There is an increased risk of malignancy after both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). In patients who undergo SOT, the second most common malignancy after nonmelanoma skin cancers is post-transplant lymphoproliferative disorders (PTLD). The term PTLD includes disorders ranging from benign hyperplasia to malignant lymphomas occurring in the setting of immunosuppression during SOT and HCT. The first cases of PTLD were described in renal transplant recipients in the late 1960s. Since then, PTLD has remained a serious and sometimes fatal complication in the posttransplant setting.

To read the full article in PDF:

Click here

There is an increased risk of malignancy after both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). In patients who undergo SOT, the second most common malignancy after nonmelanoma skin cancers is post-transplant lymphoproliferative disorders (PTLD). The term PTLD includes disorders ranging from benign hyperplasia to malignant lymphomas occurring in the setting of immunosuppression during SOT and HCT. The first cases of PTLD were described in renal transplant recipients in the late 1960s. Since then, PTLD has remained a serious and sometimes fatal complication in the posttransplant setting.

To read the full article in PDF:

Click here

There is an increased risk of malignancy after both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). In patients who undergo SOT, the second most common malignancy after nonmelanoma skin cancers is post-transplant lymphoproliferative disorders (PTLD). The term PTLD includes disorders ranging from benign hyperplasia to malignant lymphomas occurring in the setting of immunosuppression during SOT and HCT. The first cases of PTLD were described in renal transplant recipients in the late 1960s. Since then, PTLD has remained a serious and sometimes fatal complication in the posttransplant setting.

To read the full article in PDF:

Click here

Premature ventricular complexes (PVCs) are a common cause of palpitations, and are also often detected incidentally on electrocardiography (ECG), ambulatory monitoring, or inpatient telemetry. At the cellular level, ventricular myocytes spontaneously depolarize to create an extra systole that is “out of sync” with the cardiac cycle.

Although nearly everyone has some PVCs from time to time, people vary widely in their frequency of PVCs and their sensitivity to them.^1,2 Some patients are exquisitely sensitive to even a small number of PVCs, while others are completely unaware of PVCs in a bigeminal pattern (ie, every other heartbeat). This article will review the evaluation and management of PVCs with a focus on clinical aspects.

DIAGNOSTIC EVALUATION

Personal and family history

Symptoms. The initial history should establish the presence, extent, timing, and duration of symptoms. Patients may use the word “palpitations” to describe their symptoms, but they also describe them as “hard” heartbeats, “chest-thumping,” or as a “catch” or “skipped” heartbeat. Related symptoms may include difficulty breathing, chest pain, fatigue, and dizziness.

The interview should determine whether the symptoms represent a minor nuisance or a major quality-of-life issue to the patient, and whether there are any specific associations or triggers. For example, it is very common for patients to become aware of PVCs at night, particularly in certain positions, such as lying on the left side. Patients often associate PVC symptoms with emotional stress, exercise, or caffeine or stimulant use.

Medication use. An accurate and up-to-date list of prescription medications should be screened for alpha-, beta-, or dopamine-receptor agonist drugs. Similarly, any use of over-the-counter sympathomimetic medications and nonprescription supplements should be elicited, including compounded elixirs or beverages. Many commercially available products designed to treat fatigue or increase alertness contain large doses of caffeine or other stimulants. It is also important to consider the use of illicit substances such as cocaine, amphetamine, methamphetamine, and their derivatives.

The patient’s medical and surgical history should be queried for any known structural heart disease, including coronary artery disease, myocardial infarction, congestive heart failure, valvular heart disease, congenital heart disease, and heritable conditions such as hypertrophic cardiomyopathy, prolonged QT syndromes, or other channel disorders. Pulmonary disorders such as sarcoidosis, pulmonary hypertension, or obstructive sleep apnea are also relevant. Similarly, it is important to identify endocrine disorders, including thyroid problems, sex hormone abnormalities, or adrenal gland conditions.

A careful family history should include any instance of sudden death in first-degree relatives, any heritable cardiac conditions, or coronary artery disease at an early age.

Physical examination

The physical examination should focus on findings that suggest underlying structural heart disease. Findings suggestive of congestive heart failure include elevated jugular venous pressures, abnormal cardiac sounds, pulmonary rales, abnormal arterial pulses, or peripheral edema. A murmur or a pathologic heart sound should raise suspicion of valvular or congenital heart disease when present in a young patient.

Inspection and palpation of the thyroid can reveal a related disorder. Obvious skin changes or neurologic findings can similarly reveal a systemic and possibly related clinical disorder that can have cardiac manifestations (eg, muscular dystrophy).

Electrocardiography, Holter monitoring, and other monitoring

Assessment of the cardiac rhythm includes 12-lead ECG and ambulatory Holter monitoring, typically for 24 or 48 hours.

Holter monitoring provides a continuous recording, usually in at least two or three leads. Patients are given a symptom journal or are asked to keep a diary of symptoms experienced during the monitoring period. The monitor is worn underneath clothing and is returned for download upon completion. Technicians process the data with the aid of computer software, and the final output is reviewed and interpreted by a cardiologist or cardiac electrophysiologist.

Holter monitoring for at least 24 hours is a critical step in assessing any patient with known or suspected PVCs, as it can both quantify the total burden of ventricular ectopy and identify the presence of any related ventricular tachycardia. In addition, it can detect additional supraventricular arrhythmias or bradycardia during the monitoring period. The PVC burden is an important measurement; it is expressed as the percentage of heartbeats that were ventricular extrasystoles during the monitoring period.

Both ECG and Holter monitoring are limited in that they are only snapshots of the rhythm during the period when a patient is actually hooked up. Many patients experience PVCs in clusters every very few days or weeks. Such a pattern is unlikely to be detected by a single ECG or 24- or 48-hour Holter monitoring.

A 30-day ambulatory event monitor (also known as a wearable loop recorder) is an important diagnostic tool in these scenarios. The concept is very similar to that of Holter monitoring, except that the device provides a continuous loop recording of the cardiac rhythm that is digitally stored in clips when the patient activates the device. Some wearable loop recorders also have auto-save features for heart rates falling outside of a programmed range.

Mobile outpatient cardiac telemetry is the most comprehensive form of noninvasive rhythm monitoring available. This is essentially the equivalent of continuous inpatient cardiac telemetry, but in a patient who is not hospitalized. It is a wearable ambulatory device providing continuous recordings, real-time automatic detections, and patient-activated symptom recordings. It can be used for up to 6 weeks. Advantages include detection and quantification of asymptomatic events, and real-time transmissions that the physician can act upon. The major disadvantage is cost, including coverage denial by many third-party payers.

This test is rarely indicated as part of a PVC evaluation and is typically ordered only by a cardiologist or cardiac electrophysiologist.

Surface echocardiography is indicated to look for overt structural heart disease and can reliably detect abnormalities in cardiac chamber size, wall thickness, and function. Valvular heart disease is concomitantly identified by two-dimensional imaging as well as by color Doppler. The finding of significant structural heart disease in conjunction with PVCs should prompt a cardiology referral, as this carries significant prognostic implications.^3–5

Exercise treadmill stress testing is appropriate for patients who experience PVCs with exercise or for whom an evaluation for coronary artery disease is indicated. The expected finding would be an increase in PVCs or ventricular tachycardia with exercise or in the subsequent recovery period. Exercise testing can be combined with either echocardiographic or nuclear perfusion imaging to evaluate the possibility of myocardial ischemia. For patients unable to exercise, pharmacologic stress testing with dobutamine or a vasodilator agent can be performed.

Advanced noninvasive cardiac imaging— such as computed tomography, magnetic resonance imaging, or positron-emission tomography—should be reserved for specific clinical indications such as congenital heart disease, suspected cardiac sarcoidosis, and infiltrative heart disease, and for specific cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. For example, frequent PVCs with a left bundle branch block morphology and superior axis raise the concern for a right ventricular disorder and may prompt cardiac magnetic resonance imaging for either arrhythmogenic right ventricular cardiomyopathy or sarcoidosis.

PVCs WITHOUT STRUCTURAL HEART DISEASE

Outflow tract PVCs and ventricular tachycardia

The right or left ventricular outflow tracts, or the epicardial tissue immediately adjacent to the aortic sinuses of Valsalva are the most common sites of origin for ventricular ectopy in the absence of structural heart disease.^6–9 Affected cells often demonstrate a triggered activity mechanism due to cyclic adenosine monophosphate-mediated and calcium-dependent delayed after-depolarizations.^7,8

Most of these foci are in the right ventricular outflow tract, producing a left bundle branch block morphology with an inferior axis (positive R waves in limb leads II, III, and aVF) and typical precordial R-wave transition in V₃ and V₄ (Figure 1). A minority are in the left ventricular outflow tract, producing a right bundle branch block with an inferior axis pattern, or in the aortic sinuses with a left bundle branch block pattern but with early precordial R transition in V₂ and V₃.

A study in 122 patients showed that right and left outflow tract arrhythmias had similar electrophysiologic properties and pharmacologic sensitivities, providing evidence for shared mechanisms possibly due to the common embryologic origin of these structures.⁹

Such arrhythmias are typically catecholamine-sensitive and are sometimes inducible with burst pacing in the electrophysiology laboratory. The short ventricular coupling intervals can promote intracellular calcium overload in the affected cells, leading to triggered activity.

Therefore, outflow tract PVCs and ventricular tachycardia are commonly encountered clinically during exercise and, to an even greater extent, in the postexercise cool-down period. Similarly, they can be worse during periods of emotional stress or fatigue, when the body’s endogenous catecholamine production is elevated. However, it is worthwhile to note that there are exceptions to this principle in which faster sinus rates seem to overdrive the PVCs in some patients, causing them to become paradoxically more frequent at rest, or even during sleep.

Outflow tract PVCs can be managed medically with beta-blockers, nondihydropyridine calcium channel blockers (verapamil or diltiazem), or, less commonly, class IC drugs such as flecainide. They are also highly curable by catheter ablation (Figure 2), with procedure success rates greater than 90%.^9.10

However, a subset of outflow tract PVCs nested deep in a triangle of epicardial tissue between the right and left endocardial surface and underneath the left main coronary artery can be challenging. This region has been labeled the left ventricular summit, and is shielded from ablation by an epicardial fat pad in the adjacent pericardial space.¹¹ Ablation attempts made from the right and left endocardial surfaces as well as the epicardial surface (pericardial space) sometimes cannot adequately penetrate the tissue deep enough to reach the originating focus deep within this triangle. While ablation cannot always fully eliminate the PVC, ablation from more than one of the sites listed can generally reduce its burden, often in combination with suppressive medical therapy (Figure 3).

Fascicular PVCs

Fascicular PVCs originate from within the left ventricular His-Purkinje system¹² and produce a right bundle branch block morphology with either an anterior or posterior hemiblock pattern (Figure 4). Exit from the posterior fascicle causes an anterior hemiblock pattern, and exit from the anterior fascicle a posterior hemiblock pattern. Utilization of the rapidly conducting His-Purkinje system gives these PVCs a very narrow QRS duration, sometimes approaching 120 milliseconds or shorter. This occasionally causes them to be mistaken for aberrantly conducted supraventricular beats. Such spontaneous PVCs are commonly associated with both sustained and nonsustained ventricular tachycardia and are usually sensitive to verapamil.¹³

Special issues relating to mapping and catheter ablation of fascicular arrhythmias involve the identification of Purkinje fiber potentials and associated procedural diagnostic maneuvers during tachycardia.¹⁴

Other sites for PVCs

Other sites of origin for PVCs in the absence of structural heart disease include ventricular tissue adjacent to the aortomitral continuity,¹⁵ the tricuspid annulus,¹⁶ the mitral valve annulus, ¹⁷ papillary muscles,¹⁸ and other Purkinje-adjacent structures such as left ventricular false tendons.¹⁹ An example of a papillary muscle PVC is shown in Figures 5 and 6.

Curable by catheter ablation

Any of these PVCs can potentially be cured by catheter ablation when present at a sufficient burden to allow for activation mapping in the electrophysiology laboratory. The threshold for offering ablation varies among operators, but is generally around 10% or greater. Pacemapping is a technique applied in the electrophysiology laboratory when medically refractory symptomatic PVCs occurring at a lower burden require ablation.

PVCs WITH AN UNDERLYING CARDIAC CONDITION

Coronary artery disease

Tissue injury and death caused by acute myocardial infarction has long been recognized as a common cause of spontaneous ventricular ectopy attributed to infarct border zones of ischemic or hibernating myocardium.^20,21

Suppression has not been associated with improved outcomes, as shown for class IC drugs in the landmark Cardiac Arrhythmia Suppression Trial (CAST),²² or in the amiodarone treatment arm of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).²³ Therefore, treatment of ventricular ectopy in this patient population is usually symptom-driven unless there is hemodynamic intolerance, tachycardia-related cardiomyopathy, or a very high burden of PVCs in a patient who may be at risk of developing tachycardia-related cardiomyopathy. Antiarrhythmic drug treatment, when required, usually involves beta-blockers or class III medications such as sotalol or amiodarone.

Nonischemic dilated cardiomyopathy

This category includes patients with a wide variety of disease states including valvular heart disease, lymphocytic and other viral myocarditis, cardiac sarcoidosis, amyloidosis and other infiltrative diseases, familial conditions, and idiopathic dilated cardiomyopathy (ie, etiology unknown). Although it is a heterogeneous group, a common theme is that PVCs in this patient cohort may require epicardial mapping and ablation.²⁴ Similarly, epicardial PVCs and ventricular tachycardia cluster at the basal posterolateral left ventricle near the mitral annulus, for unclear reasons.²⁵

While specific criteria have been published, an epicardial focus is suggested by slowing of the initial QRS segment, pseudo-delta waves, a wider overall QRS, and Q waves in limb lead I.²⁶

Treatment is symptom-driven unless the patient has a tachycardia-related cardiomyopathy or a high burden associated with the risk for its development. Antiarrhythmic drug therapy, when required, typically involves a beta-blocker or a class III drug such as sotalol or amiodarone. Sotalol is used in this population but has limited safety data and should be used cautiously in patients without an implantable cardioverter-defibrillator.

Spontaneous ventricular ectopy and tachycardia are common, if not expected, in patients with this heritable autosomal dominant disorder. This condition is progressive and associated with the risk of sudden cardiac death. Criteria for diagnosis were established in 2010, and patients with suspected arrhythmogenic right ventricular cardiomyopathy often undergo cardiac magnetic resonance imaging.²⁷ Diagnostic findings include fibro-fatty tissue replacement, which usually starts in the right ventricle but can progress to involve the left ventricle. PVCs and ventricular tachycardia can involve the right ventricular free wall and are often epicardial.

Catheter ablation is usually palliative, as future arrhythmias are expected. Many patients with this condition require an implantable cardioverter-defibrillator for prevention of sudden cardiac death, and some go on to cardiac transplantation as the disease progresses and ventricular arrhythmias become incessant.

Other conditions

Spontaneous ventricular ectopy is common in other heritable and acquired cardiomyopathies including hypertrophic cardiomyopathy and in infiltrative or inflammatory disorders such as cardiac amyloidosis and sarcoidosis. While technically falling under the rubric of nonischemic heart disease, the presence of spontaneous ventricular ectopy carries specific prognostic implications depending on the underlying diagnosis. Therefore, an appropriate referral for complete cardiac evaluation should be considered when a heritable disorder or other acquired structural heart disease is suspected.

TACHYCARDIA-RELATED CARDIOMYOPATHY

Tachycardia-related cardiomyopathy refers to left ventricular systolic dysfunction that is primarily caused by arrhythmias. This includes frequent PVCs or ventricular tachycardia but also atrial arrhythmias occurring at a high burden that directly weaken myocardial function over time. Although much research has been devoted to this condition, our understanding of its etiology and pathology is incomplete.

PVCs and ventricular ectopy burdens in excess of 15% to 20% have been associated with the development of this condition.^28,29 However, it is important to note that cardiomyopathy can also develop at lower burdens.³⁰ One study found that a burden greater than 24% was 79% sensitive and 78% specific for development of tachycardia-related cardiomyopathy.³¹ Additional studies have demonstrated specific PVC morphologic features such as slurring in the initial QRS segment and also PVCs occurring at shorter coupling intervals as being associated with cardiomyopathy.^32–34

For these reasons, both quantification of the total burden and careful evaluation of available electrocardiograms and rhythm strips are important even in asymptomatic patients with frequent PVCs. Similarly, unexplained left ventricular dysfunction in patients with PVC burdens in these discussed ranges should raise suspicion for this diagnosis. Patients with tachycardia-related cardiomyopathy usually have at least partially reversible left ventricular dysfunction when identified or treated early.^29,35

MEDICAL AND ABLATIVE TREATMENT

Available treatments include medical suppression and catheter ablation. One needs to exercise clinical judgment and incorporate all of the PVC-related data to make treatment decisions.

Little data for trigger avoidance and behavioral modification

Some patients report a strong association between palpitations related to PVCs and caffeine intake, other stimulants, or other dietary triggers. However, few data exist to support the role of trigger avoidance and behavioral modification in treatment. In fact, an older randomized trial in 81 men found no benefit in a program of total abstinence from caffeine and smoking, moderation of alcohol intake, and physical conditioning.³⁶

Nonetheless, some argue in favor of advising patients to make these dietary and lifestyle changes, given the overall health benefits of aggressive risk-factor modification for cardiovascular disease.³⁷ Certainly, a trial of trigger avoidance and behavioral modification seems reasonable for patients who have strongly associated historical triggers in the absence of structural heart disease and PVCs occurring at a low to modest burden.

Beta-blockers are the mainstay

Beta-blockers are the mainstay of medical suppression of PVCs, primarily through their effect on beta-1 adrenergic receptors to reduce intracellular cyclic adenosine monophosphate and thus decrease automaticity. Blocking beta-1 receptors also causes a negative chronotropic effect, reducing the resting sinus rate in addition to slowing atrioventricular nodal conduction.

Cardioselective beta-blockers include atenolol, betaxolol, metoprolol, and nadolol. These drugs are effective in suppressing PVCs, or at least in reducing the burden to more tolerable levels.

Beta-blockers are most strongly indicated in patients who require PVC suppression and who have concomitant coronary artery disease, prior myocardial infarction, or other cardiomyopathy, as this drug class favorably affects long-term prognosis in these conditions.

Common side effects of beta-blockers include fatigue, shortness of breath, depressed mood, and loss of libido. Side effects can present a significant challenge, particularly for younger patients. Noncardioselective beta-blockers are less commonly prescribed, with the exception of propranolol, which is an effective sympatholytic drug that blocks both beta-1 and beta-2 receptors.

Many patients with asthma or peripheral arterial disease can tolerate these drugs well despite concerns about provoked bronchospasm or claudication, respectively, and neither of these conditions is considered an absolute contraindication. Excessive bradycardia with beta-blocker therapy can lead to dizziness, lightheadedness, or overt syncope, and these drugs should be used with caution in patients with baseline sinus node dysfunction or atrioventricular nodal disease.

Nondihydropyridine calcium channel blockers are particularly effective for PVC suppression in patients without structural heart disease by the mechanisms previously described involving intracellular calcium channels. In particular, they are highly effective and are considered the drugs of choice in treating fascicular PVCs.

Verapamil is a potent drug in this class, but it also commonly causes constipation as a side effect. Diltiazem is less constipating but can cause fatigue, drowsiness, and headaches. Both drugs reduce the resting heart rate and slow atrioventricular nodal conduction. Patients predisposed to bradycardia or atrioventricular block can develop dizziness or overt syncope. Calcium channel blockers are also used cautiously in patients with congestive heart failure, given their potential negative inotropic effects.

Overall, calcium channel blockers are a very reasonable choice for young patients without structural heart disease who need PVC suppression.

Other antiarrhythmic drugs

Sotalol merits special consideration because it has both beta-blocker and class III antiarrhythmic properties, blocking potassium channels and prolonging cardiac repolarization. It can be very effective in PVC suppression but also creates some degree of QT prolongation. The QT-prolonging effect is accentuated in patients with baseline QT prolongation or abnormal renal function. Rarely, this can lead to torsades de pointes. As a safety precaution, some patients are admitted to the hospital when they start sotalol therapy so that they can be monitored with continuous telemetry and ECG to detect excessive QT prolongation.

Amiodarone is a versatile drug with mixed pharmacologic properties that include a predominantly potassium channel-blocking class III drug effect. However, this effect is balanced by its other pharmacologic properties that make QT prolongation less of a clinical concern. Excessive QT prolongation may still occur when used concomitantly with other QT-prolonging drugs.

Amiodarone is very effective in suppressing PVCs and ventricular arrhythmias but has considerable short-term and long-term side effects. Cumulative toxicity risks include damage to the thyroid gland, liver, skin, eyes, and lungs. Routine thyroid function testing, pulmonary function testing, and eye examinations are often considered for patients on long-term amiodarone therapy. Short-term use of this drug does not typically require such surveillance.

Catheter ablation

As mentioned in the previous sections, catheter ablation is a safe and effective treatment for PVCs. It is curative in most cases, and significantly reduces the PVC burden in others.

Procedure. Patients are brought to the electrophysiology laboratory in a fasted state and are partially sedated with an intravenous drug such as midazolam or fentanyl, or both. Steerable catheters are placed into appropriate cardiac chambers from femoral access sites, which are infiltrated with local anesthesia. Sometimes sedative or analgesic drugs must be limited if they are known to suppress PVCs.

Most operators prefer a technique called activation mapping, in which the catheter is maneuvered to home in on the precise PVC origin within the heart, which is subsequently ablated. This technique has very high success rates, but having enough spontaneous PVCs to map during the procedure is essential for the technique to succeed. Conversely, not having sufficient PVCs on the day of the procedure is a common reason that ablation fails or cannot be performed at all.

Pace-mapping is an alternate technique that does not require a continuous stream of PVCs. This involves pacing from different candidate locations inside the heart in an effort to precisely match the ECG appearance of the clinical PVC and to ablate at this site. Although activation mapping generally yields higher success rates and is preferred by most operators, pace-mapping can be successful when a perfect 12–12 match is elicited. In many cases, the two techniques are used together during the same procedure, particularly if the patient’s PVCs spontaneously wax and wane, as they often do.

Risks. Like any medical procedure, catheter ablation carries some inherent risks, including rare but potentially serious events. Unstable arrhythmias may require pace-termination from the catheter or, rarely, shock-termination externally. Even more rare is cardiac arrest requiring cardiopulmonary resuscitation. Uncommon but life-threatening complications also include pericardial effusion or cardiac tamponade requiring percutaneous drainage or, rarely, emergency surgical correction. Although such events are life-threatening, death is extremely rare.

Complications causing permanent disability are also very uncommon but include the risk of collateral injury to the conduction system requiring permanent pacemaker placement, injury to the coronary vessels requiring urgent treatment, or diaphragmatic injury affecting breathing. Left-sided cardiac ablation also carries a small risk of stroke, which is mitigated by giving intravenous heparin during the procedure.

More common but generally non-life-threatening complications include femoral vascular events such as hematomas, pseudoaneurysms, or fistulas that sometimes require subsequent treatment. These complications are generally treatable but can significantly prolong the recovery period.

Catheter ablation procedures are typically 2 to 6 hours in duration, depending on the chambers involved, PVC frequency, and other considerations. Postprocedure bed rest is required for a number of hours. A Foley catheter is sometimes used for patient comfort when a prolonged procedure is anticipated. This carries a small risk of urinary tract infection. Epicardial catheter ablation that requires access to the surface of the heart (ie, the pericardial space) is uncommon but carries some unique risks, including rare injury to coronary vessels or adjacent organs such as the liver or stomach.

Overall, both endocardial and epicardial catheter ablation can be performed safely and effectively in the overwhelming majority of patients, but understanding and explaining the potential risks remains a crucial part of the informed consent process.

TAKE-HOME POINTS

• PVCs are a common cause of palpitations but are also noted as incidental findings by ECG, Holter monitoring, and inpatient telemetry.
• The diagnostic evaluation includes an assessment for underlying structural heart disease and quantification of the total PVC burden.
• Patients without structural heart disease and with low-to-modest PVC burdens may not require specific treatment. PVCs at greater burdens, typically 15% to 20%, or with specific high-risk features carry a risk of tachycardia-related cardiomyopathy and may require treatment even if they are asymptomatic. These high-risk features include initial QRS slurring and PVCs occurring at shorter coupling intervals.
• Treatment involves medical therapy with a beta-blocker, a calcium channel blocker, or another antiarrhythmic drug, and catheter ablation in selected cases.
• Catheter ablation can be curative but is typically reserved for drug-intolerant or medically refractory patients with a high PVC burden.

Premature ventricular complexes (PVCs) are a common cause of palpitations, and are also often detected incidentally on electrocardiography (ECG), ambulatory monitoring, or inpatient telemetry. At the cellular level, ventricular myocytes spontaneously depolarize to create an extra systole that is “out of sync” with the cardiac cycle.

Although nearly everyone has some PVCs from time to time, people vary widely in their frequency of PVCs and their sensitivity to them.^1,2 Some patients are exquisitely sensitive to even a small number of PVCs, while others are completely unaware of PVCs in a bigeminal pattern (ie, every other heartbeat). This article will review the evaluation and management of PVCs with a focus on clinical aspects.

DIAGNOSTIC EVALUATION

Personal and family history

Symptoms. The initial history should establish the presence, extent, timing, and duration of symptoms. Patients may use the word “palpitations” to describe their symptoms, but they also describe them as “hard” heartbeats, “chest-thumping,” or as a “catch” or “skipped” heartbeat. Related symptoms may include difficulty breathing, chest pain, fatigue, and dizziness.

The interview should determine whether the symptoms represent a minor nuisance or a major quality-of-life issue to the patient, and whether there are any specific associations or triggers. For example, it is very common for patients to become aware of PVCs at night, particularly in certain positions, such as lying on the left side. Patients often associate PVC symptoms with emotional stress, exercise, or caffeine or stimulant use.

Medication use. An accurate and up-to-date list of prescription medications should be screened for alpha-, beta-, or dopamine-receptor agonist drugs. Similarly, any use of over-the-counter sympathomimetic medications and nonprescription supplements should be elicited, including compounded elixirs or beverages. Many commercially available products designed to treat fatigue or increase alertness contain large doses of caffeine or other stimulants. It is also important to consider the use of illicit substances such as cocaine, amphetamine, methamphetamine, and their derivatives.

The patient’s medical and surgical history should be queried for any known structural heart disease, including coronary artery disease, myocardial infarction, congestive heart failure, valvular heart disease, congenital heart disease, and heritable conditions such as hypertrophic cardiomyopathy, prolonged QT syndromes, or other channel disorders. Pulmonary disorders such as sarcoidosis, pulmonary hypertension, or obstructive sleep apnea are also relevant. Similarly, it is important to identify endocrine disorders, including thyroid problems, sex hormone abnormalities, or adrenal gland conditions.

A careful family history should include any instance of sudden death in first-degree relatives, any heritable cardiac conditions, or coronary artery disease at an early age.

Physical examination

The physical examination should focus on findings that suggest underlying structural heart disease. Findings suggestive of congestive heart failure include elevated jugular venous pressures, abnormal cardiac sounds, pulmonary rales, abnormal arterial pulses, or peripheral edema. A murmur or a pathologic heart sound should raise suspicion of valvular or congenital heart disease when present in a young patient.

Inspection and palpation of the thyroid can reveal a related disorder. Obvious skin changes or neurologic findings can similarly reveal a systemic and possibly related clinical disorder that can have cardiac manifestations (eg, muscular dystrophy).

Electrocardiography, Holter monitoring, and other monitoring

Assessment of the cardiac rhythm includes 12-lead ECG and ambulatory Holter monitoring, typically for 24 or 48 hours.

Holter monitoring provides a continuous recording, usually in at least two or three leads. Patients are given a symptom journal or are asked to keep a diary of symptoms experienced during the monitoring period. The monitor is worn underneath clothing and is returned for download upon completion. Technicians process the data with the aid of computer software, and the final output is reviewed and interpreted by a cardiologist or cardiac electrophysiologist.

Holter monitoring for at least 24 hours is a critical step in assessing any patient with known or suspected PVCs, as it can both quantify the total burden of ventricular ectopy and identify the presence of any related ventricular tachycardia. In addition, it can detect additional supraventricular arrhythmias or bradycardia during the monitoring period. The PVC burden is an important measurement; it is expressed as the percentage of heartbeats that were ventricular extrasystoles during the monitoring period.

Both ECG and Holter monitoring are limited in that they are only snapshots of the rhythm during the period when a patient is actually hooked up. Many patients experience PVCs in clusters every very few days or weeks. Such a pattern is unlikely to be detected by a single ECG or 24- or 48-hour Holter monitoring.

A 30-day ambulatory event monitor (also known as a wearable loop recorder) is an important diagnostic tool in these scenarios. The concept is very similar to that of Holter monitoring, except that the device provides a continuous loop recording of the cardiac rhythm that is digitally stored in clips when the patient activates the device. Some wearable loop recorders also have auto-save features for heart rates falling outside of a programmed range.

Mobile outpatient cardiac telemetry is the most comprehensive form of noninvasive rhythm monitoring available. This is essentially the equivalent of continuous inpatient cardiac telemetry, but in a patient who is not hospitalized. It is a wearable ambulatory device providing continuous recordings, real-time automatic detections, and patient-activated symptom recordings. It can be used for up to 6 weeks. Advantages include detection and quantification of asymptomatic events, and real-time transmissions that the physician can act upon. The major disadvantage is cost, including coverage denial by many third-party payers.

This test is rarely indicated as part of a PVC evaluation and is typically ordered only by a cardiologist or cardiac electrophysiologist.

Surface echocardiography is indicated to look for overt structural heart disease and can reliably detect abnormalities in cardiac chamber size, wall thickness, and function. Valvular heart disease is concomitantly identified by two-dimensional imaging as well as by color Doppler. The finding of significant structural heart disease in conjunction with PVCs should prompt a cardiology referral, as this carries significant prognostic implications.^3–5

Exercise treadmill stress testing is appropriate for patients who experience PVCs with exercise or for whom an evaluation for coronary artery disease is indicated. The expected finding would be an increase in PVCs or ventricular tachycardia with exercise or in the subsequent recovery period. Exercise testing can be combined with either echocardiographic or nuclear perfusion imaging to evaluate the possibility of myocardial ischemia. For patients unable to exercise, pharmacologic stress testing with dobutamine or a vasodilator agent can be performed.

Advanced noninvasive cardiac imaging— such as computed tomography, magnetic resonance imaging, or positron-emission tomography—should be reserved for specific clinical indications such as congenital heart disease, suspected cardiac sarcoidosis, and infiltrative heart disease, and for specific cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. For example, frequent PVCs with a left bundle branch block morphology and superior axis raise the concern for a right ventricular disorder and may prompt cardiac magnetic resonance imaging for either arrhythmogenic right ventricular cardiomyopathy or sarcoidosis.

PVCs WITHOUT STRUCTURAL HEART DISEASE

Outflow tract PVCs and ventricular tachycardia

The right or left ventricular outflow tracts, or the epicardial tissue immediately adjacent to the aortic sinuses of Valsalva are the most common sites of origin for ventricular ectopy in the absence of structural heart disease.^6–9 Affected cells often demonstrate a triggered activity mechanism due to cyclic adenosine monophosphate-mediated and calcium-dependent delayed after-depolarizations.^7,8

Most of these foci are in the right ventricular outflow tract, producing a left bundle branch block morphology with an inferior axis (positive R waves in limb leads II, III, and aVF) and typical precordial R-wave transition in V₃ and V₄ (Figure 1). A minority are in the left ventricular outflow tract, producing a right bundle branch block with an inferior axis pattern, or in the aortic sinuses with a left bundle branch block pattern but with early precordial R transition in V₂ and V₃.

A study in 122 patients showed that right and left outflow tract arrhythmias had similar electrophysiologic properties and pharmacologic sensitivities, providing evidence for shared mechanisms possibly due to the common embryologic origin of these structures.⁹

Such arrhythmias are typically catecholamine-sensitive and are sometimes inducible with burst pacing in the electrophysiology laboratory. The short ventricular coupling intervals can promote intracellular calcium overload in the affected cells, leading to triggered activity.

Therefore, outflow tract PVCs and ventricular tachycardia are commonly encountered clinically during exercise and, to an even greater extent, in the postexercise cool-down period. Similarly, they can be worse during periods of emotional stress or fatigue, when the body’s endogenous catecholamine production is elevated. However, it is worthwhile to note that there are exceptions to this principle in which faster sinus rates seem to overdrive the PVCs in some patients, causing them to become paradoxically more frequent at rest, or even during sleep.

Outflow tract PVCs can be managed medically with beta-blockers, nondihydropyridine calcium channel blockers (verapamil or diltiazem), or, less commonly, class IC drugs such as flecainide. They are also highly curable by catheter ablation (Figure 2), with procedure success rates greater than 90%.^9.10

However, a subset of outflow tract PVCs nested deep in a triangle of epicardial tissue between the right and left endocardial surface and underneath the left main coronary artery can be challenging. This region has been labeled the left ventricular summit, and is shielded from ablation by an epicardial fat pad in the adjacent pericardial space.¹¹ Ablation attempts made from the right and left endocardial surfaces as well as the epicardial surface (pericardial space) sometimes cannot adequately penetrate the tissue deep enough to reach the originating focus deep within this triangle. While ablation cannot always fully eliminate the PVC, ablation from more than one of the sites listed can generally reduce its burden, often in combination with suppressive medical therapy (Figure 3).

Fascicular PVCs

Fascicular PVCs originate from within the left ventricular His-Purkinje system¹² and produce a right bundle branch block morphology with either an anterior or posterior hemiblock pattern (Figure 4). Exit from the posterior fascicle causes an anterior hemiblock pattern, and exit from the anterior fascicle a posterior hemiblock pattern. Utilization of the rapidly conducting His-Purkinje system gives these PVCs a very narrow QRS duration, sometimes approaching 120 milliseconds or shorter. This occasionally causes them to be mistaken for aberrantly conducted supraventricular beats. Such spontaneous PVCs are commonly associated with both sustained and nonsustained ventricular tachycardia and are usually sensitive to verapamil.¹³

Special issues relating to mapping and catheter ablation of fascicular arrhythmias involve the identification of Purkinje fiber potentials and associated procedural diagnostic maneuvers during tachycardia.¹⁴

Other sites for PVCs

Other sites of origin for PVCs in the absence of structural heart disease include ventricular tissue adjacent to the aortomitral continuity,¹⁵ the tricuspid annulus,¹⁶ the mitral valve annulus, ¹⁷ papillary muscles,¹⁸ and other Purkinje-adjacent structures such as left ventricular false tendons.¹⁹ An example of a papillary muscle PVC is shown in Figures 5 and 6.

Curable by catheter ablation

Any of these PVCs can potentially be cured by catheter ablation when present at a sufficient burden to allow for activation mapping in the electrophysiology laboratory. The threshold for offering ablation varies among operators, but is generally around 10% or greater. Pacemapping is a technique applied in the electrophysiology laboratory when medically refractory symptomatic PVCs occurring at a lower burden require ablation.

PVCs WITH AN UNDERLYING CARDIAC CONDITION

Coronary artery disease

Tissue injury and death caused by acute myocardial infarction has long been recognized as a common cause of spontaneous ventricular ectopy attributed to infarct border zones of ischemic or hibernating myocardium.^20,21

Suppression has not been associated with improved outcomes, as shown for class IC drugs in the landmark Cardiac Arrhythmia Suppression Trial (CAST),²² or in the amiodarone treatment arm of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).²³ Therefore, treatment of ventricular ectopy in this patient population is usually symptom-driven unless there is hemodynamic intolerance, tachycardia-related cardiomyopathy, or a very high burden of PVCs in a patient who may be at risk of developing tachycardia-related cardiomyopathy. Antiarrhythmic drug treatment, when required, usually involves beta-blockers or class III medications such as sotalol or amiodarone.

Nonischemic dilated cardiomyopathy

This category includes patients with a wide variety of disease states including valvular heart disease, lymphocytic and other viral myocarditis, cardiac sarcoidosis, amyloidosis and other infiltrative diseases, familial conditions, and idiopathic dilated cardiomyopathy (ie, etiology unknown). Although it is a heterogeneous group, a common theme is that PVCs in this patient cohort may require epicardial mapping and ablation.²⁴ Similarly, epicardial PVCs and ventricular tachycardia cluster at the basal posterolateral left ventricle near the mitral annulus, for unclear reasons.²⁵

While specific criteria have been published, an epicardial focus is suggested by slowing of the initial QRS segment, pseudo-delta waves, a wider overall QRS, and Q waves in limb lead I.²⁶

Treatment is symptom-driven unless the patient has a tachycardia-related cardiomyopathy or a high burden associated with the risk for its development. Antiarrhythmic drug therapy, when required, typically involves a beta-blocker or a class III drug such as sotalol or amiodarone. Sotalol is used in this population but has limited safety data and should be used cautiously in patients without an implantable cardioverter-defibrillator.

Spontaneous ventricular ectopy and tachycardia are common, if not expected, in patients with this heritable autosomal dominant disorder. This condition is progressive and associated with the risk of sudden cardiac death. Criteria for diagnosis were established in 2010, and patients with suspected arrhythmogenic right ventricular cardiomyopathy often undergo cardiac magnetic resonance imaging.²⁷ Diagnostic findings include fibro-fatty tissue replacement, which usually starts in the right ventricle but can progress to involve the left ventricle. PVCs and ventricular tachycardia can involve the right ventricular free wall and are often epicardial.

Catheter ablation is usually palliative, as future arrhythmias are expected. Many patients with this condition require an implantable cardioverter-defibrillator for prevention of sudden cardiac death, and some go on to cardiac transplantation as the disease progresses and ventricular arrhythmias become incessant.

Other conditions

Spontaneous ventricular ectopy is common in other heritable and acquired cardiomyopathies including hypertrophic cardiomyopathy and in infiltrative or inflammatory disorders such as cardiac amyloidosis and sarcoidosis. While technically falling under the rubric of nonischemic heart disease, the presence of spontaneous ventricular ectopy carries specific prognostic implications depending on the underlying diagnosis. Therefore, an appropriate referral for complete cardiac evaluation should be considered when a heritable disorder or other acquired structural heart disease is suspected.

TACHYCARDIA-RELATED CARDIOMYOPATHY

Tachycardia-related cardiomyopathy refers to left ventricular systolic dysfunction that is primarily caused by arrhythmias. This includes frequent PVCs or ventricular tachycardia but also atrial arrhythmias occurring at a high burden that directly weaken myocardial function over time. Although much research has been devoted to this condition, our understanding of its etiology and pathology is incomplete.

PVCs and ventricular ectopy burdens in excess of 15% to 20% have been associated with the development of this condition.^28,29 However, it is important to note that cardiomyopathy can also develop at lower burdens.³⁰ One study found that a burden greater than 24% was 79% sensitive and 78% specific for development of tachycardia-related cardiomyopathy.³¹ Additional studies have demonstrated specific PVC morphologic features such as slurring in the initial QRS segment and also PVCs occurring at shorter coupling intervals as being associated with cardiomyopathy.^32–34

For these reasons, both quantification of the total burden and careful evaluation of available electrocardiograms and rhythm strips are important even in asymptomatic patients with frequent PVCs. Similarly, unexplained left ventricular dysfunction in patients with PVC burdens in these discussed ranges should raise suspicion for this diagnosis. Patients with tachycardia-related cardiomyopathy usually have at least partially reversible left ventricular dysfunction when identified or treated early.^29,35

MEDICAL AND ABLATIVE TREATMENT

Available treatments include medical suppression and catheter ablation. One needs to exercise clinical judgment and incorporate all of the PVC-related data to make treatment decisions.

Little data for trigger avoidance and behavioral modification

Some patients report a strong association between palpitations related to PVCs and caffeine intake, other stimulants, or other dietary triggers. However, few data exist to support the role of trigger avoidance and behavioral modification in treatment. In fact, an older randomized trial in 81 men found no benefit in a program of total abstinence from caffeine and smoking, moderation of alcohol intake, and physical conditioning.³⁶

Nonetheless, some argue in favor of advising patients to make these dietary and lifestyle changes, given the overall health benefits of aggressive risk-factor modification for cardiovascular disease.³⁷ Certainly, a trial of trigger avoidance and behavioral modification seems reasonable for patients who have strongly associated historical triggers in the absence of structural heart disease and PVCs occurring at a low to modest burden.

Beta-blockers are the mainstay

Beta-blockers are the mainstay of medical suppression of PVCs, primarily through their effect on beta-1 adrenergic receptors to reduce intracellular cyclic adenosine monophosphate and thus decrease automaticity. Blocking beta-1 receptors also causes a negative chronotropic effect, reducing the resting sinus rate in addition to slowing atrioventricular nodal conduction.

Cardioselective beta-blockers include atenolol, betaxolol, metoprolol, and nadolol. These drugs are effective in suppressing PVCs, or at least in reducing the burden to more tolerable levels.

Beta-blockers are most strongly indicated in patients who require PVC suppression and who have concomitant coronary artery disease, prior myocardial infarction, or other cardiomyopathy, as this drug class favorably affects long-term prognosis in these conditions.

Common side effects of beta-blockers include fatigue, shortness of breath, depressed mood, and loss of libido. Side effects can present a significant challenge, particularly for younger patients. Noncardioselective beta-blockers are less commonly prescribed, with the exception of propranolol, which is an effective sympatholytic drug that blocks both beta-1 and beta-2 receptors.

Many patients with asthma or peripheral arterial disease can tolerate these drugs well despite concerns about provoked bronchospasm or claudication, respectively, and neither of these conditions is considered an absolute contraindication. Excessive bradycardia with beta-blocker therapy can lead to dizziness, lightheadedness, or overt syncope, and these drugs should be used with caution in patients with baseline sinus node dysfunction or atrioventricular nodal disease.

Nondihydropyridine calcium channel blockers are particularly effective for PVC suppression in patients without structural heart disease by the mechanisms previously described involving intracellular calcium channels. In particular, they are highly effective and are considered the drugs of choice in treating fascicular PVCs.

Verapamil is a potent drug in this class, but it also commonly causes constipation as a side effect. Diltiazem is less constipating but can cause fatigue, drowsiness, and headaches. Both drugs reduce the resting heart rate and slow atrioventricular nodal conduction. Patients predisposed to bradycardia or atrioventricular block can develop dizziness or overt syncope. Calcium channel blockers are also used cautiously in patients with congestive heart failure, given their potential negative inotropic effects.

Overall, calcium channel blockers are a very reasonable choice for young patients without structural heart disease who need PVC suppression.

Other antiarrhythmic drugs

Sotalol merits special consideration because it has both beta-blocker and class III antiarrhythmic properties, blocking potassium channels and prolonging cardiac repolarization. It can be very effective in PVC suppression but also creates some degree of QT prolongation. The QT-prolonging effect is accentuated in patients with baseline QT prolongation or abnormal renal function. Rarely, this can lead to torsades de pointes. As a safety precaution, some patients are admitted to the hospital when they start sotalol therapy so that they can be monitored with continuous telemetry and ECG to detect excessive QT prolongation.

Amiodarone is a versatile drug with mixed pharmacologic properties that include a predominantly potassium channel-blocking class III drug effect. However, this effect is balanced by its other pharmacologic properties that make QT prolongation less of a clinical concern. Excessive QT prolongation may still occur when used concomitantly with other QT-prolonging drugs.

Amiodarone is very effective in suppressing PVCs and ventricular arrhythmias but has considerable short-term and long-term side effects. Cumulative toxicity risks include damage to the thyroid gland, liver, skin, eyes, and lungs. Routine thyroid function testing, pulmonary function testing, and eye examinations are often considered for patients on long-term amiodarone therapy. Short-term use of this drug does not typically require such surveillance.

Catheter ablation

As mentioned in the previous sections, catheter ablation is a safe and effective treatment for PVCs. It is curative in most cases, and significantly reduces the PVC burden in others.

Procedure. Patients are brought to the electrophysiology laboratory in a fasted state and are partially sedated with an intravenous drug such as midazolam or fentanyl, or both. Steerable catheters are placed into appropriate cardiac chambers from femoral access sites, which are infiltrated with local anesthesia. Sometimes sedative or analgesic drugs must be limited if they are known to suppress PVCs.

Most operators prefer a technique called activation mapping, in which the catheter is maneuvered to home in on the precise PVC origin within the heart, which is subsequently ablated. This technique has very high success rates, but having enough spontaneous PVCs to map during the procedure is essential for the technique to succeed. Conversely, not having sufficient PVCs on the day of the procedure is a common reason that ablation fails or cannot be performed at all.

Pace-mapping is an alternate technique that does not require a continuous stream of PVCs. This involves pacing from different candidate locations inside the heart in an effort to precisely match the ECG appearance of the clinical PVC and to ablate at this site. Although activation mapping generally yields higher success rates and is preferred by most operators, pace-mapping can be successful when a perfect 12–12 match is elicited. In many cases, the two techniques are used together during the same procedure, particularly if the patient’s PVCs spontaneously wax and wane, as they often do.

Risks. Like any medical procedure, catheter ablation carries some inherent risks, including rare but potentially serious events. Unstable arrhythmias may require pace-termination from the catheter or, rarely, shock-termination externally. Even more rare is cardiac arrest requiring cardiopulmonary resuscitation. Uncommon but life-threatening complications also include pericardial effusion or cardiac tamponade requiring percutaneous drainage or, rarely, emergency surgical correction. Although such events are life-threatening, death is extremely rare.

Complications causing permanent disability are also very uncommon but include the risk of collateral injury to the conduction system requiring permanent pacemaker placement, injury to the coronary vessels requiring urgent treatment, or diaphragmatic injury affecting breathing. Left-sided cardiac ablation also carries a small risk of stroke, which is mitigated by giving intravenous heparin during the procedure.

More common but generally non-life-threatening complications include femoral vascular events such as hematomas, pseudoaneurysms, or fistulas that sometimes require subsequent treatment. These complications are generally treatable but can significantly prolong the recovery period.

Catheter ablation procedures are typically 2 to 6 hours in duration, depending on the chambers involved, PVC frequency, and other considerations. Postprocedure bed rest is required for a number of hours. A Foley catheter is sometimes used for patient comfort when a prolonged procedure is anticipated. This carries a small risk of urinary tract infection. Epicardial catheter ablation that requires access to the surface of the heart (ie, the pericardial space) is uncommon but carries some unique risks, including rare injury to coronary vessels or adjacent organs such as the liver or stomach.

Overall, both endocardial and epicardial catheter ablation can be performed safely and effectively in the overwhelming majority of patients, but understanding and explaining the potential risks remains a crucial part of the informed consent process.

TAKE-HOME POINTS

• PVCs are a common cause of palpitations but are also noted as incidental findings by ECG, Holter monitoring, and inpatient telemetry.
• The diagnostic evaluation includes an assessment for underlying structural heart disease and quantification of the total PVC burden.
• Patients without structural heart disease and with low-to-modest PVC burdens may not require specific treatment. PVCs at greater burdens, typically 15% to 20%, or with specific high-risk features carry a risk of tachycardia-related cardiomyopathy and may require treatment even if they are asymptomatic. These high-risk features include initial QRS slurring and PVCs occurring at shorter coupling intervals.
• Treatment involves medical therapy with a beta-blocker, a calcium channel blocker, or another antiarrhythmic drug, and catheter ablation in selected cases.
• Catheter ablation can be curative but is typically reserved for drug-intolerant or medically refractory patients with a high PVC burden.

Premature ventricular complexes (PVCs) are a common cause of palpitations, and are also often detected incidentally on electrocardiography (ECG), ambulatory monitoring, or inpatient telemetry. At the cellular level, ventricular myocytes spontaneously depolarize to create an extra systole that is “out of sync” with the cardiac cycle.

Although nearly everyone has some PVCs from time to time, people vary widely in their frequency of PVCs and their sensitivity to them.^1,2 Some patients are exquisitely sensitive to even a small number of PVCs, while others are completely unaware of PVCs in a bigeminal pattern (ie, every other heartbeat). This article will review the evaluation and management of PVCs with a focus on clinical aspects.

DIAGNOSTIC EVALUATION

Personal and family history

Symptoms. The initial history should establish the presence, extent, timing, and duration of symptoms. Patients may use the word “palpitations” to describe their symptoms, but they also describe them as “hard” heartbeats, “chest-thumping,” or as a “catch” or “skipped” heartbeat. Related symptoms may include difficulty breathing, chest pain, fatigue, and dizziness.

The interview should determine whether the symptoms represent a minor nuisance or a major quality-of-life issue to the patient, and whether there are any specific associations or triggers. For example, it is very common for patients to become aware of PVCs at night, particularly in certain positions, such as lying on the left side. Patients often associate PVC symptoms with emotional stress, exercise, or caffeine or stimulant use.

Medication use. An accurate and up-to-date list of prescription medications should be screened for alpha-, beta-, or dopamine-receptor agonist drugs. Similarly, any use of over-the-counter sympathomimetic medications and nonprescription supplements should be elicited, including compounded elixirs or beverages. Many commercially available products designed to treat fatigue or increase alertness contain large doses of caffeine or other stimulants. It is also important to consider the use of illicit substances such as cocaine, amphetamine, methamphetamine, and their derivatives.

The patient’s medical and surgical history should be queried for any known structural heart disease, including coronary artery disease, myocardial infarction, congestive heart failure, valvular heart disease, congenital heart disease, and heritable conditions such as hypertrophic cardiomyopathy, prolonged QT syndromes, or other channel disorders. Pulmonary disorders such as sarcoidosis, pulmonary hypertension, or obstructive sleep apnea are also relevant. Similarly, it is important to identify endocrine disorders, including thyroid problems, sex hormone abnormalities, or adrenal gland conditions.

A careful family history should include any instance of sudden death in first-degree relatives, any heritable cardiac conditions, or coronary artery disease at an early age.

Physical examination

The physical examination should focus on findings that suggest underlying structural heart disease. Findings suggestive of congestive heart failure include elevated jugular venous pressures, abnormal cardiac sounds, pulmonary rales, abnormal arterial pulses, or peripheral edema. A murmur or a pathologic heart sound should raise suspicion of valvular or congenital heart disease when present in a young patient.

Inspection and palpation of the thyroid can reveal a related disorder. Obvious skin changes or neurologic findings can similarly reveal a systemic and possibly related clinical disorder that can have cardiac manifestations (eg, muscular dystrophy).

Electrocardiography, Holter monitoring, and other monitoring

Assessment of the cardiac rhythm includes 12-lead ECG and ambulatory Holter monitoring, typically for 24 or 48 hours.

Holter monitoring provides a continuous recording, usually in at least two or three leads. Patients are given a symptom journal or are asked to keep a diary of symptoms experienced during the monitoring period. The monitor is worn underneath clothing and is returned for download upon completion. Technicians process the data with the aid of computer software, and the final output is reviewed and interpreted by a cardiologist or cardiac electrophysiologist.

Holter monitoring for at least 24 hours is a critical step in assessing any patient with known or suspected PVCs, as it can both quantify the total burden of ventricular ectopy and identify the presence of any related ventricular tachycardia. In addition, it can detect additional supraventricular arrhythmias or bradycardia during the monitoring period. The PVC burden is an important measurement; it is expressed as the percentage of heartbeats that were ventricular extrasystoles during the monitoring period.

Both ECG and Holter monitoring are limited in that they are only snapshots of the rhythm during the period when a patient is actually hooked up. Many patients experience PVCs in clusters every very few days or weeks. Such a pattern is unlikely to be detected by a single ECG or 24- or 48-hour Holter monitoring.

A 30-day ambulatory event monitor (also known as a wearable loop recorder) is an important diagnostic tool in these scenarios. The concept is very similar to that of Holter monitoring, except that the device provides a continuous loop recording of the cardiac rhythm that is digitally stored in clips when the patient activates the device. Some wearable loop recorders also have auto-save features for heart rates falling outside of a programmed range.

Mobile outpatient cardiac telemetry is the most comprehensive form of noninvasive rhythm monitoring available. This is essentially the equivalent of continuous inpatient cardiac telemetry, but in a patient who is not hospitalized. It is a wearable ambulatory device providing continuous recordings, real-time automatic detections, and patient-activated symptom recordings. It can be used for up to 6 weeks. Advantages include detection and quantification of asymptomatic events, and real-time transmissions that the physician can act upon. The major disadvantage is cost, including coverage denial by many third-party payers.

This test is rarely indicated as part of a PVC evaluation and is typically ordered only by a cardiologist or cardiac electrophysiologist.

Surface echocardiography is indicated to look for overt structural heart disease and can reliably detect abnormalities in cardiac chamber size, wall thickness, and function. Valvular heart disease is concomitantly identified by two-dimensional imaging as well as by color Doppler. The finding of significant structural heart disease in conjunction with PVCs should prompt a cardiology referral, as this carries significant prognostic implications.^3–5

Exercise treadmill stress testing is appropriate for patients who experience PVCs with exercise or for whom an evaluation for coronary artery disease is indicated. The expected finding would be an increase in PVCs or ventricular tachycardia with exercise or in the subsequent recovery period. Exercise testing can be combined with either echocardiographic or nuclear perfusion imaging to evaluate the possibility of myocardial ischemia. For patients unable to exercise, pharmacologic stress testing with dobutamine or a vasodilator agent can be performed.

Advanced noninvasive cardiac imaging— such as computed tomography, magnetic resonance imaging, or positron-emission tomography—should be reserved for specific clinical indications such as congenital heart disease, suspected cardiac sarcoidosis, and infiltrative heart disease, and for specific cardiomyopathies, such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy. For example, frequent PVCs with a left bundle branch block morphology and superior axis raise the concern for a right ventricular disorder and may prompt cardiac magnetic resonance imaging for either arrhythmogenic right ventricular cardiomyopathy or sarcoidosis.

PVCs WITHOUT STRUCTURAL HEART DISEASE

Outflow tract PVCs and ventricular tachycardia

The right or left ventricular outflow tracts, or the epicardial tissue immediately adjacent to the aortic sinuses of Valsalva are the most common sites of origin for ventricular ectopy in the absence of structural heart disease.^6–9 Affected cells often demonstrate a triggered activity mechanism due to cyclic adenosine monophosphate-mediated and calcium-dependent delayed after-depolarizations.^7,8

Most of these foci are in the right ventricular outflow tract, producing a left bundle branch block morphology with an inferior axis (positive R waves in limb leads II, III, and aVF) and typical precordial R-wave transition in V₃ and V₄ (Figure 1). A minority are in the left ventricular outflow tract, producing a right bundle branch block with an inferior axis pattern, or in the aortic sinuses with a left bundle branch block pattern but with early precordial R transition in V₂ and V₃.

A study in 122 patients showed that right and left outflow tract arrhythmias had similar electrophysiologic properties and pharmacologic sensitivities, providing evidence for shared mechanisms possibly due to the common embryologic origin of these structures.⁹

Such arrhythmias are typically catecholamine-sensitive and are sometimes inducible with burst pacing in the electrophysiology laboratory. The short ventricular coupling intervals can promote intracellular calcium overload in the affected cells, leading to triggered activity.

Therefore, outflow tract PVCs and ventricular tachycardia are commonly encountered clinically during exercise and, to an even greater extent, in the postexercise cool-down period. Similarly, they can be worse during periods of emotional stress or fatigue, when the body’s endogenous catecholamine production is elevated. However, it is worthwhile to note that there are exceptions to this principle in which faster sinus rates seem to overdrive the PVCs in some patients, causing them to become paradoxically more frequent at rest, or even during sleep.

Outflow tract PVCs can be managed medically with beta-blockers, nondihydropyridine calcium channel blockers (verapamil or diltiazem), or, less commonly, class IC drugs such as flecainide. They are also highly curable by catheter ablation (Figure 2), with procedure success rates greater than 90%.^9.10

However, a subset of outflow tract PVCs nested deep in a triangle of epicardial tissue between the right and left endocardial surface and underneath the left main coronary artery can be challenging. This region has been labeled the left ventricular summit, and is shielded from ablation by an epicardial fat pad in the adjacent pericardial space.¹¹ Ablation attempts made from the right and left endocardial surfaces as well as the epicardial surface (pericardial space) sometimes cannot adequately penetrate the tissue deep enough to reach the originating focus deep within this triangle. While ablation cannot always fully eliminate the PVC, ablation from more than one of the sites listed can generally reduce its burden, often in combination with suppressive medical therapy (Figure 3).

Fascicular PVCs

Fascicular PVCs originate from within the left ventricular His-Purkinje system¹² and produce a right bundle branch block morphology with either an anterior or posterior hemiblock pattern (Figure 4). Exit from the posterior fascicle causes an anterior hemiblock pattern, and exit from the anterior fascicle a posterior hemiblock pattern. Utilization of the rapidly conducting His-Purkinje system gives these PVCs a very narrow QRS duration, sometimes approaching 120 milliseconds or shorter. This occasionally causes them to be mistaken for aberrantly conducted supraventricular beats. Such spontaneous PVCs are commonly associated with both sustained and nonsustained ventricular tachycardia and are usually sensitive to verapamil.¹³

Special issues relating to mapping and catheter ablation of fascicular arrhythmias involve the identification of Purkinje fiber potentials and associated procedural diagnostic maneuvers during tachycardia.¹⁴

Other sites for PVCs

Other sites of origin for PVCs in the absence of structural heart disease include ventricular tissue adjacent to the aortomitral continuity,¹⁵ the tricuspid annulus,¹⁶ the mitral valve annulus, ¹⁷ papillary muscles,¹⁸ and other Purkinje-adjacent structures such as left ventricular false tendons.¹⁹ An example of a papillary muscle PVC is shown in Figures 5 and 6.

Curable by catheter ablation

Any of these PVCs can potentially be cured by catheter ablation when present at a sufficient burden to allow for activation mapping in the electrophysiology laboratory. The threshold for offering ablation varies among operators, but is generally around 10% or greater. Pacemapping is a technique applied in the electrophysiology laboratory when medically refractory symptomatic PVCs occurring at a lower burden require ablation.

PVCs WITH AN UNDERLYING CARDIAC CONDITION

Coronary artery disease

Tissue injury and death caused by acute myocardial infarction has long been recognized as a common cause of spontaneous ventricular ectopy attributed to infarct border zones of ischemic or hibernating myocardium.^20,21

Suppression has not been associated with improved outcomes, as shown for class IC drugs in the landmark Cardiac Arrhythmia Suppression Trial (CAST),²² or in the amiodarone treatment arm of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II).²³ Therefore, treatment of ventricular ectopy in this patient population is usually symptom-driven unless there is hemodynamic intolerance, tachycardia-related cardiomyopathy, or a very high burden of PVCs in a patient who may be at risk of developing tachycardia-related cardiomyopathy. Antiarrhythmic drug treatment, when required, usually involves beta-blockers or class III medications such as sotalol or amiodarone.

Nonischemic dilated cardiomyopathy

This category includes patients with a wide variety of disease states including valvular heart disease, lymphocytic and other viral myocarditis, cardiac sarcoidosis, amyloidosis and other infiltrative diseases, familial conditions, and idiopathic dilated cardiomyopathy (ie, etiology unknown). Although it is a heterogeneous group, a common theme is that PVCs in this patient cohort may require epicardial mapping and ablation.²⁴ Similarly, epicardial PVCs and ventricular tachycardia cluster at the basal posterolateral left ventricle near the mitral annulus, for unclear reasons.²⁵

While specific criteria have been published, an epicardial focus is suggested by slowing of the initial QRS segment, pseudo-delta waves, a wider overall QRS, and Q waves in limb lead I.²⁶

Treatment is symptom-driven unless the patient has a tachycardia-related cardiomyopathy or a high burden associated with the risk for its development. Antiarrhythmic drug therapy, when required, typically involves a beta-blocker or a class III drug such as sotalol or amiodarone. Sotalol is used in this population but has limited safety data and should be used cautiously in patients without an implantable cardioverter-defibrillator.

Spontaneous ventricular ectopy and tachycardia are common, if not expected, in patients with this heritable autosomal dominant disorder. This condition is progressive and associated with the risk of sudden cardiac death. Criteria for diagnosis were established in 2010, and patients with suspected arrhythmogenic right ventricular cardiomyopathy often undergo cardiac magnetic resonance imaging.²⁷ Diagnostic findings include fibro-fatty tissue replacement, which usually starts in the right ventricle but can progress to involve the left ventricle. PVCs and ventricular tachycardia can involve the right ventricular free wall and are often epicardial.

Catheter ablation is usually palliative, as future arrhythmias are expected. Many patients with this condition require an implantable cardioverter-defibrillator for prevention of sudden cardiac death, and some go on to cardiac transplantation as the disease progresses and ventricular arrhythmias become incessant.

Other conditions

Spontaneous ventricular ectopy is common in other heritable and acquired cardiomyopathies including hypertrophic cardiomyopathy and in infiltrative or inflammatory disorders such as cardiac amyloidosis and sarcoidosis. While technically falling under the rubric of nonischemic heart disease, the presence of spontaneous ventricular ectopy carries specific prognostic implications depending on the underlying diagnosis. Therefore, an appropriate referral for complete cardiac evaluation should be considered when a heritable disorder or other acquired structural heart disease is suspected.

TACHYCARDIA-RELATED CARDIOMYOPATHY

Tachycardia-related cardiomyopathy refers to left ventricular systolic dysfunction that is primarily caused by arrhythmias. This includes frequent PVCs or ventricular tachycardia but also atrial arrhythmias occurring at a high burden that directly weaken myocardial function over time. Although much research has been devoted to this condition, our understanding of its etiology and pathology is incomplete.

PVCs and ventricular ectopy burdens in excess of 15% to 20% have been associated with the development of this condition.^28,29 However, it is important to note that cardiomyopathy can also develop at lower burdens.³⁰ One study found that a burden greater than 24% was 79% sensitive and 78% specific for development of tachycardia-related cardiomyopathy.³¹ Additional studies have demonstrated specific PVC morphologic features such as slurring in the initial QRS segment and also PVCs occurring at shorter coupling intervals as being associated with cardiomyopathy.^32–34

For these reasons, both quantification of the total burden and careful evaluation of available electrocardiograms and rhythm strips are important even in asymptomatic patients with frequent PVCs. Similarly, unexplained left ventricular dysfunction in patients with PVC burdens in these discussed ranges should raise suspicion for this diagnosis. Patients with tachycardia-related cardiomyopathy usually have at least partially reversible left ventricular dysfunction when identified or treated early.^29,35

MEDICAL AND ABLATIVE TREATMENT

Available treatments include medical suppression and catheter ablation. One needs to exercise clinical judgment and incorporate all of the PVC-related data to make treatment decisions.

Little data for trigger avoidance and behavioral modification

Some patients report a strong association between palpitations related to PVCs and caffeine intake, other stimulants, or other dietary triggers. However, few data exist to support the role of trigger avoidance and behavioral modification in treatment. In fact, an older randomized trial in 81 men found no benefit in a program of total abstinence from caffeine and smoking, moderation of alcohol intake, and physical conditioning.³⁶

Nonetheless, some argue in favor of advising patients to make these dietary and lifestyle changes, given the overall health benefits of aggressive risk-factor modification for cardiovascular disease.³⁷ Certainly, a trial of trigger avoidance and behavioral modification seems reasonable for patients who have strongly associated historical triggers in the absence of structural heart disease and PVCs occurring at a low to modest burden.

Beta-blockers are the mainstay

Beta-blockers are the mainstay of medical suppression of PVCs, primarily through their effect on beta-1 adrenergic receptors to reduce intracellular cyclic adenosine monophosphate and thus decrease automaticity. Blocking beta-1 receptors also causes a negative chronotropic effect, reducing the resting sinus rate in addition to slowing atrioventricular nodal conduction.

Cardioselective beta-blockers include atenolol, betaxolol, metoprolol, and nadolol. These drugs are effective in suppressing PVCs, or at least in reducing the burden to more tolerable levels.

Beta-blockers are most strongly indicated in patients who require PVC suppression and who have concomitant coronary artery disease, prior myocardial infarction, or other cardiomyopathy, as this drug class favorably affects long-term prognosis in these conditions.

Common side effects of beta-blockers include fatigue, shortness of breath, depressed mood, and loss of libido. Side effects can present a significant challenge, particularly for younger patients. Noncardioselective beta-blockers are less commonly prescribed, with the exception of propranolol, which is an effective sympatholytic drug that blocks both beta-1 and beta-2 receptors.

Many patients with asthma or peripheral arterial disease can tolerate these drugs well despite concerns about provoked bronchospasm or claudication, respectively, and neither of these conditions is considered an absolute contraindication. Excessive bradycardia with beta-blocker therapy can lead to dizziness, lightheadedness, or overt syncope, and these drugs should be used with caution in patients with baseline sinus node dysfunction or atrioventricular nodal disease.

Nondihydropyridine calcium channel blockers are particularly effective for PVC suppression in patients without structural heart disease by the mechanisms previously described involving intracellular calcium channels. In particular, they are highly effective and are considered the drugs of choice in treating fascicular PVCs.

Verapamil is a potent drug in this class, but it also commonly causes constipation as a side effect. Diltiazem is less constipating but can cause fatigue, drowsiness, and headaches. Both drugs reduce the resting heart rate and slow atrioventricular nodal conduction. Patients predisposed to bradycardia or atrioventricular block can develop dizziness or overt syncope. Calcium channel blockers are also used cautiously in patients with congestive heart failure, given their potential negative inotropic effects.

Overall, calcium channel blockers are a very reasonable choice for young patients without structural heart disease who need PVC suppression.

Other antiarrhythmic drugs

Sotalol merits special consideration because it has both beta-blocker and class III antiarrhythmic properties, blocking potassium channels and prolonging cardiac repolarization. It can be very effective in PVC suppression but also creates some degree of QT prolongation. The QT-prolonging effect is accentuated in patients with baseline QT prolongation or abnormal renal function. Rarely, this can lead to torsades de pointes. As a safety precaution, some patients are admitted to the hospital when they start sotalol therapy so that they can be monitored with continuous telemetry and ECG to detect excessive QT prolongation.

Amiodarone is a versatile drug with mixed pharmacologic properties that include a predominantly potassium channel-blocking class III drug effect. However, this effect is balanced by its other pharmacologic properties that make QT prolongation less of a clinical concern. Excessive QT prolongation may still occur when used concomitantly with other QT-prolonging drugs.

Amiodarone is very effective in suppressing PVCs and ventricular arrhythmias but has considerable short-term and long-term side effects. Cumulative toxicity risks include damage to the thyroid gland, liver, skin, eyes, and lungs. Routine thyroid function testing, pulmonary function testing, and eye examinations are often considered for patients on long-term amiodarone therapy. Short-term use of this drug does not typically require such surveillance.

Catheter ablation

As mentioned in the previous sections, catheter ablation is a safe and effective treatment for PVCs. It is curative in most cases, and significantly reduces the PVC burden in others.

Procedure. Patients are brought to the electrophysiology laboratory in a fasted state and are partially sedated with an intravenous drug such as midazolam or fentanyl, or both. Steerable catheters are placed into appropriate cardiac chambers from femoral access sites, which are infiltrated with local anesthesia. Sometimes sedative or analgesic drugs must be limited if they are known to suppress PVCs.

Most operators prefer a technique called activation mapping, in which the catheter is maneuvered to home in on the precise PVC origin within the heart, which is subsequently ablated. This technique has very high success rates, but having enough spontaneous PVCs to map during the procedure is essential for the technique to succeed. Conversely, not having sufficient PVCs on the day of the procedure is a common reason that ablation fails or cannot be performed at all.

Pace-mapping is an alternate technique that does not require a continuous stream of PVCs. This involves pacing from different candidate locations inside the heart in an effort to precisely match the ECG appearance of the clinical PVC and to ablate at this site. Although activation mapping generally yields higher success rates and is preferred by most operators, pace-mapping can be successful when a perfect 12–12 match is elicited. In many cases, the two techniques are used together during the same procedure, particularly if the patient’s PVCs spontaneously wax and wane, as they often do.

Risks. Like any medical procedure, catheter ablation carries some inherent risks, including rare but potentially serious events. Unstable arrhythmias may require pace-termination from the catheter or, rarely, shock-termination externally. Even more rare is cardiac arrest requiring cardiopulmonary resuscitation. Uncommon but life-threatening complications also include pericardial effusion or cardiac tamponade requiring percutaneous drainage or, rarely, emergency surgical correction. Although such events are life-threatening, death is extremely rare.

Complications causing permanent disability are also very uncommon but include the risk of collateral injury to the conduction system requiring permanent pacemaker placement, injury to the coronary vessels requiring urgent treatment, or diaphragmatic injury affecting breathing. Left-sided cardiac ablation also carries a small risk of stroke, which is mitigated by giving intravenous heparin during the procedure.

More common but generally non-life-threatening complications include femoral vascular events such as hematomas, pseudoaneurysms, or fistulas that sometimes require subsequent treatment. These complications are generally treatable but can significantly prolong the recovery period.

Catheter ablation procedures are typically 2 to 6 hours in duration, depending on the chambers involved, PVC frequency, and other considerations. Postprocedure bed rest is required for a number of hours. A Foley catheter is sometimes used for patient comfort when a prolonged procedure is anticipated. This carries a small risk of urinary tract infection. Epicardial catheter ablation that requires access to the surface of the heart (ie, the pericardial space) is uncommon but carries some unique risks, including rare injury to coronary vessels or adjacent organs such as the liver or stomach.

Overall, both endocardial and epicardial catheter ablation can be performed safely and effectively in the overwhelming majority of patients, but understanding and explaining the potential risks remains a crucial part of the informed consent process.

TAKE-HOME POINTS

• PVCs are a common cause of palpitations but are also noted as incidental findings by ECG, Holter monitoring, and inpatient telemetry.
• The diagnostic evaluation includes an assessment for underlying structural heart disease and quantification of the total PVC burden.
• Patients without structural heart disease and with low-to-modest PVC burdens may not require specific treatment. PVCs at greater burdens, typically 15% to 20%, or with specific high-risk features carry a risk of tachycardia-related cardiomyopathy and may require treatment even if they are asymptomatic. These high-risk features include initial QRS slurring and PVCs occurring at shorter coupling intervals.
• Treatment involves medical therapy with a beta-blocker, a calcium channel blocker, or another antiarrhythmic drug, and catheter ablation in selected cases.
• Catheter ablation can be curative but is typically reserved for drug-intolerant or medically refractory patients with a high PVC burden.

Experts have argued for decades about how best to manage opiate dependence, with practitioners generally subscribing to one of two strategies: either total abstinence or medication-assisted treatment (MAT).

Although MAT has proven efficacy, it has been slow to gain acceptance, and the gold standard of care since the 1930s has been abstinence-based treatment. Among elite institutional holdouts against MAT was the Hazelden Treatment Center, a leading treatment institution and publishing house that had been wedded to the abstinence model since it was founded in 1949.¹ Now, Hazelden has gone on record as embracing MAT, raising the possibility that the two predominant treatment philosophies for opiate-dependent patients may no longer be at odds.

FROM ABSTINENCE TO METHADONE MAINTENANCE

The modern day abstinence-based movement in this country started in the decade before the founding of Hazelden. In 1935, the US government opened the first of two federal drug treatment centers, known as the United States Narcotic Farm, in Lexington, KY.² The move by the government to get into the addiction treatment business largely stemmed from frustration over the growing problem of addiction at that time, coupled with a dearth of treatment options for addicts in the wake of the 1914 Harrison Narcotics Act.

The Narcotic Farm was an impressive facility—for all intents and purposes, a specialized prison—that initially housed 1,200 people. In addition to prisoners, it also accepted voluntary, nonprisoner patients. In many ways, it was ahead of its time. It offered a wide variety of services, including detoxification, group therapy, individual therapy, psychiatric and medical services, and vocational rehabilitation.² Housed on the premises was the Addiction Research Center at Lexington, the first intramural research branch of the National Institute of Mental Health. After the “Blue Grass” mandatory commitment laws were passed in the 1940s, even the voluntary patients were ultimately committed for a 1-year sentence at Lexington. This facility, and its sister facility in Ft. Worth, TX, would have been the envy of any modern-day abstinence-based treatment center in terms of the services offered and the long lengths of stay.

The quality of the program, as evidenced by the impressive array of services and long stays, would lead one to expect that its treatment outcomes over nearly 40 years of operation were equally stellar. However, in terms of outcomes the Farm was an abysmal failure, as shown by numerous studies demonstrating relapse rates of more than 90% in the patients discharged from it.^2,3

Similar frustrations at other abstinence-based treatment centers from the 1940s through the 1960s led Dr. Vincent Dole, the “father of methadone maintenance,” to conclude in 1971 that after detoxification from opiates, “human addicts almost always return to use of narcotics after they leave the hospital where they have been detoxified.”⁴ That realization inspired Dr. Dole and his wife and colleague Dr. Marie Nyswander to revisit the idea of medication-assisted treatment, an approach previously used by the morphine maintenance clinics of the early 1900s. This work led to the development of government-sanctioned methadone clinics across America and to the realization that long-term recovery was possible with medication, even without a lengthy hospital stay. For this revolutionary work on opiate addiction, Dr. Dole won the prestigious Lasker Award in 1988.

The major reason for the success of methadone was that, because of its pharmacokinetic profile, it could stabilize the patient through once-daily dosing without sedation or narcosis. As noted by Dr. Dole, once patients are on a stable dosing regimen, the obsessive preoccupation with drug use fades away.⁵

Despite its success, methadone maintenance had its share of detractors. It was fraught with controversy because it was viewed as a crutch, and those who were on it were often not considered by their abstinent peers as being in true recovery. The reasons for the negative attitudes toward MAT are unclear but may reflect antiquated beliefs that addiction may be indicative of a failure of morals or will, and that patients ought to be able to simply stop using.

Whatever the reason for the animosity surrounding MAT, it should be noted that an expert consensus panel convened by the Betty Ford Center in 2007 agreed that patients on MAT met their consensus definition of sobriety.⁶ The issue of what constitutes recovery remains a very complex and hotly debated topic that is beyond the scope of this paper and that has been discussed elsewhere.^6,7

For more than 3 decades, methadone was the only medication available for MAT. Federal regulations limit the dispensing of methadone to licensed clinics, most of which are located in major metropolitan areas. Patients must go to the clinic every day to receive their dose of methadone—a major inconvenience, especially to those with transportation issues. Adding to the lack of appeal of methadone maintenance is that the clinics are typically located in the higher-crime areas of cities. Savvy drug dealers know the location of these clinics and often loiter on nearby street corners in an attempt to lure addicts away from recovery by flaunting their illicit drugs.

A final, very significant drawback of methadone is its safety profile. It is a full-agonist narcotic that can be fatal in overdose or in the induction phase, especially if taken with other drugs, such as benzodiazepines.

2003: BUPRENORPHINE-NALOXONE IS APPROVED

Such concerns led researchers to search for other medications to be used for MAT that could perhaps be prescribed in a typical outpatient physician practice. For many reasons, buprenorphine became the most promising candidate. In 2003, the US Food and Drug Administration approved the combination medication buprenorphine-naloxone (Sub-oxone) as only the second drug indicated for maintenance treatment of opioid dependence in the United States.

Buprenorphine differs from methadone in that it is a partial agonist at mu opiate receptors, and therefore has a “ceiling” or “plateau” effect in terms of dose-response and a much improved safety profile. Unlike methadone, buprenorphine can be prescribed in a doctor’s office and does not have to be dispensed at a government-approved clinic.

Unfortunately, buprenorphine-maintained patients seem to carry the same stigma in the recovery community as those maintained on methadone—that they are simply substituting one drug for another. Detractors usually fail to consider that, as with methadone, patients do not report getting “high” from taking buprenorphine. Patients will often state that when they first start taking it, they “feel something,” but after a few days of adjustment, they simply feel normal. They don’t feel high, they are no longer in withdrawal, their cravings are virtually eliminated, and their opiate receptors are effectively occupied and blocked, so there is no “high” in the event of a relapse.

What’s more, buprenorphine is not a medication that will help them deal with life’s stressors by “chemical coping.” Sober coping is a skill they must learn by actively participating in a solid 12-step-based recovery program and, in some cases, in psychotherapy. By removing the drug obsession, buprenorphine promotes and facilitates the important recovery goal of learning how to deal with life on life’s terms.

ADDICTION AS CHRONIC ILLNESS

Outcomes studies of addiction treatment have focused largely on rates of relapse after discharge from acute treatments such as residential rehabilitation, partial hospitalization, and intensive outpatient programs. With MAT, however, outcomes research has primarily looked at the duration of retention in treatment.

The change in focus between the two types of treatment coincides with a paradigm shift that views addiction as a chronic condition that requires ongoing care. Continued participation in prescribed care with demonstrated efficacy is considered to be the major indicator of success. Under the chronic illness model employed by MAT providers, if a patient reverted to briefly using a drug of abuse, this would be an issue to address in his ongoing treatment and would not necessarily indicate treatment failure as with the acute care model. Beyond retention rates, research has demonstrated that MAT with methadone results in reductions in rates of criminal activity, illicit drug use, acquisition of human immunodeficiency virus, and overall mortality.^8–10

In outcomes studies, MAT has repeatedly shown better efficacy than abstinence-based approaches. During the first 5 years of its implementation, in 4,000 patients, methadone maintenance boasted 1-year retention rates exceeding 98%.¹¹ Over the subsequent 3 years, with the number of patients approaching 35,000, the 1-year retention rates fell to around 60%—still far exceeding results of abstinence-based treatment and approximating the number cited in most modern studies.¹¹

The retention rates in buprenorphine programs are similarly promising. Studies of 12 to 13 weeks duration have shown retention rates of 52% to 79%.^12–15 Six-month studies have demonstrated retention rates of 43% to 100%.^16–19 Another study showed that 38% of opiate-dependent patients remained in treatment with buprenorphine at 5 years.²⁰ Surprisingly, most of the buprenorphine studies have been conducted in office-based practices, which are less structured than outpatient methadone programs.

MEDICATION-ASSISTED TREATMENT IS GAINING ACCEPTANCE

Data from decades of experience with MAT strongly support the conclusion that it is superior to abstinence-based approaches.

The importance of a patient staying in treatment cannot be overemphasized, as the consequence of failing in recovery may well be an early death. On average, heroin addicts lose about 18 years of life expectancy, and the mortality rate for injection users is roughly 2% per year.²¹ The mortality rate for heroin users is 6 to 20 times greater than for age-matched peers who are not drug users.²²

As high as these numbers are, they are even higher for abusers of prescription narcotics. The annual death rate associated with opioid pain relievers (4.8 per 100,000) is nearly double that associated with illicit drugs (2.8 per 100,000).²³

The recent and rather radical change in treatment philosophy by Hazelden came as a shock to some, a disappointment to others, and a welcome change to many who saw this as a move by one of the more respected treatment centers in the country to fall in line with the body of evidence that supports MAT for those suffering from opiate dependence. It remains a mystery why so many, if not most, addiction treatment centers in the United States cling to the abstinence-based philosophy despite the overwhelming data from decades of research and experience that show that abstinence does not work for the majority of opiate addicts.

Complete abstinence from opiate drugs of abuse and potentially addictive medications is a noble but perhaps unreachable goal for many sufferers. Hazelden’s announced acceptance of MAT gives credence to the value of recovery goals that are not entirely drug-free.

Dr. Dole was correct in stating that opiate addicts usually return to drugs if not provided with MAT. Treatment programs need to inform opiate-dependent patients that abstinence-based treatment offers only a 1 in 10 chance of success. Perhaps some patients, armed with the daunting statistics regarding abstinence, will be inspired to devote themselves wholeheartedly to their recovery in an effort to make it into that elite 10% group that achieves long-lasting recovery without the aid of medications. But for the other 90%, it is encouraging to hear that Hazelden, the model treatment center for most abstinence-based programs in this country, may now lead other abstinence-based centers to reconsider their treatment philosophies.

Historically, US doctors were not allowed by federal law to prescribe opiates for addiction treatment. With the passage of DATA 2000, buprenorphine (alone or in combination with naloxone) can be prescribed for addiction treatment only by providers who obtain a waiver from the US Drug Enforcement Administration (DEA). Any doctor can become qualified to prescribe buprenorphine or buprenorphinenaloxone after completing an 8-hour online training course (available at www.buppractice.com and at www.aaap.org/buprenorphine) and by obtaining a DATA 2000 waiver and a new prescribing number from the DEA. Doctors are initially limited to treating only 30 patients with buprenorphine-naloxone at any given time, but can apply for an extension to 100 patients after having had their waiver for 1 year.

As MAT continues to gain favor, demand will grow for more providers to obtain their waivers to prescribe buprenorphine and buprenorphine-naloxone. Historically, there have always been too few methadone clinics to meet the demand. One can hope that the growing number of waivered providers will greatly improve access to care by opiate addicts, no matter where they reside. Qualified prescribers of buprenorphine and buprenorphine-naloxone are limited by the federal restrictions on the numbers of patients they can treat. If the chronic disease of addiction is to be integrated into the continuing-care approach of modern medicine and managed alongside other chronic diseases, primary care providers who are not specialized in treating addiction will need to be become comfortable with maintaining patients on buprenorphine-naloxone.⁷ Presumably, such patients will have already been stabilized through participation in addiction treatment programs in their respective geographic areas. Primary care providers will need to develop relationships with local addictionologists and treatment programs so that they will be able to refer those in active addiction for induction and stabilization on MAT and will be able to refer those already stabilized on MAT back to such specialists when relapses occur.

We may finally be approaching a time when structured residential treatment and MAT are not mutually exclusive options for our patients. These treatment options must work together for optimal outcomes. Based on our experience with hundreds of patients at Cleveland Clinic’s Alcohol and Drug Recovery Center, we believe this change of treatment philosophy is long overdue. In clinical settings, patients do not fit cleanly into one treatment arm or another and often require a blended approach to effect long-lasting change. Hazelden’s shift of treatment philosophy is an indication that this research-supported viewpoint is gaining acceptance in the traditionally drug-free halls of addiction treatment programs.

Experts have argued for decades about how best to manage opiate dependence, with practitioners generally subscribing to one of two strategies: either total abstinence or medication-assisted treatment (MAT).

Although MAT has proven efficacy, it has been slow to gain acceptance, and the gold standard of care since the 1930s has been abstinence-based treatment. Among elite institutional holdouts against MAT was the Hazelden Treatment Center, a leading treatment institution and publishing house that had been wedded to the abstinence model since it was founded in 1949.¹ Now, Hazelden has gone on record as embracing MAT, raising the possibility that the two predominant treatment philosophies for opiate-dependent patients may no longer be at odds.

FROM ABSTINENCE TO METHADONE MAINTENANCE

The modern day abstinence-based movement in this country started in the decade before the founding of Hazelden. In 1935, the US government opened the first of two federal drug treatment centers, known as the United States Narcotic Farm, in Lexington, KY.² The move by the government to get into the addiction treatment business largely stemmed from frustration over the growing problem of addiction at that time, coupled with a dearth of treatment options for addicts in the wake of the 1914 Harrison Narcotics Act.

The Narcotic Farm was an impressive facility—for all intents and purposes, a specialized prison—that initially housed 1,200 people. In addition to prisoners, it also accepted voluntary, nonprisoner patients. In many ways, it was ahead of its time. It offered a wide variety of services, including detoxification, group therapy, individual therapy, psychiatric and medical services, and vocational rehabilitation.² Housed on the premises was the Addiction Research Center at Lexington, the first intramural research branch of the National Institute of Mental Health. After the “Blue Grass” mandatory commitment laws were passed in the 1940s, even the voluntary patients were ultimately committed for a 1-year sentence at Lexington. This facility, and its sister facility in Ft. Worth, TX, would have been the envy of any modern-day abstinence-based treatment center in terms of the services offered and the long lengths of stay.

The quality of the program, as evidenced by the impressive array of services and long stays, would lead one to expect that its treatment outcomes over nearly 40 years of operation were equally stellar. However, in terms of outcomes the Farm was an abysmal failure, as shown by numerous studies demonstrating relapse rates of more than 90% in the patients discharged from it.^2,3

Similar frustrations at other abstinence-based treatment centers from the 1940s through the 1960s led Dr. Vincent Dole, the “father of methadone maintenance,” to conclude in 1971 that after detoxification from opiates, “human addicts almost always return to use of narcotics after they leave the hospital where they have been detoxified.”⁴ That realization inspired Dr. Dole and his wife and colleague Dr. Marie Nyswander to revisit the idea of medication-assisted treatment, an approach previously used by the morphine maintenance clinics of the early 1900s. This work led to the development of government-sanctioned methadone clinics across America and to the realization that long-term recovery was possible with medication, even without a lengthy hospital stay. For this revolutionary work on opiate addiction, Dr. Dole won the prestigious Lasker Award in 1988.

The major reason for the success of methadone was that, because of its pharmacokinetic profile, it could stabilize the patient through once-daily dosing without sedation or narcosis. As noted by Dr. Dole, once patients are on a stable dosing regimen, the obsessive preoccupation with drug use fades away.⁵

Despite its success, methadone maintenance had its share of detractors. It was fraught with controversy because it was viewed as a crutch, and those who were on it were often not considered by their abstinent peers as being in true recovery. The reasons for the negative attitudes toward MAT are unclear but may reflect antiquated beliefs that addiction may be indicative of a failure of morals or will, and that patients ought to be able to simply stop using.

Whatever the reason for the animosity surrounding MAT, it should be noted that an expert consensus panel convened by the Betty Ford Center in 2007 agreed that patients on MAT met their consensus definition of sobriety.⁶ The issue of what constitutes recovery remains a very complex and hotly debated topic that is beyond the scope of this paper and that has been discussed elsewhere.^6,7

For more than 3 decades, methadone was the only medication available for MAT. Federal regulations limit the dispensing of methadone to licensed clinics, most of which are located in major metropolitan areas. Patients must go to the clinic every day to receive their dose of methadone—a major inconvenience, especially to those with transportation issues. Adding to the lack of appeal of methadone maintenance is that the clinics are typically located in the higher-crime areas of cities. Savvy drug dealers know the location of these clinics and often loiter on nearby street corners in an attempt to lure addicts away from recovery by flaunting their illicit drugs.

A final, very significant drawback of methadone is its safety profile. It is a full-agonist narcotic that can be fatal in overdose or in the induction phase, especially if taken with other drugs, such as benzodiazepines.

2003: BUPRENORPHINE-NALOXONE IS APPROVED

Such concerns led researchers to search for other medications to be used for MAT that could perhaps be prescribed in a typical outpatient physician practice. For many reasons, buprenorphine became the most promising candidate. In 2003, the US Food and Drug Administration approved the combination medication buprenorphine-naloxone (Sub-oxone) as only the second drug indicated for maintenance treatment of opioid dependence in the United States.

Buprenorphine differs from methadone in that it is a partial agonist at mu opiate receptors, and therefore has a “ceiling” or “plateau” effect in terms of dose-response and a much improved safety profile. Unlike methadone, buprenorphine can be prescribed in a doctor’s office and does not have to be dispensed at a government-approved clinic.

Unfortunately, buprenorphine-maintained patients seem to carry the same stigma in the recovery community as those maintained on methadone—that they are simply substituting one drug for another. Detractors usually fail to consider that, as with methadone, patients do not report getting “high” from taking buprenorphine. Patients will often state that when they first start taking it, they “feel something,” but after a few days of adjustment, they simply feel normal. They don’t feel high, they are no longer in withdrawal, their cravings are virtually eliminated, and their opiate receptors are effectively occupied and blocked, so there is no “high” in the event of a relapse.

What’s more, buprenorphine is not a medication that will help them deal with life’s stressors by “chemical coping.” Sober coping is a skill they must learn by actively participating in a solid 12-step-based recovery program and, in some cases, in psychotherapy. By removing the drug obsession, buprenorphine promotes and facilitates the important recovery goal of learning how to deal with life on life’s terms.

ADDICTION AS CHRONIC ILLNESS

Outcomes studies of addiction treatment have focused largely on rates of relapse after discharge from acute treatments such as residential rehabilitation, partial hospitalization, and intensive outpatient programs. With MAT, however, outcomes research has primarily looked at the duration of retention in treatment.

The change in focus between the two types of treatment coincides with a paradigm shift that views addiction as a chronic condition that requires ongoing care. Continued participation in prescribed care with demonstrated efficacy is considered to be the major indicator of success. Under the chronic illness model employed by MAT providers, if a patient reverted to briefly using a drug of abuse, this would be an issue to address in his ongoing treatment and would not necessarily indicate treatment failure as with the acute care model. Beyond retention rates, research has demonstrated that MAT with methadone results in reductions in rates of criminal activity, illicit drug use, acquisition of human immunodeficiency virus, and overall mortality.^8–10

In outcomes studies, MAT has repeatedly shown better efficacy than abstinence-based approaches. During the first 5 years of its implementation, in 4,000 patients, methadone maintenance boasted 1-year retention rates exceeding 98%.¹¹ Over the subsequent 3 years, with the number of patients approaching 35,000, the 1-year retention rates fell to around 60%—still far exceeding results of abstinence-based treatment and approximating the number cited in most modern studies.¹¹

The retention rates in buprenorphine programs are similarly promising. Studies of 12 to 13 weeks duration have shown retention rates of 52% to 79%.^12–15 Six-month studies have demonstrated retention rates of 43% to 100%.^16–19 Another study showed that 38% of opiate-dependent patients remained in treatment with buprenorphine at 5 years.²⁰ Surprisingly, most of the buprenorphine studies have been conducted in office-based practices, which are less structured than outpatient methadone programs.

MEDICATION-ASSISTED TREATMENT IS GAINING ACCEPTANCE

Data from decades of experience with MAT strongly support the conclusion that it is superior to abstinence-based approaches.

The importance of a patient staying in treatment cannot be overemphasized, as the consequence of failing in recovery may well be an early death. On average, heroin addicts lose about 18 years of life expectancy, and the mortality rate for injection users is roughly 2% per year.²¹ The mortality rate for heroin users is 6 to 20 times greater than for age-matched peers who are not drug users.²²

As high as these numbers are, they are even higher for abusers of prescription narcotics. The annual death rate associated with opioid pain relievers (4.8 per 100,000) is nearly double that associated with illicit drugs (2.8 per 100,000).²³

The recent and rather radical change in treatment philosophy by Hazelden came as a shock to some, a disappointment to others, and a welcome change to many who saw this as a move by one of the more respected treatment centers in the country to fall in line with the body of evidence that supports MAT for those suffering from opiate dependence. It remains a mystery why so many, if not most, addiction treatment centers in the United States cling to the abstinence-based philosophy despite the overwhelming data from decades of research and experience that show that abstinence does not work for the majority of opiate addicts.

Complete abstinence from opiate drugs of abuse and potentially addictive medications is a noble but perhaps unreachable goal for many sufferers. Hazelden’s announced acceptance of MAT gives credence to the value of recovery goals that are not entirely drug-free.

Dr. Dole was correct in stating that opiate addicts usually return to drugs if not provided with MAT. Treatment programs need to inform opiate-dependent patients that abstinence-based treatment offers only a 1 in 10 chance of success. Perhaps some patients, armed with the daunting statistics regarding abstinence, will be inspired to devote themselves wholeheartedly to their recovery in an effort to make it into that elite 10% group that achieves long-lasting recovery without the aid of medications. But for the other 90%, it is encouraging to hear that Hazelden, the model treatment center for most abstinence-based programs in this country, may now lead other abstinence-based centers to reconsider their treatment philosophies.

Historically, US doctors were not allowed by federal law to prescribe opiates for addiction treatment. With the passage of DATA 2000, buprenorphine (alone or in combination with naloxone) can be prescribed for addiction treatment only by providers who obtain a waiver from the US Drug Enforcement Administration (DEA). Any doctor can become qualified to prescribe buprenorphine or buprenorphinenaloxone after completing an 8-hour online training course (available at www.buppractice.com and at www.aaap.org/buprenorphine) and by obtaining a DATA 2000 waiver and a new prescribing number from the DEA. Doctors are initially limited to treating only 30 patients with buprenorphine-naloxone at any given time, but can apply for an extension to 100 patients after having had their waiver for 1 year.

As MAT continues to gain favor, demand will grow for more providers to obtain their waivers to prescribe buprenorphine and buprenorphine-naloxone. Historically, there have always been too few methadone clinics to meet the demand. One can hope that the growing number of waivered providers will greatly improve access to care by opiate addicts, no matter where they reside. Qualified prescribers of buprenorphine and buprenorphine-naloxone are limited by the federal restrictions on the numbers of patients they can treat. If the chronic disease of addiction is to be integrated into the continuing-care approach of modern medicine and managed alongside other chronic diseases, primary care providers who are not specialized in treating addiction will need to be become comfortable with maintaining patients on buprenorphine-naloxone.⁷ Presumably, such patients will have already been stabilized through participation in addiction treatment programs in their respective geographic areas. Primary care providers will need to develop relationships with local addictionologists and treatment programs so that they will be able to refer those in active addiction for induction and stabilization on MAT and will be able to refer those already stabilized on MAT back to such specialists when relapses occur.

We may finally be approaching a time when structured residential treatment and MAT are not mutually exclusive options for our patients. These treatment options must work together for optimal outcomes. Based on our experience with hundreds of patients at Cleveland Clinic’s Alcohol and Drug Recovery Center, we believe this change of treatment philosophy is long overdue. In clinical settings, patients do not fit cleanly into one treatment arm or another and often require a blended approach to effect long-lasting change. Hazelden’s shift of treatment philosophy is an indication that this research-supported viewpoint is gaining acceptance in the traditionally drug-free halls of addiction treatment programs.

Experts have argued for decades about how best to manage opiate dependence, with practitioners generally subscribing to one of two strategies: either total abstinence or medication-assisted treatment (MAT).

Although MAT has proven efficacy, it has been slow to gain acceptance, and the gold standard of care since the 1930s has been abstinence-based treatment. Among elite institutional holdouts against MAT was the Hazelden Treatment Center, a leading treatment institution and publishing house that had been wedded to the abstinence model since it was founded in 1949.¹ Now, Hazelden has gone on record as embracing MAT, raising the possibility that the two predominant treatment philosophies for opiate-dependent patients may no longer be at odds.

FROM ABSTINENCE TO METHADONE MAINTENANCE

The modern day abstinence-based movement in this country started in the decade before the founding of Hazelden. In 1935, the US government opened the first of two federal drug treatment centers, known as the United States Narcotic Farm, in Lexington, KY.² The move by the government to get into the addiction treatment business largely stemmed from frustration over the growing problem of addiction at that time, coupled with a dearth of treatment options for addicts in the wake of the 1914 Harrison Narcotics Act.

The Narcotic Farm was an impressive facility—for all intents and purposes, a specialized prison—that initially housed 1,200 people. In addition to prisoners, it also accepted voluntary, nonprisoner patients. In many ways, it was ahead of its time. It offered a wide variety of services, including detoxification, group therapy, individual therapy, psychiatric and medical services, and vocational rehabilitation.² Housed on the premises was the Addiction Research Center at Lexington, the first intramural research branch of the National Institute of Mental Health. After the “Blue Grass” mandatory commitment laws were passed in the 1940s, even the voluntary patients were ultimately committed for a 1-year sentence at Lexington. This facility, and its sister facility in Ft. Worth, TX, would have been the envy of any modern-day abstinence-based treatment center in terms of the services offered and the long lengths of stay.

The quality of the program, as evidenced by the impressive array of services and long stays, would lead one to expect that its treatment outcomes over nearly 40 years of operation were equally stellar. However, in terms of outcomes the Farm was an abysmal failure, as shown by numerous studies demonstrating relapse rates of more than 90% in the patients discharged from it.^2,3

Similar frustrations at other abstinence-based treatment centers from the 1940s through the 1960s led Dr. Vincent Dole, the “father of methadone maintenance,” to conclude in 1971 that after detoxification from opiates, “human addicts almost always return to use of narcotics after they leave the hospital where they have been detoxified.”⁴ That realization inspired Dr. Dole and his wife and colleague Dr. Marie Nyswander to revisit the idea of medication-assisted treatment, an approach previously used by the morphine maintenance clinics of the early 1900s. This work led to the development of government-sanctioned methadone clinics across America and to the realization that long-term recovery was possible with medication, even without a lengthy hospital stay. For this revolutionary work on opiate addiction, Dr. Dole won the prestigious Lasker Award in 1988.

The major reason for the success of methadone was that, because of its pharmacokinetic profile, it could stabilize the patient through once-daily dosing without sedation or narcosis. As noted by Dr. Dole, once patients are on a stable dosing regimen, the obsessive preoccupation with drug use fades away.⁵

Despite its success, methadone maintenance had its share of detractors. It was fraught with controversy because it was viewed as a crutch, and those who were on it were often not considered by their abstinent peers as being in true recovery. The reasons for the negative attitudes toward MAT are unclear but may reflect antiquated beliefs that addiction may be indicative of a failure of morals or will, and that patients ought to be able to simply stop using.

Whatever the reason for the animosity surrounding MAT, it should be noted that an expert consensus panel convened by the Betty Ford Center in 2007 agreed that patients on MAT met their consensus definition of sobriety.⁶ The issue of what constitutes recovery remains a very complex and hotly debated topic that is beyond the scope of this paper and that has been discussed elsewhere.^6,7

For more than 3 decades, methadone was the only medication available for MAT. Federal regulations limit the dispensing of methadone to licensed clinics, most of which are located in major metropolitan areas. Patients must go to the clinic every day to receive their dose of methadone—a major inconvenience, especially to those with transportation issues. Adding to the lack of appeal of methadone maintenance is that the clinics are typically located in the higher-crime areas of cities. Savvy drug dealers know the location of these clinics and often loiter on nearby street corners in an attempt to lure addicts away from recovery by flaunting their illicit drugs.

A final, very significant drawback of methadone is its safety profile. It is a full-agonist narcotic that can be fatal in overdose or in the induction phase, especially if taken with other drugs, such as benzodiazepines.

2003: BUPRENORPHINE-NALOXONE IS APPROVED

Such concerns led researchers to search for other medications to be used for MAT that could perhaps be prescribed in a typical outpatient physician practice. For many reasons, buprenorphine became the most promising candidate. In 2003, the US Food and Drug Administration approved the combination medication buprenorphine-naloxone (Sub-oxone) as only the second drug indicated for maintenance treatment of opioid dependence in the United States.

Buprenorphine differs from methadone in that it is a partial agonist at mu opiate receptors, and therefore has a “ceiling” or “plateau” effect in terms of dose-response and a much improved safety profile. Unlike methadone, buprenorphine can be prescribed in a doctor’s office and does not have to be dispensed at a government-approved clinic.

Unfortunately, buprenorphine-maintained patients seem to carry the same stigma in the recovery community as those maintained on methadone—that they are simply substituting one drug for another. Detractors usually fail to consider that, as with methadone, patients do not report getting “high” from taking buprenorphine. Patients will often state that when they first start taking it, they “feel something,” but after a few days of adjustment, they simply feel normal. They don’t feel high, they are no longer in withdrawal, their cravings are virtually eliminated, and their opiate receptors are effectively occupied and blocked, so there is no “high” in the event of a relapse.

What’s more, buprenorphine is not a medication that will help them deal with life’s stressors by “chemical coping.” Sober coping is a skill they must learn by actively participating in a solid 12-step-based recovery program and, in some cases, in psychotherapy. By removing the drug obsession, buprenorphine promotes and facilitates the important recovery goal of learning how to deal with life on life’s terms.

ADDICTION AS CHRONIC ILLNESS

Outcomes studies of addiction treatment have focused largely on rates of relapse after discharge from acute treatments such as residential rehabilitation, partial hospitalization, and intensive outpatient programs. With MAT, however, outcomes research has primarily looked at the duration of retention in treatment.

The change in focus between the two types of treatment coincides with a paradigm shift that views addiction as a chronic condition that requires ongoing care. Continued participation in prescribed care with demonstrated efficacy is considered to be the major indicator of success. Under the chronic illness model employed by MAT providers, if a patient reverted to briefly using a drug of abuse, this would be an issue to address in his ongoing treatment and would not necessarily indicate treatment failure as with the acute care model. Beyond retention rates, research has demonstrated that MAT with methadone results in reductions in rates of criminal activity, illicit drug use, acquisition of human immunodeficiency virus, and overall mortality.^8–10

In outcomes studies, MAT has repeatedly shown better efficacy than abstinence-based approaches. During the first 5 years of its implementation, in 4,000 patients, methadone maintenance boasted 1-year retention rates exceeding 98%.¹¹ Over the subsequent 3 years, with the number of patients approaching 35,000, the 1-year retention rates fell to around 60%—still far exceeding results of abstinence-based treatment and approximating the number cited in most modern studies.¹¹

The retention rates in buprenorphine programs are similarly promising. Studies of 12 to 13 weeks duration have shown retention rates of 52% to 79%.^12–15 Six-month studies have demonstrated retention rates of 43% to 100%.^16–19 Another study showed that 38% of opiate-dependent patients remained in treatment with buprenorphine at 5 years.²⁰ Surprisingly, most of the buprenorphine studies have been conducted in office-based practices, which are less structured than outpatient methadone programs.

MEDICATION-ASSISTED TREATMENT IS GAINING ACCEPTANCE

Data from decades of experience with MAT strongly support the conclusion that it is superior to abstinence-based approaches.

The importance of a patient staying in treatment cannot be overemphasized, as the consequence of failing in recovery may well be an early death. On average, heroin addicts lose about 18 years of life expectancy, and the mortality rate for injection users is roughly 2% per year.²¹ The mortality rate for heroin users is 6 to 20 times greater than for age-matched peers who are not drug users.²²

As high as these numbers are, they are even higher for abusers of prescription narcotics. The annual death rate associated with opioid pain relievers (4.8 per 100,000) is nearly double that associated with illicit drugs (2.8 per 100,000).²³

The recent and rather radical change in treatment philosophy by Hazelden came as a shock to some, a disappointment to others, and a welcome change to many who saw this as a move by one of the more respected treatment centers in the country to fall in line with the body of evidence that supports MAT for those suffering from opiate dependence. It remains a mystery why so many, if not most, addiction treatment centers in the United States cling to the abstinence-based philosophy despite the overwhelming data from decades of research and experience that show that abstinence does not work for the majority of opiate addicts.

Complete abstinence from opiate drugs of abuse and potentially addictive medications is a noble but perhaps unreachable goal for many sufferers. Hazelden’s announced acceptance of MAT gives credence to the value of recovery goals that are not entirely drug-free.

Dr. Dole was correct in stating that opiate addicts usually return to drugs if not provided with MAT. Treatment programs need to inform opiate-dependent patients that abstinence-based treatment offers only a 1 in 10 chance of success. Perhaps some patients, armed with the daunting statistics regarding abstinence, will be inspired to devote themselves wholeheartedly to their recovery in an effort to make it into that elite 10% group that achieves long-lasting recovery without the aid of medications. But for the other 90%, it is encouraging to hear that Hazelden, the model treatment center for most abstinence-based programs in this country, may now lead other abstinence-based centers to reconsider their treatment philosophies.

Historically, US doctors were not allowed by federal law to prescribe opiates for addiction treatment. With the passage of DATA 2000, buprenorphine (alone or in combination with naloxone) can be prescribed for addiction treatment only by providers who obtain a waiver from the US Drug Enforcement Administration (DEA). Any doctor can become qualified to prescribe buprenorphine or buprenorphinenaloxone after completing an 8-hour online training course (available at www.buppractice.com and at www.aaap.org/buprenorphine) and by obtaining a DATA 2000 waiver and a new prescribing number from the DEA. Doctors are initially limited to treating only 30 patients with buprenorphine-naloxone at any given time, but can apply for an extension to 100 patients after having had their waiver for 1 year.

As MAT continues to gain favor, demand will grow for more providers to obtain their waivers to prescribe buprenorphine and buprenorphine-naloxone. Historically, there have always been too few methadone clinics to meet the demand. One can hope that the growing number of waivered providers will greatly improve access to care by opiate addicts, no matter where they reside. Qualified prescribers of buprenorphine and buprenorphine-naloxone are limited by the federal restrictions on the numbers of patients they can treat. If the chronic disease of addiction is to be integrated into the continuing-care approach of modern medicine and managed alongside other chronic diseases, primary care providers who are not specialized in treating addiction will need to be become comfortable with maintaining patients on buprenorphine-naloxone.⁷ Presumably, such patients will have already been stabilized through participation in addiction treatment programs in their respective geographic areas. Primary care providers will need to develop relationships with local addictionologists and treatment programs so that they will be able to refer those in active addiction for induction and stabilization on MAT and will be able to refer those already stabilized on MAT back to such specialists when relapses occur.

We may finally be approaching a time when structured residential treatment and MAT are not mutually exclusive options for our patients. These treatment options must work together for optimal outcomes. Based on our experience with hundreds of patients at Cleveland Clinic’s Alcohol and Drug Recovery Center, we believe this change of treatment philosophy is long overdue. In clinical settings, patients do not fit cleanly into one treatment arm or another and often require a blended approach to effect long-lasting change. Hazelden’s shift of treatment philosophy is an indication that this research-supported viewpoint is gaining acceptance in the traditionally drug-free halls of addiction treatment programs.

Applied molecular profiling is a method for helping clinicians select the most appropriate therapy for a patient with cancer by determining the level of gene and/or protein expression within the cancer and comparing that expression pattern with the expression profiles of cancers with known outcomes. This approach facilitates the development and selection of tumor-specific therapies based on the identification of biomarkers within a tumor. Molecular characterization techniques such as immunohistochemistry, microarray analysis, and fluorescence in situ hybridization have facilitated identification and validation of a number of important solid tumor biomarkers, including HER2/neu, EGFR, EML4/ALK, and KIT, and can also be used to identify biomarkers (eg, BCR-ABL, CD20, CD30) in various hematologic malignancies. It is of note that molecular profiling can be used to identify targets in tumors for which a therapeutic agent may already be available, thus avoiding the administration of an unproven investigational agent. As the field of molecular profiling continues to evolve and next-generation techniques such as exome sequencing – sequencing 1% of the genome – and whole gene sequencing gain currency, biomarker identification and analysis will become less expensive and more efficient, and possibly allow for a pathway-oriented approach to treatment selection. Wider acceptance and use of molecular profiling should therefore help practicing physicians and oncology researchers keep pace with advances in the understanding of oncogenic expression in various malignancies and encourage the use of molecular profiling in earlier stages of cancer rather than as an option of last resort...

*Click on the link to the left for a PDF of the full article.

Applied molecular profiling is a method for helping clinicians select the most appropriate therapy for a patient with cancer by determining the level of gene and/or protein expression within the cancer and comparing that expression pattern with the expression profiles of cancers with known outcomes. This approach facilitates the development and selection of tumor-specific therapies based on the identification of biomarkers within a tumor. Molecular characterization techniques such as immunohistochemistry, microarray analysis, and fluorescence in situ hybridization have facilitated identification and validation of a number of important solid tumor biomarkers, including HER2/neu, EGFR, EML4/ALK, and KIT, and can also be used to identify biomarkers (eg, BCR-ABL, CD20, CD30) in various hematologic malignancies. It is of note that molecular profiling can be used to identify targets in tumors for which a therapeutic agent may already be available, thus avoiding the administration of an unproven investigational agent. As the field of molecular profiling continues to evolve and next-generation techniques such as exome sequencing – sequencing 1% of the genome – and whole gene sequencing gain currency, biomarker identification and analysis will become less expensive and more efficient, and possibly allow for a pathway-oriented approach to treatment selection. Wider acceptance and use of molecular profiling should therefore help practicing physicians and oncology researchers keep pace with advances in the understanding of oncogenic expression in various malignancies and encourage the use of molecular profiling in earlier stages of cancer rather than as an option of last resort...

*Click on the link to the left for a PDF of the full article.

Applied molecular profiling is a method for helping clinicians select the most appropriate therapy for a patient with cancer by determining the level of gene and/or protein expression within the cancer and comparing that expression pattern with the expression profiles of cancers with known outcomes. This approach facilitates the development and selection of tumor-specific therapies based on the identification of biomarkers within a tumor. Molecular characterization techniques such as immunohistochemistry, microarray analysis, and fluorescence in situ hybridization have facilitated identification and validation of a number of important solid tumor biomarkers, including HER2/neu, EGFR, EML4/ALK, and KIT, and can also be used to identify biomarkers (eg, BCR-ABL, CD20, CD30) in various hematologic malignancies. It is of note that molecular profiling can be used to identify targets in tumors for which a therapeutic agent may already be available, thus avoiding the administration of an unproven investigational agent. As the field of molecular profiling continues to evolve and next-generation techniques such as exome sequencing – sequencing 1% of the genome – and whole gene sequencing gain currency, biomarker identification and analysis will become less expensive and more efficient, and possibly allow for a pathway-oriented approach to treatment selection. Wider acceptance and use of molecular profiling should therefore help practicing physicians and oncology researchers keep pace with advances in the understanding of oncogenic expression in various malignancies and encourage the use of molecular profiling in earlier stages of cancer rather than as an option of last resort...

*Click on the link to the left for a PDF of the full article.

Gastrointestinal mucosal toxicity is extremely common following cytotoxic therapies. The alimentary mucosa is particularly susceptible to injury and dysfunction, leading to many debilitating complications. Despite much research, there is currently no single noninvasive biomarker to detect gut injury. Several biomarkers have been investigated in the context of gastrointestinal diseases, which may prove useful in the oncology arena. Identification of a biomarker that is easy to obtain and measure and that accurately identifies mucosal damage would allow for improved patient diagnosis of toxicities and for personalized treatment regimens. In this review, we highlight the effectiveness of urine and breath tests as potential clinically effective biomarkers, with significant focus placed on the emerging role of the carbon-13 sucrose breath test (13C SBT). The 13C SBT provides a simple, noninvasive, and integrated measure of gut function. The 13C SBT also has the potential to monitor gut function in the setting of cytotoxic therapy–induced mucositis, or in the assessment of the efficacy of antimucositis agents.

*For a PDF of the full article, click on the link to the left of this introduction.

Gastrointestinal mucosal toxicity is extremely common following cytotoxic therapies. The alimentary mucosa is particularly susceptible to injury and dysfunction, leading to many debilitating complications. Despite much research, there is currently no single noninvasive biomarker to detect gut injury. Several biomarkers have been investigated in the context of gastrointestinal diseases, which may prove useful in the oncology arena. Identification of a biomarker that is easy to obtain and measure and that accurately identifies mucosal damage would allow for improved patient diagnosis of toxicities and for personalized treatment regimens. In this review, we highlight the effectiveness of urine and breath tests as potential clinically effective biomarkers, with significant focus placed on the emerging role of the carbon-13 sucrose breath test (13C SBT). The 13C SBT provides a simple, noninvasive, and integrated measure of gut function. The 13C SBT also has the potential to monitor gut function in the setting of cytotoxic therapy–induced mucositis, or in the assessment of the efficacy of antimucositis agents.

*For a PDF of the full article, click on the link to the left of this introduction.

Gastrointestinal mucosal toxicity is extremely common following cytotoxic therapies. The alimentary mucosa is particularly susceptible to injury and dysfunction, leading to many debilitating complications. Despite much research, there is currently no single noninvasive biomarker to detect gut injury. Several biomarkers have been investigated in the context of gastrointestinal diseases, which may prove useful in the oncology arena. Identification of a biomarker that is easy to obtain and measure and that accurately identifies mucosal damage would allow for improved patient diagnosis of toxicities and for personalized treatment regimens. In this review, we highlight the effectiveness of urine and breath tests as potential clinically effective biomarkers, with significant focus placed on the emerging role of the carbon-13 sucrose breath test (13C SBT). The 13C SBT provides a simple, noninvasive, and integrated measure of gut function. The 13C SBT also has the potential to monitor gut function in the setting of cytotoxic therapy–induced mucositis, or in the assessment of the efficacy of antimucositis agents.

*For a PDF of the full article, click on the link to the left of this introduction.

ABSTRACT

Oncologists frequently face the difficult task of estimating prognosis in patients with incurable malignancies. Their prediction of prognosis informs decision-making ranging from recommendations of cancer treatments to hospice enrollment. Unfortunately, physicians’ estimates of prognosis are often inaccurate and overly optimistic. Further, physicians often fail to disclose their prognosis estimates, despite patient wishes to the contrary. Several studies have examined patient factors that might improve physicians’ prognostic accuracy, including performance status, clinical symptoms and laboratory values. Prognostic models have been developed and validated but, to date, none are able to provide accurate estimates throughout the spectrum of advanced illness. This review examines tools utilized to predict life expectancy for patients with advanced, incurable cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

ABSTRACT

Oncologists frequently face the difficult task of estimating prognosis in patients with incurable malignancies. Their prediction of prognosis informs decision-making ranging from recommendations of cancer treatments to hospice enrollment. Unfortunately, physicians’ estimates of prognosis are often inaccurate and overly optimistic. Further, physicians often fail to disclose their prognosis estimates, despite patient wishes to the contrary. Several studies have examined patient factors that might improve physicians’ prognostic accuracy, including performance status, clinical symptoms and laboratory values. Prognostic models have been developed and validated but, to date, none are able to provide accurate estimates throughout the spectrum of advanced illness. This review examines tools utilized to predict life expectancy for patients with advanced, incurable cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

ABSTRACT

Oncologists frequently face the difficult task of estimating prognosis in patients with incurable malignancies. Their prediction of prognosis informs decision-making ranging from recommendations of cancer treatments to hospice enrollment. Unfortunately, physicians’ estimates of prognosis are often inaccurate and overly optimistic. Further, physicians often fail to disclose their prognosis estimates, despite patient wishes to the contrary. Several studies have examined patient factors that might improve physicians’ prognostic accuracy, including performance status, clinical symptoms and laboratory values. Prognostic models have been developed and validated but, to date, none are able to provide accurate estimates throughout the spectrum of advanced illness. This review examines tools utilized to predict life expectancy for patients with advanced, incurable cancer.

*For a PDF of the full article, click on the link to the left of this introduction.