procedure. Because symptoms are subjective, patients should play a key role in deciding whether PCI is appropriate for them.

The American Medical Association states that a physician providing any treatment or procedure should disclose and discuss with patients the risks and benefits. Unfortunately, a substantial body of evidence demonstrates that this is not occurring in practice.

Patients and cardiologists have conflicting beliefs about PCI

Studies over the past 20 years demonstrate that patients with chronic stable angina consistently overestimate the benefits of PCI, with 71% to 88% believing that it will reduce their chance of death.^16–19 Patients also understand that PCI can relieve their symptoms, though no study seems to have assessed the perceived magnitude of this benefit.

In contrast, when cardiologists were asked about the benefits their patients could expect from PCI, only 20% said that it would reduce mortality and 25% said it would prevent MI.¹⁸ These are still surprisingly high percentages, since the study was conducted after the COURAGE trial.

Nevertheless, these differences in perception show that cardiologists fail to successfully communicate the benefits of the procedure to their patients. Without complete information, patients cannot make informed decisions.

If PCI cannot improve hard outcomes like MI or death in stable coronary disease, why do cardiologists continue to perform it so frequently?

Soon after the COURAGE trial, Lin et al conducted focus groups with cardiologists to find out.²⁰ Some said that they doubted the clinical trial evidence, given the reduction in the cardiac mortality rate over the past 30 years. Others remarked that their overriding goal is to stamp out ischemia, and that once a lesion is found by catheterization, one must proceed with PCI. This has been termed the “oculostenotic reflex,” ie, the interventionist sees coronary artery disease and immediately places a stent.

Atreya et al found objective evidence of this practice.²¹ In a 2016 study of 207 patients with obstructive lesions amenable to PCI, the only factors associated with medical management were those that increased the risk of the procedure: age, chronic kidney disease, distal location of the lesion, and type C lesions (the most difficult ones to treat by PCI). More important, evidence of ischemia, presence of angina, and being on optimal medical therapy or maximal antianginal therapy were not associated with PCI.

When surveyed, cardiologists offered reasons similar to those identified by Lin et al, including a positive stress test (70%) and significant myocardium at risk (50%).¹⁸ Optimal medical therapy failure was cited less often (40%). Over 30% identified relief of chest pain for patients who were not prescribed optimal medical therapy. Another 30% said that patient anxiety contributed to their decision, but patients who reported anxiety were not more likely to get PCI than those who did not.

True informed consent rarely occurs

Surveys of patients and recordings of doctor visits suggest that doctors often discuss the risks of the procedure but rarely accurately describe the benefits or mention alternative treatments, including optimal medical therapy.

Fowler et al²² surveyed 472 Medicare patients who had undergone PCI in the past year about their consent discussion, particularly regarding alternative options. Only 6% of patients recalled discussing medication as a serious option with their doctor.

In 2 published studies,^23,24 we analyzed recorded conversations between doctors and patients in which angiography and PCI were discussed.

In a qualitative assessment of how cardiologists presented the rationale for PCI to patients,²³ we observed that cardiologists gave an accurate presentation of the benefits in only 5% of cases. In 13% of the conversations the benefits were explicitly overstated (eg, “If you don’t do it [angiogram/PCI], what could happen? Well, you could…have a heart attack involving that area which can lead to a sudden death”). In another 35% of cases, physicians offered an implicit overstatement of the benefit by saying they could “fix” the problem (eg, “So that’s where we start thinking, Well maybe we better try to fix that [blockage]”), without specifically stating that fixing the problem would offer any benefit. Patients were left to fill in the blanks. Conversations frequently focused on the rationale for performing PCI (eg, ischemia on a stress test) and a description of the procedure, rather than on the risks and benefits.

In a quantitative study of the same data set, we assessed how often physicians addressed the 7 elements of informed decision-making as defined by Braddock et al.²⁴

• Explaining the patient’s role in decision-making (ie, that the patient has a choice to make) was present in half of the conversations. Sometimes a doctor would simply say, “The next step is to perform catheterization.”
• Discussion of clinical issues (eg, having a blockage, stress test results) was performed in almost every case, demonstrating physicians’ comfort with that element.
• Discussing treatment alternatives occurred in only 1 in 4 conversations. This was more frequent than previously reported, and appeared most often when patients expressed hesitancy about proceeding to PCI.
• Discussing pros and cons of the alternatives was done in 42%.
• Uncertainty about the procedure (eg, that it might not relieve the angina) was expressed in only 10% of conversations.
• Assessment of patient understanding was done in 65% of cases. This included even minimal efforts (eg, “Do you have any questions?”). More advanced methods such as teach-back were never used.
• Exploration of patient preferences (eg, asking patients which treatment they prefer, or attempting to understand how angina affects a patient’s life) the final element, occurred in 73% of conversations.

Only 3% of the conversations contained all 7 elements. Even using a more relaxed definition of 3 critical elements (ie, discussing clinical issues, treatment alternatives, and pros and cons), only 13% of conversations included them all.

Discussion affects decisions

Informed decision-making is not only important because of its ethical implications. Offering patients more information was associated with their choosing not to have PCI. The probability of a patient undergoing PCI was negatively associated with 3 specific elements of informed decision-making. Patients were less likely to choose PCI if the patient’s role in decision-making was discussed (61% vs 86% chose PCI, P < .03); if alternatives were discussed (31% vs 89% chose PCI, P < .01); and if uncertainties were discussed (17% vs 80% chose PCI, P < .01).

There was also a linear relationship between the total number of elements discussed and the probability of choosing PCI: it ranged from 100% of patients choosing PCI when just 1 element was present to 3% of patients choosing PCI when all 7 elements were present. The relationship is not entirely causal, since doctors were more likely to talk about alternatives and risks if patients hesitated and raised questions. Cautious patients received more information.

From these observational studies, we know that physicians do not generally communicate the benefits of PCI, and patients make incorrect assumptions about the benefits they can expect. We know that those who receive more information are less likely to choose PCI, but what would happen if patients were randomly assigned to receive complete information?

We conducted an online survey of more than 1,000 participants over age 50 who had never undergone PCI, asking them to imagine visiting a cardiologist after having a positive stress test for stable chest pain.²⁵ Three intervention groups read different scenarios couched as information provided by their cardiologist:

• The “standard care” group received no specific information about the effects of PCI on the risk of myocardial infarction
• The “specific information” group was specifically told that PCI does not reduce the risk of myocardial infarction
• The “explanatory information” group was told how medications work and why PCI does not reduce the risk of myocardial infarction.

All 3 groups received information about the risks of PCI, its role in reducing angina, and the risks and benefits of optimal medical therapy.

After reading their scenario, all participants completed an identical questionnaire, which asked if they would opt for PCI, medical therapy, or both. Overall, 55% chose PCI, ranging from 70% in the standard care group to 46% in the group given explanatory information. Rates in the specific-information and explanatory-information groups were not statistically different from each other, but both were significantly different from that in the standard-care group. Interestingly, the more information patients were given about PCI, the more likely they were to choose optimal medical therapy.

After reading the scenario, participants were also asked if PCI would “prevent a heart attack.” Of those who received standard care, 71% endorsed that belief, which is remarkably similar to studies of real patients who have received standard care. In contrast, only 39% of those given specific information and 31% given explanatory information held that belief. Moreover, the belief that PCI prevented MI was the strongest predictor of choosing PCI (odds ratio 5.82, 95% confidence interval 4.13–8.26).²⁵

Interestingly, 52% of the standard care group falsely remembered that the doctor had told them that PCI would prevent an MI, even though the doctor said nothing about it one way or the other. It appears that participants were projecting their own beliefs onto the encounter. This highlights the importance of providing full information to patients who are considering this procedure.

TOWARD SHARED DECISION-MAKING

Shared decision-making is a process in which physicians enter into a partnership with a patient, offer information, elicit the patient’s preferences, and then come to a decision in concert with the patient.

Although many decisions can and should involve elements of shared decision-making, the decision to proceed with PCI for stable angina is particularly well-suited to shared decision-making. This is because the benefit of PCI depends on the value a patient attaches to being free of angina sooner. Since there is no difference in the risk of MI or death, the patient must decide if the risks of the procedure and the inconvenience of taking dual antiplatelet therapy are worth the benefit of improving symptoms faster. Presumably, patients who have more severe symptoms or experienced side effects from antianginal therapy would be more likely to choose PCI.

Despite having substantial experience educating patients, most physicians are unfamiliar with the process of shared decision-making. In particular, the process of eliciting preferences is often overlooked.

To address this issue, researchers at the Mayo Clinic developed a decision aid that compares PCI plus optimal medical therapy vs optimal medical therapy alone in an easily understandable information card.¹⁵ On one side, the 2 options are clearly stated, with the magnitude of symptom improvement over time graphically illustrated and the statement, “NO DIFFERENCE in heart attack or death,” prominently displayed. The back of the card discusses the risks of each option in easily understood tables.

The decision aid was compared with standard care in a randomized trial involving patients who were referred for catheterization and possible PCI.²⁶ The decision aid improved patients’ overall knowledge about PCI. In particular, 60% of those who used the decision aid knew that PCI did not prevent death or MI vs 40% of usual-care patients—results similar to those of the online experiment.

Interestingly, the decision about whether to undergo PCI did not differ significantly between the 2 groups, although there was a trend toward more patients in the decision-aid group choosing medical therapy alone (53%) vs the standard-care patients (39%).

To understand why the decision aid did not make more of a difference, the investigators performed qualitative interviews of the cardiologists in the study.²⁷ One theme was the timing of the intervention. Patients using the decision aid had already been referred for catheterization, and some felt the process should have occurred earlier. Engaging in shared decision-making with a general cardiologist before referral could help to improve the quality of patient decisions.

Cardiologists also noted the difficulty in changing their work flow to incorporate the decision aid. Although some embraced the idea of shared decision-making, others were concerned that many patients could not participate, and there was confusion about the difference between an educational tool, which could be used by a patient alone, and a decision aid, which is meant to generate discussion between the doctor and patient. Some expressed interest in using the tool in the future.

These findings serve to emphasize that providing information alone is not enough. If the physician does not “buy in” to the idea of shared decision-making, it will not occur.

PRACTICE IMPLICATIONS

Based on the pathophysiology of coronary artery disease and the results of multiple randomized controlled trials, it is evident that PCI does not prevent heart attacks in patients with chronic stable angina. However, most patients who undergo PCI are unaware of this and therefore do not truly give informed consent. In the absence of explicit information to the contrary, most patients with stable angina assume that PCI prevents MI and thus are biased toward choosing PCI.

Even minimal amounts of explicit information can partially overcome that bias and influence decision-making. In particular, explaining why PCI does not prevent MI was the most effective means of overcoming the bias.

To this end, shared decision aids may help physicians to engage in shared decision-making. Shared decision-making is most likely to occur if physicians are trained in the concept of shared decision-making, are committed to practicing it, and can fit it into their work flow. Ideally, this would occur in the office of a general cardiologist before referral for PCI.

For those practicing in accountable-care organizations, Medicare has recently introduced the shared decision-making model for 6 preference-sensitive conditions, including stable ischemic heart disease. Participants in this program will have the opportunity to receive payments for shared decision-making services and to share in any savings that result from reduced use of resources. Use of these tools holds the promise for providing more patient-centered care at lower cost.

Invented by Andreas Grüntzig in 1977, percutaneous coronary intervention (PCI) has revolutionized the management of coronary artery disease.¹ Initially, PCI was more attractive than conventional revascularization with coronary artery bypass grafting because it was less invasive, but as time went on PCI acquired its own evidence base of improved clinical outcomes. In fact, for ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and cardiogenic shock, there is clear evidence that PCI saves lives in both the short and long term.^2,3

See related article

But PCI is also used widely in stable coronary artery disease, and in contrast to the clear-cut benefit in the acute conditions noted above, a series of reports culminating in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial has shown that PCI in stable coronary artery disease does not reduce the risk of death or of subsequent myocardial infarction.^4,5 Cardiologists have heeded the COURAGE trial findings in their clinical decision-making, and the rate of PCI for stable coronary artery disease dropped by 60% from 2006 to 2011.⁶

In an article in this issue,⁷ Dr. Michael Rothberg describes a 55-year-old man who develops new-onset angina and then undergoes a Bruce protocol stress test that is stopped at 6 minutes due to chest pain and ST-segment depression. Dr. Rothberg argues that, based on COURAGE trial data, this patient and other patients with stable coronary artery disease should not be treated with PCI but instead should receive optimal medical therapy.

KEY ISSUES ABOUT THE COURAGE TRIAL

To understand the applicability of the results of the COURAGE trial to patient care, it is important to examine a number of key issues about this trial.

First, COURAGE enrolled a narrow group of patients with stable coronary artery disease and excluded many common patient subgroups, such as those with heart failure, severe anginal symptoms, or left main artery stenosis, who would benefit from revascularization.⁵ Specifically, for every 100 patients enrolled in COURAGE, 161 were excluded for having heart failure, 39 were excluded for class IV angina, and 31 were excluded for left main stenosis.

Second, although COURAGE has been described as a trial of PCI vs optimal medical therapy, it was not. Rather, it was a trial of optimal medical therapy with PCI first vs optimal medical therapy with crossover PCI if medical therapy failed.⁵ The crossover rate was not insubstantial: 16.1% of the patients in the medical therapy group underwent PCI by the end of the first year, increasing to 32.6% at a median of 4.6 years of follow-up.^5,7 And patients with more intense and frequent angina and resulting worse quality of life were the ones who required crossover PCI.⁸

Third, it has been proposed that patients with suspicious cardiac symptoms or abnormal stress test findings can be managed with optimal medical therapy initially, based on the COURAGE findings. However, the COURAGE trial required diagnostic angiography both to confirm underlying coronary artery disease and to exclude left main disease.⁵ Thus, regardless of one’s position on the role of PCI in stable coronary artery disease, diagnostic investigation by cardiac catheterization or computed tomographic angiography to confirm the presence or absence of coronary artery disease remains mandatory.

Fourth, optimal medical therapy was prescribed by the trial’s protocol, so that one would expect that both treatment groups received similar levels of optimal medical therapy. However, the optimal medical therapy group required more medications to achieve the same outcome as the PCI group.⁵

Finally, although it has been reported that the COURAGE trial showed no benefit for PCI, in fact, for the outcome of symptom relief, initial PCI was clearly superior to optimal medical therapy beginning at 3 months and extending out to 24 months—a result for which the magnitude of benefit is underestimated due to the occurrence of crossover PCI.⁹ In particular, women and patients with a high frequency of angina derived improvement in angina-related quality of life from PCI compared with optimal medical therapy.^8,10

For these reasons, the role of PCI in stable coronary disease is more nuanced than simply stating that the COURAGE trial results were “negative” for PCI. It is more accurate to say that in selected patients with moderate symptoms of angina and without heart failure or left main artery disease, a PCI-first strategy has no advantage over an optimal medical treatment-first strategy for the risk of death and myocardial infarction but does lead to earlier angina relief and less long-term need for medication. In addition, in up to one-third of cases, an optimal medical treatment-first strategy fails and requires crossover to PCI.⁵

Dr. Rothberg is correct in highlighting the crucial importance of optimal medical therapy in the management of stable coronary artery disease. In fact, cardiologists strive to prescribe optimal medical treatment for all coronary artery disease patients irrespective of treatment strategy. However, 3 important issues in his analysis need to be highlighted.

Controlling symptoms is important, and we should not underrate it. The patient described in Dr. Rothberg’s article could exercise for only 6 minutes on a Bruce treadmill test, indicating a quite limited functional capacity of only 5.8 metabolic equivalents of the task (METs).¹¹ (A healthy 55-year-old man should be able to achieve 10.5 METs.¹²) Inability to achieve 6 METs precludes the ability to dance, to ride a bike at a moderate pace, or to go on a hike.¹³ For many patients, these limitations are serious and important concerns for their lifestyle and quality of life. PCI has been shown to be superior to medical therapy in improving functional capacity, improving it by 20% vs 2% in one trial¹⁴ and 26% vs 7% in a second trial.¹⁴ Patients undergoing PCI were twice as likely to have a greater than 2-minute increase in exercise capacity.¹⁵ Recognizing the importance of symptom control in stable coronary artery disease is patient-centered care.

Patient decision-making is complicated, and we should not assume that patients choose PCI primarily to reduce their risk of death. A randomized trial showed that patients continued to select PCI as initial treatment even when they clearly knew that it would not prevent death or myocardial infarction.¹⁶ As noted above, patients may value earlier symptom relief, particularly if their angina is frequent or limiting. In addition, patients strongly desire to minimize medical therapy and may be willing to trade decreased life expectancy to reduce the need to take medications.¹⁷ Finally, some patients may want to be able to continue to participate in certain lifestyle activities.

PCI is expensive, but less so over the long run. With a PCI-first strategy, costs are front-loaded, and studies with short-term follow-up show a marked increase in cost. However, long-term follow-up shows that the cost differences diminish dramatically due to high rates of crossover to revascularization and increased medical care in the optimal medical therapy arm. The cumulative lifetime costs in the COURAGE trial with a PCI-first strategy, although statistically significant, were only 10% higher than with the optimal medical treatment-first strategy ($99,820 vs $90,370).¹⁸ Therefore, substantial long-term cost-savings by shifting from an initial PCI strategy to initial optimal medical therapy are unlikely to be delivered when measured over the long term.

NEWER TRIALS SUPPORT A BALANCED APPROACH

The most recent studies of the management of stable coronary artery disease support a balanced approach.

The ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), on one hand, showed limited benefit of PCI vs medical therapy in patients with single-vessel coronary artery disease, preserved functional capacity, and mild symptoms.¹⁹ There was no significant improvement in exercise capacity or angina frequency, although baseline angina frequency after medical stabilization was quite low.

The FAME 2 trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), on the other hand, studied patients with positive fractional flow reserve coronary artery disease (ie, using an invasive technique to confirm the hemodynamic significance of the coronary stenosis) and showed markedly better outcomes with PCI than with medical therapy.²⁰ Specifically, the PCI-first group had improved quality of life and dramatically less need for urgent revascularization.

Furthermore, as in the COURAGE trial, the optimal medical therapy group had a high crossover rate to PCI (44.2%), leading to the complete elimination of the early cost advantage of medical therapy by 3 years. The initial costs with PCI vs medical therapy were $9,944 vs $4,439 (P < .001); the 3-year costs were $16,792 vs $16,737 (P = .94).

For these reasons, a balanced approach to recommending PCI first vs optimal medical treatment first remains the best strategy.

TOWARD PATIENT-CENTERED CARE

For the 55-year-old patient in Dr. Rothberg’s article, the first step in making an appropriate decision would be to understand the severity of symptoms relative to the patient’s lifestyle. The second step is to assess the patient’s interest in an invasive procedure such as PCI relative to optimal medical therapy, as the patient may have a strong preference for one option or the other.

Finally, with the understanding that there is no difference in hard end points of myocardial infarction and death, a balanced discussion of the advantages and disadvantages of both PCI and optimal medical therapy would be needed. For PCI, advantages include earlier symptom control and improved quality of the life, particularly if symptoms are severe, with disadvantages of an invasive procedure with its attendant risks. For optimal medical therapy, advantages include improved symptom control and avoidance of an invasive procedure, while disadvantages include increased medication use and a high rate of eventual crossover to PCI. This important discussion integrating both patient and medical perspectives ultimately leads to the best decision for the individual patient.

A patient-centered approach to clinical decision-making mandates inclusion of PCI first as an option in the management of stable coronary artery disease. After confirming the patient has coronary artery disease, patients with heart failure, class IV angina at rest, or left main artery stenosis should be referred for revascularization. In the remaining patients with confirmed coronary artery disease and moderate angina symptoms, either PCI first or optimal medical therapy first is an appropriate initial strategy that considers coronary anatomy, symptom burden, and patient desires.

Invented by Andreas Grüntzig in 1977, percutaneous coronary intervention (PCI) has revolutionized the management of coronary artery disease.¹ Initially, PCI was more attractive than conventional revascularization with coronary artery bypass grafting because it was less invasive, but as time went on PCI acquired its own evidence base of improved clinical outcomes. In fact, for ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and cardiogenic shock, there is clear evidence that PCI saves lives in both the short and long term.^2,3

See related article

But PCI is also used widely in stable coronary artery disease, and in contrast to the clear-cut benefit in the acute conditions noted above, a series of reports culminating in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial has shown that PCI in stable coronary artery disease does not reduce the risk of death or of subsequent myocardial infarction.^4,5 Cardiologists have heeded the COURAGE trial findings in their clinical decision-making, and the rate of PCI for stable coronary artery disease dropped by 60% from 2006 to 2011.⁶

In an article in this issue,⁷ Dr. Michael Rothberg describes a 55-year-old man who develops new-onset angina and then undergoes a Bruce protocol stress test that is stopped at 6 minutes due to chest pain and ST-segment depression. Dr. Rothberg argues that, based on COURAGE trial data, this patient and other patients with stable coronary artery disease should not be treated with PCI but instead should receive optimal medical therapy.

KEY ISSUES ABOUT THE COURAGE TRIAL

To understand the applicability of the results of the COURAGE trial to patient care, it is important to examine a number of key issues about this trial.

First, COURAGE enrolled a narrow group of patients with stable coronary artery disease and excluded many common patient subgroups, such as those with heart failure, severe anginal symptoms, or left main artery stenosis, who would benefit from revascularization.⁵ Specifically, for every 100 patients enrolled in COURAGE, 161 were excluded for having heart failure, 39 were excluded for class IV angina, and 31 were excluded for left main stenosis.

Second, although COURAGE has been described as a trial of PCI vs optimal medical therapy, it was not. Rather, it was a trial of optimal medical therapy with PCI first vs optimal medical therapy with crossover PCI if medical therapy failed.⁵ The crossover rate was not insubstantial: 16.1% of the patients in the medical therapy group underwent PCI by the end of the first year, increasing to 32.6% at a median of 4.6 years of follow-up.^5,7 And patients with more intense and frequent angina and resulting worse quality of life were the ones who required crossover PCI.⁸

Third, it has been proposed that patients with suspicious cardiac symptoms or abnormal stress test findings can be managed with optimal medical therapy initially, based on the COURAGE findings. However, the COURAGE trial required diagnostic angiography both to confirm underlying coronary artery disease and to exclude left main disease.⁵ Thus, regardless of one’s position on the role of PCI in stable coronary artery disease, diagnostic investigation by cardiac catheterization or computed tomographic angiography to confirm the presence or absence of coronary artery disease remains mandatory.

Fourth, optimal medical therapy was prescribed by the trial’s protocol, so that one would expect that both treatment groups received similar levels of optimal medical therapy. However, the optimal medical therapy group required more medications to achieve the same outcome as the PCI group.⁵

Finally, although it has been reported that the COURAGE trial showed no benefit for PCI, in fact, for the outcome of symptom relief, initial PCI was clearly superior to optimal medical therapy beginning at 3 months and extending out to 24 months—a result for which the magnitude of benefit is underestimated due to the occurrence of crossover PCI.⁹ In particular, women and patients with a high frequency of angina derived improvement in angina-related quality of life from PCI compared with optimal medical therapy.^8,10

For these reasons, the role of PCI in stable coronary disease is more nuanced than simply stating that the COURAGE trial results were “negative” for PCI. It is more accurate to say that in selected patients with moderate symptoms of angina and without heart failure or left main artery disease, a PCI-first strategy has no advantage over an optimal medical treatment-first strategy for the risk of death and myocardial infarction but does lead to earlier angina relief and less long-term need for medication. In addition, in up to one-third of cases, an optimal medical treatment-first strategy fails and requires crossover to PCI.⁵

Dr. Rothberg is correct in highlighting the crucial importance of optimal medical therapy in the management of stable coronary artery disease. In fact, cardiologists strive to prescribe optimal medical treatment for all coronary artery disease patients irrespective of treatment strategy. However, 3 important issues in his analysis need to be highlighted.

Controlling symptoms is important, and we should not underrate it. The patient described in Dr. Rothberg’s article could exercise for only 6 minutes on a Bruce treadmill test, indicating a quite limited functional capacity of only 5.8 metabolic equivalents of the task (METs).¹¹ (A healthy 55-year-old man should be able to achieve 10.5 METs.¹²) Inability to achieve 6 METs precludes the ability to dance, to ride a bike at a moderate pace, or to go on a hike.¹³ For many patients, these limitations are serious and important concerns for their lifestyle and quality of life. PCI has been shown to be superior to medical therapy in improving functional capacity, improving it by 20% vs 2% in one trial¹⁴ and 26% vs 7% in a second trial.¹⁴ Patients undergoing PCI were twice as likely to have a greater than 2-minute increase in exercise capacity.¹⁵ Recognizing the importance of symptom control in stable coronary artery disease is patient-centered care.

Patient decision-making is complicated, and we should not assume that patients choose PCI primarily to reduce their risk of death. A randomized trial showed that patients continued to select PCI as initial treatment even when they clearly knew that it would not prevent death or myocardial infarction.¹⁶ As noted above, patients may value earlier symptom relief, particularly if their angina is frequent or limiting. In addition, patients strongly desire to minimize medical therapy and may be willing to trade decreased life expectancy to reduce the need to take medications.¹⁷ Finally, some patients may want to be able to continue to participate in certain lifestyle activities.

PCI is expensive, but less so over the long run. With a PCI-first strategy, costs are front-loaded, and studies with short-term follow-up show a marked increase in cost. However, long-term follow-up shows that the cost differences diminish dramatically due to high rates of crossover to revascularization and increased medical care in the optimal medical therapy arm. The cumulative lifetime costs in the COURAGE trial with a PCI-first strategy, although statistically significant, were only 10% higher than with the optimal medical treatment-first strategy ($99,820 vs $90,370).¹⁸ Therefore, substantial long-term cost-savings by shifting from an initial PCI strategy to initial optimal medical therapy are unlikely to be delivered when measured over the long term.

NEWER TRIALS SUPPORT A BALANCED APPROACH

The most recent studies of the management of stable coronary artery disease support a balanced approach.

The ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), on one hand, showed limited benefit of PCI vs medical therapy in patients with single-vessel coronary artery disease, preserved functional capacity, and mild symptoms.¹⁹ There was no significant improvement in exercise capacity or angina frequency, although baseline angina frequency after medical stabilization was quite low.

The FAME 2 trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), on the other hand, studied patients with positive fractional flow reserve coronary artery disease (ie, using an invasive technique to confirm the hemodynamic significance of the coronary stenosis) and showed markedly better outcomes with PCI than with medical therapy.²⁰ Specifically, the PCI-first group had improved quality of life and dramatically less need for urgent revascularization.

Furthermore, as in the COURAGE trial, the optimal medical therapy group had a high crossover rate to PCI (44.2%), leading to the complete elimination of the early cost advantage of medical therapy by 3 years. The initial costs with PCI vs medical therapy were $9,944 vs $4,439 (P < .001); the 3-year costs were $16,792 vs $16,737 (P = .94).

For these reasons, a balanced approach to recommending PCI first vs optimal medical treatment first remains the best strategy.

TOWARD PATIENT-CENTERED CARE

For the 55-year-old patient in Dr. Rothberg’s article, the first step in making an appropriate decision would be to understand the severity of symptoms relative to the patient’s lifestyle. The second step is to assess the patient’s interest in an invasive procedure such as PCI relative to optimal medical therapy, as the patient may have a strong preference for one option or the other.

Finally, with the understanding that there is no difference in hard end points of myocardial infarction and death, a balanced discussion of the advantages and disadvantages of both PCI and optimal medical therapy would be needed. For PCI, advantages include earlier symptom control and improved quality of the life, particularly if symptoms are severe, with disadvantages of an invasive procedure with its attendant risks. For optimal medical therapy, advantages include improved symptom control and avoidance of an invasive procedure, while disadvantages include increased medication use and a high rate of eventual crossover to PCI. This important discussion integrating both patient and medical perspectives ultimately leads to the best decision for the individual patient.

A patient-centered approach to clinical decision-making mandates inclusion of PCI first as an option in the management of stable coronary artery disease. After confirming the patient has coronary artery disease, patients with heart failure, class IV angina at rest, or left main artery stenosis should be referred for revascularization. In the remaining patients with confirmed coronary artery disease and moderate angina symptoms, either PCI first or optimal medical therapy first is an appropriate initial strategy that considers coronary anatomy, symptom burden, and patient desires.

Invented by Andreas Grüntzig in 1977, percutaneous coronary intervention (PCI) has revolutionized the management of coronary artery disease.¹ Initially, PCI was more attractive than conventional revascularization with coronary artery bypass grafting because it was less invasive, but as time went on PCI acquired its own evidence base of improved clinical outcomes. In fact, for ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and cardiogenic shock, there is clear evidence that PCI saves lives in both the short and long term.^2,3

See related article

But PCI is also used widely in stable coronary artery disease, and in contrast to the clear-cut benefit in the acute conditions noted above, a series of reports culminating in the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial has shown that PCI in stable coronary artery disease does not reduce the risk of death or of subsequent myocardial infarction.^4,5 Cardiologists have heeded the COURAGE trial findings in their clinical decision-making, and the rate of PCI for stable coronary artery disease dropped by 60% from 2006 to 2011.⁶

In an article in this issue,⁷ Dr. Michael Rothberg describes a 55-year-old man who develops new-onset angina and then undergoes a Bruce protocol stress test that is stopped at 6 minutes due to chest pain and ST-segment depression. Dr. Rothberg argues that, based on COURAGE trial data, this patient and other patients with stable coronary artery disease should not be treated with PCI but instead should receive optimal medical therapy.

KEY ISSUES ABOUT THE COURAGE TRIAL

To understand the applicability of the results of the COURAGE trial to patient care, it is important to examine a number of key issues about this trial.

First, COURAGE enrolled a narrow group of patients with stable coronary artery disease and excluded many common patient subgroups, such as those with heart failure, severe anginal symptoms, or left main artery stenosis, who would benefit from revascularization.⁵ Specifically, for every 100 patients enrolled in COURAGE, 161 were excluded for having heart failure, 39 were excluded for class IV angina, and 31 were excluded for left main stenosis.

Second, although COURAGE has been described as a trial of PCI vs optimal medical therapy, it was not. Rather, it was a trial of optimal medical therapy with PCI first vs optimal medical therapy with crossover PCI if medical therapy failed.⁵ The crossover rate was not insubstantial: 16.1% of the patients in the medical therapy group underwent PCI by the end of the first year, increasing to 32.6% at a median of 4.6 years of follow-up.^5,7 And patients with more intense and frequent angina and resulting worse quality of life were the ones who required crossover PCI.⁸

Third, it has been proposed that patients with suspicious cardiac symptoms or abnormal stress test findings can be managed with optimal medical therapy initially, based on the COURAGE findings. However, the COURAGE trial required diagnostic angiography both to confirm underlying coronary artery disease and to exclude left main disease.⁵ Thus, regardless of one’s position on the role of PCI in stable coronary artery disease, diagnostic investigation by cardiac catheterization or computed tomographic angiography to confirm the presence or absence of coronary artery disease remains mandatory.

Fourth, optimal medical therapy was prescribed by the trial’s protocol, so that one would expect that both treatment groups received similar levels of optimal medical therapy. However, the optimal medical therapy group required more medications to achieve the same outcome as the PCI group.⁵

Finally, although it has been reported that the COURAGE trial showed no benefit for PCI, in fact, for the outcome of symptom relief, initial PCI was clearly superior to optimal medical therapy beginning at 3 months and extending out to 24 months—a result for which the magnitude of benefit is underestimated due to the occurrence of crossover PCI.⁹ In particular, women and patients with a high frequency of angina derived improvement in angina-related quality of life from PCI compared with optimal medical therapy.^8,10

For these reasons, the role of PCI in stable coronary disease is more nuanced than simply stating that the COURAGE trial results were “negative” for PCI. It is more accurate to say that in selected patients with moderate symptoms of angina and without heart failure or left main artery disease, a PCI-first strategy has no advantage over an optimal medical treatment-first strategy for the risk of death and myocardial infarction but does lead to earlier angina relief and less long-term need for medication. In addition, in up to one-third of cases, an optimal medical treatment-first strategy fails and requires crossover to PCI.⁵

Dr. Rothberg is correct in highlighting the crucial importance of optimal medical therapy in the management of stable coronary artery disease. In fact, cardiologists strive to prescribe optimal medical treatment for all coronary artery disease patients irrespective of treatment strategy. However, 3 important issues in his analysis need to be highlighted.

Controlling symptoms is important, and we should not underrate it. The patient described in Dr. Rothberg’s article could exercise for only 6 minutes on a Bruce treadmill test, indicating a quite limited functional capacity of only 5.8 metabolic equivalents of the task (METs).¹¹ (A healthy 55-year-old man should be able to achieve 10.5 METs.¹²) Inability to achieve 6 METs precludes the ability to dance, to ride a bike at a moderate pace, or to go on a hike.¹³ For many patients, these limitations are serious and important concerns for their lifestyle and quality of life. PCI has been shown to be superior to medical therapy in improving functional capacity, improving it by 20% vs 2% in one trial¹⁴ and 26% vs 7% in a second trial.¹⁴ Patients undergoing PCI were twice as likely to have a greater than 2-minute increase in exercise capacity.¹⁵ Recognizing the importance of symptom control in stable coronary artery disease is patient-centered care.

Patient decision-making is complicated, and we should not assume that patients choose PCI primarily to reduce their risk of death. A randomized trial showed that patients continued to select PCI as initial treatment even when they clearly knew that it would not prevent death or myocardial infarction.¹⁶ As noted above, patients may value earlier symptom relief, particularly if their angina is frequent or limiting. In addition, patients strongly desire to minimize medical therapy and may be willing to trade decreased life expectancy to reduce the need to take medications.¹⁷ Finally, some patients may want to be able to continue to participate in certain lifestyle activities.

PCI is expensive, but less so over the long run. With a PCI-first strategy, costs are front-loaded, and studies with short-term follow-up show a marked increase in cost. However, long-term follow-up shows that the cost differences diminish dramatically due to high rates of crossover to revascularization and increased medical care in the optimal medical therapy arm. The cumulative lifetime costs in the COURAGE trial with a PCI-first strategy, although statistically significant, were only 10% higher than with the optimal medical treatment-first strategy ($99,820 vs $90,370).¹⁸ Therefore, substantial long-term cost-savings by shifting from an initial PCI strategy to initial optimal medical therapy are unlikely to be delivered when measured over the long term.

NEWER TRIALS SUPPORT A BALANCED APPROACH

The most recent studies of the management of stable coronary artery disease support a balanced approach.

The ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), on one hand, showed limited benefit of PCI vs medical therapy in patients with single-vessel coronary artery disease, preserved functional capacity, and mild symptoms.¹⁹ There was no significant improvement in exercise capacity or angina frequency, although baseline angina frequency after medical stabilization was quite low.

The FAME 2 trial (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), on the other hand, studied patients with positive fractional flow reserve coronary artery disease (ie, using an invasive technique to confirm the hemodynamic significance of the coronary stenosis) and showed markedly better outcomes with PCI than with medical therapy.²⁰ Specifically, the PCI-first group had improved quality of life and dramatically less need for urgent revascularization.

Furthermore, as in the COURAGE trial, the optimal medical therapy group had a high crossover rate to PCI (44.2%), leading to the complete elimination of the early cost advantage of medical therapy by 3 years. The initial costs with PCI vs medical therapy were $9,944 vs $4,439 (P < .001); the 3-year costs were $16,792 vs $16,737 (P = .94).

For these reasons, a balanced approach to recommending PCI first vs optimal medical treatment first remains the best strategy.

TOWARD PATIENT-CENTERED CARE

For the 55-year-old patient in Dr. Rothberg’s article, the first step in making an appropriate decision would be to understand the severity of symptoms relative to the patient’s lifestyle. The second step is to assess the patient’s interest in an invasive procedure such as PCI relative to optimal medical therapy, as the patient may have a strong preference for one option or the other.

Finally, with the understanding that there is no difference in hard end points of myocardial infarction and death, a balanced discussion of the advantages and disadvantages of both PCI and optimal medical therapy would be needed. For PCI, advantages include earlier symptom control and improved quality of the life, particularly if symptoms are severe, with disadvantages of an invasive procedure with its attendant risks. For optimal medical therapy, advantages include improved symptom control and avoidance of an invasive procedure, while disadvantages include increased medication use and a high rate of eventual crossover to PCI. This important discussion integrating both patient and medical perspectives ultimately leads to the best decision for the individual patient.

A patient-centered approach to clinical decision-making mandates inclusion of PCI first as an option in the management of stable coronary artery disease. After confirming the patient has coronary artery disease, patients with heart failure, class IV angina at rest, or left main artery stenosis should be referred for revascularization. In the remaining patients with confirmed coronary artery disease and moderate angina symptoms, either PCI first or optimal medical therapy first is an appropriate initial strategy that considers coronary anatomy, symptom burden, and patient desires.

It is difficult to provide enough information for informed consent and to ensure that the patient and his or her family fully understand what we are saying. Patients often come in with their own preferences and biases based on anecdote, dinner conversations, or the Internet. The physician must push hard to dispel a patient’s bias with the facts, while recognizing that we too regularly present “facts” and recommendations colored by our own biases based on anecdotal experience, professional ritual, and intellectual hubris.

Two articles in this issue of the Journal, one by Dr. Michael Rothberg¹ and the other by Dr. Umesh Khot,² examine percutaneous coronary intervention (PCI) in patients with stable chronic angina. Both discuss the findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial³ and how to use these findings in helping patients decide whether to undergo PCI.

Rothberg and Khot agree that in the COURAGE trial, PCI effectively if not completely reduced angina but did not decrease the likelihood of death or subsequent myocardial infarction (MI). Patients were excluded from the study if they had a likelihood of left main disease, heart failure, or severe angina. All underwent catheterization, and all were given optimal medical therapy. Thus, the trial results do not directly relate to every patient with stable angina.

While the patient may find it confusing that angina and the risk of MI are not reduced in parallel, since both are due to atherosclerosis, their dynamic pathophysiology is different. The COURAGE results are the mirror image of those in some early studies of aspirin in coronary disease, in which aspirin reduced the incidence of MI but did not significantly affect angina.

In view of the COURAGE results, Rothberg seems surprised that PCI continues to be frequently used in patients with stable angina. He points out that according to some surveys,⁴ not all cardiologists have embraced these (and other similar study) results. But as Khot notes, the use of PCI in stable angina has decreased. More interesting to me were the results of an online study conducted by Rothberg and colleagues in which participants were provided different background information about PCI.⁵ Even if given explicit information that PCI did not prevent MI, a fair number still said they would choose it and still believed it would prevent this outcome. Bias clearly influences what patients read and hear, and they bring these biases into the shared decision-making process.

While some patients may not fully understand PCI’s risks and putative benefits, others may choose it because of their personal knowledge of others’ experience or perhaps because the “softer” benefits demonstrated in COURAGE and other trials are important to them. As outlined by Khot, patients who underwent PCI had more rapid relief of angina symptoms, possibly experienced greater relief of symptoms even if incomplete, and needed less medication. More patients needed urgent revascularization in the medical group than in the PCI group. Rothberg appropriately notes that this did not “equate to a reduction in the rate of MI,” but to some patients (eg, international travelers, caregivers) this higher possibility of needing an urgent procedure may be enough to make them want the initial elective procedure. While patients should be told that many of the patients in the medical therapy group in COURAGE crossed over to get PCI (16% at 1 year, and about 1/3 after a median of 4.6 years of follow-up), a patient for whom avoiding invasive procedures is the highest priority will likely “hear” that he or she has a 2/3 likelihood of not needing PCI without being at increased risk of death or MI with medical therapy.

As Rothberg points out, “providing information alone is not enough.” The patient needs to recognize, verbalize, and perhaps rank his or her own biases, fears, and desires. Equally important, we need to recognize our own biases and not let them overshadow the patient’s concerns.

I urge you to read both articles, not only because they offer excellent critiques of the COURAGE results and what they mean in practice, but also because they should make us reflect on how often and well we engage in shared decision-making with our patients. Reading these made me realize that I need to better understand my patients’ concerns. Discussing my interpretation of clinical study results, no matter how sophisticated or correct, and then offering a recommendation without fully understanding the patient’s treatment goals is not shared decision-making. The seemingly “wrong” decision may be right for the patient.

It is difficult to provide enough information for informed consent and to ensure that the patient and his or her family fully understand what we are saying. Patients often come in with their own preferences and biases based on anecdote, dinner conversations, or the Internet. The physician must push hard to dispel a patient’s bias with the facts, while recognizing that we too regularly present “facts” and recommendations colored by our own biases based on anecdotal experience, professional ritual, and intellectual hubris.

Two articles in this issue of the Journal, one by Dr. Michael Rothberg¹ and the other by Dr. Umesh Khot,² examine percutaneous coronary intervention (PCI) in patients with stable chronic angina. Both discuss the findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial³ and how to use these findings in helping patients decide whether to undergo PCI.

Rothberg and Khot agree that in the COURAGE trial, PCI effectively if not completely reduced angina but did not decrease the likelihood of death or subsequent myocardial infarction (MI). Patients were excluded from the study if they had a likelihood of left main disease, heart failure, or severe angina. All underwent catheterization, and all were given optimal medical therapy. Thus, the trial results do not directly relate to every patient with stable angina.

While the patient may find it confusing that angina and the risk of MI are not reduced in parallel, since both are due to atherosclerosis, their dynamic pathophysiology is different. The COURAGE results are the mirror image of those in some early studies of aspirin in coronary disease, in which aspirin reduced the incidence of MI but did not significantly affect angina.

In view of the COURAGE results, Rothberg seems surprised that PCI continues to be frequently used in patients with stable angina. He points out that according to some surveys,⁴ not all cardiologists have embraced these (and other similar study) results. But as Khot notes, the use of PCI in stable angina has decreased. More interesting to me were the results of an online study conducted by Rothberg and colleagues in which participants were provided different background information about PCI.⁵ Even if given explicit information that PCI did not prevent MI, a fair number still said they would choose it and still believed it would prevent this outcome. Bias clearly influences what patients read and hear, and they bring these biases into the shared decision-making process.

While some patients may not fully understand PCI’s risks and putative benefits, others may choose it because of their personal knowledge of others’ experience or perhaps because the “softer” benefits demonstrated in COURAGE and other trials are important to them. As outlined by Khot, patients who underwent PCI had more rapid relief of angina symptoms, possibly experienced greater relief of symptoms even if incomplete, and needed less medication. More patients needed urgent revascularization in the medical group than in the PCI group. Rothberg appropriately notes that this did not “equate to a reduction in the rate of MI,” but to some patients (eg, international travelers, caregivers) this higher possibility of needing an urgent procedure may be enough to make them want the initial elective procedure. While patients should be told that many of the patients in the medical therapy group in COURAGE crossed over to get PCI (16% at 1 year, and about 1/3 after a median of 4.6 years of follow-up), a patient for whom avoiding invasive procedures is the highest priority will likely “hear” that he or she has a 2/3 likelihood of not needing PCI without being at increased risk of death or MI with medical therapy.

As Rothberg points out, “providing information alone is not enough.” The patient needs to recognize, verbalize, and perhaps rank his or her own biases, fears, and desires. Equally important, we need to recognize our own biases and not let them overshadow the patient’s concerns.

I urge you to read both articles, not only because they offer excellent critiques of the COURAGE results and what they mean in practice, but also because they should make us reflect on how often and well we engage in shared decision-making with our patients. Reading these made me realize that I need to better understand my patients’ concerns. Discussing my interpretation of clinical study results, no matter how sophisticated or correct, and then offering a recommendation without fully understanding the patient’s treatment goals is not shared decision-making. The seemingly “wrong” decision may be right for the patient.

It is difficult to provide enough information for informed consent and to ensure that the patient and his or her family fully understand what we are saying. Patients often come in with their own preferences and biases based on anecdote, dinner conversations, or the Internet. The physician must push hard to dispel a patient’s bias with the facts, while recognizing that we too regularly present “facts” and recommendations colored by our own biases based on anecdotal experience, professional ritual, and intellectual hubris.

Two articles in this issue of the Journal, one by Dr. Michael Rothberg¹ and the other by Dr. Umesh Khot,² examine percutaneous coronary intervention (PCI) in patients with stable chronic angina. Both discuss the findings of the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial³ and how to use these findings in helping patients decide whether to undergo PCI.

Rothberg and Khot agree that in the COURAGE trial, PCI effectively if not completely reduced angina but did not decrease the likelihood of death or subsequent myocardial infarction (MI). Patients were excluded from the study if they had a likelihood of left main disease, heart failure, or severe angina. All underwent catheterization, and all were given optimal medical therapy. Thus, the trial results do not directly relate to every patient with stable angina.

While the patient may find it confusing that angina and the risk of MI are not reduced in parallel, since both are due to atherosclerosis, their dynamic pathophysiology is different. The COURAGE results are the mirror image of those in some early studies of aspirin in coronary disease, in which aspirin reduced the incidence of MI but did not significantly affect angina.

In view of the COURAGE results, Rothberg seems surprised that PCI continues to be frequently used in patients with stable angina. He points out that according to some surveys,⁴ not all cardiologists have embraced these (and other similar study) results. But as Khot notes, the use of PCI in stable angina has decreased. More interesting to me were the results of an online study conducted by Rothberg and colleagues in which participants were provided different background information about PCI.⁵ Even if given explicit information that PCI did not prevent MI, a fair number still said they would choose it and still believed it would prevent this outcome. Bias clearly influences what patients read and hear, and they bring these biases into the shared decision-making process.

While some patients may not fully understand PCI’s risks and putative benefits, others may choose it because of their personal knowledge of others’ experience or perhaps because the “softer” benefits demonstrated in COURAGE and other trials are important to them. As outlined by Khot, patients who underwent PCI had more rapid relief of angina symptoms, possibly experienced greater relief of symptoms even if incomplete, and needed less medication. More patients needed urgent revascularization in the medical group than in the PCI group. Rothberg appropriately notes that this did not “equate to a reduction in the rate of MI,” but to some patients (eg, international travelers, caregivers) this higher possibility of needing an urgent procedure may be enough to make them want the initial elective procedure. While patients should be told that many of the patients in the medical therapy group in COURAGE crossed over to get PCI (16% at 1 year, and about 1/3 after a median of 4.6 years of follow-up), a patient for whom avoiding invasive procedures is the highest priority will likely “hear” that he or she has a 2/3 likelihood of not needing PCI without being at increased risk of death or MI with medical therapy.

As Rothberg points out, “providing information alone is not enough.” The patient needs to recognize, verbalize, and perhaps rank his or her own biases, fears, and desires. Equally important, we need to recognize our own biases and not let them overshadow the patient’s concerns.

I urge you to read both articles, not only because they offer excellent critiques of the COURAGE results and what they mean in practice, but also because they should make us reflect on how often and well we engage in shared decision-making with our patients. Reading these made me realize that I need to better understand my patients’ concerns. Discussing my interpretation of clinical study results, no matter how sophisticated or correct, and then offering a recommendation without fully understanding the patient’s treatment goals is not shared decision-making. The seemingly “wrong” decision may be right for the patient.

Medications started for appropriate indications in middle age may need to be monitored more closely as the patient ages. Some drugs may become unnecessary or even dangerous as the patient ages, functional status and renal function decline, and goals of care change.

See related editorial

Older adults tend to have multiple illnesses and therefore take more drugs, and polypharmacy increases the risk of poor outcomes. The number of medications a person uses is a risk factor for adverse drug reactions, nonadherence, financial burden, drug-drug interactions, and worse outcomes.¹

The prevalence of polypharmacy increased from an estimated 8.2% to 15% from 1999 to 2011 based on the National Health and Nutrition Examination Survey.² Guideline-based therapy for specific diseases may lead to the addition of more medications to reach disease targets.³ Most older adults in the United States compound the risk of prescribed medications by also taking over-the-counter medications and dietary supplements.⁴

In addition, medications are often used in older adults based on studies of younger persons without significant comorbidities. Applying clinical guidelines based on these studies to older adults with comorbidity and functional impairment is challenging.⁵ Age-related pharmacokinetic and pharmacodynamic changes increase the risk of adverse drug reactions.⁶

In this article, we review commonly used medications that are potentially inappropriate based on clinical practice. We also review tools to evaluate appropriate drug therapy in older adults.

DRUGS THAT ARE COMMONLY USED, BUT POTENTIALLY INAPPROPRIATE

Statins

Statins are effective when used as secondary prevention in older adults,⁷ but their efficacy when used as primary prevention of atherosclerotic cardiovascular disease in people age 75 and older is questionable.⁸ Nevertheless, they are widely used for this purpose. For example, before the 2013 joint guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA) were released, 22% of patients age 80 and older in the Geisinger health system were taking a statin for primary prevention.⁹

The 2013 ACC/AHA guidelines included a limited recommendation for statins for primary prevention of atherosclerotic cardiovascular disease in adults age 75 and older.¹⁰ The guideline noted, however, that few data were available to support this recommendation.¹⁰

In a systematic review of 18 randomized clinical trials of statins for primary prevention of atherosclerotic cardiovascular disease, the mean age was 57, yet conclusions were extrapolated to an older patient population.¹¹ The estimated 10-year risk of atherosclerotic cardiovascular disease based on pooled cohort risk equations of adults age 75 and older always exceeds the 7.5% treatment threshold recommended by the guidelines.⁸

Myopathy is a common adverse effect of statins. In addition, statins interact with other drugs that inhibit the cytochrome P450 3A4 isoenzyme, such as amlodipine, amiodarone, and diltiazem.^8,12 If statin therapy caused no functional limitation due to muscle pain or weakness, statins for primary prevention would be cost-effective, but even a small increase in adverse effects in an elderly patient can offset the cardiovascular benefit.¹³ A recent post hoc secondary analysis found no benefit of pravastatin for primary prevention in adults age 75 and older.¹⁴

Thus, statin treatment for primary prevention in older patients should be individualized, based on life expectancy, function, and cardiovascular risk. Statin therapy does not replace modification of other risk factors.

Anticholinergics

Drugs with anticholinergic properties are commonly prescribed in the elderly for conditions such as muscle spasm, overactive bladder, psychiatric disorders, insomnia, extrapyramidal symptoms, vertigo, pruritus, peptic ulcer disease, seasonal allergies, and even the common cold,¹⁵ and many of the drugs often prescribed have strong anticholinergic properties (Table 1). Taking multiple medications with anticholinergic properties results in a high “anticholinergic burden,” which is associated with falls, impulsive behavior, poor physical performance, loss of independence, dementia, delirium, and brain atrophy.^15–18

The 2014 American College of Physicians guideline on nonsurgical management of urinary incontinence in women recommends pharmacologic treatment for urgency and stress urinary incontinence after failure of nonpharmacologic therapy,¹⁹ and many drugs for these urinary symptoms have anticholinergic properties. If an anticholinergic is necessary, an agent that results in a lower anticholinergic burden should be considered in older patients.

A pharmacist-initiated medication review and intervention may be another way to adjust medications to reduce the patient’s anticholinergic burden.^20,21 The common use of anticholinergic drugs in older adults reminds us to monitor their use closely.²²

Benzodiazepines are among the most commonly prescribed psychotropics in developed countries and are prescribed mainly by primary care physicians rather than psychiatrists.²³

In 2008, 5.2% of US adults ages 18 to 80 used a benzodiazepine, and long-term use was more prevalent in older patients (ages 65–80).²³

Benzodiazepines are prescribed for anxiety,²⁴ insomnia,²⁵ and agitation. They can cause withdrawal²⁶ and have potential for abuse.²⁷ Benzodiazepines are associated with cognitive decline,²⁸ impaired driving,²⁹ falls,³⁰ and hip fractures³¹ in older adults.

In addition, use of nonbenzodiazepine hypnotics (eg, zolpidem) is on the rise,³² and these drugs are known to increase the risk of hip fracture in nursing home residents.³³

The American Geriatrics Society, through the American Board of Internal Medicine’s Choosing Wisely campaign, recommends avoiding benzodiazepines as a first-line treatment for insomnia, agitation, or delirium in older adults.³⁴ Yet prescribing practices with these drugs in primary care settings conflict with guidelines, partly due to lack of training in constructive strategies regarding appropriate use of benzodiazepines.³⁵ Educating patients on the risks and benefits of benzodiazepine treatment, especially long-term use, has been shown to reduce the rate of benzodiazepine-associated secondary events.³⁶

Antipsychotics

Off-label use of antipsychotics is common and is increasing in the United States. In 2008, off-label use of antipsychotic drugs accounted for an estimated $6 billion.³⁷ A common off-label use is to manage behavioral symptoms of dementia, despite a black-box warning about an increased risk of death in patients with dementia who are treated with antipsychotics.^38,39 The Choosing Wisely campaign recommends against prescribing antipsychotics as a first-line treatment of behavioral and psychological symptoms of dementia.³⁴

Antipsychotic drugs are associated with risk of acute kidney injury,⁴⁰ as well as increased risk of falls and fractures (eg, a 52% higher risk of a serious fall, and a 50% higher risk of a nonvertebral osteoporotic fracture).⁴¹

Patients with dementia often exhibit aggression, resistance to care, and other challenging or disruptive behaviors. In such instances, antipsychotic drugs are often prescribed, but they provide limited and inconsistent benefits, while causing oversedation and worsening of cognitive function and increasing the likelihood of falling, stroke, and death.^38,39,41

Because pharmacologic treatments for dementia are only modestly effective, have notable risks, and do not treat some of the behaviors that family members and caregivers find most distressing, nonpharmacologic measures are recommended as first-line treatment.⁴² These include caregiver education and support, training in problem-solving, and targeted therapy directed at the underlying causes of specific behaviors (eg, implementing nighttime routines to address sleep disturbances).⁴² Nonpharmacologic management of behavioral symptoms in dementia can significantly improve quality of life for patients and caregivers.⁴² Use of antipsychotic drugs in patients with dementia should be limited to cases in which nonpharmacologic measures have failed and patients pose an imminent threat to themselves or others.⁴³

Proton pump inhibitors

Proton pump inhibitors are among the most commonly prescribed medications in the United States, and their use has increased significantly over the decade. It has been estimated that between 25% and 70% of these prescriptions have no appropriate indication.⁴⁴

There is considerable excess use of acid suppressants in both inpatient and outpatient settings.^45,46 In one study, at discharge from an internal medicine service, almost half of patients were taking a proton pump inhibitor.⁴⁷

Evidence-based guidelines recommend these drugs to treat gastroesophageal reflux disease, nonerosive reflux disease, erosive esophagitis, dyspepsia, and peptic ulcer disease. However, long-term use (ie, beyond 8 weeks) is recommended only for patients with erosive esophagitis, Barrett esophagus, a pathologic hypersecretory condition, or a demonstrated need for maintenance treatment for reflux disease.⁴⁸

Although proton pump inhibitors are highly effective and have low toxicity, there are reports of an association with Clostridium difficile infection,⁴⁹ community-acquired pneumonia,⁵⁰ hip fracture,⁵¹ vitamin B₁₂ deficiency,⁵² atrophic gastritis,⁵³ kidney disease,⁵⁴ and dementia.⁵⁵

Nondrug therapies such as weight loss and elevation of the head of the bed may improve esophageal pH levels and reflux symptoms.⁵⁶

Deprescribing.org has practical advice for healthcare providers, patients, and caregivers on how to discontinue proton pump inhibitors, including videos, algorithms, and guidelines.

TOOLS TO EVALUATE APPROPRIATE DRUG THERAPY

Beers criteria

The Beers criteria (Table 2), developed in 1991 by a geriatrician as an approach to safer, more effective drug therapy in frail elderly nursing home patients,⁵⁷ were updated by the American Geriatrics Society in 2015 for use in any clinical setting.⁵⁸ (The criteria are also available as a smartphone application through the American Geriatrics Society at www.americangeriatrics.org.)

The Beers criteria offer evidence-based recommendations on drugs to avoid in the elderly, along with the rationale for use, the quality of evidence behind the recommendation, and the graded strength of the recommendation. The Beers criteria should be viewed through the lens of clinical judgment to offer safer nonpharmacologic and pharmacologic treatments.

The Joint Commission recommends medication reconciliation at every transition of care.⁵⁹ The Beers criteria are a good starting point for a comprehensive medication review.

STOPP/START criteria

Another tool to aid safe prescribing in older adults is the Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions (STOPP), used in conjuction with the Screening Tool to Alert Doctors to Right Treatment (START). The STOPP/START criteria^60,61 are based on an up-to-date literature review and consensus (Table 3).

THE BOTTOM LINE

Physicians caring for older adults need to diligently weigh the benefits of drug therapy and consider the patient’s care goals, current level of functioning, life expectancy, values, and preferences. Statin therapy for primary prevention, anticholinergics, benzodiazepines, antipsychotics, and proton pump inhibitors are widely used without proper indications, pointing to the need for a periodic comprehensive review of medications to reevaluate the risks vs the benefits of the patient’s medications. The Beers criteria and the STOPP/ START criteria can be useful tools for this purpose.

Medications started for appropriate indications in middle age may need to be monitored more closely as the patient ages. Some drugs may become unnecessary or even dangerous as the patient ages, functional status and renal function decline, and goals of care change.

See related editorial

Older adults tend to have multiple illnesses and therefore take more drugs, and polypharmacy increases the risk of poor outcomes. The number of medications a person uses is a risk factor for adverse drug reactions, nonadherence, financial burden, drug-drug interactions, and worse outcomes.¹

The prevalence of polypharmacy increased from an estimated 8.2% to 15% from 1999 to 2011 based on the National Health and Nutrition Examination Survey.² Guideline-based therapy for specific diseases may lead to the addition of more medications to reach disease targets.³ Most older adults in the United States compound the risk of prescribed medications by also taking over-the-counter medications and dietary supplements.⁴

In addition, medications are often used in older adults based on studies of younger persons without significant comorbidities. Applying clinical guidelines based on these studies to older adults with comorbidity and functional impairment is challenging.⁵ Age-related pharmacokinetic and pharmacodynamic changes increase the risk of adverse drug reactions.⁶

In this article, we review commonly used medications that are potentially inappropriate based on clinical practice. We also review tools to evaluate appropriate drug therapy in older adults.

DRUGS THAT ARE COMMONLY USED, BUT POTENTIALLY INAPPROPRIATE

Statins

Statins are effective when used as secondary prevention in older adults,⁷ but their efficacy when used as primary prevention of atherosclerotic cardiovascular disease in people age 75 and older is questionable.⁸ Nevertheless, they are widely used for this purpose. For example, before the 2013 joint guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA) were released, 22% of patients age 80 and older in the Geisinger health system were taking a statin for primary prevention.⁹

The 2013 ACC/AHA guidelines included a limited recommendation for statins for primary prevention of atherosclerotic cardiovascular disease in adults age 75 and older.¹⁰ The guideline noted, however, that few data were available to support this recommendation.¹⁰

In a systematic review of 18 randomized clinical trials of statins for primary prevention of atherosclerotic cardiovascular disease, the mean age was 57, yet conclusions were extrapolated to an older patient population.¹¹ The estimated 10-year risk of atherosclerotic cardiovascular disease based on pooled cohort risk equations of adults age 75 and older always exceeds the 7.5% treatment threshold recommended by the guidelines.⁸

Myopathy is a common adverse effect of statins. In addition, statins interact with other drugs that inhibit the cytochrome P450 3A4 isoenzyme, such as amlodipine, amiodarone, and diltiazem.^8,12 If statin therapy caused no functional limitation due to muscle pain or weakness, statins for primary prevention would be cost-effective, but even a small increase in adverse effects in an elderly patient can offset the cardiovascular benefit.¹³ A recent post hoc secondary analysis found no benefit of pravastatin for primary prevention in adults age 75 and older.¹⁴

Thus, statin treatment for primary prevention in older patients should be individualized, based on life expectancy, function, and cardiovascular risk. Statin therapy does not replace modification of other risk factors.

Anticholinergics

Drugs with anticholinergic properties are commonly prescribed in the elderly for conditions such as muscle spasm, overactive bladder, psychiatric disorders, insomnia, extrapyramidal symptoms, vertigo, pruritus, peptic ulcer disease, seasonal allergies, and even the common cold,¹⁵ and many of the drugs often prescribed have strong anticholinergic properties (Table 1). Taking multiple medications with anticholinergic properties results in a high “anticholinergic burden,” which is associated with falls, impulsive behavior, poor physical performance, loss of independence, dementia, delirium, and brain atrophy.^15–18

The 2014 American College of Physicians guideline on nonsurgical management of urinary incontinence in women recommends pharmacologic treatment for urgency and stress urinary incontinence after failure of nonpharmacologic therapy,¹⁹ and many drugs for these urinary symptoms have anticholinergic properties. If an anticholinergic is necessary, an agent that results in a lower anticholinergic burden should be considered in older patients.

A pharmacist-initiated medication review and intervention may be another way to adjust medications to reduce the patient’s anticholinergic burden.^20,21 The common use of anticholinergic drugs in older adults reminds us to monitor their use closely.²²

Benzodiazepines are among the most commonly prescribed psychotropics in developed countries and are prescribed mainly by primary care physicians rather than psychiatrists.²³

In 2008, 5.2% of US adults ages 18 to 80 used a benzodiazepine, and long-term use was more prevalent in older patients (ages 65–80).²³

Benzodiazepines are prescribed for anxiety,²⁴ insomnia,²⁵ and agitation. They can cause withdrawal²⁶ and have potential for abuse.²⁷ Benzodiazepines are associated with cognitive decline,²⁸ impaired driving,²⁹ falls,³⁰ and hip fractures³¹ in older adults.

In addition, use of nonbenzodiazepine hypnotics (eg, zolpidem) is on the rise,³² and these drugs are known to increase the risk of hip fracture in nursing home residents.³³

The American Geriatrics Society, through the American Board of Internal Medicine’s Choosing Wisely campaign, recommends avoiding benzodiazepines as a first-line treatment for insomnia, agitation, or delirium in older adults.³⁴ Yet prescribing practices with these drugs in primary care settings conflict with guidelines, partly due to lack of training in constructive strategies regarding appropriate use of benzodiazepines.³⁵ Educating patients on the risks and benefits of benzodiazepine treatment, especially long-term use, has been shown to reduce the rate of benzodiazepine-associated secondary events.³⁶

Antipsychotics

Off-label use of antipsychotics is common and is increasing in the United States. In 2008, off-label use of antipsychotic drugs accounted for an estimated $6 billion.³⁷ A common off-label use is to manage behavioral symptoms of dementia, despite a black-box warning about an increased risk of death in patients with dementia who are treated with antipsychotics.^38,39 The Choosing Wisely campaign recommends against prescribing antipsychotics as a first-line treatment of behavioral and psychological symptoms of dementia.³⁴

Antipsychotic drugs are associated with risk of acute kidney injury,⁴⁰ as well as increased risk of falls and fractures (eg, a 52% higher risk of a serious fall, and a 50% higher risk of a nonvertebral osteoporotic fracture).⁴¹

Patients with dementia often exhibit aggression, resistance to care, and other challenging or disruptive behaviors. In such instances, antipsychotic drugs are often prescribed, but they provide limited and inconsistent benefits, while causing oversedation and worsening of cognitive function and increasing the likelihood of falling, stroke, and death.^38,39,41

Because pharmacologic treatments for dementia are only modestly effective, have notable risks, and do not treat some of the behaviors that family members and caregivers find most distressing, nonpharmacologic measures are recommended as first-line treatment.⁴² These include caregiver education and support, training in problem-solving, and targeted therapy directed at the underlying causes of specific behaviors (eg, implementing nighttime routines to address sleep disturbances).⁴² Nonpharmacologic management of behavioral symptoms in dementia can significantly improve quality of life for patients and caregivers.⁴² Use of antipsychotic drugs in patients with dementia should be limited to cases in which nonpharmacologic measures have failed and patients pose an imminent threat to themselves or others.⁴³

Proton pump inhibitors

Proton pump inhibitors are among the most commonly prescribed medications in the United States, and their use has increased significantly over the decade. It has been estimated that between 25% and 70% of these prescriptions have no appropriate indication.⁴⁴

There is considerable excess use of acid suppressants in both inpatient and outpatient settings.^45,46 In one study, at discharge from an internal medicine service, almost half of patients were taking a proton pump inhibitor.⁴⁷

Evidence-based guidelines recommend these drugs to treat gastroesophageal reflux disease, nonerosive reflux disease, erosive esophagitis, dyspepsia, and peptic ulcer disease. However, long-term use (ie, beyond 8 weeks) is recommended only for patients with erosive esophagitis, Barrett esophagus, a pathologic hypersecretory condition, or a demonstrated need for maintenance treatment for reflux disease.⁴⁸

Although proton pump inhibitors are highly effective and have low toxicity, there are reports of an association with Clostridium difficile infection,⁴⁹ community-acquired pneumonia,⁵⁰ hip fracture,⁵¹ vitamin B₁₂ deficiency,⁵² atrophic gastritis,⁵³ kidney disease,⁵⁴ and dementia.⁵⁵

Nondrug therapies such as weight loss and elevation of the head of the bed may improve esophageal pH levels and reflux symptoms.⁵⁶

Deprescribing.org has practical advice for healthcare providers, patients, and caregivers on how to discontinue proton pump inhibitors, including videos, algorithms, and guidelines.

TOOLS TO EVALUATE APPROPRIATE DRUG THERAPY

Beers criteria

The Beers criteria (Table 2), developed in 1991 by a geriatrician as an approach to safer, more effective drug therapy in frail elderly nursing home patients,⁵⁷ were updated by the American Geriatrics Society in 2015 for use in any clinical setting.⁵⁸ (The criteria are also available as a smartphone application through the American Geriatrics Society at www.americangeriatrics.org.)

The Beers criteria offer evidence-based recommendations on drugs to avoid in the elderly, along with the rationale for use, the quality of evidence behind the recommendation, and the graded strength of the recommendation. The Beers criteria should be viewed through the lens of clinical judgment to offer safer nonpharmacologic and pharmacologic treatments.

The Joint Commission recommends medication reconciliation at every transition of care.⁵⁹ The Beers criteria are a good starting point for a comprehensive medication review.

STOPP/START criteria

Another tool to aid safe prescribing in older adults is the Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions (STOPP), used in conjuction with the Screening Tool to Alert Doctors to Right Treatment (START). The STOPP/START criteria^60,61 are based on an up-to-date literature review and consensus (Table 3).

THE BOTTOM LINE

Physicians caring for older adults need to diligently weigh the benefits of drug therapy and consider the patient’s care goals, current level of functioning, life expectancy, values, and preferences. Statin therapy for primary prevention, anticholinergics, benzodiazepines, antipsychotics, and proton pump inhibitors are widely used without proper indications, pointing to the need for a periodic comprehensive review of medications to reevaluate the risks vs the benefits of the patient’s medications. The Beers criteria and the STOPP/ START criteria can be useful tools for this purpose.

Medications started for appropriate indications in middle age may need to be monitored more closely as the patient ages. Some drugs may become unnecessary or even dangerous as the patient ages, functional status and renal function decline, and goals of care change.

See related editorial

Older adults tend to have multiple illnesses and therefore take more drugs, and polypharmacy increases the risk of poor outcomes. The number of medications a person uses is a risk factor for adverse drug reactions, nonadherence, financial burden, drug-drug interactions, and worse outcomes.¹

The prevalence of polypharmacy increased from an estimated 8.2% to 15% from 1999 to 2011 based on the National Health and Nutrition Examination Survey.² Guideline-based therapy for specific diseases may lead to the addition of more medications to reach disease targets.³ Most older adults in the United States compound the risk of prescribed medications by also taking over-the-counter medications and dietary supplements.⁴

In addition, medications are often used in older adults based on studies of younger persons without significant comorbidities. Applying clinical guidelines based on these studies to older adults with comorbidity and functional impairment is challenging.⁵ Age-related pharmacokinetic and pharmacodynamic changes increase the risk of adverse drug reactions.⁶

In this article, we review commonly used medications that are potentially inappropriate based on clinical practice. We also review tools to evaluate appropriate drug therapy in older adults.

DRUGS THAT ARE COMMONLY USED, BUT POTENTIALLY INAPPROPRIATE

Statins

Statins are effective when used as secondary prevention in older adults,⁷ but their efficacy when used as primary prevention of atherosclerotic cardiovascular disease in people age 75 and older is questionable.⁸ Nevertheless, they are widely used for this purpose. For example, before the 2013 joint guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA) were released, 22% of patients age 80 and older in the Geisinger health system were taking a statin for primary prevention.⁹

The 2013 ACC/AHA guidelines included a limited recommendation for statins for primary prevention of atherosclerotic cardiovascular disease in adults age 75 and older.¹⁰ The guideline noted, however, that few data were available to support this recommendation.¹⁰

In a systematic review of 18 randomized clinical trials of statins for primary prevention of atherosclerotic cardiovascular disease, the mean age was 57, yet conclusions were extrapolated to an older patient population.¹¹ The estimated 10-year risk of atherosclerotic cardiovascular disease based on pooled cohort risk equations of adults age 75 and older always exceeds the 7.5% treatment threshold recommended by the guidelines.⁸

Myopathy is a common adverse effect of statins. In addition, statins interact with other drugs that inhibit the cytochrome P450 3A4 isoenzyme, such as amlodipine, amiodarone, and diltiazem.^8,12 If statin therapy caused no functional limitation due to muscle pain or weakness, statins for primary prevention would be cost-effective, but even a small increase in adverse effects in an elderly patient can offset the cardiovascular benefit.¹³ A recent post hoc secondary analysis found no benefit of pravastatin for primary prevention in adults age 75 and older.¹⁴

Thus, statin treatment for primary prevention in older patients should be individualized, based on life expectancy, function, and cardiovascular risk. Statin therapy does not replace modification of other risk factors.

Anticholinergics

Drugs with anticholinergic properties are commonly prescribed in the elderly for conditions such as muscle spasm, overactive bladder, psychiatric disorders, insomnia, extrapyramidal symptoms, vertigo, pruritus, peptic ulcer disease, seasonal allergies, and even the common cold,¹⁵ and many of the drugs often prescribed have strong anticholinergic properties (Table 1). Taking multiple medications with anticholinergic properties results in a high “anticholinergic burden,” which is associated with falls, impulsive behavior, poor physical performance, loss of independence, dementia, delirium, and brain atrophy.^15–18

The 2014 American College of Physicians guideline on nonsurgical management of urinary incontinence in women recommends pharmacologic treatment for urgency and stress urinary incontinence after failure of nonpharmacologic therapy,¹⁹ and many drugs for these urinary symptoms have anticholinergic properties. If an anticholinergic is necessary, an agent that results in a lower anticholinergic burden should be considered in older patients.

A pharmacist-initiated medication review and intervention may be another way to adjust medications to reduce the patient’s anticholinergic burden.^20,21 The common use of anticholinergic drugs in older adults reminds us to monitor their use closely.²²

Benzodiazepines are among the most commonly prescribed psychotropics in developed countries and are prescribed mainly by primary care physicians rather than psychiatrists.²³

In 2008, 5.2% of US adults ages 18 to 80 used a benzodiazepine, and long-term use was more prevalent in older patients (ages 65–80).²³

Benzodiazepines are prescribed for anxiety,²⁴ insomnia,²⁵ and agitation. They can cause withdrawal²⁶ and have potential for abuse.²⁷ Benzodiazepines are associated with cognitive decline,²⁸ impaired driving,²⁹ falls,³⁰ and hip fractures³¹ in older adults.

In addition, use of nonbenzodiazepine hypnotics (eg, zolpidem) is on the rise,³² and these drugs are known to increase the risk of hip fracture in nursing home residents.³³

The American Geriatrics Society, through the American Board of Internal Medicine’s Choosing Wisely campaign, recommends avoiding benzodiazepines as a first-line treatment for insomnia, agitation, or delirium in older adults.³⁴ Yet prescribing practices with these drugs in primary care settings conflict with guidelines, partly due to lack of training in constructive strategies regarding appropriate use of benzodiazepines.³⁵ Educating patients on the risks and benefits of benzodiazepine treatment, especially long-term use, has been shown to reduce the rate of benzodiazepine-associated secondary events.³⁶

Antipsychotics

Off-label use of antipsychotics is common and is increasing in the United States. In 2008, off-label use of antipsychotic drugs accounted for an estimated $6 billion.³⁷ A common off-label use is to manage behavioral symptoms of dementia, despite a black-box warning about an increased risk of death in patients with dementia who are treated with antipsychotics.^38,39 The Choosing Wisely campaign recommends against prescribing antipsychotics as a first-line treatment of behavioral and psychological symptoms of dementia.³⁴

Antipsychotic drugs are associated with risk of acute kidney injury,⁴⁰ as well as increased risk of falls and fractures (eg, a 52% higher risk of a serious fall, and a 50% higher risk of a nonvertebral osteoporotic fracture).⁴¹

Patients with dementia often exhibit aggression, resistance to care, and other challenging or disruptive behaviors. In such instances, antipsychotic drugs are often prescribed, but they provide limited and inconsistent benefits, while causing oversedation and worsening of cognitive function and increasing the likelihood of falling, stroke, and death.^38,39,41

Because pharmacologic treatments for dementia are only modestly effective, have notable risks, and do not treat some of the behaviors that family members and caregivers find most distressing, nonpharmacologic measures are recommended as first-line treatment.⁴² These include caregiver education and support, training in problem-solving, and targeted therapy directed at the underlying causes of specific behaviors (eg, implementing nighttime routines to address sleep disturbances).⁴² Nonpharmacologic management of behavioral symptoms in dementia can significantly improve quality of life for patients and caregivers.⁴² Use of antipsychotic drugs in patients with dementia should be limited to cases in which nonpharmacologic measures have failed and patients pose an imminent threat to themselves or others.⁴³

Proton pump inhibitors

Proton pump inhibitors are among the most commonly prescribed medications in the United States, and their use has increased significantly over the decade. It has been estimated that between 25% and 70% of these prescriptions have no appropriate indication.⁴⁴

There is considerable excess use of acid suppressants in both inpatient and outpatient settings.^45,46 In one study, at discharge from an internal medicine service, almost half of patients were taking a proton pump inhibitor.⁴⁷

Evidence-based guidelines recommend these drugs to treat gastroesophageal reflux disease, nonerosive reflux disease, erosive esophagitis, dyspepsia, and peptic ulcer disease. However, long-term use (ie, beyond 8 weeks) is recommended only for patients with erosive esophagitis, Barrett esophagus, a pathologic hypersecretory condition, or a demonstrated need for maintenance treatment for reflux disease.⁴⁸

Although proton pump inhibitors are highly effective and have low toxicity, there are reports of an association with Clostridium difficile infection,⁴⁹ community-acquired pneumonia,⁵⁰ hip fracture,⁵¹ vitamin B₁₂ deficiency,⁵² atrophic gastritis,⁵³ kidney disease,⁵⁴ and dementia.⁵⁵

Nondrug therapies such as weight loss and elevation of the head of the bed may improve esophageal pH levels and reflux symptoms.⁵⁶

Deprescribing.org has practical advice for healthcare providers, patients, and caregivers on how to discontinue proton pump inhibitors, including videos, algorithms, and guidelines.

TOOLS TO EVALUATE APPROPRIATE DRUG THERAPY

Beers criteria

The Beers criteria (Table 2), developed in 1991 by a geriatrician as an approach to safer, more effective drug therapy in frail elderly nursing home patients,⁵⁷ were updated by the American Geriatrics Society in 2015 for use in any clinical setting.⁵⁸ (The criteria are also available as a smartphone application through the American Geriatrics Society at www.americangeriatrics.org.)

The Beers criteria offer evidence-based recommendations on drugs to avoid in the elderly, along with the rationale for use, the quality of evidence behind the recommendation, and the graded strength of the recommendation. The Beers criteria should be viewed through the lens of clinical judgment to offer safer nonpharmacologic and pharmacologic treatments.

The Joint Commission recommends medication reconciliation at every transition of care.⁵⁹ The Beers criteria are a good starting point for a comprehensive medication review.

STOPP/START criteria

Another tool to aid safe prescribing in older adults is the Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions (STOPP), used in conjuction with the Screening Tool to Alert Doctors to Right Treatment (START). The STOPP/START criteria^60,61 are based on an up-to-date literature review and consensus (Table 3).

THE BOTTOM LINE

Physicians caring for older adults need to diligently weigh the benefits of drug therapy and consider the patient’s care goals, current level of functioning, life expectancy, values, and preferences. Statin therapy for primary prevention, anticholinergics, benzodiazepines, antipsychotics, and proton pump inhibitors are widely used without proper indications, pointing to the need for a periodic comprehensive review of medications to reevaluate the risks vs the benefits of the patient’s medications. The Beers criteria and the STOPP/ START criteria can be useful tools for this purpose.

According to a 2016 study, more than one-third of older adults in the United States take 5 or more medications.¹ This is a growing problem. Not only do older patients take more drugs than younger patients, they are also at higher risk of adverse drug events, drug-drug interactions, geriatric syndromes, and lower adherence.²

See related article

Many drugs that older patients are given are potentially inappropriate, ie, their risks outweigh the expected benefits, particularly when effective and safer alternative therapies exist. Although many clinicians are aware of the risks of polypharmacy, they may not be confident in discontinuing potentially inappropriate medications. The process of deliberately tapering, stopping, or reducing doses of medications with the goal of reducing harm and improving patient outcomes is known as deprescribing.³

In this issue, Kim et al⁴ review several medications that are overused or often used inappropriately in older adults: statins for primary prevention of atherosclerotic cardiovascular disease, anticholinergic drugs, benzodiazepines, antipsychotics, and proton pump inhibitors. They offer guidance about the situations in which these drugs may be inappropriate as well as alternative drug and nondrug treatments. Further, they suggest that, when prescribing or deprescribing drugs in older adults, clinicians consult tools such as the Beers criteria and the STOPP/START criteria (the Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions, and the Screening Tool to Alert Doctors to Right Treatment).

The issues Kim et al review are highly relevant and may increase awareness of specific potentially inappropriate medications. They also remind us that nonpharmacologic treatments are first-line for many medical conditions. In an era of a pill for every ill and a quick-fix mentality among both patients and providers, lifestyle changes and other nonpharmacologic treatments may be overlooked. Similarly, the STOPP/START criteria, which are concrete, evidence-based recommendations that can be applied to patient care, are likely underused in clinical practice.

Although necessary and valuable, simply arming clinicians with knowledge is insufficient to tackle the problems of polypharmacy and inappropriate prescribing. As the authors note in their discussion of benzodiazepines, practice guidelines exist regarding prescribing these agents, and data from randomized trials support specific interventions to deprescribe them.⁵ Nevertheless, clinicians report feeling inadequately prepared to discontinue benzodiazepines, particularly when patients perceive benefit from them. As such, user-friendly tools and specific strategies for weighing risks vs benefits are critical for clinicians.

PUTTING KNOWLEDGE INTO PRACTICE

How do we translate knowledge into practice with regard to deprescribing potentially inappropriate medications in older patients—or prescribing drugs only if appropriate in the first place?

An opportunity arises when patients are in the hospital. Taking a medication history on admission and matching medications with indications are key starting points. Clinical pharmacists can help screen for side effects and potential interactions and can provide deprescribing recommendations. Meticulous discharge medication reconciliation, patient education, and communication of the updated medication list to the outpatient provider are central to ensuring that patients adhere to medication adjustments after they go home.

A MATTER OF BALANCE

Another factor to consider is the patient’s physiologic age compared with his or her chronologic age. If a patient has multiple comorbidities, frailty, limited life expectancy, or poor renal function, we may consider her older than her chronologic age. In this case, a drug’s risks may outweigh its benefit, which is something to be discussed. On the other hand, a high-functioning and relatively healthy elderly patient may be a candidate for medications known to reduce the risk of death or control a chronic disease better. Incorporating a patient’s goals of care and using shared decision-making are also likely to yield an optimal medication regimen.

Smartphone apps and resources embedded in electronic health records provide additional decision support. Used when prescribing or reconciling medications, these supplemental brains offer instant feedback and information on dose adjustments, drug interactions, clinical guidelines, and even potentially inappropriate medications. While the impacts of these electronic tools on prescribing patterns and outcomes in geriatric populations remain unclear, new ones are being developed and studied.⁶ This may be the most promising way to translate knowledge into practice, as it is more easily integrated with existing clinician workflows.

AN OPPORTUNITY TO IMPROVE

There is significant opportunity to reduce polypharmacy and optimize medication prescribing practices for older adults. Awareness of potentially inappropriate medications and clinical situations in which the use of certain classes of medications should be minimized is the first step in addressing this problem. Using tools such as the STOPP/START criteria, reviewing medications at critical transition points, prioritizing patient function and goals, and using electronic clinical decision support should aid prescribing decisions.

Whenever possible, collaborating with other care team members such as pharmacists may increase efficiency and effectiveness of medication management. Ultimately, inclusion of more older adults in clinical trials may provide data-driven guidance for weighing risks and benefits. Finally, further study of the effects of deprescribing on clinical outcomes may be the missing piece to help clinicians and patients find balance in prescription management.

According to a 2016 study, more than one-third of older adults in the United States take 5 or more medications.¹ This is a growing problem. Not only do older patients take more drugs than younger patients, they are also at higher risk of adverse drug events, drug-drug interactions, geriatric syndromes, and lower adherence.²

See related article

Many drugs that older patients are given are potentially inappropriate, ie, their risks outweigh the expected benefits, particularly when effective and safer alternative therapies exist. Although many clinicians are aware of the risks of polypharmacy, they may not be confident in discontinuing potentially inappropriate medications. The process of deliberately tapering, stopping, or reducing doses of medications with the goal of reducing harm and improving patient outcomes is known as deprescribing.³

In this issue, Kim et al⁴ review several medications that are overused or often used inappropriately in older adults: statins for primary prevention of atherosclerotic cardiovascular disease, anticholinergic drugs, benzodiazepines, antipsychotics, and proton pump inhibitors. They offer guidance about the situations in which these drugs may be inappropriate as well as alternative drug and nondrug treatments. Further, they suggest that, when prescribing or deprescribing drugs in older adults, clinicians consult tools such as the Beers criteria and the STOPP/START criteria (the Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions, and the Screening Tool to Alert Doctors to Right Treatment).

The issues Kim et al review are highly relevant and may increase awareness of specific potentially inappropriate medications. They also remind us that nonpharmacologic treatments are first-line for many medical conditions. In an era of a pill for every ill and a quick-fix mentality among both patients and providers, lifestyle changes and other nonpharmacologic treatments may be overlooked. Similarly, the STOPP/START criteria, which are concrete, evidence-based recommendations that can be applied to patient care, are likely underused in clinical practice.

Although necessary and valuable, simply arming clinicians with knowledge is insufficient to tackle the problems of polypharmacy and inappropriate prescribing. As the authors note in their discussion of benzodiazepines, practice guidelines exist regarding prescribing these agents, and data from randomized trials support specific interventions to deprescribe them.⁵ Nevertheless, clinicians report feeling inadequately prepared to discontinue benzodiazepines, particularly when patients perceive benefit from them. As such, user-friendly tools and specific strategies for weighing risks vs benefits are critical for clinicians.

PUTTING KNOWLEDGE INTO PRACTICE

How do we translate knowledge into practice with regard to deprescribing potentially inappropriate medications in older patients—or prescribing drugs only if appropriate in the first place?

An opportunity arises when patients are in the hospital. Taking a medication history on admission and matching medications with indications are key starting points. Clinical pharmacists can help screen for side effects and potential interactions and can provide deprescribing recommendations. Meticulous discharge medication reconciliation, patient education, and communication of the updated medication list to the outpatient provider are central to ensuring that patients adhere to medication adjustments after they go home.

A MATTER OF BALANCE

Another factor to consider is the patient’s physiologic age compared with his or her chronologic age. If a patient has multiple comorbidities, frailty, limited life expectancy, or poor renal function, we may consider her older than her chronologic age. In this case, a drug’s risks may outweigh its benefit, which is something to be discussed. On the other hand, a high-functioning and relatively healthy elderly patient may be a candidate for medications known to reduce the risk of death or control a chronic disease better. Incorporating a patient’s goals of care and using shared decision-making are also likely to yield an optimal medication regimen.

Smartphone apps and resources embedded in electronic health records provide additional decision support. Used when prescribing or reconciling medications, these supplemental brains offer instant feedback and information on dose adjustments, drug interactions, clinical guidelines, and even potentially inappropriate medications. While the impacts of these electronic tools on prescribing patterns and outcomes in geriatric populations remain unclear, new ones are being developed and studied.⁶ This may be the most promising way to translate knowledge into practice, as it is more easily integrated with existing clinician workflows.

AN OPPORTUNITY TO IMPROVE

There is significant opportunity to reduce polypharmacy and optimize medication prescribing practices for older adults. Awareness of potentially inappropriate medications and clinical situations in which the use of certain classes of medications should be minimized is the first step in addressing this problem. Using tools such as the STOPP/START criteria, reviewing medications at critical transition points, prioritizing patient function and goals, and using electronic clinical decision support should aid prescribing decisions.

Whenever possible, collaborating with other care team members such as pharmacists may increase efficiency and effectiveness of medication management. Ultimately, inclusion of more older adults in clinical trials may provide data-driven guidance for weighing risks and benefits. Finally, further study of the effects of deprescribing on clinical outcomes may be the missing piece to help clinicians and patients find balance in prescription management.

According to a 2016 study, more than one-third of older adults in the United States take 5 or more medications.¹ This is a growing problem. Not only do older patients take more drugs than younger patients, they are also at higher risk of adverse drug events, drug-drug interactions, geriatric syndromes, and lower adherence.²

See related article

Many drugs that older patients are given are potentially inappropriate, ie, their risks outweigh the expected benefits, particularly when effective and safer alternative therapies exist. Although many clinicians are aware of the risks of polypharmacy, they may not be confident in discontinuing potentially inappropriate medications. The process of deliberately tapering, stopping, or reducing doses of medications with the goal of reducing harm and improving patient outcomes is known as deprescribing.³

In this issue, Kim et al⁴ review several medications that are overused or often used inappropriately in older adults: statins for primary prevention of atherosclerotic cardiovascular disease, anticholinergic drugs, benzodiazepines, antipsychotics, and proton pump inhibitors. They offer guidance about the situations in which these drugs may be inappropriate as well as alternative drug and nondrug treatments. Further, they suggest that, when prescribing or deprescribing drugs in older adults, clinicians consult tools such as the Beers criteria and the STOPP/START criteria (the Screening Tool of Older Persons’ Potentially Inappropriate Prescriptions, and the Screening Tool to Alert Doctors to Right Treatment).

The issues Kim et al review are highly relevant and may increase awareness of specific potentially inappropriate medications. They also remind us that nonpharmacologic treatments are first-line for many medical conditions. In an era of a pill for every ill and a quick-fix mentality among both patients and providers, lifestyle changes and other nonpharmacologic treatments may be overlooked. Similarly, the STOPP/START criteria, which are concrete, evidence-based recommendations that can be applied to patient care, are likely underused in clinical practice.

Although necessary and valuable, simply arming clinicians with knowledge is insufficient to tackle the problems of polypharmacy and inappropriate prescribing. As the authors note in their discussion of benzodiazepines, practice guidelines exist regarding prescribing these agents, and data from randomized trials support specific interventions to deprescribe them.⁵ Nevertheless, clinicians report feeling inadequately prepared to discontinue benzodiazepines, particularly when patients perceive benefit from them. As such, user-friendly tools and specific strategies for weighing risks vs benefits are critical for clinicians.

PUTTING KNOWLEDGE INTO PRACTICE

How do we translate knowledge into practice with regard to deprescribing potentially inappropriate medications in older patients—or prescribing drugs only if appropriate in the first place?

An opportunity arises when patients are in the hospital. Taking a medication history on admission and matching medications with indications are key starting points. Clinical pharmacists can help screen for side effects and potential interactions and can provide deprescribing recommendations. Meticulous discharge medication reconciliation, patient education, and communication of the updated medication list to the outpatient provider are central to ensuring that patients adhere to medication adjustments after they go home.

A MATTER OF BALANCE

Another factor to consider is the patient’s physiologic age compared with his or her chronologic age. If a patient has multiple comorbidities, frailty, limited life expectancy, or poor renal function, we may consider her older than her chronologic age. In this case, a drug’s risks may outweigh its benefit, which is something to be discussed. On the other hand, a high-functioning and relatively healthy elderly patient may be a candidate for medications known to reduce the risk of death or control a chronic disease better. Incorporating a patient’s goals of care and using shared decision-making are also likely to yield an optimal medication regimen.

Smartphone apps and resources embedded in electronic health records provide additional decision support. Used when prescribing or reconciling medications, these supplemental brains offer instant feedback and information on dose adjustments, drug interactions, clinical guidelines, and even potentially inappropriate medications. While the impacts of these electronic tools on prescribing patterns and outcomes in geriatric populations remain unclear, new ones are being developed and studied.⁶ This may be the most promising way to translate knowledge into practice, as it is more easily integrated with existing clinician workflows.

AN OPPORTUNITY TO IMPROVE

There is significant opportunity to reduce polypharmacy and optimize medication prescribing practices for older adults. Awareness of potentially inappropriate medications and clinical situations in which the use of certain classes of medications should be minimized is the first step in addressing this problem. Using tools such as the STOPP/START criteria, reviewing medications at critical transition points, prioritizing patient function and goals, and using electronic clinical decision support should aid prescribing decisions.

Whenever possible, collaborating with other care team members such as pharmacists may increase efficiency and effectiveness of medication management. Ultimately, inclusion of more older adults in clinical trials may provide data-driven guidance for weighing risks and benefits. Finally, further study of the effects of deprescribing on clinical outcomes may be the missing piece to help clinicians and patients find balance in prescription management.

A 66-year-old man presented to the hospital with 3 days of nausea, vomiting, and abdominal pain. He had come to the emergency department several times during this period, but the cause of his symptoms had not been determined.

The patient was successfully treated with urgent right hemicolectomy.

THE CHILAIDITI SIGN AND SYNDROME

The Chilaiditi sign is an infrequent anomaly found incidentally on chest or abdominal radiography as a colonic interposition between the liver and right hemidiaphragm.¹ It is often asymptomatic but is sometimes accompanied by nausea, vomiting, abdominal pain, and constipation, ie, Chilaiditi syndrome.

Generally, after conservative treatment with fasting and pain control, symptoms may subside and follow-up should be sufficient. However, nasogastric decompression and laxatives are occasionally needed and are often effective in patients with Chilaiditi syndrome. Urgent abdominal surgery is indicated for patients with symptoms of volvulus of the colon, stomach, or small intestine.²

DISTINGUISHING CHARACTERISTICS

The Chilaiditi sign is often confused with pneumoperitoneum, which usually requires urgent abdominal surgery. But the presence of haustration or valvulae conniventes (folds in the small bowel mucosa) in the hepatodiaphragmatic space helps distinguish between intraluminal gas and free air. If the patient presents with abdominal pain without signs of peritonitis, and if imaging indicates the Chilaiditi sign, then supplementary imaging (eg, decubitus radiography, chest CT, abdominal CT) is recommended to make the definitive diagnosis and to avoid unnecessary surgery.

Gas under the diaphragm on standing chest radiography without signs of peritonitis may also be seen after laparotomy and after scuba diving as well as in cases of biliary enteric fistula, incompetent sphincter of Oddi, gallstone ileus, and pneumatosis cystoides intestinalis. The incidence rate of the Chilaiditi sign detected by radiography is between 0.025% and 0.28%.³

PREDISPOSING FACTORS

The cause of the Chilaiditi sign remains unknown. Predisposing factors can be categorized as diaphragmatic (diaphragmatic thinning, phrenic nerve injury, expanded thoracic cavity), intestinal (megacolon, increased intra-abdominal pressure), and hepatic (hepatic atrophy, cirrhosis, ascites).

In healthy people, Chilaiditi syndrome is usually attributed to a congenital abnormal lengthening of the colon or to undue looseness of ligaments of the colon and liver.

Recognizing the Chilaiditi sign is particularly important in patients scheduled to undergo a percutaneous transhepatic procedure or colonoscopic examination, as these procedures increase the risk of perforation.

A 66-year-old man presented to the hospital with 3 days of nausea, vomiting, and abdominal pain. He had come to the emergency department several times during this period, but the cause of his symptoms had not been determined.

The patient was successfully treated with urgent right hemicolectomy.

THE CHILAIDITI SIGN AND SYNDROME

The Chilaiditi sign is an infrequent anomaly found incidentally on chest or abdominal radiography as a colonic interposition between the liver and right hemidiaphragm.¹ It is often asymptomatic but is sometimes accompanied by nausea, vomiting, abdominal pain, and constipation, ie, Chilaiditi syndrome.

Generally, after conservative treatment with fasting and pain control, symptoms may subside and follow-up should be sufficient. However, nasogastric decompression and laxatives are occasionally needed and are often effective in patients with Chilaiditi syndrome. Urgent abdominal surgery is indicated for patients with symptoms of volvulus of the colon, stomach, or small intestine.²

DISTINGUISHING CHARACTERISTICS

The Chilaiditi sign is often confused with pneumoperitoneum, which usually requires urgent abdominal surgery. But the presence of haustration or valvulae conniventes (folds in the small bowel mucosa) in the hepatodiaphragmatic space helps distinguish between intraluminal gas and free air. If the patient presents with abdominal pain without signs of peritonitis, and if imaging indicates the Chilaiditi sign, then supplementary imaging (eg, decubitus radiography, chest CT, abdominal CT) is recommended to make the definitive diagnosis and to avoid unnecessary surgery.

Gas under the diaphragm on standing chest radiography without signs of peritonitis may also be seen after laparotomy and after scuba diving as well as in cases of biliary enteric fistula, incompetent sphincter of Oddi, gallstone ileus, and pneumatosis cystoides intestinalis. The incidence rate of the Chilaiditi sign detected by radiography is between 0.025% and 0.28%.³

PREDISPOSING FACTORS

The cause of the Chilaiditi sign remains unknown. Predisposing factors can be categorized as diaphragmatic (diaphragmatic thinning, phrenic nerve injury, expanded thoracic cavity), intestinal (megacolon, increased intra-abdominal pressure), and hepatic (hepatic atrophy, cirrhosis, ascites).

In healthy people, Chilaiditi syndrome is usually attributed to a congenital abnormal lengthening of the colon or to undue looseness of ligaments of the colon and liver.

Recognizing the Chilaiditi sign is particularly important in patients scheduled to undergo a percutaneous transhepatic procedure or colonoscopic examination, as these procedures increase the risk of perforation.

A 66-year-old man presented to the hospital with 3 days of nausea, vomiting, and abdominal pain. He had come to the emergency department several times during this period, but the cause of his symptoms had not been determined.

The patient was successfully treated with urgent right hemicolectomy.

THE CHILAIDITI SIGN AND SYNDROME

The Chilaiditi sign is an infrequent anomaly found incidentally on chest or abdominal radiography as a colonic interposition between the liver and right hemidiaphragm.¹ It is often asymptomatic but is sometimes accompanied by nausea, vomiting, abdominal pain, and constipation, ie, Chilaiditi syndrome.

Generally, after conservative treatment with fasting and pain control, symptoms may subside and follow-up should be sufficient. However, nasogastric decompression and laxatives are occasionally needed and are often effective in patients with Chilaiditi syndrome. Urgent abdominal surgery is indicated for patients with symptoms of volvulus of the colon, stomach, or small intestine.²

DISTINGUISHING CHARACTERISTICS

The Chilaiditi sign is often confused with pneumoperitoneum, which usually requires urgent abdominal surgery. But the presence of haustration or valvulae conniventes (folds in the small bowel mucosa) in the hepatodiaphragmatic space helps distinguish between intraluminal gas and free air. If the patient presents with abdominal pain without signs of peritonitis, and if imaging indicates the Chilaiditi sign, then supplementary imaging (eg, decubitus radiography, chest CT, abdominal CT) is recommended to make the definitive diagnosis and to avoid unnecessary surgery.

Gas under the diaphragm on standing chest radiography without signs of peritonitis may also be seen after laparotomy and after scuba diving as well as in cases of biliary enteric fistula, incompetent sphincter of Oddi, gallstone ileus, and pneumatosis cystoides intestinalis. The incidence rate of the Chilaiditi sign detected by radiography is between 0.025% and 0.28%.³

PREDISPOSING FACTORS

The cause of the Chilaiditi sign remains unknown. Predisposing factors can be categorized as diaphragmatic (diaphragmatic thinning, phrenic nerve injury, expanded thoracic cavity), intestinal (megacolon, increased intra-abdominal pressure), and hepatic (hepatic atrophy, cirrhosis, ascites).

In healthy people, Chilaiditi syndrome is usually attributed to a congenital abnormal lengthening of the colon or to undue looseness of ligaments of the colon and liver.

Recognizing the Chilaiditi sign is particularly important in patients scheduled to undergo a percutaneous transhepatic procedure or colonoscopic examination, as these procedures increase the risk of perforation.