Reviews

The management of hypertension has advanced significantly in the last few decades. But the race for more effective means to control this epidemic and its associated complications is far from won. A high percentage of patients in the United States have hypertension that is uncontrolled. Most of these belong to the most rapidly growing demographic group in the United States, ie, the elderly.

It is estimated that more than 70% of medical practice will be directed to geriatric needs in the coming years. It is therefore very important for clinicians to be comfortable with managing hypertension in the elderly.

A GROWING PROBLEM IN AN AGING POPULATION

Between 1980 and 2009, the US population age 65 and older increased from 25.6 million to 39.6 million, of which 42% are men and 58% women.¹ This number is expected to reach 75 million by the year 2040. People over 85 years of age are the fastest growing subset of the US population.² As many as 50% of people who were born recently in countries such as the United States, the United Kingdom, France, Denmark, and Japan will live to celebrate their 100th birthday.³

According to the Framingham Heart Study, by age 60 approximately 60% of the population develops hypertension, and by 70 years about 65% of men and about 75% of women have the disease. In the same study, 90% of those who were normotensive at age 55 went on to develop hypertension. The elderly also are more likely to suffer from the complications of hypertension and are more likely to have uncontrolled disease.

Compared with younger patients with similar blood pressure, elderly hypertensive patients have lower cardiac output, higher peripheral resistance, wider pulse pressure, lower intravascular volume, and lower renal blood flow.⁴ These age-related pathophysiologic differences must be considered when treating antihypertension in the elderly.

IS TREATING THE ELDERLY BENEFICIAL?

Most elderly hypertensive patients have multiple comorbidities, which tremendously affect the management of their hypertension. They are also more likely than younger patients to have resistant hypertension and to need multiple drugs to control their blood pressure. In the process, these frail patients are exposed to a host of drug-related adverse effects. Thus, it is relevant to question the net benefit of treatment in this age group.

Many studies have indeed shown that treating hypertension reduces the risk of stroke and other adverse cardiovascular events. A decade ago, Staessen et al,⁵ in a meta-analysis of more than 15,000 patients between ages 62 and 76, showed that treating isolated systolic hypertension substantially reduced morbidity and mortality rates. Moreover, a 2011 meta-analysis of randomized controlled trials in hypertensive patients age 75 and over also concluded that treatment reduced cardiovascular morbidity and mortality rates and the incidence of heart failure, even though the total mortality rate was not affected.⁶

Opinion on treating the very elderly (≥ 80 years of age) was divided until the results of the Hypertension in the Very Elderly trial (HYVET)⁷ came out in 2008. This study documented major benefits of treatment in the very elderly age group as well.

The consensus, therefore, is that it is appropriate, even imperative, to treat elderly hypertensive patients (with some cautions—see the sections that follow).

GOAL OF TREATMENT IN THE ELDERLY

Targets for blood pressure management have been based primarily on observational data in middle-aged patients. There is no such thing as an ideal blood pressure that has been derived from randomized controlled trials for any population, let alone the elderly. The generally recommended blood pressure goal of 140/90 mm Hg for elderly hypertensive patients is based on expert opinion.

Moreover, it is unclear if the same target should apply to octogenarians. According to a 2011 American College of Cardiology/American Heart Association (ACC/AHA) expert consensus report,⁸ an achieved systolic blood pressure of 140 to 145 mm Hg, if tolerated, can be acceptable in this age group.

An orthostatic decline in blood pressure accompanies advanced age and is an inevitable adverse effect of some antihypertensive drugs. Accordingly, systolic blood pressure lower than 130 and diastolic blood pressure lower than 70 mm Hg are best avoided in octogenarians.⁸ Therefore, when hypertension is complicated by coexisting conditions that require a specific blood pressure goal, it would seem reasonable to not pursue the lower target as aggressively in octogenarians as in elderly patients under age 80.

Having stated the limitations in the quality of data at hand—largely observational—it is relevant to mention the Systolic Blood Pressure Intervention trial (SPRINT).⁹ This ongoing randomized, multicenter trial, launched by the National Institutes of Health, is assessing whether maintaining blood pressure levels lower than current recommendations further reduces the risk of cardiovascular and kidney diseases or, in the SPRINT-MIND substudy, of age-related cognitive decline, regardless of the type of antihypertensive drug taken. Initially planning to enroll close to 10,000 participants over the age of 55 without specifying any agegroup ranges, the investigators later decided to conduct a substudy called SPRINT Senior that will enroll about 1,750 participants over the age of 75 to determine whether a lower blood pressure range will have the same beneficial effects in older adults.

Given the limitations in the quality and applicability of published data (coming from small, nonrandomized studies with no long-term follow-up), SPRINT is expected to provide the evidence needed to support standard vs aggressive hypertension control among the elderly. The trial is projected to run until late 2018.

MANAGEMENT APPROACH IN THE ELDERLY

Blood pressure should be recorded in both arms before a diagnosis is made. In a number of patients, particularly the elderly, there are significant differences in blood pressure readings between the two arms. The higher reading should be relied on and the corresponding arm used for subsequent measurements.

Lifestyle interventions

Similar to the approach in younger patients with hypertension, lifestyle interventions are the first step to managing high blood pressure in the elderly. The diet and exercise interventions in the Dietary Approaches to Stop Hypertension (DASH) trial have both been shown to lower blood pressure.^10,11

Restricting sodium intake has been shown to lower blood pressure more in older adults than in younger adults. In the DASH trial,¹² systolic blood pressure decreased by 8.1 mm Hg with sodium restriction in hypertensive patients age 55 to 76 years, compared with 4.8 mm Hg for adults aged 23 to 41 years. In the Trial of Nonpharmacologic Interventions in the Elderly (TONE),¹³ in people ages 60 to 80 who were randomized to reduce their salt intake, urinary sodium excretion was 40 mmol/day lower and blood pressure was 4.3/2.0 mm Hg lower than in a group that received usual care. Accordingly, reducing salt intake is particularly valuable for blood pressure management in the salt-sensitive elderly.¹⁴

Drug therapy

The hypertension pandemic has driven extensive pharmaceutical research, and new drugs continue to be introduced. The major classes of drugs commonly used for treating hypertension are diuretics, calcium channel blockers, and renin-angiotensin system blockers. Each class has specific benefits and adverse-effect profiles.

It is appropriate to start antihypertensive drug therapy with the lowest dose and to monitor for adverse effects, including orthostatic hypotension. The choice of drug should be guided by the patient’s comorbid conditions (Table 1) and the other drugs the patient is taking.¹⁵ If the blood pressure response is inadequate, a second drug from a different class should be added. In the same manner, a third drug from a different class should be added if the blood pressure remains outside the optimal range on two drugs.

The average elderly American is on more than six medications.¹⁶ Some of these are for high blood pressure, but others interact with antihypertensive drugs (Table 2), and some, including nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, directly affect blood pressure. Therefore, the drug regimen of an elderly hypertensive patient should be reviewed carefully at every visit. The Screening Tool of Older Person’s Prescriptions (STOPP), a list of 65 rules relating to the most common and most potentially dangerous instances of inappropriate prescribing and overprescribing in the elderly,¹⁷ has been found to be a reliable tool in this regard, with a kappa-coefficient of 0.75. Together with the Screening Tool to Alert Doctors to Right [ie, Appropriate, Indicated] Treatment (START),¹⁷ which lists 22 evidence-based prescribing indicators for common conditions in the elderly, these criteria provide clinicians with an easy screening tool to combat polypharmacy.

Given the multitude of factors that go into deciding on a specific management strategy in the elderly, it is not possible to discuss individualized care in all patients in the scope of one paper. Below, we present several case scenarios that internists commonly encounter, and suggest ways to approach each.

CASE 1: SECONDARY HYPERTENSION

A 69-year-old obese man who has hypertension of recent onset, long-standing gastroesophageal reflux disease, and benign prostatic hypertrophy comes to your office, accompanied by his wife. He has never had hypertension before. His body mass index is 34 kg/m². On physical examination, his blood pressure is 180/112 mm Hg.

We start with this case to emphasize the importance of considering causes of secondary hypertension in all patients with the disease (Table 3).¹⁸ Further workup should be pursued in those who appear to have “inappropriate” hypertension. This could present as refractory hypertension, abrupt-onset hypertension, hypertension that is first diagnosed before age 20 or after age 60, or loss of control over previously well-controlled blood pressure. Secondary hypertension must always be considered when the history or physical examination suggests a possible cause.

Renal artery stenosis increases in incidence with age. Its prevalence is reported to be as high as 50% in elderly patients with other signs of atherosclerosis such as widespread peripheral artery disease.¹⁹

Obstructive sleep apnea also commonly coexists with hypertension and its prevalence also increases with age. In addition, elderly patients with obstructive sleep apnea have a higher incidence of cardiovascular complications, including hypertension, than middle-aged people.²⁰ Numerous studies have found that the severity of obstructive sleep apnea corresponds with the likelihood of systemic hypertension.^21–23 Randomized trials and meta-analyses have also concluded that effective treatment with continuous positive airway pressure reduces systemic blood pressure,^24–27 although by less than antihypertensive medications do.

A causal relationship between obstructive sleep apnea and hypertension has not been established with certainty. It is recommended, however, that patients with resistant hypertension be screened for obstructive sleep apnea as a possible cause of their disease.

Other causes of secondary hypertension to keep in mind when evaluating patients who have inappropriate hypertension include thyroid disorders, alcohol and tobacco use, and chronic steroid or NSAID use. Pheochromocytoma and adrenal adenoma, though possible, are less prevalent in the elderly.

Case continued

Physical examination in the above patient revealed an epigastric systolic-diastolic bruit, a sign that, although not sensitive, is highly specific for renal artery stenosis, raising the suspicion of this condition. Duplex ultrasonography of the renal arteries confirmed this suspicion. The patient underwent angiography and revascularization, resulting in a distinct fall in, but not normalization of, his blood pressure.

Though we do not intend to detail the diagnostic approaches and treatments for the various causes of secondary hypertension, we need to briefly mention those for renal artery stenosis.

According to the 2006 ACC/AHA guidelines on peripheral artery disease,²⁸ testing for renal artery stenosis is indicated only if a subsequent corrective procedure is a viable option.

Renal arteriography remains the gold standard for diagnosing renal artery stenosis. However, noninvasive imaging has largely replaced it.

Duplex Doppler ultrasonography, compared with angiography, has a sensitivity of 84% to 98% depending on operator experience, and a specificity of 62% to 99% for detecting renal artery stenosis.²⁹ Some of its limiting factors are the time needed to do the study, its steep learning curve and operator-dependence, and interference with the results by body fat and intestinal gas.

Computed tomographic angiography has a sensitivity of over 90% for detecting renal artery stenosis, and its specificity has been shown to be as high as 99% in certain studies.²⁹ Use of contrast can be a limiting factor in some clinical settings.

Magnetic resonance angiography also offers a sensitivity of 90% to 100% and specificities of 76% to 94% for detecting renal artery stenosis.²⁹ On the other hand, it is costly, and the gadolinium contrast solution used is nephrotoxic, though not as toxic as the contrast used in computed tomographic angiography.

As previously stated, these imaging studies should be used only if corrective measures will be undertaken if clinically significant renal artery stenosis is found. Even in such cases, revascularization may not be curative in all cases. Its effectiveness has been compared with that of medical management alone in a number of studies.^30,31 A meta-analysis³² of six key trials involving more than 1,200 patients showed no difference in systolic and diastolic blood pressures and other clinical outcomes, including all-cause mortality, between the two treatment groups over a 29-month follow-up period.

Hence, although we advise that causes of secondary hypertension be considered in cases of inappropriate hypertension, aggressive management must be pursued on a case-by-case basis.

CASE 2: DRUG ADVERSE EFFECTS

A 75-year-old Hispanic woman with a history of treated breast cancer was recently diagnosed with hypertension. Her blood pressure is controlled on amlodipine (Norvasc) 10 mg daily, and her blood pressure today is 128/80 mm Hg. Her only complaint during this office visit is some swelling of her ankles.

Edema and dihydropyridine calcium channel blockers

Like all drugs, antihypertensive medications come with their own set of adverse effects. These are more common as people age—hence the importance of identifying and effectively managing them in the elderly population.

Calcium channel blockers, especially the dihydropyridines—ie, nifedipine (Adalat), amlodipine, felodipine (Plendil), and isradipine (DynaCirc)—are known to cause peripheral vasodilation. Peripheral edema is a common dose-related effect in people on these drugs. In one study, median leg weight increased by 80 g after amlodipine 5 mg was given for 4 weeks, and by another 68 g on a 10-mg dose.³³

Ankle swelling, encountered more in women, can be very bothersome. The swelling is related to hyperfiltration of fluid into the interstitial space secondary to intracapillary hypertension. Calcium channel blockers predominantly cause arteriolar dilation by paralyzing the precapillary sphincter, thereby elevating intracapillary pressure.

Traditionally, physicians have lowered the dose of the calcium channel blocker, switched to another drug, or added a diuretic to alleviate the swelling. However, giving a diuretic for edema induced by a calcium channel blocker may not relieve the edema.³⁴

Peripheral edema is much less encountered when a calcium channel blocker is given with an inhibitor of the renin-angiotensin system.³⁵ A meta-analysis concluded that the incidence of peripheral edema was lowered by 38% with such a combination. The same study found angiotensin-converting enzyme (ACE) inhibitors significantly more efficacious for this effect than angiotensin receptor blockers (ARBs).³⁵

ACE inhibitors and ARBs are known to cause venodilation, thereby lowering intra-capillary pressure. It is probable that this effect helps remove the extra fluid sequestered in the capillary bed by the arteriolar dilation from the calcium channel blocker.

Pedal edema associated with use of a calcium channel blocker occurs much more commonly in the elderly than in the young. It is clearly dose-dependent, and the incidence peaks after 6 months of therapy. In the patient described above, adding a low dose of an ACE inhibitor or an ARB (if the patient is ACE inhibitor-intolerant) should relieve the swelling.

Hyponatremia and diuretics

Electrolyte imbalances are another common problem encountered in the elderly. Even though for years attention has been directed to the potassium level, hyponatremia has been equally associated with adverse effects in the elderly, such as an increased risk of fractures as shown in the Rotterdam study.³⁶

In 180 hypertensive inpatients, mean age 76.4, Sharabi et al³⁷ found the incidence of hyponatremia to be three times higher in women than in men (odds ratio 3.10, 95% confidence interval 2.07 to 4.67). Patients were 10 times more likely to be affected after age 65 and 14 times more likely after age 75. Most of the patients affected (74.5%) used a thiazide-type diuretic. Even though in many of the patients diuretics were used for more than 1 year before hyponatremia developed, susceptible patients—such as the frail elderly—can develop severe hyponatremia within days of starting to use a thiazide.³⁸

Severe hyponatremia is potentially life-threatening. Most cases are caused by thiazide rather than loop diuretics.³⁸ Thiazides inhibit electrolyte transport at the cortical diluting sites. As they decrease the glomerular filtration rate acutely, they increase proximal water reabsorption (making the plasma hypotonic), reducing water delivery distally. Loop diuretics, on the other hand, have their main effect at the thick ascending limb, reducing the osmolality at the medullary interstitium and not affecting proximal water reabsorption. Additionally, loop diuretics have a shorter half-life than thiazides, which makes hyponatremia more likely to happen with thiazides.

In patients who develop hyponatremia secondary to diuretic use, appropriate treatment includes stopping the medication, restricting water intake, and repleting electrolyte stores.³⁸ As with any cause of chronic hyponatremia, correction must be cautiously monitored and not hastily done.

Therefore, we advise adding a thiazide diuric with caution in the elderly, and we advise avoiding thiazides in patients with high water or alcohol intake.

CASE 3: DEMENTIA AND HYPERTENSION

A 74-year-old man with long-standing hypertension, gout, and chronic obstructive pulmonary disease was recently diagnosed with Alzheimer dementia. He takes enalapril (Vasotec) 10 mg daily for his blood pressure. His blood pressure is 130/78 mm Hg.

Dementia is one of the most important and common neurologic disorders in the elderly. With the rise in average life expectancy, its magnitude has grown to cause a substantial emotional and economic burden on society and health care.

Midlife hypertension has been demonstrated to be an important modifiable risk factor for late-life cognitive decline,³⁹ mild cognitive impairment,⁴⁰ and dementia of all causes.⁴¹ It has been suggested that hypertension might be part of the pathogenesis of dementia, and targeting high blood pressure might prevent its onset.

Moreover, a significant reduction in both Alzheimer and vascular dementia was demonstrated (risk reduction 55%) with the use of a long-acting dihydropyridine calcium channel blocker (nitrendipine) in the Syst-Eur study.⁴² However, data from studies such as Systolic Hypertension in the Elderly Program (SHEP) and the HYVET substudy of cognitive function assessement⁴³ showed no difference in dementia between placebo and active therapy with chlorthalidone (Hygroton) (in SHEP) or indapamide (Lozol) (in the HYVET substudy).

Disorders of calcium homeostasis are associated with the brain’s aging process. Probably, the neuroprotective effect of nitrendipine seen in Syst-Eur was due to its ability to affect this process, independent of its blood pressure-lowering effect.

In another prospective study, people over 60 years of age who complained of subjective memory loss showed a significant and positive association between memory scores and the use of calcium channel blockers (+0.14 ± 0.09 in users vs −0.12 ± 0.06 in nonusers; P = .016) independently of age, sex, white matter hyperintensities, and carotid wall cross-sectional area, all of which were associated with worse memory scores.⁴⁴

Drugs that block the renin-angiotensin system have also been proposed to delay the onset and slow the progression of dementia.⁴⁵ A small randomized, controlled trial suggested that centrally active ACE inhibitors—those that cross the blood-brain barrier, such as captopril (Capoten), lisinopril (Prinivil), ramipril (Altace), and fosinopril (Monopril)—slow cognitive decline in Alzheimer dementia more than non-centrally active ACE inhibitors or calcium channel blockers.⁴⁶

Sink et al⁴⁷ examined data from participants in the Cognition Substudy of the Cardiovascular Health Study⁴⁸ on the effect of ACE inhibitors on cognitive decline. ACE inhibitors, as a class, showed no benefit in reducing the risk of dementia compared with other antihypertensive drug classes. However, centrally active ACE inhibitors, compared with other medications, were associated with a 65% reduction in cognitive decline per year of drug exposure (P = .01). Non-centrally active ACE inhibitors worsened cognitive decline.

It appears that the brain’s renin-angiotensin system plays a role in the pathogenesis of dementia. Indeed, ACE has been shown to degrade amyloid-beta protein, and its level was increased in brain tissue of Alzheimer patients postmortem.⁴⁹

The relationship between blood pressure and cognitive function appears to be curvilinear, so that low blood pressure in late life is also associated with dementia and Alzheimer dementia.⁵⁰ In 5,816 patients age 65 and older, Morris et al⁵¹ calculated the percentile scores of four cognitive tests according to the level of blood pressure. Patients with systolic blood pressures of 100 mm Hg, 120 mm Hg, and 180 mm Hg scored lower on the Mini Mental State Examination than those in the 140 to 160 mm Hg range. Patients with diastolic blood pressures between 80 and 90 mm Hg appeared to have the best cognitive function. This further emphasizes that blood pressure control must be pursued in the very elderly, albeit less aggressively. The MIND substudy of the SPRINT trial⁹ is likely to shed more light on this relationship.

When needed for optimal blood pressure control in a hypertensive patient at risk of dementia, a calcium channel blocker of the dihydropyridine type or a centrally active ACE inhibitor, or both, is preferable.

CASE 4: LABILE HYPERTENSION

A 74-year-old man with hypertension and diabetes mellitus comes to see you in the office. On physical examination, his blood pressure is 175/110 mm Hg. His blood pressure during his last visit 3 months ago was 120/75. He brings a log with him that shows random fluctuations in his blood pressure readings. He takes hydrochlorothiazide 25 mg daily for his blood pressure.

Hypertension in some patients continuously fluctuates between low and high levels. A study in Canada found that up to 15% of all adult hypertensive patients might have labile hypertension.⁵² In the presence of a normal average blood pressure, visit-to-visit blood pressure variability is usually considered a trivial matter. However, some but not all studies have shown that such visit-to-visit variability in blood pressure is an independent predictor of future cardiovascular events in hypertensive patients, independent of the mean systolic blood pressure.^52–54

Blood pressure fluctuates from heartbeat to heartbeat, from morning to night, from winter to summer, and from sitting to standing, and it is prone to increase with exertion, stress, and other factors. But excessive fluctuations in the elderly are most likely the result of excessive stiffness of the arterial tree and a decrease in the windkessel (cushioning) function of the aorta. As a consequence, even small-volume changes in the intravascular system can trigger large blood pressure fluctuations.

There is some evidence that antihypertensive drug classes may differ in their effects on visit-to-visit blood pressure variability. In a 2010 study comparing the effects of different antihypertensive drugs on blood pressure variation, calcium channel blockers and non-loop diuretics were associated with less variation in systolic blood pressure, and calcium channel blockers reduced it the most.⁵⁵

In the patient described above, switching to a low-dose calcium channel blocker with a thorough follow-up is a reasonable plan.

CASE 5: ORTHOSTATIC HYPOTENSION

A 73-year-old woman with long-standing hypertension complains of some dizziness, especially when getting out of bed in the morning. On physical examination, her blood pressure is 134/100 mm Hg sitting and 115/90 standing. She takes amlodipine 10 mg daily, enalapril 10 mg daily, and chlorthalidone 25 mg daily. Chlorthalidone had been added on her last visit 1 month before.

As a result of the increase in the number of elderly patients with hypertension and guidelines recommending better control in this age group, the number of elderly patients on anti-hypertensive drugs has risen significantly. At the same time, the elderly have increasingly presented with adverse effects of treatment.

Orthostatic hypotension is a drop in systolic pressure of 20 mm Hg or more or a drop in diastolic pressure of 10 mm Hg or more on standing, with or without symptoms. These are caused by cerebral hypoperfusion and include dizziness, lightheadedness, generalized weakness, visual blurring, and, in severe cases, syncope.

Alpha-blockers and nitrates have been most commonly implicated in causing orthostatic hypotension, due to venous pooling. Clearly, not all antihypertensive drugs are equal with regard to their venodilatory effects. Thiazide diuretics, by causing fluid volume depletion, and beta-blockers, by interfering with compensatory cardioacceleration with upright posture, are also commonly involved in causing an excessive blood pressure drop with standing.

Systolic orthostatic hypotension has been shown to be a significant and independent predictor of cardiovascular morbidity and death.⁵⁶ Moreover, syncope and subsequent falls are an important cause of injury and death in the elderly.⁵⁷ The clinical combination of hypertension and orthostatic hypotension is, therefore, especially challenging. A compromise between accepting a higher cardiovascular risk at either end of the spectrum with an added higher risk for fall at the lower end has to be made.

To prevent orthostatic hypotension in the elderly, it is important to avoid prescribing high-risk drugs. When starting antihypertensive therapy, a low dose should be used, and the dose should be titrated upward very slowly and cautiously. If orthostatic hypotension is suggested by the history or by the orthostatic test, which is warranted in all elderly hypertensive patients before starting or significantly altering therapy, the potential culprit drug should be withdrawn and the patient reassessed. Improved hydration, elevating the head of the bed, and taking the antihypertensive drug at night are ways to improve symptoms, but these remain largely unproven.

In this patient, the newly added chlorthalidone was stopped, and her symptoms improved.

PSEUDOHYPERTENSION

Since hypertension is defined by a numerical value, it is prudent that this value be accurate. Treating a falsely high reading or leaving a falsely low reading untreated will predispose the elderly patient to increased risk either way. One rare condition in the elderly that can give a falsely high blood pressure reading is pseudohypertension.

Pseudohypertension is a condition in which indirect blood pressure measured by the cuff method overestimates the true intra-arterial blood pressure due to marked underlying arteriosclerosis. The Osler maneuver can be used to differentiate true hypertension from pseudohypertension.⁵⁸ This is performed by palpating the pulseless radial or brachial artery distal to the inflated cuff. If the artery is palpable despite being pulseless, the patient is said to be “Osler-positive” and likely has pseudohypertension.⁵⁸

Pseudohypertension should be suspected if the patient has orthostatic hypotension despite normal blood pressure sitting and standing. Also, elevated blood pressure without appropriate target organ disease should raise the suspicion of pseudohypertension. Apart from the Osler maneuver, measuring the intraarterial pressure can confirm this diagnosis.

The management of hypertension has advanced significantly in the last few decades. But the race for more effective means to control this epidemic and its associated complications is far from won. A high percentage of patients in the United States have hypertension that is uncontrolled. Most of these belong to the most rapidly growing demographic group in the United States, ie, the elderly.

It is estimated that more than 70% of medical practice will be directed to geriatric needs in the coming years. It is therefore very important for clinicians to be comfortable with managing hypertension in the elderly.

A GROWING PROBLEM IN AN AGING POPULATION

Between 1980 and 2009, the US population age 65 and older increased from 25.6 million to 39.6 million, of which 42% are men and 58% women.¹ This number is expected to reach 75 million by the year 2040. People over 85 years of age are the fastest growing subset of the US population.² As many as 50% of people who were born recently in countries such as the United States, the United Kingdom, France, Denmark, and Japan will live to celebrate their 100th birthday.³

According to the Framingham Heart Study, by age 60 approximately 60% of the population develops hypertension, and by 70 years about 65% of men and about 75% of women have the disease. In the same study, 90% of those who were normotensive at age 55 went on to develop hypertension. The elderly also are more likely to suffer from the complications of hypertension and are more likely to have uncontrolled disease.

Compared with younger patients with similar blood pressure, elderly hypertensive patients have lower cardiac output, higher peripheral resistance, wider pulse pressure, lower intravascular volume, and lower renal blood flow.⁴ These age-related pathophysiologic differences must be considered when treating antihypertension in the elderly.

IS TREATING THE ELDERLY BENEFICIAL?

Most elderly hypertensive patients have multiple comorbidities, which tremendously affect the management of their hypertension. They are also more likely than younger patients to have resistant hypertension and to need multiple drugs to control their blood pressure. In the process, these frail patients are exposed to a host of drug-related adverse effects. Thus, it is relevant to question the net benefit of treatment in this age group.

Many studies have indeed shown that treating hypertension reduces the risk of stroke and other adverse cardiovascular events. A decade ago, Staessen et al,⁵ in a meta-analysis of more than 15,000 patients between ages 62 and 76, showed that treating isolated systolic hypertension substantially reduced morbidity and mortality rates. Moreover, a 2011 meta-analysis of randomized controlled trials in hypertensive patients age 75 and over also concluded that treatment reduced cardiovascular morbidity and mortality rates and the incidence of heart failure, even though the total mortality rate was not affected.⁶

Opinion on treating the very elderly (≥ 80 years of age) was divided until the results of the Hypertension in the Very Elderly trial (HYVET)⁷ came out in 2008. This study documented major benefits of treatment in the very elderly age group as well.

The consensus, therefore, is that it is appropriate, even imperative, to treat elderly hypertensive patients (with some cautions—see the sections that follow).

GOAL OF TREATMENT IN THE ELDERLY

Targets for blood pressure management have been based primarily on observational data in middle-aged patients. There is no such thing as an ideal blood pressure that has been derived from randomized controlled trials for any population, let alone the elderly. The generally recommended blood pressure goal of 140/90 mm Hg for elderly hypertensive patients is based on expert opinion.

Moreover, it is unclear if the same target should apply to octogenarians. According to a 2011 American College of Cardiology/American Heart Association (ACC/AHA) expert consensus report,⁸ an achieved systolic blood pressure of 140 to 145 mm Hg, if tolerated, can be acceptable in this age group.

An orthostatic decline in blood pressure accompanies advanced age and is an inevitable adverse effect of some antihypertensive drugs. Accordingly, systolic blood pressure lower than 130 and diastolic blood pressure lower than 70 mm Hg are best avoided in octogenarians.⁸ Therefore, when hypertension is complicated by coexisting conditions that require a specific blood pressure goal, it would seem reasonable to not pursue the lower target as aggressively in octogenarians as in elderly patients under age 80.

Having stated the limitations in the quality of data at hand—largely observational—it is relevant to mention the Systolic Blood Pressure Intervention trial (SPRINT).⁹ This ongoing randomized, multicenter trial, launched by the National Institutes of Health, is assessing whether maintaining blood pressure levels lower than current recommendations further reduces the risk of cardiovascular and kidney diseases or, in the SPRINT-MIND substudy, of age-related cognitive decline, regardless of the type of antihypertensive drug taken. Initially planning to enroll close to 10,000 participants over the age of 55 without specifying any agegroup ranges, the investigators later decided to conduct a substudy called SPRINT Senior that will enroll about 1,750 participants over the age of 75 to determine whether a lower blood pressure range will have the same beneficial effects in older adults.

Given the limitations in the quality and applicability of published data (coming from small, nonrandomized studies with no long-term follow-up), SPRINT is expected to provide the evidence needed to support standard vs aggressive hypertension control among the elderly. The trial is projected to run until late 2018.

MANAGEMENT APPROACH IN THE ELDERLY

Blood pressure should be recorded in both arms before a diagnosis is made. In a number of patients, particularly the elderly, there are significant differences in blood pressure readings between the two arms. The higher reading should be relied on and the corresponding arm used for subsequent measurements.

Lifestyle interventions

Similar to the approach in younger patients with hypertension, lifestyle interventions are the first step to managing high blood pressure in the elderly. The diet and exercise interventions in the Dietary Approaches to Stop Hypertension (DASH) trial have both been shown to lower blood pressure.^10,11

Restricting sodium intake has been shown to lower blood pressure more in older adults than in younger adults. In the DASH trial,¹² systolic blood pressure decreased by 8.1 mm Hg with sodium restriction in hypertensive patients age 55 to 76 years, compared with 4.8 mm Hg for adults aged 23 to 41 years. In the Trial of Nonpharmacologic Interventions in the Elderly (TONE),¹³ in people ages 60 to 80 who were randomized to reduce their salt intake, urinary sodium excretion was 40 mmol/day lower and blood pressure was 4.3/2.0 mm Hg lower than in a group that received usual care. Accordingly, reducing salt intake is particularly valuable for blood pressure management in the salt-sensitive elderly.¹⁴

Drug therapy

The hypertension pandemic has driven extensive pharmaceutical research, and new drugs continue to be introduced. The major classes of drugs commonly used for treating hypertension are diuretics, calcium channel blockers, and renin-angiotensin system blockers. Each class has specific benefits and adverse-effect profiles.

It is appropriate to start antihypertensive drug therapy with the lowest dose and to monitor for adverse effects, including orthostatic hypotension. The choice of drug should be guided by the patient’s comorbid conditions (Table 1) and the other drugs the patient is taking.¹⁵ If the blood pressure response is inadequate, a second drug from a different class should be added. In the same manner, a third drug from a different class should be added if the blood pressure remains outside the optimal range on two drugs.

The average elderly American is on more than six medications.¹⁶ Some of these are for high blood pressure, but others interact with antihypertensive drugs (Table 2), and some, including nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, directly affect blood pressure. Therefore, the drug regimen of an elderly hypertensive patient should be reviewed carefully at every visit. The Screening Tool of Older Person’s Prescriptions (STOPP), a list of 65 rules relating to the most common and most potentially dangerous instances of inappropriate prescribing and overprescribing in the elderly,¹⁷ has been found to be a reliable tool in this regard, with a kappa-coefficient of 0.75. Together with the Screening Tool to Alert Doctors to Right [ie, Appropriate, Indicated] Treatment (START),¹⁷ which lists 22 evidence-based prescribing indicators for common conditions in the elderly, these criteria provide clinicians with an easy screening tool to combat polypharmacy.

Given the multitude of factors that go into deciding on a specific management strategy in the elderly, it is not possible to discuss individualized care in all patients in the scope of one paper. Below, we present several case scenarios that internists commonly encounter, and suggest ways to approach each.

CASE 1: SECONDARY HYPERTENSION

A 69-year-old obese man who has hypertension of recent onset, long-standing gastroesophageal reflux disease, and benign prostatic hypertrophy comes to your office, accompanied by his wife. He has never had hypertension before. His body mass index is 34 kg/m². On physical examination, his blood pressure is 180/112 mm Hg.

We start with this case to emphasize the importance of considering causes of secondary hypertension in all patients with the disease (Table 3).¹⁸ Further workup should be pursued in those who appear to have “inappropriate” hypertension. This could present as refractory hypertension, abrupt-onset hypertension, hypertension that is first diagnosed before age 20 or after age 60, or loss of control over previously well-controlled blood pressure. Secondary hypertension must always be considered when the history or physical examination suggests a possible cause.

Renal artery stenosis increases in incidence with age. Its prevalence is reported to be as high as 50% in elderly patients with other signs of atherosclerosis such as widespread peripheral artery disease.¹⁹

Obstructive sleep apnea also commonly coexists with hypertension and its prevalence also increases with age. In addition, elderly patients with obstructive sleep apnea have a higher incidence of cardiovascular complications, including hypertension, than middle-aged people.²⁰ Numerous studies have found that the severity of obstructive sleep apnea corresponds with the likelihood of systemic hypertension.^21–23 Randomized trials and meta-analyses have also concluded that effective treatment with continuous positive airway pressure reduces systemic blood pressure,^24–27 although by less than antihypertensive medications do.

A causal relationship between obstructive sleep apnea and hypertension has not been established with certainty. It is recommended, however, that patients with resistant hypertension be screened for obstructive sleep apnea as a possible cause of their disease.

Other causes of secondary hypertension to keep in mind when evaluating patients who have inappropriate hypertension include thyroid disorders, alcohol and tobacco use, and chronic steroid or NSAID use. Pheochromocytoma and adrenal adenoma, though possible, are less prevalent in the elderly.

Case continued

Physical examination in the above patient revealed an epigastric systolic-diastolic bruit, a sign that, although not sensitive, is highly specific for renal artery stenosis, raising the suspicion of this condition. Duplex ultrasonography of the renal arteries confirmed this suspicion. The patient underwent angiography and revascularization, resulting in a distinct fall in, but not normalization of, his blood pressure.

Though we do not intend to detail the diagnostic approaches and treatments for the various causes of secondary hypertension, we need to briefly mention those for renal artery stenosis.

According to the 2006 ACC/AHA guidelines on peripheral artery disease,²⁸ testing for renal artery stenosis is indicated only if a subsequent corrective procedure is a viable option.

Renal arteriography remains the gold standard for diagnosing renal artery stenosis. However, noninvasive imaging has largely replaced it.

Duplex Doppler ultrasonography, compared with angiography, has a sensitivity of 84% to 98% depending on operator experience, and a specificity of 62% to 99% for detecting renal artery stenosis.²⁹ Some of its limiting factors are the time needed to do the study, its steep learning curve and operator-dependence, and interference with the results by body fat and intestinal gas.

Computed tomographic angiography has a sensitivity of over 90% for detecting renal artery stenosis, and its specificity has been shown to be as high as 99% in certain studies.²⁹ Use of contrast can be a limiting factor in some clinical settings.

Magnetic resonance angiography also offers a sensitivity of 90% to 100% and specificities of 76% to 94% for detecting renal artery stenosis.²⁹ On the other hand, it is costly, and the gadolinium contrast solution used is nephrotoxic, though not as toxic as the contrast used in computed tomographic angiography.

As previously stated, these imaging studies should be used only if corrective measures will be undertaken if clinically significant renal artery stenosis is found. Even in such cases, revascularization may not be curative in all cases. Its effectiveness has been compared with that of medical management alone in a number of studies.^30,31 A meta-analysis³² of six key trials involving more than 1,200 patients showed no difference in systolic and diastolic blood pressures and other clinical outcomes, including all-cause mortality, between the two treatment groups over a 29-month follow-up period.

Hence, although we advise that causes of secondary hypertension be considered in cases of inappropriate hypertension, aggressive management must be pursued on a case-by-case basis.

CASE 2: DRUG ADVERSE EFFECTS

A 75-year-old Hispanic woman with a history of treated breast cancer was recently diagnosed with hypertension. Her blood pressure is controlled on amlodipine (Norvasc) 10 mg daily, and her blood pressure today is 128/80 mm Hg. Her only complaint during this office visit is some swelling of her ankles.

Edema and dihydropyridine calcium channel blockers

Like all drugs, antihypertensive medications come with their own set of adverse effects. These are more common as people age—hence the importance of identifying and effectively managing them in the elderly population.

Calcium channel blockers, especially the dihydropyridines—ie, nifedipine (Adalat), amlodipine, felodipine (Plendil), and isradipine (DynaCirc)—are known to cause peripheral vasodilation. Peripheral edema is a common dose-related effect in people on these drugs. In one study, median leg weight increased by 80 g after amlodipine 5 mg was given for 4 weeks, and by another 68 g on a 10-mg dose.³³

Ankle swelling, encountered more in women, can be very bothersome. The swelling is related to hyperfiltration of fluid into the interstitial space secondary to intracapillary hypertension. Calcium channel blockers predominantly cause arteriolar dilation by paralyzing the precapillary sphincter, thereby elevating intracapillary pressure.

Traditionally, physicians have lowered the dose of the calcium channel blocker, switched to another drug, or added a diuretic to alleviate the swelling. However, giving a diuretic for edema induced by a calcium channel blocker may not relieve the edema.³⁴

Peripheral edema is much less encountered when a calcium channel blocker is given with an inhibitor of the renin-angiotensin system.³⁵ A meta-analysis concluded that the incidence of peripheral edema was lowered by 38% with such a combination. The same study found angiotensin-converting enzyme (ACE) inhibitors significantly more efficacious for this effect than angiotensin receptor blockers (ARBs).³⁵

ACE inhibitors and ARBs are known to cause venodilation, thereby lowering intra-capillary pressure. It is probable that this effect helps remove the extra fluid sequestered in the capillary bed by the arteriolar dilation from the calcium channel blocker.

Pedal edema associated with use of a calcium channel blocker occurs much more commonly in the elderly than in the young. It is clearly dose-dependent, and the incidence peaks after 6 months of therapy. In the patient described above, adding a low dose of an ACE inhibitor or an ARB (if the patient is ACE inhibitor-intolerant) should relieve the swelling.

Hyponatremia and diuretics

Electrolyte imbalances are another common problem encountered in the elderly. Even though for years attention has been directed to the potassium level, hyponatremia has been equally associated with adverse effects in the elderly, such as an increased risk of fractures as shown in the Rotterdam study.³⁶

In 180 hypertensive inpatients, mean age 76.4, Sharabi et al³⁷ found the incidence of hyponatremia to be three times higher in women than in men (odds ratio 3.10, 95% confidence interval 2.07 to 4.67). Patients were 10 times more likely to be affected after age 65 and 14 times more likely after age 75. Most of the patients affected (74.5%) used a thiazide-type diuretic. Even though in many of the patients diuretics were used for more than 1 year before hyponatremia developed, susceptible patients—such as the frail elderly—can develop severe hyponatremia within days of starting to use a thiazide.³⁸

Severe hyponatremia is potentially life-threatening. Most cases are caused by thiazide rather than loop diuretics.³⁸ Thiazides inhibit electrolyte transport at the cortical diluting sites. As they decrease the glomerular filtration rate acutely, they increase proximal water reabsorption (making the plasma hypotonic), reducing water delivery distally. Loop diuretics, on the other hand, have their main effect at the thick ascending limb, reducing the osmolality at the medullary interstitium and not affecting proximal water reabsorption. Additionally, loop diuretics have a shorter half-life than thiazides, which makes hyponatremia more likely to happen with thiazides.

In patients who develop hyponatremia secondary to diuretic use, appropriate treatment includes stopping the medication, restricting water intake, and repleting electrolyte stores.³⁸ As with any cause of chronic hyponatremia, correction must be cautiously monitored and not hastily done.

Therefore, we advise adding a thiazide diuric with caution in the elderly, and we advise avoiding thiazides in patients with high water or alcohol intake.

CASE 3: DEMENTIA AND HYPERTENSION

A 74-year-old man with long-standing hypertension, gout, and chronic obstructive pulmonary disease was recently diagnosed with Alzheimer dementia. He takes enalapril (Vasotec) 10 mg daily for his blood pressure. His blood pressure is 130/78 mm Hg.

Dementia is one of the most important and common neurologic disorders in the elderly. With the rise in average life expectancy, its magnitude has grown to cause a substantial emotional and economic burden on society and health care.

Midlife hypertension has been demonstrated to be an important modifiable risk factor for late-life cognitive decline,³⁹ mild cognitive impairment,⁴⁰ and dementia of all causes.⁴¹ It has been suggested that hypertension might be part of the pathogenesis of dementia, and targeting high blood pressure might prevent its onset.

Moreover, a significant reduction in both Alzheimer and vascular dementia was demonstrated (risk reduction 55%) with the use of a long-acting dihydropyridine calcium channel blocker (nitrendipine) in the Syst-Eur study.⁴² However, data from studies such as Systolic Hypertension in the Elderly Program (SHEP) and the HYVET substudy of cognitive function assessement⁴³ showed no difference in dementia between placebo and active therapy with chlorthalidone (Hygroton) (in SHEP) or indapamide (Lozol) (in the HYVET substudy).

Disorders of calcium homeostasis are associated with the brain’s aging process. Probably, the neuroprotective effect of nitrendipine seen in Syst-Eur was due to its ability to affect this process, independent of its blood pressure-lowering effect.

In another prospective study, people over 60 years of age who complained of subjective memory loss showed a significant and positive association between memory scores and the use of calcium channel blockers (+0.14 ± 0.09 in users vs −0.12 ± 0.06 in nonusers; P = .016) independently of age, sex, white matter hyperintensities, and carotid wall cross-sectional area, all of which were associated with worse memory scores.⁴⁴

Drugs that block the renin-angiotensin system have also been proposed to delay the onset and slow the progression of dementia.⁴⁵ A small randomized, controlled trial suggested that centrally active ACE inhibitors—those that cross the blood-brain barrier, such as captopril (Capoten), lisinopril (Prinivil), ramipril (Altace), and fosinopril (Monopril)—slow cognitive decline in Alzheimer dementia more than non-centrally active ACE inhibitors or calcium channel blockers.⁴⁶

Sink et al⁴⁷ examined data from participants in the Cognition Substudy of the Cardiovascular Health Study⁴⁸ on the effect of ACE inhibitors on cognitive decline. ACE inhibitors, as a class, showed no benefit in reducing the risk of dementia compared with other antihypertensive drug classes. However, centrally active ACE inhibitors, compared with other medications, were associated with a 65% reduction in cognitive decline per year of drug exposure (P = .01). Non-centrally active ACE inhibitors worsened cognitive decline.

It appears that the brain’s renin-angiotensin system plays a role in the pathogenesis of dementia. Indeed, ACE has been shown to degrade amyloid-beta protein, and its level was increased in brain tissue of Alzheimer patients postmortem.⁴⁹

The relationship between blood pressure and cognitive function appears to be curvilinear, so that low blood pressure in late life is also associated with dementia and Alzheimer dementia.⁵⁰ In 5,816 patients age 65 and older, Morris et al⁵¹ calculated the percentile scores of four cognitive tests according to the level of blood pressure. Patients with systolic blood pressures of 100 mm Hg, 120 mm Hg, and 180 mm Hg scored lower on the Mini Mental State Examination than those in the 140 to 160 mm Hg range. Patients with diastolic blood pressures between 80 and 90 mm Hg appeared to have the best cognitive function. This further emphasizes that blood pressure control must be pursued in the very elderly, albeit less aggressively. The MIND substudy of the SPRINT trial⁹ is likely to shed more light on this relationship.

When needed for optimal blood pressure control in a hypertensive patient at risk of dementia, a calcium channel blocker of the dihydropyridine type or a centrally active ACE inhibitor, or both, is preferable.

CASE 4: LABILE HYPERTENSION

A 74-year-old man with hypertension and diabetes mellitus comes to see you in the office. On physical examination, his blood pressure is 175/110 mm Hg. His blood pressure during his last visit 3 months ago was 120/75. He brings a log with him that shows random fluctuations in his blood pressure readings. He takes hydrochlorothiazide 25 mg daily for his blood pressure.

Hypertension in some patients continuously fluctuates between low and high levels. A study in Canada found that up to 15% of all adult hypertensive patients might have labile hypertension.⁵² In the presence of a normal average blood pressure, visit-to-visit blood pressure variability is usually considered a trivial matter. However, some but not all studies have shown that such visit-to-visit variability in blood pressure is an independent predictor of future cardiovascular events in hypertensive patients, independent of the mean systolic blood pressure.^52–54

Blood pressure fluctuates from heartbeat to heartbeat, from morning to night, from winter to summer, and from sitting to standing, and it is prone to increase with exertion, stress, and other factors. But excessive fluctuations in the elderly are most likely the result of excessive stiffness of the arterial tree and a decrease in the windkessel (cushioning) function of the aorta. As a consequence, even small-volume changes in the intravascular system can trigger large blood pressure fluctuations.

There is some evidence that antihypertensive drug classes may differ in their effects on visit-to-visit blood pressure variability. In a 2010 study comparing the effects of different antihypertensive drugs on blood pressure variation, calcium channel blockers and non-loop diuretics were associated with less variation in systolic blood pressure, and calcium channel blockers reduced it the most.⁵⁵

In the patient described above, switching to a low-dose calcium channel blocker with a thorough follow-up is a reasonable plan.

CASE 5: ORTHOSTATIC HYPOTENSION

A 73-year-old woman with long-standing hypertension complains of some dizziness, especially when getting out of bed in the morning. On physical examination, her blood pressure is 134/100 mm Hg sitting and 115/90 standing. She takes amlodipine 10 mg daily, enalapril 10 mg daily, and chlorthalidone 25 mg daily. Chlorthalidone had been added on her last visit 1 month before.

As a result of the increase in the number of elderly patients with hypertension and guidelines recommending better control in this age group, the number of elderly patients on anti-hypertensive drugs has risen significantly. At the same time, the elderly have increasingly presented with adverse effects of treatment.

Orthostatic hypotension is a drop in systolic pressure of 20 mm Hg or more or a drop in diastolic pressure of 10 mm Hg or more on standing, with or without symptoms. These are caused by cerebral hypoperfusion and include dizziness, lightheadedness, generalized weakness, visual blurring, and, in severe cases, syncope.

Alpha-blockers and nitrates have been most commonly implicated in causing orthostatic hypotension, due to venous pooling. Clearly, not all antihypertensive drugs are equal with regard to their venodilatory effects. Thiazide diuretics, by causing fluid volume depletion, and beta-blockers, by interfering with compensatory cardioacceleration with upright posture, are also commonly involved in causing an excessive blood pressure drop with standing.

Systolic orthostatic hypotension has been shown to be a significant and independent predictor of cardiovascular morbidity and death.⁵⁶ Moreover, syncope and subsequent falls are an important cause of injury and death in the elderly.⁵⁷ The clinical combination of hypertension and orthostatic hypotension is, therefore, especially challenging. A compromise between accepting a higher cardiovascular risk at either end of the spectrum with an added higher risk for fall at the lower end has to be made.

To prevent orthostatic hypotension in the elderly, it is important to avoid prescribing high-risk drugs. When starting antihypertensive therapy, a low dose should be used, and the dose should be titrated upward very slowly and cautiously. If orthostatic hypotension is suggested by the history or by the orthostatic test, which is warranted in all elderly hypertensive patients before starting or significantly altering therapy, the potential culprit drug should be withdrawn and the patient reassessed. Improved hydration, elevating the head of the bed, and taking the antihypertensive drug at night are ways to improve symptoms, but these remain largely unproven.

In this patient, the newly added chlorthalidone was stopped, and her symptoms improved.

PSEUDOHYPERTENSION

Since hypertension is defined by a numerical value, it is prudent that this value be accurate. Treating a falsely high reading or leaving a falsely low reading untreated will predispose the elderly patient to increased risk either way. One rare condition in the elderly that can give a falsely high blood pressure reading is pseudohypertension.

Pseudohypertension is a condition in which indirect blood pressure measured by the cuff method overestimates the true intra-arterial blood pressure due to marked underlying arteriosclerosis. The Osler maneuver can be used to differentiate true hypertension from pseudohypertension.⁵⁸ This is performed by palpating the pulseless radial or brachial artery distal to the inflated cuff. If the artery is palpable despite being pulseless, the patient is said to be “Osler-positive” and likely has pseudohypertension.⁵⁸

Pseudohypertension should be suspected if the patient has orthostatic hypotension despite normal blood pressure sitting and standing. Also, elevated blood pressure without appropriate target organ disease should raise the suspicion of pseudohypertension. Apart from the Osler maneuver, measuring the intraarterial pressure can confirm this diagnosis.

The management of hypertension has advanced significantly in the last few decades. But the race for more effective means to control this epidemic and its associated complications is far from won. A high percentage of patients in the United States have hypertension that is uncontrolled. Most of these belong to the most rapidly growing demographic group in the United States, ie, the elderly.

It is estimated that more than 70% of medical practice will be directed to geriatric needs in the coming years. It is therefore very important for clinicians to be comfortable with managing hypertension in the elderly.

A GROWING PROBLEM IN AN AGING POPULATION

Between 1980 and 2009, the US population age 65 and older increased from 25.6 million to 39.6 million, of which 42% are men and 58% women.¹ This number is expected to reach 75 million by the year 2040. People over 85 years of age are the fastest growing subset of the US population.² As many as 50% of people who were born recently in countries such as the United States, the United Kingdom, France, Denmark, and Japan will live to celebrate their 100th birthday.³

According to the Framingham Heart Study, by age 60 approximately 60% of the population develops hypertension, and by 70 years about 65% of men and about 75% of women have the disease. In the same study, 90% of those who were normotensive at age 55 went on to develop hypertension. The elderly also are more likely to suffer from the complications of hypertension and are more likely to have uncontrolled disease.

Compared with younger patients with similar blood pressure, elderly hypertensive patients have lower cardiac output, higher peripheral resistance, wider pulse pressure, lower intravascular volume, and lower renal blood flow.⁴ These age-related pathophysiologic differences must be considered when treating antihypertension in the elderly.

IS TREATING THE ELDERLY BENEFICIAL?

Most elderly hypertensive patients have multiple comorbidities, which tremendously affect the management of their hypertension. They are also more likely than younger patients to have resistant hypertension and to need multiple drugs to control their blood pressure. In the process, these frail patients are exposed to a host of drug-related adverse effects. Thus, it is relevant to question the net benefit of treatment in this age group.

Many studies have indeed shown that treating hypertension reduces the risk of stroke and other adverse cardiovascular events. A decade ago, Staessen et al,⁵ in a meta-analysis of more than 15,000 patients between ages 62 and 76, showed that treating isolated systolic hypertension substantially reduced morbidity and mortality rates. Moreover, a 2011 meta-analysis of randomized controlled trials in hypertensive patients age 75 and over also concluded that treatment reduced cardiovascular morbidity and mortality rates and the incidence of heart failure, even though the total mortality rate was not affected.⁶

Opinion on treating the very elderly (≥ 80 years of age) was divided until the results of the Hypertension in the Very Elderly trial (HYVET)⁷ came out in 2008. This study documented major benefits of treatment in the very elderly age group as well.

The consensus, therefore, is that it is appropriate, even imperative, to treat elderly hypertensive patients (with some cautions—see the sections that follow).

GOAL OF TREATMENT IN THE ELDERLY

Targets for blood pressure management have been based primarily on observational data in middle-aged patients. There is no such thing as an ideal blood pressure that has been derived from randomized controlled trials for any population, let alone the elderly. The generally recommended blood pressure goal of 140/90 mm Hg for elderly hypertensive patients is based on expert opinion.

Moreover, it is unclear if the same target should apply to octogenarians. According to a 2011 American College of Cardiology/American Heart Association (ACC/AHA) expert consensus report,⁸ an achieved systolic blood pressure of 140 to 145 mm Hg, if tolerated, can be acceptable in this age group.

An orthostatic decline in blood pressure accompanies advanced age and is an inevitable adverse effect of some antihypertensive drugs. Accordingly, systolic blood pressure lower than 130 and diastolic blood pressure lower than 70 mm Hg are best avoided in octogenarians.⁸ Therefore, when hypertension is complicated by coexisting conditions that require a specific blood pressure goal, it would seem reasonable to not pursue the lower target as aggressively in octogenarians as in elderly patients under age 80.

Having stated the limitations in the quality of data at hand—largely observational—it is relevant to mention the Systolic Blood Pressure Intervention trial (SPRINT).⁹ This ongoing randomized, multicenter trial, launched by the National Institutes of Health, is assessing whether maintaining blood pressure levels lower than current recommendations further reduces the risk of cardiovascular and kidney diseases or, in the SPRINT-MIND substudy, of age-related cognitive decline, regardless of the type of antihypertensive drug taken. Initially planning to enroll close to 10,000 participants over the age of 55 without specifying any agegroup ranges, the investigators later decided to conduct a substudy called SPRINT Senior that will enroll about 1,750 participants over the age of 75 to determine whether a lower blood pressure range will have the same beneficial effects in older adults.

Given the limitations in the quality and applicability of published data (coming from small, nonrandomized studies with no long-term follow-up), SPRINT is expected to provide the evidence needed to support standard vs aggressive hypertension control among the elderly. The trial is projected to run until late 2018.

MANAGEMENT APPROACH IN THE ELDERLY

Blood pressure should be recorded in both arms before a diagnosis is made. In a number of patients, particularly the elderly, there are significant differences in blood pressure readings between the two arms. The higher reading should be relied on and the corresponding arm used for subsequent measurements.

Lifestyle interventions

Similar to the approach in younger patients with hypertension, lifestyle interventions are the first step to managing high blood pressure in the elderly. The diet and exercise interventions in the Dietary Approaches to Stop Hypertension (DASH) trial have both been shown to lower blood pressure.^10,11

Restricting sodium intake has been shown to lower blood pressure more in older adults than in younger adults. In the DASH trial,¹² systolic blood pressure decreased by 8.1 mm Hg with sodium restriction in hypertensive patients age 55 to 76 years, compared with 4.8 mm Hg for adults aged 23 to 41 years. In the Trial of Nonpharmacologic Interventions in the Elderly (TONE),¹³ in people ages 60 to 80 who were randomized to reduce their salt intake, urinary sodium excretion was 40 mmol/day lower and blood pressure was 4.3/2.0 mm Hg lower than in a group that received usual care. Accordingly, reducing salt intake is particularly valuable for blood pressure management in the salt-sensitive elderly.¹⁴

Drug therapy

The hypertension pandemic has driven extensive pharmaceutical research, and new drugs continue to be introduced. The major classes of drugs commonly used for treating hypertension are diuretics, calcium channel blockers, and renin-angiotensin system blockers. Each class has specific benefits and adverse-effect profiles.

It is appropriate to start antihypertensive drug therapy with the lowest dose and to monitor for adverse effects, including orthostatic hypotension. The choice of drug should be guided by the patient’s comorbid conditions (Table 1) and the other drugs the patient is taking.¹⁵ If the blood pressure response is inadequate, a second drug from a different class should be added. In the same manner, a third drug from a different class should be added if the blood pressure remains outside the optimal range on two drugs.

The average elderly American is on more than six medications.¹⁶ Some of these are for high blood pressure, but others interact with antihypertensive drugs (Table 2), and some, including nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, directly affect blood pressure. Therefore, the drug regimen of an elderly hypertensive patient should be reviewed carefully at every visit. The Screening Tool of Older Person’s Prescriptions (STOPP), a list of 65 rules relating to the most common and most potentially dangerous instances of inappropriate prescribing and overprescribing in the elderly,¹⁷ has been found to be a reliable tool in this regard, with a kappa-coefficient of 0.75. Together with the Screening Tool to Alert Doctors to Right [ie, Appropriate, Indicated] Treatment (START),¹⁷ which lists 22 evidence-based prescribing indicators for common conditions in the elderly, these criteria provide clinicians with an easy screening tool to combat polypharmacy.

Given the multitude of factors that go into deciding on a specific management strategy in the elderly, it is not possible to discuss individualized care in all patients in the scope of one paper. Below, we present several case scenarios that internists commonly encounter, and suggest ways to approach each.

CASE 1: SECONDARY HYPERTENSION

A 69-year-old obese man who has hypertension of recent onset, long-standing gastroesophageal reflux disease, and benign prostatic hypertrophy comes to your office, accompanied by his wife. He has never had hypertension before. His body mass index is 34 kg/m². On physical examination, his blood pressure is 180/112 mm Hg.

We start with this case to emphasize the importance of considering causes of secondary hypertension in all patients with the disease (Table 3).¹⁸ Further workup should be pursued in those who appear to have “inappropriate” hypertension. This could present as refractory hypertension, abrupt-onset hypertension, hypertension that is first diagnosed before age 20 or after age 60, or loss of control over previously well-controlled blood pressure. Secondary hypertension must always be considered when the history or physical examination suggests a possible cause.

Renal artery stenosis increases in incidence with age. Its prevalence is reported to be as high as 50% in elderly patients with other signs of atherosclerosis such as widespread peripheral artery disease.¹⁹

Obstructive sleep apnea also commonly coexists with hypertension and its prevalence also increases with age. In addition, elderly patients with obstructive sleep apnea have a higher incidence of cardiovascular complications, including hypertension, than middle-aged people.²⁰ Numerous studies have found that the severity of obstructive sleep apnea corresponds with the likelihood of systemic hypertension.^21–23 Randomized trials and meta-analyses have also concluded that effective treatment with continuous positive airway pressure reduces systemic blood pressure,^24–27 although by less than antihypertensive medications do.

A causal relationship between obstructive sleep apnea and hypertension has not been established with certainty. It is recommended, however, that patients with resistant hypertension be screened for obstructive sleep apnea as a possible cause of their disease.

Other causes of secondary hypertension to keep in mind when evaluating patients who have inappropriate hypertension include thyroid disorders, alcohol and tobacco use, and chronic steroid or NSAID use. Pheochromocytoma and adrenal adenoma, though possible, are less prevalent in the elderly.

Case continued

Physical examination in the above patient revealed an epigastric systolic-diastolic bruit, a sign that, although not sensitive, is highly specific for renal artery stenosis, raising the suspicion of this condition. Duplex ultrasonography of the renal arteries confirmed this suspicion. The patient underwent angiography and revascularization, resulting in a distinct fall in, but not normalization of, his blood pressure.

Though we do not intend to detail the diagnostic approaches and treatments for the various causes of secondary hypertension, we need to briefly mention those for renal artery stenosis.

According to the 2006 ACC/AHA guidelines on peripheral artery disease,²⁸ testing for renal artery stenosis is indicated only if a subsequent corrective procedure is a viable option.

Renal arteriography remains the gold standard for diagnosing renal artery stenosis. However, noninvasive imaging has largely replaced it.

Duplex Doppler ultrasonography, compared with angiography, has a sensitivity of 84% to 98% depending on operator experience, and a specificity of 62% to 99% for detecting renal artery stenosis.²⁹ Some of its limiting factors are the time needed to do the study, its steep learning curve and operator-dependence, and interference with the results by body fat and intestinal gas.

Computed tomographic angiography has a sensitivity of over 90% for detecting renal artery stenosis, and its specificity has been shown to be as high as 99% in certain studies.²⁹ Use of contrast can be a limiting factor in some clinical settings.

Magnetic resonance angiography also offers a sensitivity of 90% to 100% and specificities of 76% to 94% for detecting renal artery stenosis.²⁹ On the other hand, it is costly, and the gadolinium contrast solution used is nephrotoxic, though not as toxic as the contrast used in computed tomographic angiography.

As previously stated, these imaging studies should be used only if corrective measures will be undertaken if clinically significant renal artery stenosis is found. Even in such cases, revascularization may not be curative in all cases. Its effectiveness has been compared with that of medical management alone in a number of studies.^30,31 A meta-analysis³² of six key trials involving more than 1,200 patients showed no difference in systolic and diastolic blood pressures and other clinical outcomes, including all-cause mortality, between the two treatment groups over a 29-month follow-up period.

Hence, although we advise that causes of secondary hypertension be considered in cases of inappropriate hypertension, aggressive management must be pursued on a case-by-case basis.

CASE 2: DRUG ADVERSE EFFECTS

A 75-year-old Hispanic woman with a history of treated breast cancer was recently diagnosed with hypertension. Her blood pressure is controlled on amlodipine (Norvasc) 10 mg daily, and her blood pressure today is 128/80 mm Hg. Her only complaint during this office visit is some swelling of her ankles.

Edema and dihydropyridine calcium channel blockers

Like all drugs, antihypertensive medications come with their own set of adverse effects. These are more common as people age—hence the importance of identifying and effectively managing them in the elderly population.

Calcium channel blockers, especially the dihydropyridines—ie, nifedipine (Adalat), amlodipine, felodipine (Plendil), and isradipine (DynaCirc)—are known to cause peripheral vasodilation. Peripheral edema is a common dose-related effect in people on these drugs. In one study, median leg weight increased by 80 g after amlodipine 5 mg was given for 4 weeks, and by another 68 g on a 10-mg dose.³³

Ankle swelling, encountered more in women, can be very bothersome. The swelling is related to hyperfiltration of fluid into the interstitial space secondary to intracapillary hypertension. Calcium channel blockers predominantly cause arteriolar dilation by paralyzing the precapillary sphincter, thereby elevating intracapillary pressure.

Traditionally, physicians have lowered the dose of the calcium channel blocker, switched to another drug, or added a diuretic to alleviate the swelling. However, giving a diuretic for edema induced by a calcium channel blocker may not relieve the edema.³⁴

Peripheral edema is much less encountered when a calcium channel blocker is given with an inhibitor of the renin-angiotensin system.³⁵ A meta-analysis concluded that the incidence of peripheral edema was lowered by 38% with such a combination. The same study found angiotensin-converting enzyme (ACE) inhibitors significantly more efficacious for this effect than angiotensin receptor blockers (ARBs).³⁵

ACE inhibitors and ARBs are known to cause venodilation, thereby lowering intra-capillary pressure. It is probable that this effect helps remove the extra fluid sequestered in the capillary bed by the arteriolar dilation from the calcium channel blocker.

Pedal edema associated with use of a calcium channel blocker occurs much more commonly in the elderly than in the young. It is clearly dose-dependent, and the incidence peaks after 6 months of therapy. In the patient described above, adding a low dose of an ACE inhibitor or an ARB (if the patient is ACE inhibitor-intolerant) should relieve the swelling.

Hyponatremia and diuretics

Electrolyte imbalances are another common problem encountered in the elderly. Even though for years attention has been directed to the potassium level, hyponatremia has been equally associated with adverse effects in the elderly, such as an increased risk of fractures as shown in the Rotterdam study.³⁶

In 180 hypertensive inpatients, mean age 76.4, Sharabi et al³⁷ found the incidence of hyponatremia to be three times higher in women than in men (odds ratio 3.10, 95% confidence interval 2.07 to 4.67). Patients were 10 times more likely to be affected after age 65 and 14 times more likely after age 75. Most of the patients affected (74.5%) used a thiazide-type diuretic. Even though in many of the patients diuretics were used for more than 1 year before hyponatremia developed, susceptible patients—such as the frail elderly—can develop severe hyponatremia within days of starting to use a thiazide.³⁸

Severe hyponatremia is potentially life-threatening. Most cases are caused by thiazide rather than loop diuretics.³⁸ Thiazides inhibit electrolyte transport at the cortical diluting sites. As they decrease the glomerular filtration rate acutely, they increase proximal water reabsorption (making the plasma hypotonic), reducing water delivery distally. Loop diuretics, on the other hand, have their main effect at the thick ascending limb, reducing the osmolality at the medullary interstitium and not affecting proximal water reabsorption. Additionally, loop diuretics have a shorter half-life than thiazides, which makes hyponatremia more likely to happen with thiazides.

In patients who develop hyponatremia secondary to diuretic use, appropriate treatment includes stopping the medication, restricting water intake, and repleting electrolyte stores.³⁸ As with any cause of chronic hyponatremia, correction must be cautiously monitored and not hastily done.

Therefore, we advise adding a thiazide diuric with caution in the elderly, and we advise avoiding thiazides in patients with high water or alcohol intake.

CASE 3: DEMENTIA AND HYPERTENSION

A 74-year-old man with long-standing hypertension, gout, and chronic obstructive pulmonary disease was recently diagnosed with Alzheimer dementia. He takes enalapril (Vasotec) 10 mg daily for his blood pressure. His blood pressure is 130/78 mm Hg.

Dementia is one of the most important and common neurologic disorders in the elderly. With the rise in average life expectancy, its magnitude has grown to cause a substantial emotional and economic burden on society and health care.

Midlife hypertension has been demonstrated to be an important modifiable risk factor for late-life cognitive decline,³⁹ mild cognitive impairment,⁴⁰ and dementia of all causes.⁴¹ It has been suggested that hypertension might be part of the pathogenesis of dementia, and targeting high blood pressure might prevent its onset.

Moreover, a significant reduction in both Alzheimer and vascular dementia was demonstrated (risk reduction 55%) with the use of a long-acting dihydropyridine calcium channel blocker (nitrendipine) in the Syst-Eur study.⁴² However, data from studies such as Systolic Hypertension in the Elderly Program (SHEP) and the HYVET substudy of cognitive function assessement⁴³ showed no difference in dementia between placebo and active therapy with chlorthalidone (Hygroton) (in SHEP) or indapamide (Lozol) (in the HYVET substudy).

Disorders of calcium homeostasis are associated with the brain’s aging process. Probably, the neuroprotective effect of nitrendipine seen in Syst-Eur was due to its ability to affect this process, independent of its blood pressure-lowering effect.

In another prospective study, people over 60 years of age who complained of subjective memory loss showed a significant and positive association between memory scores and the use of calcium channel blockers (+0.14 ± 0.09 in users vs −0.12 ± 0.06 in nonusers; P = .016) independently of age, sex, white matter hyperintensities, and carotid wall cross-sectional area, all of which were associated with worse memory scores.⁴⁴

Drugs that block the renin-angiotensin system have also been proposed to delay the onset and slow the progression of dementia.⁴⁵ A small randomized, controlled trial suggested that centrally active ACE inhibitors—those that cross the blood-brain barrier, such as captopril (Capoten), lisinopril (Prinivil), ramipril (Altace), and fosinopril (Monopril)—slow cognitive decline in Alzheimer dementia more than non-centrally active ACE inhibitors or calcium channel blockers.⁴⁶

Sink et al⁴⁷ examined data from participants in the Cognition Substudy of the Cardiovascular Health Study⁴⁸ on the effect of ACE inhibitors on cognitive decline. ACE inhibitors, as a class, showed no benefit in reducing the risk of dementia compared with other antihypertensive drug classes. However, centrally active ACE inhibitors, compared with other medications, were associated with a 65% reduction in cognitive decline per year of drug exposure (P = .01). Non-centrally active ACE inhibitors worsened cognitive decline.

It appears that the brain’s renin-angiotensin system plays a role in the pathogenesis of dementia. Indeed, ACE has been shown to degrade amyloid-beta protein, and its level was increased in brain tissue of Alzheimer patients postmortem.⁴⁹

The relationship between blood pressure and cognitive function appears to be curvilinear, so that low blood pressure in late life is also associated with dementia and Alzheimer dementia.⁵⁰ In 5,816 patients age 65 and older, Morris et al⁵¹ calculated the percentile scores of four cognitive tests according to the level of blood pressure. Patients with systolic blood pressures of 100 mm Hg, 120 mm Hg, and 180 mm Hg scored lower on the Mini Mental State Examination than those in the 140 to 160 mm Hg range. Patients with diastolic blood pressures between 80 and 90 mm Hg appeared to have the best cognitive function. This further emphasizes that blood pressure control must be pursued in the very elderly, albeit less aggressively. The MIND substudy of the SPRINT trial⁹ is likely to shed more light on this relationship.

When needed for optimal blood pressure control in a hypertensive patient at risk of dementia, a calcium channel blocker of the dihydropyridine type or a centrally active ACE inhibitor, or both, is preferable.

CASE 4: LABILE HYPERTENSION

A 74-year-old man with hypertension and diabetes mellitus comes to see you in the office. On physical examination, his blood pressure is 175/110 mm Hg. His blood pressure during his last visit 3 months ago was 120/75. He brings a log with him that shows random fluctuations in his blood pressure readings. He takes hydrochlorothiazide 25 mg daily for his blood pressure.

Hypertension in some patients continuously fluctuates between low and high levels. A study in Canada found that up to 15% of all adult hypertensive patients might have labile hypertension.⁵² In the presence of a normal average blood pressure, visit-to-visit blood pressure variability is usually considered a trivial matter. However, some but not all studies have shown that such visit-to-visit variability in blood pressure is an independent predictor of future cardiovascular events in hypertensive patients, independent of the mean systolic blood pressure.^52–54

Blood pressure fluctuates from heartbeat to heartbeat, from morning to night, from winter to summer, and from sitting to standing, and it is prone to increase with exertion, stress, and other factors. But excessive fluctuations in the elderly are most likely the result of excessive stiffness of the arterial tree and a decrease in the windkessel (cushioning) function of the aorta. As a consequence, even small-volume changes in the intravascular system can trigger large blood pressure fluctuations.

There is some evidence that antihypertensive drug classes may differ in their effects on visit-to-visit blood pressure variability. In a 2010 study comparing the effects of different antihypertensive drugs on blood pressure variation, calcium channel blockers and non-loop diuretics were associated with less variation in systolic blood pressure, and calcium channel blockers reduced it the most.⁵⁵

In the patient described above, switching to a low-dose calcium channel blocker with a thorough follow-up is a reasonable plan.

CASE 5: ORTHOSTATIC HYPOTENSION

A 73-year-old woman with long-standing hypertension complains of some dizziness, especially when getting out of bed in the morning. On physical examination, her blood pressure is 134/100 mm Hg sitting and 115/90 standing. She takes amlodipine 10 mg daily, enalapril 10 mg daily, and chlorthalidone 25 mg daily. Chlorthalidone had been added on her last visit 1 month before.

As a result of the increase in the number of elderly patients with hypertension and guidelines recommending better control in this age group, the number of elderly patients on anti-hypertensive drugs has risen significantly. At the same time, the elderly have increasingly presented with adverse effects of treatment.

Orthostatic hypotension is a drop in systolic pressure of 20 mm Hg or more or a drop in diastolic pressure of 10 mm Hg or more on standing, with or without symptoms. These are caused by cerebral hypoperfusion and include dizziness, lightheadedness, generalized weakness, visual blurring, and, in severe cases, syncope.

Alpha-blockers and nitrates have been most commonly implicated in causing orthostatic hypotension, due to venous pooling. Clearly, not all antihypertensive drugs are equal with regard to their venodilatory effects. Thiazide diuretics, by causing fluid volume depletion, and beta-blockers, by interfering with compensatory cardioacceleration with upright posture, are also commonly involved in causing an excessive blood pressure drop with standing.

Systolic orthostatic hypotension has been shown to be a significant and independent predictor of cardiovascular morbidity and death.⁵⁶ Moreover, syncope and subsequent falls are an important cause of injury and death in the elderly.⁵⁷ The clinical combination of hypertension and orthostatic hypotension is, therefore, especially challenging. A compromise between accepting a higher cardiovascular risk at either end of the spectrum with an added higher risk for fall at the lower end has to be made.

To prevent orthostatic hypotension in the elderly, it is important to avoid prescribing high-risk drugs. When starting antihypertensive therapy, a low dose should be used, and the dose should be titrated upward very slowly and cautiously. If orthostatic hypotension is suggested by the history or by the orthostatic test, which is warranted in all elderly hypertensive patients before starting or significantly altering therapy, the potential culprit drug should be withdrawn and the patient reassessed. Improved hydration, elevating the head of the bed, and taking the antihypertensive drug at night are ways to improve symptoms, but these remain largely unproven.

In this patient, the newly added chlorthalidone was stopped, and her symptoms improved.

PSEUDOHYPERTENSION

Since hypertension is defined by a numerical value, it is prudent that this value be accurate. Treating a falsely high reading or leaving a falsely low reading untreated will predispose the elderly patient to increased risk either way. One rare condition in the elderly that can give a falsely high blood pressure reading is pseudohypertension.

Pseudohypertension is a condition in which indirect blood pressure measured by the cuff method overestimates the true intra-arterial blood pressure due to marked underlying arteriosclerosis. The Osler maneuver can be used to differentiate true hypertension from pseudohypertension.⁵⁸ This is performed by palpating the pulseless radial or brachial artery distal to the inflated cuff. If the artery is palpable despite being pulseless, the patient is said to be “Osler-positive” and likely has pseudohypertension.⁵⁸

Pseudohypertension should be suspected if the patient has orthostatic hypotension despite normal blood pressure sitting and standing. Also, elevated blood pressure without appropriate target organ disease should raise the suspicion of pseudohypertension. Apart from the Osler maneuver, measuring the intraarterial pressure can confirm this diagnosis.

In July 2012, the US Food and Drug Administration approved the first over-the-counter test kit for human immunodeficiency virus (HIV) infection, the OraQuick In-Home HIV Test (OraSure Technologies, Bethlehem, PA). This test is a variation of the currently available OraQuick ADVANCE Rapid HIV-1/2 Antibody Test used in clinical settings by trained personnel for rapid detection of HIV.

The home HIV test is expected to become available in the fall of 2012 from the company’s Web site and at retail drugstores. This will put the power of HIV testing into the hands of anyone able to afford the estimated $60 price and willing to purchase the item online or in stores.

GOAL: TO REDUCE THE NUMBER OF INFECTED PEOPLE WHO ARE UNAWARE

How home testing will change the demographics of HIV testing is not clear, but the intention is to reduce the number of HIV-infected people who are unaware of their infection and to get them in for care. Anthony Fauci, MD, the director of the National Institutes of Allergy and Infectious Diseases, has called the new test a “positive step forward” in bringing the HIV epidemic under control.¹

Recent figures from the US Centers for Disease Control and Prevention (CDC) indicate that, of the 1.2 million HIV-infected people in the United States, up to 220,000 are unaware of their infection.^2,3 Since antiretroviral therapy is now considered beneficial even in the early stages of HIV infection, those who are unaware of their infection are missing an opportunity for the most effective therapies.

They may also be unknowingly transmitting the virus, thus perpetuating the HIV epidemic. Awareness of one’s HIV infection may lead to behavioral changes that can reduce the risk of transmission. It has also become clear that antiretroviral therapy can dramatically reduce transmission rates, a concept known as “treatment as prevention.” ⁴ Thus, access to care and initiation of antiretroviral therapy have the potential to prevent progression to acquired immunodeficiency syndrome (AIDS) in the individual and to interrupt the spread of the virus in the community.

There are several steps between awareness of HIV infection and full engagement in HIV care that require attention from the health care community.⁵ Only a quarter of those with known HIV infection are in care and adherent to antiretroviral therapy, leaving much work to be done on removing barriers to effective treatment.⁵ The first step is still to identify those infected. The effort to increase the percentage of HIV-infected individuals who know their HIV status is one of the goals of the National HIV/AIDS Strategy and HealthyPeople2020.⁶

HOW THE TEST IS USED

The OraQuick In-Home Test consists of the device and reagents, instructional materials, information on interpreting the results, and contact information for the OraQuick Answer Center for information, support, and local medical referral.⁷ The overall time needed for testing is 20 to 40 minutes.

To perform the test, an oral fluid specimen is collected by swabbing the upper and lower buccal mucosa along the gum line. Once inserted into the developer solution the swabbed sample is carried onto a membrane strip containing HIV-1/2 antigens.

The device has two windows, one labelled “T” (for test) and the other labelled “C” (for control). If the patient has sufficient antibodies to HIV proteins, the “T” window indicates a positive result if a band is visible. The “C” (control) window displays a band to indicate if the device and reagents are working. If the control window does not show a band, then the kit has not functioned properly and the test result is not reliable.

SOME PEOPLE MAY STILL NEED HELP

For the test to succeed in informing people of their HIV status, it must be used effectively and the results must be interpretable. Of 5,662 participants in phase III investigational-device studies, 99% were able to use the kit and determine a result.⁷ While the test’s simplicity is similar to that of pregnancy test kits, it is possible that some people (at least 1% of those using the kit) may seek guidance from medical practitioners because they are unable to understand the test results.

For a test result to have the desired outcome of leading to HIV care, individuals must act on a positive result. When home test results are positive, the instructions indicate that “you may have HIV” and provide contact information for the OraQuick Answer Center. It is unclear how reliable the counseling, information, and referral process from OraSure will be and if people will use the service.

Individuals may access medical care at a variety of levels for further assistance if they have a positive test result. These may include primary care offices, emergency and urgent care settings, health departments, and HIV clinics.

LESS SENSITIVE THAN BLOOD TESTS

To provide additional care, clinicians must understand the performance of the home HIV test. Most importantly, the test result must be confirmed.

The In-Home test is less sensitive than currently available HIV blood tests used in the clinical setting, particularly the HIV-1/2 enzyme immunoassay (EIA) with confirmatory Western blot testing. The In-Home test is less likely to detect HIV infection during the 90-day “window period” when seroconversion is occurring, and so it should not be relied on to rule out HIV during this early period after infection.

The sensitivity and specificity of the OraQuick In-Home HIV test were determined in a phase III trial in 5,662 people (80% at risk of HIV), who were tested concurrently with the “gold standard” blood tests (EIA and Western blot). The sensitivity was 93% (giving a positive result in 106 of 114 patients who had a positive result on blood testing), and the specificity was 99.9% (giving a negative result in 5,384 of 5,385 patients who had a negative result on blood testing).⁷

Therefore, a positive In-Home test result is likely to be truly positive, but a negative result is not as reliably truly negative. False-negative results may occur particularly in the window period early after HIV infection, so the test should not be relied on within 90 days of high-risk behavior. In contrast, with the fourth-generation blood HIV tests, the window period is approximately 16 days.

The predictive value of the test will depend on the population using it and on the patient’s pretest probability of disease at the time of testing. In the population tested by OraQuick, the positive predictive value was 99.1% and the negative predictive value was 99.9%.⁷ Mathematical modeling has been done to examine the potential outcomes for use in subpopulations at lower risk and at higher risk.

As clinicians, we will have to address the potential for both false-positive and false-negative test results. False-positive results may be more likely in low-risk populations and may occur in the setting of cross-reactive antibodies from pregnancy, autoimmune diseases, or previous receipt of an experimental HIV vaccination. False-negative results may occur in the setting of acute HIV infection and in those with severely impaired immunity (eg, from agammaglobulinemia or immunosuppressive drugs) and will be more likely in higher-risk populations, such as men who have sex with men, intravenous drug users, blacks, and Hispanics ages 18 to 35 with multiple sexual partners. A positive In-Home HIV test should be followed up with a blood EIA and confirmed with Western blot in all patients.

WHO WILL USE THIS TEST?

It is unclear who will use this new test. In OraSure’s clinical trial, the percentages of people who indicated they would “definitely or probably buy” the test were:

• 20% of the general population
• 27% of those ages 18 to 35
• 49% of blacks ages 18 to 35
• 47% of homosexual men
• 43% of people who said they had more than two sexual partners per year
• 32% who said they use condoms inconsistently.

If this is true, the test may appropriately target several populations that are not currently being tested, either because they lack access to care or because they do not see themselves as being at high risk. Of those with newly diagnosed HIV infection from 2006 to 2009, 40% had had no prior testing, and the groups with the highest percentages of people in this category were black, men with injection drug use as their sole risk factor, those older than 50 years, and those with heterosexual contact as their sole risk factor.⁸ Because of difficulties in identifying some of these groups as “at risk,” the current CDC guidelines recommend that HIV testing be offered to all patients ages 13 to 64, regardless of their risk factors.⁹

The home HIV test may fill a gap in testing, extending it to those still not tested in the health care setting or to those who have not sought health care. For the home test to fill that gap, people still have to perceive themselves as at risk and then purchase the test. Through public health strategies and at clinical points of care, we must continue to inform our patients about HIV risk and work to identify new or ongoing risk factors that would prompt additional testing.

MANY QUESTIONS REMAIN

• Will those who need testing want to use this test? People will buy the test only if they perceive themselves to be at risk.
• Is this test affordable for the target populations? $60 will be unaffordable to some.
• Will the directions be followed effectively?
• Will home testing reduce opportunities to counsel patients on their HIV risk factors?
• Will there be situations in which individuals are socially pressured to take the test?
• Can users of the test expect the appropriate amount of privacy? Availability on the Internet and in drug stores is not a guarantee of privacy when purchasing the test, although the result presumably will not be known.
• Will those with positive results seek medical care?
• Will those with negative results who are still at high risk forgo more sensitive testing and continue to engage in high-risk activities?

Nevertheless, since early and continued treatment prevents disease progression and reduces HIV transmission, testing is the first step toward access to effective HIV care. The home HIV test is a step forward in providing high-quality HIV testing to the wider population.

In July 2012, the US Food and Drug Administration approved the first over-the-counter test kit for human immunodeficiency virus (HIV) infection, the OraQuick In-Home HIV Test (OraSure Technologies, Bethlehem, PA). This test is a variation of the currently available OraQuick ADVANCE Rapid HIV-1/2 Antibody Test used in clinical settings by trained personnel for rapid detection of HIV.

The home HIV test is expected to become available in the fall of 2012 from the company’s Web site and at retail drugstores. This will put the power of HIV testing into the hands of anyone able to afford the estimated $60 price and willing to purchase the item online or in stores.

GOAL: TO REDUCE THE NUMBER OF INFECTED PEOPLE WHO ARE UNAWARE

How home testing will change the demographics of HIV testing is not clear, but the intention is to reduce the number of HIV-infected people who are unaware of their infection and to get them in for care. Anthony Fauci, MD, the director of the National Institutes of Allergy and Infectious Diseases, has called the new test a “positive step forward” in bringing the HIV epidemic under control.¹

Recent figures from the US Centers for Disease Control and Prevention (CDC) indicate that, of the 1.2 million HIV-infected people in the United States, up to 220,000 are unaware of their infection.^2,3 Since antiretroviral therapy is now considered beneficial even in the early stages of HIV infection, those who are unaware of their infection are missing an opportunity for the most effective therapies.

They may also be unknowingly transmitting the virus, thus perpetuating the HIV epidemic. Awareness of one’s HIV infection may lead to behavioral changes that can reduce the risk of transmission. It has also become clear that antiretroviral therapy can dramatically reduce transmission rates, a concept known as “treatment as prevention.” ⁴ Thus, access to care and initiation of antiretroviral therapy have the potential to prevent progression to acquired immunodeficiency syndrome (AIDS) in the individual and to interrupt the spread of the virus in the community.

There are several steps between awareness of HIV infection and full engagement in HIV care that require attention from the health care community.⁵ Only a quarter of those with known HIV infection are in care and adherent to antiretroviral therapy, leaving much work to be done on removing barriers to effective treatment.⁵ The first step is still to identify those infected. The effort to increase the percentage of HIV-infected individuals who know their HIV status is one of the goals of the National HIV/AIDS Strategy and HealthyPeople2020.⁶

HOW THE TEST IS USED

The OraQuick In-Home Test consists of the device and reagents, instructional materials, information on interpreting the results, and contact information for the OraQuick Answer Center for information, support, and local medical referral.⁷ The overall time needed for testing is 20 to 40 minutes.

To perform the test, an oral fluid specimen is collected by swabbing the upper and lower buccal mucosa along the gum line. Once inserted into the developer solution the swabbed sample is carried onto a membrane strip containing HIV-1/2 antigens.

The device has two windows, one labelled “T” (for test) and the other labelled “C” (for control). If the patient has sufficient antibodies to HIV proteins, the “T” window indicates a positive result if a band is visible. The “C” (control) window displays a band to indicate if the device and reagents are working. If the control window does not show a band, then the kit has not functioned properly and the test result is not reliable.

SOME PEOPLE MAY STILL NEED HELP

For the test to succeed in informing people of their HIV status, it must be used effectively and the results must be interpretable. Of 5,662 participants in phase III investigational-device studies, 99% were able to use the kit and determine a result.⁷ While the test’s simplicity is similar to that of pregnancy test kits, it is possible that some people (at least 1% of those using the kit) may seek guidance from medical practitioners because they are unable to understand the test results.

For a test result to have the desired outcome of leading to HIV care, individuals must act on a positive result. When home test results are positive, the instructions indicate that “you may have HIV” and provide contact information for the OraQuick Answer Center. It is unclear how reliable the counseling, information, and referral process from OraSure will be and if people will use the service.

Individuals may access medical care at a variety of levels for further assistance if they have a positive test result. These may include primary care offices, emergency and urgent care settings, health departments, and HIV clinics.

LESS SENSITIVE THAN BLOOD TESTS

To provide additional care, clinicians must understand the performance of the home HIV test. Most importantly, the test result must be confirmed.

The In-Home test is less sensitive than currently available HIV blood tests used in the clinical setting, particularly the HIV-1/2 enzyme immunoassay (EIA) with confirmatory Western blot testing. The In-Home test is less likely to detect HIV infection during the 90-day “window period” when seroconversion is occurring, and so it should not be relied on to rule out HIV during this early period after infection.

The sensitivity and specificity of the OraQuick In-Home HIV test were determined in a phase III trial in 5,662 people (80% at risk of HIV), who were tested concurrently with the “gold standard” blood tests (EIA and Western blot). The sensitivity was 93% (giving a positive result in 106 of 114 patients who had a positive result on blood testing), and the specificity was 99.9% (giving a negative result in 5,384 of 5,385 patients who had a negative result on blood testing).⁷

Therefore, a positive In-Home test result is likely to be truly positive, but a negative result is not as reliably truly negative. False-negative results may occur particularly in the window period early after HIV infection, so the test should not be relied on within 90 days of high-risk behavior. In contrast, with the fourth-generation blood HIV tests, the window period is approximately 16 days.

The predictive value of the test will depend on the population using it and on the patient’s pretest probability of disease at the time of testing. In the population tested by OraQuick, the positive predictive value was 99.1% and the negative predictive value was 99.9%.⁷ Mathematical modeling has been done to examine the potential outcomes for use in subpopulations at lower risk and at higher risk.

As clinicians, we will have to address the potential for both false-positive and false-negative test results. False-positive results may be more likely in low-risk populations and may occur in the setting of cross-reactive antibodies from pregnancy, autoimmune diseases, or previous receipt of an experimental HIV vaccination. False-negative results may occur in the setting of acute HIV infection and in those with severely impaired immunity (eg, from agammaglobulinemia or immunosuppressive drugs) and will be more likely in higher-risk populations, such as men who have sex with men, intravenous drug users, blacks, and Hispanics ages 18 to 35 with multiple sexual partners. A positive In-Home HIV test should be followed up with a blood EIA and confirmed with Western blot in all patients.

WHO WILL USE THIS TEST?

It is unclear who will use this new test. In OraSure’s clinical trial, the percentages of people who indicated they would “definitely or probably buy” the test were:

• 20% of the general population
• 27% of those ages 18 to 35
• 49% of blacks ages 18 to 35
• 47% of homosexual men
• 43% of people who said they had more than two sexual partners per year
• 32% who said they use condoms inconsistently.

If this is true, the test may appropriately target several populations that are not currently being tested, either because they lack access to care or because they do not see themselves as being at high risk. Of those with newly diagnosed HIV infection from 2006 to 2009, 40% had had no prior testing, and the groups with the highest percentages of people in this category were black, men with injection drug use as their sole risk factor, those older than 50 years, and those with heterosexual contact as their sole risk factor.⁸ Because of difficulties in identifying some of these groups as “at risk,” the current CDC guidelines recommend that HIV testing be offered to all patients ages 13 to 64, regardless of their risk factors.⁹

The home HIV test may fill a gap in testing, extending it to those still not tested in the health care setting or to those who have not sought health care. For the home test to fill that gap, people still have to perceive themselves as at risk and then purchase the test. Through public health strategies and at clinical points of care, we must continue to inform our patients about HIV risk and work to identify new or ongoing risk factors that would prompt additional testing.

MANY QUESTIONS REMAIN

• Will those who need testing want to use this test? People will buy the test only if they perceive themselves to be at risk.
• Is this test affordable for the target populations? $60 will be unaffordable to some.
• Will the directions be followed effectively?
• Will home testing reduce opportunities to counsel patients on their HIV risk factors?
• Will there be situations in which individuals are socially pressured to take the test?
• Can users of the test expect the appropriate amount of privacy? Availability on the Internet and in drug stores is not a guarantee of privacy when purchasing the test, although the result presumably will not be known.
• Will those with positive results seek medical care?
• Will those with negative results who are still at high risk forgo more sensitive testing and continue to engage in high-risk activities?

Nevertheless, since early and continued treatment prevents disease progression and reduces HIV transmission, testing is the first step toward access to effective HIV care. The home HIV test is a step forward in providing high-quality HIV testing to the wider population.

In July 2012, the US Food and Drug Administration approved the first over-the-counter test kit for human immunodeficiency virus (HIV) infection, the OraQuick In-Home HIV Test (OraSure Technologies, Bethlehem, PA). This test is a variation of the currently available OraQuick ADVANCE Rapid HIV-1/2 Antibody Test used in clinical settings by trained personnel for rapid detection of HIV.

The home HIV test is expected to become available in the fall of 2012 from the company’s Web site and at retail drugstores. This will put the power of HIV testing into the hands of anyone able to afford the estimated $60 price and willing to purchase the item online or in stores.

GOAL: TO REDUCE THE NUMBER OF INFECTED PEOPLE WHO ARE UNAWARE

How home testing will change the demographics of HIV testing is not clear, but the intention is to reduce the number of HIV-infected people who are unaware of their infection and to get them in for care. Anthony Fauci, MD, the director of the National Institutes of Allergy and Infectious Diseases, has called the new test a “positive step forward” in bringing the HIV epidemic under control.¹

Recent figures from the US Centers for Disease Control and Prevention (CDC) indicate that, of the 1.2 million HIV-infected people in the United States, up to 220,000 are unaware of their infection.^2,3 Since antiretroviral therapy is now considered beneficial even in the early stages of HIV infection, those who are unaware of their infection are missing an opportunity for the most effective therapies.

They may also be unknowingly transmitting the virus, thus perpetuating the HIV epidemic. Awareness of one’s HIV infection may lead to behavioral changes that can reduce the risk of transmission. It has also become clear that antiretroviral therapy can dramatically reduce transmission rates, a concept known as “treatment as prevention.” ⁴ Thus, access to care and initiation of antiretroviral therapy have the potential to prevent progression to acquired immunodeficiency syndrome (AIDS) in the individual and to interrupt the spread of the virus in the community.

There are several steps between awareness of HIV infection and full engagement in HIV care that require attention from the health care community.⁵ Only a quarter of those with known HIV infection are in care and adherent to antiretroviral therapy, leaving much work to be done on removing barriers to effective treatment.⁵ The first step is still to identify those infected. The effort to increase the percentage of HIV-infected individuals who know their HIV status is one of the goals of the National HIV/AIDS Strategy and HealthyPeople2020.⁶

HOW THE TEST IS USED

The OraQuick In-Home Test consists of the device and reagents, instructional materials, information on interpreting the results, and contact information for the OraQuick Answer Center for information, support, and local medical referral.⁷ The overall time needed for testing is 20 to 40 minutes.

To perform the test, an oral fluid specimen is collected by swabbing the upper and lower buccal mucosa along the gum line. Once inserted into the developer solution the swabbed sample is carried onto a membrane strip containing HIV-1/2 antigens.

The device has two windows, one labelled “T” (for test) and the other labelled “C” (for control). If the patient has sufficient antibodies to HIV proteins, the “T” window indicates a positive result if a band is visible. The “C” (control) window displays a band to indicate if the device and reagents are working. If the control window does not show a band, then the kit has not functioned properly and the test result is not reliable.

SOME PEOPLE MAY STILL NEED HELP

For the test to succeed in informing people of their HIV status, it must be used effectively and the results must be interpretable. Of 5,662 participants in phase III investigational-device studies, 99% were able to use the kit and determine a result.⁷ While the test’s simplicity is similar to that of pregnancy test kits, it is possible that some people (at least 1% of those using the kit) may seek guidance from medical practitioners because they are unable to understand the test results.

For a test result to have the desired outcome of leading to HIV care, individuals must act on a positive result. When home test results are positive, the instructions indicate that “you may have HIV” and provide contact information for the OraQuick Answer Center. It is unclear how reliable the counseling, information, and referral process from OraSure will be and if people will use the service.

Individuals may access medical care at a variety of levels for further assistance if they have a positive test result. These may include primary care offices, emergency and urgent care settings, health departments, and HIV clinics.

LESS SENSITIVE THAN BLOOD TESTS

To provide additional care, clinicians must understand the performance of the home HIV test. Most importantly, the test result must be confirmed.

The In-Home test is less sensitive than currently available HIV blood tests used in the clinical setting, particularly the HIV-1/2 enzyme immunoassay (EIA) with confirmatory Western blot testing. The In-Home test is less likely to detect HIV infection during the 90-day “window period” when seroconversion is occurring, and so it should not be relied on to rule out HIV during this early period after infection.

The sensitivity and specificity of the OraQuick In-Home HIV test were determined in a phase III trial in 5,662 people (80% at risk of HIV), who were tested concurrently with the “gold standard” blood tests (EIA and Western blot). The sensitivity was 93% (giving a positive result in 106 of 114 patients who had a positive result on blood testing), and the specificity was 99.9% (giving a negative result in 5,384 of 5,385 patients who had a negative result on blood testing).⁷

Therefore, a positive In-Home test result is likely to be truly positive, but a negative result is not as reliably truly negative. False-negative results may occur particularly in the window period early after HIV infection, so the test should not be relied on within 90 days of high-risk behavior. In contrast, with the fourth-generation blood HIV tests, the window period is approximately 16 days.

The predictive value of the test will depend on the population using it and on the patient’s pretest probability of disease at the time of testing. In the population tested by OraQuick, the positive predictive value was 99.1% and the negative predictive value was 99.9%.⁷ Mathematical modeling has been done to examine the potential outcomes for use in subpopulations at lower risk and at higher risk.

As clinicians, we will have to address the potential for both false-positive and false-negative test results. False-positive results may be more likely in low-risk populations and may occur in the setting of cross-reactive antibodies from pregnancy, autoimmune diseases, or previous receipt of an experimental HIV vaccination. False-negative results may occur in the setting of acute HIV infection and in those with severely impaired immunity (eg, from agammaglobulinemia or immunosuppressive drugs) and will be more likely in higher-risk populations, such as men who have sex with men, intravenous drug users, blacks, and Hispanics ages 18 to 35 with multiple sexual partners. A positive In-Home HIV test should be followed up with a blood EIA and confirmed with Western blot in all patients.

WHO WILL USE THIS TEST?

It is unclear who will use this new test. In OraSure’s clinical trial, the percentages of people who indicated they would “definitely or probably buy” the test were:

• 20% of the general population
• 27% of those ages 18 to 35
• 49% of blacks ages 18 to 35
• 47% of homosexual men
• 43% of people who said they had more than two sexual partners per year
• 32% who said they use condoms inconsistently.

If this is true, the test may appropriately target several populations that are not currently being tested, either because they lack access to care or because they do not see themselves as being at high risk. Of those with newly diagnosed HIV infection from 2006 to 2009, 40% had had no prior testing, and the groups with the highest percentages of people in this category were black, men with injection drug use as their sole risk factor, those older than 50 years, and those with heterosexual contact as their sole risk factor.⁸ Because of difficulties in identifying some of these groups as “at risk,” the current CDC guidelines recommend that HIV testing be offered to all patients ages 13 to 64, regardless of their risk factors.⁹

The home HIV test may fill a gap in testing, extending it to those still not tested in the health care setting or to those who have not sought health care. For the home test to fill that gap, people still have to perceive themselves as at risk and then purchase the test. Through public health strategies and at clinical points of care, we must continue to inform our patients about HIV risk and work to identify new or ongoing risk factors that would prompt additional testing.

MANY QUESTIONS REMAIN

• Will those who need testing want to use this test? People will buy the test only if they perceive themselves to be at risk.
• Is this test affordable for the target populations? $60 will be unaffordable to some.
• Will the directions be followed effectively?
• Will home testing reduce opportunities to counsel patients on their HIV risk factors?
• Will there be situations in which individuals are socially pressured to take the test?
• Can users of the test expect the appropriate amount of privacy? Availability on the Internet and in drug stores is not a guarantee of privacy when purchasing the test, although the result presumably will not be known.
• Will those with positive results seek medical care?
• Will those with negative results who are still at high risk forgo more sensitive testing and continue to engage in high-risk activities?

Nevertheless, since early and continued treatment prevents disease progression and reduces HIV transmission, testing is the first step toward access to effective HIV care. The home HIV test is a step forward in providing high-quality HIV testing to the wider population.

In 2006, the FDA issued a warning of the risk of potentially fatal serotonin syndrome when 5-hydroxytryptamine receptor agonist antimigraine medications (triptans) and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) are coprescribed.¹ As a result, most drug interaction programs trigger a serotonin syndrome warning when triptans are prescribed with an SSRI or SNRI.² However, many patients with depression or anxiety also suffer from migraines and require treatment with both triptans and an SSRI or SNRI.^3,4 Kalaydjian et al⁴ found the incidence of major depression and generalized anxiety disorder were approximately 3 times greater in patients with migraines than in those without migraines. Should we avoid coprescribing triptans and SSRIs or SNRIs?

What is serotonin syndrome?

Serotonin syndrome is an adverse drug reaction that results from excessive serotonin stimulation. There are 2 sets of validated diagnostic criteria: the Sternbach Criteria and the Hunter Serotonin Toxicity Criteria; the latter is considered more stringent.^3,5-7 Symptoms of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular changes such as muscle rigidity.^5-7 Typical manifestations of serotonin syndrome on physical exam include spontaneous and/or inducible clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature >38°C.⁶ In severe cases, serotonin syndrome can lead to seizures, coma, and death. Management includes supportive treatment, discontinuing the offending agents, controlling agitation with medications such as benzodiazepines, and possibly administering cyproheptadine, a 5HT2A antagonist.⁸ Most cases resolve within 24 hours of discontinuing the offending agents or appropriate treatment.⁵

What did the FDA say?

The 2006 FDA warning initially was based on 27 reports of serotonin syndrome in patients receiving triptans and SSRIs or SNRIs; this was later expanded to include 29 patients.^1,9 No patients died but 13 required hospitalization and 2 had life-threatening symptoms. However, most cases lacked data necessary to diagnose serotonin syndrome.⁹ Further, reviews of the available clinical information have suggested that in some cases, clinicians did not rule out other disorders as required by diagnostic criteria, while others were viral in nature or resolved despite ongoing treatment with the presumed offending agents.^9-11

Some clinicians met the FDA’s assessment with skepticism. Only 10 of the 29 cases met the Sternbach criteria of serotonin syndrome and none met the more rigorous Hunter criteria. Additionally, the theoretical basis has been questioned.^9-11 Available evidence indicates that serotonin syndrome requires activation of 5HT2A receptors and a possible limited role of 5HT1A.^9-12 However, triptans are agonists at the 5HT1B/1D/1F receptor subtypes, with weak affinity for 5HT1A receptors and no activity at the 5HT2 receptors.^13,14 Additionally, triptan medications are used as needed, not as standing treatments, with parameters limiting the maximum dose, dosing interval, and frequency of use. In clinical practice, it appears that these dosing guidelines are being followed: Tepper et al¹⁵ found the typical female patient experiences 1 to 2 migraines per month; on average, patients use 1.2 to 1.8 triptan tablets per month.

Our opinion

We believe it is reasonable to coprescribe SSRIs or SNRIs with triptans because:

• data indicate that many patients are treated with a combination of triptans and SSRIs or SNRIs but the number of reported cases of serotonin syndrome is extremely limited
• the nature of serotonin syndrome cases reported in the literature is questionable
• the interaction is biologically implausible
• triptans remain in the body for a limited time
• triptans are used infrequently.^5-11

This view is supported by the most recent American Headache Society position paper,¹¹ which states that inadequate data are available to assess the risk but current evidence does not support limiting use of triptans with SSRIs and SNRIs.

How we deal with the warning in clinical practice. In practice we are alerted to this interaction by notification in our e-prescribing systems, by pharmacists calling with concerns about dispensing an SSRI or SNRI for a patient already receiving a triptan, and during patient visits that involve prescribing an SSRI or SNRI.

Although it is relatively easy to override a drug interaction warning in our e-prescribing system, we discuss the issue with pharmacists and patients. We provide information about the signs and symptoms of serotonin syndrome and its potential dangerousness. We note that serotonin syndrome is a theoretical concern, but highly unlikely with this combination of medications because of their pharmacologic properties. We explain the parameters of triptan use, recommend that our patients use triptans for migraines when needed, and reassure patients we are available to answer questions. When a patient uses triptans more than twice monthly, we consider discussing this usage with the patient and the treating physician.

Related Resource

• Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012. www.headachejournal.org/SpringboardWebApp/userfiles/headache/file/sclar.pdf.

Drug Brand Name

• Cyproheptadine • Perinctin

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In 2006, the FDA issued a warning of the risk of potentially fatal serotonin syndrome when 5-hydroxytryptamine receptor agonist antimigraine medications (triptans) and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) are coprescribed.¹ As a result, most drug interaction programs trigger a serotonin syndrome warning when triptans are prescribed with an SSRI or SNRI.² However, many patients with depression or anxiety also suffer from migraines and require treatment with both triptans and an SSRI or SNRI.^3,4 Kalaydjian et al⁴ found the incidence of major depression and generalized anxiety disorder were approximately 3 times greater in patients with migraines than in those without migraines. Should we avoid coprescribing triptans and SSRIs or SNRIs?

What is serotonin syndrome?

Serotonin syndrome is an adverse drug reaction that results from excessive serotonin stimulation. There are 2 sets of validated diagnostic criteria: the Sternbach Criteria and the Hunter Serotonin Toxicity Criteria; the latter is considered more stringent.^3,5-7 Symptoms of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular changes such as muscle rigidity.^5-7 Typical manifestations of serotonin syndrome on physical exam include spontaneous and/or inducible clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature >38°C.⁶ In severe cases, serotonin syndrome can lead to seizures, coma, and death. Management includes supportive treatment, discontinuing the offending agents, controlling agitation with medications such as benzodiazepines, and possibly administering cyproheptadine, a 5HT2A antagonist.⁸ Most cases resolve within 24 hours of discontinuing the offending agents or appropriate treatment.⁵

What did the FDA say?

The 2006 FDA warning initially was based on 27 reports of serotonin syndrome in patients receiving triptans and SSRIs or SNRIs; this was later expanded to include 29 patients.^1,9 No patients died but 13 required hospitalization and 2 had life-threatening symptoms. However, most cases lacked data necessary to diagnose serotonin syndrome.⁹ Further, reviews of the available clinical information have suggested that in some cases, clinicians did not rule out other disorders as required by diagnostic criteria, while others were viral in nature or resolved despite ongoing treatment with the presumed offending agents.^9-11

Some clinicians met the FDA’s assessment with skepticism. Only 10 of the 29 cases met the Sternbach criteria of serotonin syndrome and none met the more rigorous Hunter criteria. Additionally, the theoretical basis has been questioned.^9-11 Available evidence indicates that serotonin syndrome requires activation of 5HT2A receptors and a possible limited role of 5HT1A.^9-12 However, triptans are agonists at the 5HT1B/1D/1F receptor subtypes, with weak affinity for 5HT1A receptors and no activity at the 5HT2 receptors.^13,14 Additionally, triptan medications are used as needed, not as standing treatments, with parameters limiting the maximum dose, dosing interval, and frequency of use. In clinical practice, it appears that these dosing guidelines are being followed: Tepper et al¹⁵ found the typical female patient experiences 1 to 2 migraines per month; on average, patients use 1.2 to 1.8 triptan tablets per month.

Our opinion

We believe it is reasonable to coprescribe SSRIs or SNRIs with triptans because:

• data indicate that many patients are treated with a combination of triptans and SSRIs or SNRIs but the number of reported cases of serotonin syndrome is extremely limited
• the nature of serotonin syndrome cases reported in the literature is questionable
• the interaction is biologically implausible
• triptans remain in the body for a limited time
• triptans are used infrequently.^5-11

This view is supported by the most recent American Headache Society position paper,¹¹ which states that inadequate data are available to assess the risk but current evidence does not support limiting use of triptans with SSRIs and SNRIs.

How we deal with the warning in clinical practice. In practice we are alerted to this interaction by notification in our e-prescribing systems, by pharmacists calling with concerns about dispensing an SSRI or SNRI for a patient already receiving a triptan, and during patient visits that involve prescribing an SSRI or SNRI.

Although it is relatively easy to override a drug interaction warning in our e-prescribing system, we discuss the issue with pharmacists and patients. We provide information about the signs and symptoms of serotonin syndrome and its potential dangerousness. We note that serotonin syndrome is a theoretical concern, but highly unlikely with this combination of medications because of their pharmacologic properties. We explain the parameters of triptan use, recommend that our patients use triptans for migraines when needed, and reassure patients we are available to answer questions. When a patient uses triptans more than twice monthly, we consider discussing this usage with the patient and the treating physician.

Related Resource

• Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012. www.headachejournal.org/SpringboardWebApp/userfiles/headache/file/sclar.pdf.

Drug Brand Name

• Cyproheptadine • Perinctin

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

In 2006, the FDA issued a warning of the risk of potentially fatal serotonin syndrome when 5-hydroxytryptamine receptor agonist antimigraine medications (triptans) and selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRI) are coprescribed.¹ As a result, most drug interaction programs trigger a serotonin syndrome warning when triptans are prescribed with an SSRI or SNRI.² However, many patients with depression or anxiety also suffer from migraines and require treatment with both triptans and an SSRI or SNRI.^3,4 Kalaydjian et al⁴ found the incidence of major depression and generalized anxiety disorder were approximately 3 times greater in patients with migraines than in those without migraines. Should we avoid coprescribing triptans and SSRIs or SNRIs?

What is serotonin syndrome?

Serotonin syndrome is an adverse drug reaction that results from excessive serotonin stimulation. There are 2 sets of validated diagnostic criteria: the Sternbach Criteria and the Hunter Serotonin Toxicity Criteria; the latter is considered more stringent.^3,5-7 Symptoms of serotonin syndrome include mental status changes, autonomic hyperactivity, and neuromuscular changes such as muscle rigidity.^5-7 Typical manifestations of serotonin syndrome on physical exam include spontaneous and/or inducible clonus, agitation, diaphoresis, tremor, hyperreflexia, hypertonia, and temperature >38°C.⁶ In severe cases, serotonin syndrome can lead to seizures, coma, and death. Management includes supportive treatment, discontinuing the offending agents, controlling agitation with medications such as benzodiazepines, and possibly administering cyproheptadine, a 5HT2A antagonist.⁸ Most cases resolve within 24 hours of discontinuing the offending agents or appropriate treatment.⁵

What did the FDA say?

The 2006 FDA warning initially was based on 27 reports of serotonin syndrome in patients receiving triptans and SSRIs or SNRIs; this was later expanded to include 29 patients.^1,9 No patients died but 13 required hospitalization and 2 had life-threatening symptoms. However, most cases lacked data necessary to diagnose serotonin syndrome.⁹ Further, reviews of the available clinical information have suggested that in some cases, clinicians did not rule out other disorders as required by diagnostic criteria, while others were viral in nature or resolved despite ongoing treatment with the presumed offending agents.^9-11

Some clinicians met the FDA’s assessment with skepticism. Only 10 of the 29 cases met the Sternbach criteria of serotonin syndrome and none met the more rigorous Hunter criteria. Additionally, the theoretical basis has been questioned.^9-11 Available evidence indicates that serotonin syndrome requires activation of 5HT2A receptors and a possible limited role of 5HT1A.^9-12 However, triptans are agonists at the 5HT1B/1D/1F receptor subtypes, with weak affinity for 5HT1A receptors and no activity at the 5HT2 receptors.^13,14 Additionally, triptan medications are used as needed, not as standing treatments, with parameters limiting the maximum dose, dosing interval, and frequency of use. In clinical practice, it appears that these dosing guidelines are being followed: Tepper et al¹⁵ found the typical female patient experiences 1 to 2 migraines per month; on average, patients use 1.2 to 1.8 triptan tablets per month.

Our opinion

We believe it is reasonable to coprescribe SSRIs or SNRIs with triptans because:

• data indicate that many patients are treated with a combination of triptans and SSRIs or SNRIs but the number of reported cases of serotonin syndrome is extremely limited
• the nature of serotonin syndrome cases reported in the literature is questionable
• the interaction is biologically implausible
• triptans remain in the body for a limited time
• triptans are used infrequently.^5-11

This view is supported by the most recent American Headache Society position paper,¹¹ which states that inadequate data are available to assess the risk but current evidence does not support limiting use of triptans with SSRIs and SNRIs.

How we deal with the warning in clinical practice. In practice we are alerted to this interaction by notification in our e-prescribing systems, by pharmacists calling with concerns about dispensing an SSRI or SNRI for a patient already receiving a triptan, and during patient visits that involve prescribing an SSRI or SNRI.

Although it is relatively easy to override a drug interaction warning in our e-prescribing system, we discuss the issue with pharmacists and patients. We provide information about the signs and symptoms of serotonin syndrome and its potential dangerousness. We note that serotonin syndrome is a theoretical concern, but highly unlikely with this combination of medications because of their pharmacologic properties. We explain the parameters of triptan use, recommend that our patients use triptans for migraines when needed, and reassure patients we are available to answer questions. When a patient uses triptans more than twice monthly, we consider discussing this usage with the patient and the treating physician.

Related Resource

• Sclar DA, Robison LM, Castillo LV, et al. Concomitant use of triptan, and SSRI or SNRI after the US Food and Drug Administration alert on serotonin syndrome. Headache. 2012. www.headachejournal.org/SpringboardWebApp/userfiles/headache/file/sclar.pdf.

Drug Brand Name

• Cyproheptadine • Perinctin

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.