Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

DABIGATRAN, A THROMBIN INHIBITOR

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

DABIGATRAN, A THROMBIN INHIBITOR

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Dabigatran etexilate (Pradaxa) is a new oral anticoagulant that has distinct advantages over warfarin (Coumadin) in terms of its ease of administration, efficacy, and safety.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY trial),¹ in patients with nonvalvular atrial fibrillation, dabigatran 110 mg twice a day was found to be as good as warfarin in preventing systemic embolization and stroke (the primary outcome of the study), and at 150 mg twice a day it was superior.¹ It has also shown efficacy in treating acute deep vein thrombosis and pulmonary embolism and in preventing these complications in orthopedic surgical patients.^2–4

Dabigatran has been approved in 75 countries. It carries the trade name Pradaxa in Europe and the United States and Pradax in Canada. In October 2010, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee endorsed two twice-daily doses (75 mg and 150 mg) of dabigatran for the prevention of systemic embolization and stroke in patients with nonvalvular atrial fibrillation.

However, dabigatran is relatively expensive, and its current high cost might be a barrier to its wider use.

MANY PATIENTS NEED ANTICOAGULATION

Anticoagulation plays a vital role in the primary and secondary prevention of stroke in patients with atrial fibrillation and of pulmonary embolism in patients with venous thromboembolism. It is also used during cardiothoracic and vascular surgery, endovascular procedures, and dialysis and in patients with mechanical heart valves and hypercoagulable conditions.

Atrial fibrillation affects 3.03 million people in the United States (2005 figures), and this number is predicted to be as high as 7.56 million by 2050.⁵ More than 10% of people over the age of 80 years have it, and the lifetime risk of developing it is approximately 25%.^6,7 Its most serious complication is ischemic stroke (the risk of which increases with age) and systemic embolization.^5,8

Until the recent introduction of dabigatran, the only oral anticoagulant available in the United States for treating patients with atrial fibrillation was warfarin. Although warfarin has a number of disadvantages (see below), it is actually very effective for preventing ischemic stroke, reducing the incidence by as much as 65%.^9,10

Venous thromboembolism is the third most common cardiovascular disorder after myocardial infarction and stroke.¹¹ Although its exact incidence is unknown, nearly 1 million cases of it (incident or recurrent, fatal and nonfatal events) occur in the United States each year.¹² Many patients with venous thromboembolism need oral anticoagulation long-term, and currently warfarin remains the only option for them as well.

NEEDED: A BETTER ANTICOAGULANT

Warfarin has been the most commonly prescribed oral anticoagulant in the United States for more than 60 years. As of 2004, more than 30 million outpatient prescriptions for it were filled annually in this country alone.¹³ However, warfarin has several important limitations.

Warfarin has a narrow therapeutic index. Patients taking it require monitoring of their international normalized ratio (INR) and frequent dose adjustments, and this is time-consuming and inconvenient. The target INR for patients with venous thromboembolism and atrial fibrillation is 2.0 to 3.0, whereas patients with a mechanical heart valve need a higher INR (2.5 to 3.5). If the INR is below these ranges, warfarin is less effective, with a risk of new thrombosis. On the other hand, if the INR is too high, there is a risk of bleeding.¹⁴ In fact, the most important side effect of warfarin is the risk of major and minor bleeding.¹³ However, even in well-designed clinical trials in which patients are closely managed, only 55% to 60% of patients regularly achieve their therapeutic target INR.^1,2,14,15

Warfarin also interacts with many drugs and with some foods. Compliance is difficult. It has a slow onset of action. Genetic variations require dose adjustments. When switching from a parenteral anticoagulant, overlapping is required. Skin necrosis is a possible side effect. And warfarin is teratogenic.

Despite these limitations, the American College of Chest Physicians endorses warfarin to prevent or treat venous thromboembolism, and to prevent stroke in patients with atrial fibrillation.¹⁶

DABIGATRAN, A THROMBIN INHIBITOR

A prodrug, dabigatran is rapidly absorbed and converted to its active form. Its plasma concentration reaches a peak 1.5 to 3 hours after an oral dose, and it has an elimination half-life of 12 to 14 hours. About 80% of its excretion is by the kidneys and the remaining 20% is through bile.

Dabigatran is not metabolized by cytochrome P450 isoenzymes, and therefore it has few major interactions with other drugs. An exception is rifampin, a P-glycoprotein inducer that blocks dabigatran’s absorption in the gut, so this combination should be avoided. Another is quinidine, a strong P-glycoprotein inhibitor that is contraindicated for use with dabigatran. Also, amiodarone (Cordarone), another P-glycoprotein inhibitor, increases blood levels of dabigatran, and therefore a lower dose of dabigatran is recommended if these drugs are given together.^18–20

DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.^18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.²⁰

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.¹⁹ Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.^18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.^18,19,21

EVALUATED IN CLINICAL TRIALS

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.^26,27

Warfarin, in contrast, costs as little as $50 per year.²⁸ However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.²⁹ In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.³⁰

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al³¹ analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS₂ score of 1 or higher or equivalent. (The CHADS₂ score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS₂ score who is considered at a higher risk for stroke.³¹

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.¹⁴ In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.^1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.¹

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.³³ The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.³⁴

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.¹

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

SPECIAL CONDITIONS

Switching from other anticoagulants to dabigatran

When making the transition from a subcutaneously administered anticoagulant, ie, a low-molecular-weight heparin or the anti-Xa inhibitor fondaparinux (Arixtra), dabigatran should be started 0 to 2 hours before the next subcutaneous dose of the parenteral anticoagulant was to be given.^21,35

When switching from unfractionated heparin given by continuous intravenous infusion, the first dose of dabigatran should be given at the time the infusion is stopped.

When switching from warfarin, dabigatran should be started once the patient’s INR is less than 2.0.

Switching from dabigatran to a parenteral anticoagulant

When switching from dabigatran back to a parenteral anticoagulant, allow 12 to 24 hours after the last dabigatran dose before starting the parenteral agent.^21,35

Elective surgery or invasive procedures

The manufacturer recommends stopping dabigatran 1 to 2 days before elective surgery for patients who have normal renal function and a low risk of bleeding, or 3 to 5 days before surgery for patients who have a creatinine clearance of 50 mL/min or less. Before major surgery or placement of a spinal or epidural catheter, the manufacturer recommends that dabigatran be held even longer.³⁵

If emergency surgery is needed

If emergency surgery is needed, the clinician must use his or her judgment as to the risks of bleeding vs those of postponing the surgery.^21,35

Overdose or bleeding

No antidote for dabigatran is currently available. It has a short half-life (12–14 hours), and the treatment for overdose or bleeding is to discontinue it immediately, maintain adequate diuresis, and transfuse fresh-frozen plasma or red blood cells as indicated.

The role of activated charcoal given orally to reduce absorption is under evaluation, but the charcoal must be given within 1 to 2 hours after the overdose is taken.²¹

Dabigatran does not bind very much to plasma proteins and hence is dialyzable—an approach that may be necessary in cases of persistent or life-threatening bleeding.

Recombinant activated factor VII or prothrombin complex concentrates may be additional options in cases of severe bleeding.^18,21

TOPICS OF FUTURE RESEARCH

A limitation of the dabigatran trials was that they did not enroll patients who had renal or liver impairment, cancer, or other comorbidities; pregnant women; or children. Other topics of future research include its use in patients weighing less than 48 kg or more than 110 kg, its efficacy in patients with thrombophilia, in patients with mechanical heart valves, and in long-term follow-up and the use of thrombolytics in patients with acute stroke who are on dabigatran.

WILL DABIGATRAN CHANGE CLINICAL PRACTICE?

Despite some of the challenges listed above, we believe that dabigatran is likely to change medical practice in patients requiring anticoagulation.

Dabigatran’s biggest use will most likely be in patients with atrial fibrillation, mainly because this is the largest group of people receiving anticoagulation. In addition, the incidence of atrial fibrillation rises with age, the US population is living longer, and patients generally require life-long anticoagulation once this condition develops.

Dabigatran may be approved for additional indications in the near future. It has already shown efficacy in primary and secondary prevention of venous thromboembolism. Other important areas to be studied include its use in patients with mechanical heart valves and thrombophilia.

Whether dabigatran will be a worthy substitute for the parenteral anticoagulants (heparin, low-molecular-weight heparins, or factor Xa inhibitors) is not yet known, but it will have an enormous impact on anticoagulation management if proved efficacious.

If dabigatran becomes a major substitute for warfarin, it will affect the anticoagulation clinics, with their well-trained staff, that are currently monitoring millions of patients in the United States. These clinics would no longer be needed, and laboratory and technical costs could be saved. A downside is that patients on dabigatran will not be as closely supervised and reminded to take their medication as patients on warfarin are now at these clinics. Instead, they will likely be supervised by their own physician (or assistants), who will need to become familiar with this anticoagulant. This may affect compliance with dabigatran.

OTHER NEW ORAL ANTICOAGULANTS ARE ON THE WAY

Other oral anticoagulants, including rivaroxaban (Xarelto) and apixaban (Eliquis), have been under study and show promise in preventing both thrombotic stroke and venous thromboembolism. They will likely compete with dabigatran once they are approved.

Rivaroxaban, an oral direct factor Xa inhibitor, is being investigated for stroke prevention in patients with atrial fibrillation. It has also been shown to be not inferior to (and to be less expensive than) enoxaparin in treating and preventing venous thromboembolism in patients undergoing hip or knee arthroplasty.^32,36,37 Rivaroxaban has recently been approved by the FDA for this indication.

Apixaban, another direct factor Xa inhibitor, is also being studied for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. To date, there are no head-to-head trials comparing dabigatran with either of these new oral anticoagulants.

Popular questionnaires to screen for alcohol misuse include the CAGE, the TWEAK, and the short form of the Alcohol Use Disorder Identification Test (AUDIT-C). Any of these is recommended. The important thing is to be proactive about screening for this very common and underrecognized problem.

A COMMON PROBLEM, NOT OFTEN ADMITTED

Alcohol use disorder, which ranges from hazardous drinking to binge drinking and alcohol dependence, is more common than admitted and often goes undiagnosed. Its personal, societal, and economic consequences cannot be overemphasized. Alcohol use is responsible for 85,000 deaths each year in the United States, and it is linked to substantial medical and psychiatric consequences and injuries, especially motor vehicle accidents. The estimated annual cost of problems attributed to alcohol use is over $185 billion.¹

About three in 10 US adults drink at levels that increase their risk for alcohol-related consequences, and about one in four adults currently abuses alcohol or is dependent on it.² In 2009, 6.8% of the US population age 12 and above reported heavy drinking, with highest rates in those ages 21 to 29.³ The rate of alcohol use was higher in men than in women, but about 10% of pregnant women ages 15 to 44 reported current alcohol use.³

The prevalence of alcohol use disorder ranges from 2% to 29% in a typical ambulatory primary care medical practice.⁴ And only one-third of people with alcohol use disorder are diagnosed.

Studies and experience have shown that problem drinkers tend to not seek help until they have advanced dependence, often with associated medical and sociolegal complications. It is also well established that the earlier the diagnosis is made and appropriate intervention is offered, the better the prognosis.

WHAT IS THE GOAL OF SCREENING?

The goals of screening for alcohol use disorder are to estimate the patient’s risk level, to identify those at risk because they exceed defined limits, and to identify those with evidence of an active problem, ie, with adverse consequences related to their drinking. This screening paves the way for further assessment, definitive diagnosis, and a treatment plan.

The US Preventive Services Task Force recommends screening and behavioral counseling interventions (such as a brief intervention) in the primary care setting to reduce alcohol misuse by adults, including pregnant women.⁵ In addition, most primary care patients who screen positive for heavy drinking or alcohol use disorder show motivation and readiness to change, and those with the most severe symptoms tend to be the most ready.⁶

THE IDEAL QUESTIONNAIRE: SENSITIVE, SPECIFIC, AND SHORT

The ideal alcohol screening questionnaire for a busy practice should be brief and highly sensitive and specific for identifying the spectrum of alcohol misuse. Also, it should be easy to recall so it can be part of routine face-to-face discussion with the patient during an office visit.

Further, it should include questions that focus on the consequences of drinking as well as on quantity and frequency. It should also take into account factors such as the patient’s age, sex, race or ethnicity, and pregnancy status, as these can influence the effectiveness of the screening method.

Problems with focusing on quantity alone

“Risky use” is defined (in a non-alcohol-dependent person or one with no alcohol-related consequences) as more than seven standard drinks per week or more than three per occasion for women, and more than 14 standard drinks per week or more than four per occasion for men.²

A standard drink in the United States contains about 12 to 14 g of ethanol: a 12-oz can or bottle of beer, a 5-oz glass of wine, or about 1.5 oz of 80-proof liquor.²

The common single-item screening test asks, “How many times in the past year have you had more than four drinks (for women) or five drinks (for men) in a day?” This is recommended by the National Institute on Alcohol Abuse and Alcoholism for brief screening in primary care. However, a positive answer (ie, one or more times in the past year) has a sensitivity of only 82% and a specificity of only 79% for detecting unhealthy alcohol use, and an even lower specificity (67%) for detecting current alcohol use disorder.⁷

The CAGE questionnaire

The four-item CAGE questionnaire⁸ focuses on the consequences of drinking:

• C: Have you felt the need to cut down on your drinking?
• A: Have you ever felt annoyed by someone criticizing your drinking?
• G: Have you ever felt bad or guilty about your drinking?
• E: Have you ever had an eye-opener—a drink the first thing in the morning to steady your nerves?

A yes to one or more of the questions denotes a need for further assessment.

The CAGE questionnaire is simple, non-threatening, brief, and easy to remember. A yes answer to two or more items has a sensitivity of 75% to 95% and a specificity of 84% to 97% for alcohol dependence.⁹ However, CAGE is less sensitive for identifying nonalcohol-dependent at-risk drinkers. The patient’s sex and ethnicity have also been found to affect its performance somewhat, with some studies showing a sensitivity as low as 50% in adult white women and as low as 40% in at-risk groups ages 60 and over.

 

 

The TWEAK questionnaire

The TWEAK is a modification of the CAGE and includes a question about tolerance; it has a sensitivity of 87% for harmful drinking and 84% for dependence, especially in trauma-related cases.⁹ It has also been found to be better than the CAGE for screening pregnant patients.

• Tolerance: How many drinks can you hold without falling asleep or passing out? (2 points if six drinks or more)
• Worried: Have friends or relatives worried about your drinking? (2 points if yes)
• Eye-opener: Do you sometimes take a drink in the morning when you first get up? (1 point if yes)
• Amnesia: Have friends or relatives told you about things you said or did while drinking that you could not remember? (1 point if yes)
• Cut down: Do you sometimes feel the need to cut down on your drinking? (1 point if yes)

An answer of ≥ 6 to the first question or a total score of 3 or more denotes a problem with alcohol use and a need for further assessment.¹⁰

The AUDIT-C

The AUDIT-C, a shorter form of the 10-item AUDIT developed by the World Health Organization, uses only the first three questions of the full-length AUDIT. The three-item AUDIT-C has a sensitivity ranging from 85% in Hispanic women to 95% in white men.^9,11 The questions center on the quantity and frequency of alcohol use:

• How often do you have a drink containing alcohol? Answer choices: never; monthly or less often; 2 to 4 times a month; 2 to 3 times a week; 4 or more times a week.
• How many standard drinks containing alcohol do you have on a typical day when you are drinking? Answer choices: one or two; three or four; five or six; seven to nine; 10 or more.
• How often do you have six or more drinks on one occasion? Answer choices: never, less than monthly; monthly; weekly; daily or almost.

Scoring is 0 for never, and 1, 2, 3, or 4 for the subsequent answer choices in each question.

The cut-off score for the AUDIT-C is usually a total of 3 points for women and 4 for men: ie, a score of 3 or higher for women and a score of 4 or higher for men indicate alcohol use disorder and the need for further assessment.

The AUDIT questionnaire has been found not only to have a high sensitivity (83%) and specificity (90%) for identifying alcohol dependence, but also to be more sensitive than the CAGE questionnaire (85% vs 75%) for identifying harmful drinking, hazardous drinking, and at-risk drinking. (Note: The full version of AUDIT performed similarly to the three-item AUDIT-C for detecting heavy drinking and active abuse or dependence.¹²) Furthermore, it has performed well as a screening test in many multinational trials of alcohol brief intervention. The questions about quantity of alcohol consumed may be even more suitable for adolescents and young adults, who tend to fall into the harmful-hazardous drinking category rather than the dependent category. In some studies, patients tended to reveal less with the CAGE questionnaire when it was preceded by direct and close-ended questions about the quantity and frequency of alcohol use, thus reducing its sensitivity.¹³

The AUDIT and TWEAK questionnaires showed greater sensitivity in both men and women than the CAGE questionnaire and were equally sensitive in African Americans.¹⁴

HOW TO FIT ALCOHOL SCREENING INTO AN OFFICE VISIT

A practical way to fit alcohol screening into an office visit is to include a questionnaire in the assessment papers completed by the patient while in the waiting room. In other settings, these questions may be asked by trained nursing staff as part of the initial assessment, ie, while obtaining the patient’s weight and vital statistics. This can be briefly reviewed by the physician during the face-to-face history and physical examination.

A concerted effort is needed to proactively screen for alcohol use. A combination of questions about the effect, the quantity, and the frequency of alcohol use is the best way to screen for the many different aspects of alcohol use disorder—many of which can be managed in the primary care setting through brief interventions without referral to a specialist.

When screening for alcohol misuse, it is also important to consider factors such as age, sex, race or ethnicity, pregnancy, and history of recent trauma or surgery.

Popular questionnaires to screen for alcohol misuse include the CAGE, the TWEAK, and the short form of the Alcohol Use Disorder Identification Test (AUDIT-C). Any of these is recommended. The important thing is to be proactive about screening for this very common and underrecognized problem.

A COMMON PROBLEM, NOT OFTEN ADMITTED

Alcohol use disorder, which ranges from hazardous drinking to binge drinking and alcohol dependence, is more common than admitted and often goes undiagnosed. Its personal, societal, and economic consequences cannot be overemphasized. Alcohol use is responsible for 85,000 deaths each year in the United States, and it is linked to substantial medical and psychiatric consequences and injuries, especially motor vehicle accidents. The estimated annual cost of problems attributed to alcohol use is over $185 billion.¹

About three in 10 US adults drink at levels that increase their risk for alcohol-related consequences, and about one in four adults currently abuses alcohol or is dependent on it.² In 2009, 6.8% of the US population age 12 and above reported heavy drinking, with highest rates in those ages 21 to 29.³ The rate of alcohol use was higher in men than in women, but about 10% of pregnant women ages 15 to 44 reported current alcohol use.³

The prevalence of alcohol use disorder ranges from 2% to 29% in a typical ambulatory primary care medical practice.⁴ And only one-third of people with alcohol use disorder are diagnosed.

Studies and experience have shown that problem drinkers tend to not seek help until they have advanced dependence, often with associated medical and sociolegal complications. It is also well established that the earlier the diagnosis is made and appropriate intervention is offered, the better the prognosis.

WHAT IS THE GOAL OF SCREENING?

The goals of screening for alcohol use disorder are to estimate the patient’s risk level, to identify those at risk because they exceed defined limits, and to identify those with evidence of an active problem, ie, with adverse consequences related to their drinking. This screening paves the way for further assessment, definitive diagnosis, and a treatment plan.

The US Preventive Services Task Force recommends screening and behavioral counseling interventions (such as a brief intervention) in the primary care setting to reduce alcohol misuse by adults, including pregnant women.⁵ In addition, most primary care patients who screen positive for heavy drinking or alcohol use disorder show motivation and readiness to change, and those with the most severe symptoms tend to be the most ready.⁶

THE IDEAL QUESTIONNAIRE: SENSITIVE, SPECIFIC, AND SHORT

The ideal alcohol screening questionnaire for a busy practice should be brief and highly sensitive and specific for identifying the spectrum of alcohol misuse. Also, it should be easy to recall so it can be part of routine face-to-face discussion with the patient during an office visit.

Further, it should include questions that focus on the consequences of drinking as well as on quantity and frequency. It should also take into account factors such as the patient’s age, sex, race or ethnicity, and pregnancy status, as these can influence the effectiveness of the screening method.

Problems with focusing on quantity alone

“Risky use” is defined (in a non-alcohol-dependent person or one with no alcohol-related consequences) as more than seven standard drinks per week or more than three per occasion for women, and more than 14 standard drinks per week or more than four per occasion for men.²

A standard drink in the United States contains about 12 to 14 g of ethanol: a 12-oz can or bottle of beer, a 5-oz glass of wine, or about 1.5 oz of 80-proof liquor.²

The common single-item screening test asks, “How many times in the past year have you had more than four drinks (for women) or five drinks (for men) in a day?” This is recommended by the National Institute on Alcohol Abuse and Alcoholism for brief screening in primary care. However, a positive answer (ie, one or more times in the past year) has a sensitivity of only 82% and a specificity of only 79% for detecting unhealthy alcohol use, and an even lower specificity (67%) for detecting current alcohol use disorder.⁷

The CAGE questionnaire

The four-item CAGE questionnaire⁸ focuses on the consequences of drinking:

• C: Have you felt the need to cut down on your drinking?
• A: Have you ever felt annoyed by someone criticizing your drinking?
• G: Have you ever felt bad or guilty about your drinking?
• E: Have you ever had an eye-opener—a drink the first thing in the morning to steady your nerves?

A yes to one or more of the questions denotes a need for further assessment.

The CAGE questionnaire is simple, non-threatening, brief, and easy to remember. A yes answer to two or more items has a sensitivity of 75% to 95% and a specificity of 84% to 97% for alcohol dependence.⁹ However, CAGE is less sensitive for identifying nonalcohol-dependent at-risk drinkers. The patient’s sex and ethnicity have also been found to affect its performance somewhat, with some studies showing a sensitivity as low as 50% in adult white women and as low as 40% in at-risk groups ages 60 and over.

 

 

The TWEAK questionnaire

The TWEAK is a modification of the CAGE and includes a question about tolerance; it has a sensitivity of 87% for harmful drinking and 84% for dependence, especially in trauma-related cases.⁹ It has also been found to be better than the CAGE for screening pregnant patients.

• Tolerance: How many drinks can you hold without falling asleep or passing out? (2 points if six drinks or more)
• Worried: Have friends or relatives worried about your drinking? (2 points if yes)
• Eye-opener: Do you sometimes take a drink in the morning when you first get up? (1 point if yes)
• Amnesia: Have friends or relatives told you about things you said or did while drinking that you could not remember? (1 point if yes)
• Cut down: Do you sometimes feel the need to cut down on your drinking? (1 point if yes)

An answer of ≥ 6 to the first question or a total score of 3 or more denotes a problem with alcohol use and a need for further assessment.¹⁰

The AUDIT-C

The AUDIT-C, a shorter form of the 10-item AUDIT developed by the World Health Organization, uses only the first three questions of the full-length AUDIT. The three-item AUDIT-C has a sensitivity ranging from 85% in Hispanic women to 95% in white men.^9,11 The questions center on the quantity and frequency of alcohol use:

• How often do you have a drink containing alcohol? Answer choices: never; monthly or less often; 2 to 4 times a month; 2 to 3 times a week; 4 or more times a week.
• How many standard drinks containing alcohol do you have on a typical day when you are drinking? Answer choices: one or two; three or four; five or six; seven to nine; 10 or more.
• How often do you have six or more drinks on one occasion? Answer choices: never, less than monthly; monthly; weekly; daily or almost.

Scoring is 0 for never, and 1, 2, 3, or 4 for the subsequent answer choices in each question.

The cut-off score for the AUDIT-C is usually a total of 3 points for women and 4 for men: ie, a score of 3 or higher for women and a score of 4 or higher for men indicate alcohol use disorder and the need for further assessment.

The AUDIT questionnaire has been found not only to have a high sensitivity (83%) and specificity (90%) for identifying alcohol dependence, but also to be more sensitive than the CAGE questionnaire (85% vs 75%) for identifying harmful drinking, hazardous drinking, and at-risk drinking. (Note: The full version of AUDIT performed similarly to the three-item AUDIT-C for detecting heavy drinking and active abuse or dependence.¹²) Furthermore, it has performed well as a screening test in many multinational trials of alcohol brief intervention. The questions about quantity of alcohol consumed may be even more suitable for adolescents and young adults, who tend to fall into the harmful-hazardous drinking category rather than the dependent category. In some studies, patients tended to reveal less with the CAGE questionnaire when it was preceded by direct and close-ended questions about the quantity and frequency of alcohol use, thus reducing its sensitivity.¹³

The AUDIT and TWEAK questionnaires showed greater sensitivity in both men and women than the CAGE questionnaire and were equally sensitive in African Americans.¹⁴

HOW TO FIT ALCOHOL SCREENING INTO AN OFFICE VISIT

A practical way to fit alcohol screening into an office visit is to include a questionnaire in the assessment papers completed by the patient while in the waiting room. In other settings, these questions may be asked by trained nursing staff as part of the initial assessment, ie, while obtaining the patient’s weight and vital statistics. This can be briefly reviewed by the physician during the face-to-face history and physical examination.

A concerted effort is needed to proactively screen for alcohol use. A combination of questions about the effect, the quantity, and the frequency of alcohol use is the best way to screen for the many different aspects of alcohol use disorder—many of which can be managed in the primary care setting through brief interventions without referral to a specialist.

When screening for alcohol misuse, it is also important to consider factors such as age, sex, race or ethnicity, pregnancy, and history of recent trauma or surgery.

Popular questionnaires to screen for alcohol misuse include the CAGE, the TWEAK, and the short form of the Alcohol Use Disorder Identification Test (AUDIT-C). Any of these is recommended. The important thing is to be proactive about screening for this very common and underrecognized problem.

A COMMON PROBLEM, NOT OFTEN ADMITTED

Alcohol use disorder, which ranges from hazardous drinking to binge drinking and alcohol dependence, is more common than admitted and often goes undiagnosed. Its personal, societal, and economic consequences cannot be overemphasized. Alcohol use is responsible for 85,000 deaths each year in the United States, and it is linked to substantial medical and psychiatric consequences and injuries, especially motor vehicle accidents. The estimated annual cost of problems attributed to alcohol use is over $185 billion.¹

About three in 10 US adults drink at levels that increase their risk for alcohol-related consequences, and about one in four adults currently abuses alcohol or is dependent on it.² In 2009, 6.8% of the US population age 12 and above reported heavy drinking, with highest rates in those ages 21 to 29.³ The rate of alcohol use was higher in men than in women, but about 10% of pregnant women ages 15 to 44 reported current alcohol use.³

The prevalence of alcohol use disorder ranges from 2% to 29% in a typical ambulatory primary care medical practice.⁴ And only one-third of people with alcohol use disorder are diagnosed.

Studies and experience have shown that problem drinkers tend to not seek help until they have advanced dependence, often with associated medical and sociolegal complications. It is also well established that the earlier the diagnosis is made and appropriate intervention is offered, the better the prognosis.

WHAT IS THE GOAL OF SCREENING?

The goals of screening for alcohol use disorder are to estimate the patient’s risk level, to identify those at risk because they exceed defined limits, and to identify those with evidence of an active problem, ie, with adverse consequences related to their drinking. This screening paves the way for further assessment, definitive diagnosis, and a treatment plan.

The US Preventive Services Task Force recommends screening and behavioral counseling interventions (such as a brief intervention) in the primary care setting to reduce alcohol misuse by adults, including pregnant women.⁵ In addition, most primary care patients who screen positive for heavy drinking or alcohol use disorder show motivation and readiness to change, and those with the most severe symptoms tend to be the most ready.⁶

THE IDEAL QUESTIONNAIRE: SENSITIVE, SPECIFIC, AND SHORT

The ideal alcohol screening questionnaire for a busy practice should be brief and highly sensitive and specific for identifying the spectrum of alcohol misuse. Also, it should be easy to recall so it can be part of routine face-to-face discussion with the patient during an office visit.

Further, it should include questions that focus on the consequences of drinking as well as on quantity and frequency. It should also take into account factors such as the patient’s age, sex, race or ethnicity, and pregnancy status, as these can influence the effectiveness of the screening method.

Problems with focusing on quantity alone

“Risky use” is defined (in a non-alcohol-dependent person or one with no alcohol-related consequences) as more than seven standard drinks per week or more than three per occasion for women, and more than 14 standard drinks per week or more than four per occasion for men.²

A standard drink in the United States contains about 12 to 14 g of ethanol: a 12-oz can or bottle of beer, a 5-oz glass of wine, or about 1.5 oz of 80-proof liquor.²

The common single-item screening test asks, “How many times in the past year have you had more than four drinks (for women) or five drinks (for men) in a day?” This is recommended by the National Institute on Alcohol Abuse and Alcoholism for brief screening in primary care. However, a positive answer (ie, one or more times in the past year) has a sensitivity of only 82% and a specificity of only 79% for detecting unhealthy alcohol use, and an even lower specificity (67%) for detecting current alcohol use disorder.⁷

The CAGE questionnaire

The four-item CAGE questionnaire⁸ focuses on the consequences of drinking:

• C: Have you felt the need to cut down on your drinking?
• A: Have you ever felt annoyed by someone criticizing your drinking?
• G: Have you ever felt bad or guilty about your drinking?
• E: Have you ever had an eye-opener—a drink the first thing in the morning to steady your nerves?

A yes to one or more of the questions denotes a need for further assessment.

The CAGE questionnaire is simple, non-threatening, brief, and easy to remember. A yes answer to two or more items has a sensitivity of 75% to 95% and a specificity of 84% to 97% for alcohol dependence.⁹ However, CAGE is less sensitive for identifying nonalcohol-dependent at-risk drinkers. The patient’s sex and ethnicity have also been found to affect its performance somewhat, with some studies showing a sensitivity as low as 50% in adult white women and as low as 40% in at-risk groups ages 60 and over.

 

 

The TWEAK questionnaire

The TWEAK is a modification of the CAGE and includes a question about tolerance; it has a sensitivity of 87% for harmful drinking and 84% for dependence, especially in trauma-related cases.⁹ It has also been found to be better than the CAGE for screening pregnant patients.

• Tolerance: How many drinks can you hold without falling asleep or passing out? (2 points if six drinks or more)
• Worried: Have friends or relatives worried about your drinking? (2 points if yes)
• Eye-opener: Do you sometimes take a drink in the morning when you first get up? (1 point if yes)
• Amnesia: Have friends or relatives told you about things you said or did while drinking that you could not remember? (1 point if yes)
• Cut down: Do you sometimes feel the need to cut down on your drinking? (1 point if yes)

An answer of ≥ 6 to the first question or a total score of 3 or more denotes a problem with alcohol use and a need for further assessment.¹⁰

The AUDIT-C

The AUDIT-C, a shorter form of the 10-item AUDIT developed by the World Health Organization, uses only the first three questions of the full-length AUDIT. The three-item AUDIT-C has a sensitivity ranging from 85% in Hispanic women to 95% in white men.^9,11 The questions center on the quantity and frequency of alcohol use:

• How often do you have a drink containing alcohol? Answer choices: never; monthly or less often; 2 to 4 times a month; 2 to 3 times a week; 4 or more times a week.
• How many standard drinks containing alcohol do you have on a typical day when you are drinking? Answer choices: one or two; three or four; five or six; seven to nine; 10 or more.
• How often do you have six or more drinks on one occasion? Answer choices: never, less than monthly; monthly; weekly; daily or almost.

Scoring is 0 for never, and 1, 2, 3, or 4 for the subsequent answer choices in each question.

The cut-off score for the AUDIT-C is usually a total of 3 points for women and 4 for men: ie, a score of 3 or higher for women and a score of 4 or higher for men indicate alcohol use disorder and the need for further assessment.

The AUDIT questionnaire has been found not only to have a high sensitivity (83%) and specificity (90%) for identifying alcohol dependence, but also to be more sensitive than the CAGE questionnaire (85% vs 75%) for identifying harmful drinking, hazardous drinking, and at-risk drinking. (Note: The full version of AUDIT performed similarly to the three-item AUDIT-C for detecting heavy drinking and active abuse or dependence.¹²) Furthermore, it has performed well as a screening test in many multinational trials of alcohol brief intervention. The questions about quantity of alcohol consumed may be even more suitable for adolescents and young adults, who tend to fall into the harmful-hazardous drinking category rather than the dependent category. In some studies, patients tended to reveal less with the CAGE questionnaire when it was preceded by direct and close-ended questions about the quantity and frequency of alcohol use, thus reducing its sensitivity.¹³

The AUDIT and TWEAK questionnaires showed greater sensitivity in both men and women than the CAGE questionnaire and were equally sensitive in African Americans.¹⁴

HOW TO FIT ALCOHOL SCREENING INTO AN OFFICE VISIT

A practical way to fit alcohol screening into an office visit is to include a questionnaire in the assessment papers completed by the patient while in the waiting room. In other settings, these questions may be asked by trained nursing staff as part of the initial assessment, ie, while obtaining the patient’s weight and vital statistics. This can be briefly reviewed by the physician during the face-to-face history and physical examination.

A concerted effort is needed to proactively screen for alcohol use. A combination of questions about the effect, the quantity, and the frequency of alcohol use is the best way to screen for the many different aspects of alcohol use disorder—many of which can be managed in the primary care setting through brief interventions without referral to a specialist.

When screening for alcohol misuse, it is also important to consider factors such as age, sex, race or ethnicity, pregnancy, and history of recent trauma or surgery.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

Current laboratory values:

• Serum calcium concentration 7.8 mg/dL (reference range 8.5–10.5)
• Phosphorus 6.4 mg/dL (2.5–4.5)
• Corrected calcium-phosphorus product 55
• Parathyroid hormone 275 pg/mL (10–60)
• 25-hydroxyvitamin D 7.4 ng/mL (31–80).

Q: Given the patient’s history, which of the following does her skin lesion likely represent?

• Necrotizing fasciitis
• Calciphylaxis
• Disseminated intravascular coagulation
• Anticoagulant-induced skin necrosis

A: Calciphylaxis, or calcific uremic arteriolopathy, is the most likely. It is rare in people with normal renal function, and still rare but somewhat less so in end-stage renal disease patients undergoing chronic hemodialysis.

WHAT CAUSED IT IN OUR PATIENT?

The cause of calciphylaxis is unknown. Theories have focused on protein C and parathyroid hormone. Putative precipitating factors include acute tubular necrosis, albumin infusion with paracentesis, deficiency of protein C or S, hyperparathyroidism, hyperphosphatemia, hypercalcemia, vitamin D supplementation, steroids, trauma, and warfarin use.

Our patient had a history of hypothyroidism, ulcerative colitis, and end-stage liver disease due to primary sclerosing cholangitis, but no previous history of renal disease.

At the time of her acute renal failure, her calcium-phosphorus level was 55, parathyroid hormone level 274 pg/mL (normal 10–60), and protein C level 26% (normal 76%–147%). At the time the skin lesions were discovered, her protein C level had dropped to 14%; her parathyroid level had returned to normal.

Her home medications included furosemide (Lasix), levothyroxine (Synthroid), mesalamine (Pentasa), azathioprine (Imuran), ursodiol (Actigall), spironolactone (Aldactone), and omeprazole (Prilosec).

NONHEALING LESIONS

The skin lesions of calciphylaxis usually occur in areas of increased adipose tissue. The lesions may not manifest until several weeks after the initial insult (ie, the elevated calcium-phosphate level). Skin biopsy is recommended if a necrotic skin lesion is identified in a patient with an elevated calcium-phosphate level or in a patient with risk factors for renal, liver, or parathyroid disease.

PROGNOSIS IS POOR

Treatment is supportive. Intensive wound care (with surgical evaluation for skin grafting), hyperbaric oxygen, and possibly tissue plasminogen activator (if there is evidence of a hypercoagulable state and occlusive vasculopathy) may be the most beneficial. Identifying the underlying cause and regulating the calcium-phosphorus product level with diet, phosphate binders, bisphosphonates, and sodium thiosulfate are also important in wound healing. Cinacalcet (Sensipar) and parathyroidectomy should be considered in cases of secondary hyperparathyroidism.

Calciphylaxis is important to recognize early in its course and may require a multidisciplinary approach to treatment. Its prognosis is poor, with death rates ranging from 40% to 60%.

Our patient developed recurrent hepatorenal syndrome and sepsis and eventually died of septic shock.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

Dr. Alan C. Braverman, in this issue of the Journal, discusses thoracic aortic dissection. To most of us who do not routinely treat aortic disease, it may not seem that much has changed since that Thanksgiving in Philadelphia. Atherosclerosis is still a common risk, surgery is the treatment for ascending dissection, beta-blockers are useful for chronic descending dissections, and the mortality rate is enormously high when dissections bleed.

As internists, we consider the possibility of genetic disorders in patients with a family history of dissection or aneurysm, but we don’t really expect to find many, and most of us don’t often track advances in the understanding of these disorders at the molecular level. At the time I was working in that emergency room, Marfan syndrome was viewed as a connective tissue disorder, with a structurally weak aortic wall and variable other morphologic features. When the molecular defect was defined as fibrillin-1 deficiency, I didn’t think much more than that the weak link of the aorta’s fibrous belt was identified.

But it turns out that fibrillin is not just an aortic girdle; fibrillin lowers the concentration of the cytokine transforming growth factor (TGF)-beta in the aorta (and other organs) by promoting its sequestration in the extracellular matrix. Absence of fibrillin enhances TGF-beta activity, and excess TGF-beta can produce Marfan syndrome in young mice. In maybe the most striking consequence of this line of research, Dietz and colleagues¹ have demonstrated that the specific antagonism of the angiotensin II type 1 receptor by the drug losartan (Cozaar) also blocks the effects of TGF-beta and consequently blocks the development of murine Marfan syndrome. And in a preliminary study, it slowed aneurysm progression in a small group of children with Marfan syndrome.

This does not imply that the same pathophysiology is at play in all aortic aneurysms. But at a time of new guidelines for screening for abdominal aneurysm, these observations offer a novel paradigm for developing drug therapies as an alternative to the mad rush for the vascular operating suite.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

 

 

Genetic evaluation

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

 

 

Genetic evaluation

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

A 50-year-old man developed severe chest pain and collapsed to the floor. The pain was sudden in onset, was burning in quality, and was located in the center of his chest. Emergency medical services arrived a few minutes later and found the patient diaphoretic and cyanotic, with an initial blood pressure of 74/54 mm Hg and a heart rate of 125 beats per minute. He was rushed to the hospital.

His medical history was unremarkable. He smoked one pack of cigarettes per day for 20 years. His father died of a “heart attack” at age 52.

In the emergency department he underwent echocardiography with a portable handheld unit, which showed a pericardial effusion and cardiac tamponade. He was sent for emergency computed tomography of the chest, which revealed an aneurysm of the aortic root and acute type A (Stanford classification) aortic dissection with hemopericardium.

He underwent emergency cardiac surgery. At the time of surgery, he was in cardiogenic shock from aortic dissection complicated by severe aortic regurgitation and cardiac tamponade with hemopericardium. The aortic valve was trileaflet. A 27-mm St. Jude composite valve graft root replacement was performed.

The patient did well and was discharged home 7 days after surgery. Pathologic study of the aorta revealed cystic medial degeneration. He did not have any features of Marfan syndrome or Loeys-Dietz syndrome. His three children underwent evaluation, and each had a normal physical examination and echocardiographic test results.

A HIGH INDEX OF SUSPICION IS CRITICAL

Acute aortic dissection is the most common aortic catastrophe, with an incidence estimated at 5 to 30 per 1 million people per year, amounting to nearly 10,000 cases per year in the United States.^1–4

The diagnosis of acute aortic dissection has many potential pitfalls.^2,3 Aortic dissection may mimic other more common conditions, such as coronary ischemia, pleurisy, heart failure, stroke, and acute abdominal illness. Because acute aortic dissection may be rapidly fatal, one must maintain a high index of suspicion.^2,3 Prompt diagnosis and emergency treatment are critical.

WHAT CAUSES AORTIC DISSECTION?

One hypothesis is that acute aortic dissection is caused by a primary tear in the aortic intima, with blood from the aortic lumen penetrating into the diseased media leading to dissection and creating a true and false lumen.² Another is that rupture of the vasa vasorum leads to hemorrhage in the aortic wall with subsequent intimal disruption, creating the intimal tear and aortic dissection.

Once a dissection starts, pulsatile flow of blood within the aortic wall causes it to extend. The dissection flap may be localized, but it often spirals the entire length of the aorta. Distention of the false lumen with blood may cause the intimal flap to compress the true lumen and potentially lead to malperfusion syndromes.

CLASSIFIED ACCORDING TO LOCATION

It is important to recognize the location of the dissection, as the prognosis and treatment depend on whether the ascending aorta is involved.^2,3 For classification purposes, the ascending aorta is the portion proximal to the brachiocephalic artery, while the descending aorta is the portion distal to the left subclavian artery.³

The DeBakey classification defines a type I aortic dissection as one that begins in the ascending aorta and extends at least to the aortic arch or beyond. Type II dissections involve the ascending aorta only, while type III dissections begin in the descending aorta, most often just distal to the left subclavian artery.

The Stanford classification scheme divides dissections into type A and type B. Type A dissections involve the ascending aorta, while type B dissections do not involve the ascending aorta.

Which classification scheme is used is not important. However, identifying patients with dissection of the ascending aorta (DeBakey type I or type II or Stanford type A) is critical, as emergency cardiac surgery is recommended for this type of dissection.^2,3 For the purposes of this paper, the Stanford classification scheme will be used.

Dissection that involves the ascending aorta most commonly occurs in people ages 50 to 60, whereas acute dissection of the descending aorta typically occurs in people 10 years older.^1,2

An acute aortic dissection is one that has occurred within 2 weeks of symptom onset. A chronic dissection is one that occurred more than 2 weeks after symptoms began.

DISEASES AND CONDITIONS ASSOCIATED WITH AORTIC DISSECTION

Hypertension and disorders leading to disruption of the normal structure and function of the aortic wall. About 75% of patients with acute aortic dissection have underlying hypertension.^1–3

Cystic medial degeneration is a common pathologic feature in many cases of aortic dissection.

Cocaine use and intense weight-lifting increase the shear stresses on the aorta.^2,3

Inflammatory aortic diseases such as giant cell arteritis.

Pregnancy can be complicated by aortic dissection, usually in the setting of an underlying aortopathy.⁵

Iatrogenic aortic dissection accounts for about 4% of cases, as a result of cardiac surgery, catheterization, stenting, or use of an intra-aortic balloon pump.¹

Aortic aneurysm. Patients with thoracic aortic aneurysm are at higher risk of aortic dissection, and the larger the aortic diameter, the higher the risk.^2,3,6 In the International Registry of Acute Aortic Dissection (IRAD), the average size of the aorta was about 5.3 cm at the time of acute dissection. Importantly, about 40% of acute dissections of the ascending aorta occur in patients with ascending aortic diameters less than 5.0 cm.^7,8

Thus, many factors are associated with acute dissection, and specific reasons leading to an individual’s susceptibility to sudden dissection are poorly understood.

CLINICAL FEATURES OF ACUTE AORTIC DISSECTION

Because the symptoms of acute dissection may mimic other, more common conditions, one of the most important factors in the diagnosis of aortic dissection is a high clinical suspicion.^1–3

What is the pretest risk of disease?

Recently, the American College of Cardiology (ACC) and the American Heart Association (AHA) released joint guidelines on thoracic aortic disease.³ These guidelines provide an approach to patients who have complaints that may represent acute thoracic aortic dissection, the intent being to establish a pretest risk of disease to be used to guide decision-making.³

The focused evaluation includes specific questions about underlying conditions, symptoms, and findings on examination that may greatly increase the likelihood of acute dissection. These include:

• High-risk conditions and historical features associated with aortic dissection, such as Marfan syndrome and other genetic disorders (Table 2), bicuspid aortic valve, family history of thoracic aortic aneurysm or dissection, known thoracic aortic aneurysm, and recent aortic manipulation
• Pain in the chest, back, or abdomen with high-risk features (eg, abrupt onset, severe intensity, or a ripping or tearing quality)
• High-risk findings on examination (eg, pulse deficits, new aortic regurgitation, hypotension, shock, or systolic blood pressure differences).

Using this information, expedited aortic imaging and treatment algorithms have been devised to improve the diagnosis.³

Using the IRAD database of more than 2,500 acute dissections, the diagnostic algorithm proposed in the ACC/AHA guidelines was shown to be highly sensitive (about 95%) for detecting acute aortic dissection.⁴ In addition, using this score may expedite evaluation by classifying certain patients as being at high risk of acute dissection.^3,4

Important to recognize is that almost two-thirds of patients who suffered dissection in this large database did not have one of the “high-risk conditions” associated with dissection.⁴ Additionally, the specificity of the ACC/AHA algorithm is unknown, and further testing is necessary.⁴

Acute onset of severe pain

More than 90% of acute dissections present with acute pain in the chest or the back, or both.^1–3 The pain is usually severe, of sudden onset, and often described as sharp or, occasionally, tearing, ripping, or stabbing. The pain usually differs from that of coronary ischemia, being most severe at its onset as opposed to the less intense, crescendo-like pain of angina or myocardial infarction. The pain may migrate as the dissection progresses along the length of the aorta or to branch vessels. It may abate, leading to a false sense of security in the patient and the physician.³ “Painless” dissection occurs in a minority, usually in those with syncope, neurologic symptoms, or heart failure.^1–3

The patient with acute dissection may be anxious and may feel a sense of doom.

Acute heart failure, related to severe aortic regurgitation, may be a predominant symptom in dissection of the ascending aorta.

Syncope may occur as a result of aortic rupture, hemopericardium with cardiac tamponade, or acute neurologic complications.

Vascular insufficiency may occur in any branch vessel, leading to clinical syndromes that include acute myocardial infarction, stroke, paraplegia, paraparesis, mesenteric ischemia, and limb ischemia.

PHYSICAL FINDINGS CAN VARY WIDELY

Findings on physical examination in acute aortic dissection vary widely depending on underlying conditions and on the specific complications of the dissection.

Although the classic presentation is acute, severe pain in the chest or back in a severely hypertensive patient with aortic regurgitation and pulse deficits, most patients do not have all these characteristics.⁴ Most patients with type B dissection are hypertensive on presentation, but many with type A dissection present with normal blood pressure or hypotension.¹ Pulse deficits (unequal or absent pulses) are reported in 10% to 30% of acute dissections and may be intermittent as the dynamic movement of the dissection flap interferes with branch vessel perfusion.^1–3

• Aortic leaflet prolapse or distortion of the leaflet alignment
• Malcoaptation of the aortic leaflets from dilation of the aortic root and annulus
• Prolapse of the intimal flap across the aortic valve, interfering with valve function
• Preexisting aortic regurgitation from underlying aortic root aneurysm or primary aortic valve disease (such as a bicuspid aortic valve).

Neurologic manifestations are most common in dissection of the ascending aorta and are particularly important to recognize, as they may dominate the clinical presentation and lead to delay in the diagnosis of dissection.^2,3 Neurologic syndromes include:

• Persistent or transient ischemic stroke
• Spinal cord ischemia
• Ischemic neuropathy
• Hypoxic encephalopathy.

These manifestations are related to malperfusion to branches supplying the brain, spinal cord, or peripheral nerves.⁹

Syncope is relatively common in aortic dissection and may be related to acute hypotension caused by cardiac tamponade or aortic rupture, cerebral vessel obstruction, or activation of cerebral baroreceptors.^2,9 It is important to consider aortic dissection in the differential diagnosis in cases of unexplained syncope.³

Aortic dissections may extend into the abdominal aorta, leading to vascular complications involving one or more branch vessels.¹⁰ The renal artery is involved in at least 5% to 10% of cases and may lead to renal ischemia, infarction, renal insufficiency, or refractory hypertension.²Mesenteric ischemia or infarction occurs in about 5% of dissections, may be difficult to diagnose, and is particularly dangerous.^2,8 Aortic dissection may extend into the iliac arteries and may cause acute lower extremity ischemia.

Acute myocardial infarction due to involvement of the dissection flap causing malperfusion of a coronary artery occurs in 1% to 7% of acute type A aortic dissections.^1–3 The right coronary artery (Figure 2) is most commonly involved, leading to acute inferior myocardial infarction. Acute myocardial ischemia and infarction in the setting of dissection may lead to a delay in the diagnosis of dissection and to bleeding complications from antiplatelet and anticoagulant drugs given to treat the acute coronary syndrome.

Cardiac tamponade, occurring in about 10% of acute type A dissections, portends a higher risk of death.^2,3

Additional clinical features of aortic dissection include a left-sided pleural effusion, usually related to an inflammatory response. An acute hemothorax may occur from rupture or leaking of a descending aortic dissection.

FINDINGS ON RADIOGRAPHY AND ELECTROCARDIOGRAPHY

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Electrocardiography usually has normal or nonspecific findings, unless acute myocardial infarction complicates the dissection.

D-DIMER LEVELS

Biomarkers for the diagnosis of acute aortic dissection are of great interest.

D-dimer levels rise in acute aortic dissection as they do in pulmonary embolism.¹¹ A D-dimer level greater than 1,600 ng/mL within the first 6 hours has a very high positive likelihood ratio for dissection, so this test may be useful in identifying patients with a high probability for dissection. In the first 24 hours after symptom onset, a D-dimer level of less than 500 ng/mL has a negative predictive value of 95%. Thus, elevations in D-dimer may help decide which imaging to perform in a patient presenting with chest pain or suspicion of dissection.¹¹

However, D-dimer levels may not be elevated in dissection variants, such as aortic intramural hematoma or penetrating aortic ulcer. Additionally, once 24 hours have elapsed since the dissection started, D-dimer levels may no longer be elevated. The current ACC/AHA guidelines on thoracic aortic disease concluded that the D-dimer level cannot be used to rule out aortic dissection in high-risk individuals.³

Additional studies may clarify the appropriate role of the D-dimer assay in diagnosing aortic dissection.

DEFINITIVE IMAGING STUDIES: CT, MRI, TEE

Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and transesophageal echocardiography (TEE) all have very high sensitivity and specificity for the diagnosis of aortic dissection.^2,3 The choice of imaging study often depends on the availability of these studies, with CT and TEE being the most commonly performed initial studies.

MRI is outstanding for detecting and following aortic dissection, but it is usually not the initial study performed because of the time required for image acquisition and because it is generally not available on an emergency basis.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

While transthoracic echocardiography (TTE) can detect aortic dissection, its sensitivity is much lower than that of other imaging tests.^2,3 Therefore, negative findings on TTE do not exclude aortic dissection.

MANAGEMENT OF AORTIC DISSECTION

When acute aortic dissection is diagnosed, multidisciplinary evaluation and treatment are necessary. Time is of the essence, as the death rate in acute dissection may be as high as 1% per hour during the first 24 hours.^1–3 All patients with acute aortic dissection, whether type A or type B, should be transferred to a tertiary care center with a staff experienced in managing aortic dissection and its complications.³ Emergency surgery is recommended for type A aortic dissection, whereas type B dissection is generally treated medically unless complications occur.^2,3

The cornerstone of drug therapy is the prompt reduction in blood pressure with a beta-blocker to reduce shear stresses on the aorta. Intravenous agents such as esmolol (Brevibloc) or labetalol (Normodyne) are usually chosen. Sodium nitroprusside may be added to beta-blocker therapy for rapid blood pressure control in appropriate patients. The patient may require multiple antihypertensive medications. If hypertension is refractory, one must consider renal artery hypertension due to the dissection causing renal malperfusion.² Acute pain may also worsen hypertension, and appropriate analgesia should be used.

Definitive therapy in acute dissection

Patients with acute type A dissection require emergency surgery,^2,3 as they are at risk for life-threatening complications including cardiac tamponade from hemopericardium, aortic rupture, stroke, visceral ischemia, and heart failure due to severe aortic regurgitation. When aortic regurgitation complicates acute type A dissection, some patients are adequately treated by resuspension of the aortic valve leaflets, while others require valve-sparing root replacement or prosthetic aortic valve replacement.

Surgical therapy is associated with a survival benefit compared with medical therapy in acute type A dissection.¹ The 14-day mortality rate for acute type A dissection treated surgically is about 25%.¹ Patients with high-risk features such as heart failure, shock, tamponade, and mesenteric ischemia have a worse prognosis compared with those without these features.^2,12,13

Acute type B aortic dissection carries a lower rate of death than type A dissection.^1–3 In the IRAD cohort, the early mortality rate in those with type B dissection treated medically was about 10%.¹ However, when complications such as malperfusion, shock, or requirement for surgery occur in type B dissection, the mortality rate is much higher,^2,14 with rates of 25% to 50% reported.²

Thus, initial medical therapy is the preferred approach to acute type B dissection, and surgery or endovascular therapy is reserved for patients with acute complications.^2,3 Typical indications for surgery or endovascular therapy in type B dissection include visceral or limb ischemia, aortic rupture, refractory pain, and aneurysmal dilation (Table 3).²

Endovascular therapy in aortic dissection

The high mortality rate with open surgery in acute type B dissection has spurred tremendous interest in endovascular treatments for complications involving the descending aorta and branch vessels.²

Fenestration of the aorta and stenting of branch vessels were the earliest techniques used in complicated type B dissection. By fenestrating (ie, opening) the intimal flap, blood can flow from the false lumen into the true lumen, decompressing the distended false lumen.

Endovascular stenting is used for acute aortic rupture, for malperfusion syndromes, and for rapidly enlarging false lumens. Endovascular grafts may cover the area of a primary intimal tear and thus eliminate the flow into the false channel and promote false-lumen thrombosis. Many patients with complicated type B dissection are treated with a hybrid approach, in which one segment of the aorta, such as the aortic arch, is treated surgically, while the descending aorta receives an endovascular graft.²

Patients with a type B dissection treated medically are at risk for late complications, including aneurysmal enlargement and subsequent aortic rupture. The Investigation of Stent Grafts in Aortic Dissection (INSTEAD) trial included 140 patients with uncomplicated type B dissection and compared drug therapy with endovascular stent grafting.¹⁵ After 2 years of follow-up, there was no difference in the rate of death between the two treatment groups. Patients receiving endovascular grafts had a higher rate of false-lumen thrombosis.

More studies are under way to examine the role of endovascular therapy in uncomplicated type B dissection.

AORTIC DISSECTION VARIANTS

Aortic intramural hematoma

Aortic intramural hematoma is a form of acute aortic syndrome in which a hematoma develops in the aortic media and no intimal flap is visualized either by imaging or at surgery.^2,3,16 It is important to recognize this clinical entity in a patient presenting with acute chest or back pain, as sometimes it is mistaken for a “thrombus in a nonaneurysmal aorta.” Intramural hematoma accounts for 5% to 25% of acute aortic syndromes, depending on the study population (it is more common in Asian studies).^2,3,17 It may present with symptoms similar to classic aortic dissection and is classified as type A or type B, depending on whether the ascending aorta is involved.

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

Patients with an intramural hematoma may progress to having complications such as hemopericardium, classic aortic dissection, aortic rupture, or aneurysmal dilation.^2,3 However, many cases of type B aortic intramural hematoma result in complete resorption of the hematoma over time. In general, like classic aortic dissection, type A intramural hematoma is treated with emergency surgery and type B with initial medical therapy.^2,3

There are reports from Southeast Asia of successful initial medical therapy for type A intramural hematoma, with surgery used for acute complications.¹⁸ In the Western literature, improved outcomes are reported with initial surgical therapy.¹⁷ Given the unpredictable nature of type A intramural hematoma, most experts recommend surgical therapy for appropriate candidates with acute type A intramural hematoma.^2,3,19

Penetrating atherosclerotic ulcer of the aorta

Penetrating atherosclerotic ulcer of the aorta, another acute aortic syndrome, results from acute penetration of an atherosclerotic aortic lesion through the internal elastic lamina into the media.^2,3,20 It is often associated with bleeding into the media, or intramural hematoma. While the ulcer may be found incidentally on imaging studies, especially in patients with severe aortic atherosclerosis, the typical presentation is acute, severe chest or back pain. It occurs most often in the descending aorta and the abdominal aorta.

Penetrating atherosclerotic ulcer may lead to pseudoaneurysm formation, focal aortic dissection, aortic rupture, or late aortic aneurysm.²

Reproduced with permission from: Braverman AC, et al. Diseases of the aorta. In: Bonow RO, et al. Braunwald's Heart Disease, 9th edition. Elsevier: Philadelphia, PA; 2011.

LONG-TERM MANAGEMENT AFTER AORTIC DISSECTION

After hospital discharge, patients with aortic dissection require lifelong management. This includes blood pressure control, lifestyle modification, serial imaging of the aorta with CT or MRI, patient education about the condition, and, when appropriate, screening of family members for aortic disease.^5,21

Reported survival rates after hospitalization for type A dissection are 52% to 94% at 1 year and 45% to 88% at 5 years.^2,22 The 10-year actuarial survival rate for those with acute dissection who survive the acute hospitalization is reported as 30% to 60%. Long-term survival rates after acute type B dissection have been reported at 56% to 92% at 1 year and 48% to 82% at 5 years.²³ Survival rates depend on many factors, including the underlying condition, the age of the patient, and comorbidities.

It is important to treat hypertension after aortic dissection, with a goal blood pressure of 120/80 mm Hg or less for most patients. Older studies found higher mortality rates with poorly controlled hypertension. Beta-blockers are the drugs of first choice. Even in the absence of hypertension, long-term beta-blocker therapy should be used to lessen the aortic stress and force of ventricular contraction.

 

 

Genetic evaluation

Genetically triggered causes of aortic dissection should be considered. In many circumstances, referral to a medical geneticist or other practitioner knowledgeable in these conditions is important when these disorders are being evaluated (Table 2).

Many of these disorders have an autosomal dominant inheritance, and the patient should be asked about a family history of aortic disease, aortic dissection, or unexplained sudden death. Features of Marfan syndrome, Loeys-Dietz syndrome, and familial thoracic aortic aneurysm syndromes should be sought. Through comprehensive family studies, it is now recognized that up to 20% of patients with thoracic aortic disease (such as aneurysm or dissection) have another first-degree relative with thoracic aortic disease.^2,3,24 Thus, first-degree relatives of patients with aortic aneurysm or dissection should be screened for thoracic aortic aneurysm disease.

Research into molecular genetics is providing a better understanding of the genetics of aortic dissection.³ New mutations associated with aortic dissection are being discovered in signaling pathways as well as elements critical for the integrity of the vascular wall.^2,3 However, at present, most patients with aortic dissection will not have a specific identifiable genetic defect.

Not only does genetic testing enable the accurate diagnosis of the affected individual, but also treatments are often based on this diagnosis.³ Importantly, the identification of a specific gene mutation (ie, in TGFBR1 or 2, FBN1, ACTA2, MYH11, and COL3A1) in an affected individual has the potential to identify other family members at risk.³

Follow-up imaging

It is important to continue to image the aorta after aortic dissection. Patients may develop progressive dilation or aneurysm formation of the dissected aorta, pseudoaneurysm formation after repair, or recurrent dissection. Many patients require additional surgery on the aorta because of late aneurysm formation.

CT or MRI is usually performed at least every 6 months in the first 2 years after dissection and at least annually thereafter. More centers are choosing MRI for long-term follow-up to avoid the repeated radiation exposure with serial CT.

Patient education

Besides receiving medical therapy and undergoing imaging, patients with aortic dissection should be educated about this condition.^5,21 The patient should be aware of symptoms suggesting dissection and should be instructed to seek attention for any concerning symptoms.

Lifestyle modifications are also important. The patient should be educated about safe activity levels and to avoid heavy isometric exercise, such as weight-lifting. Some patients will have to cease their current occupation because of activity restrictions.

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Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole

Other potential explanations

Aripiprazole’s manufacturer reported the incidence of psychosis-related adverse events in an analysis of 9 randomized schizophrenia trials.²⁷ The rates of psychosis-related adverse events ranged from 0.6% to 18%, but there was no apparent relationship to study design or method of transitioning to aripiprazole. Rates of psychosis-related adverse events were similar between aripiprazole and the control group (placebo in 3 studies, another antipsychotic in 2 studies).

Emergence or worsening of psychotic symptoms temporally associated with aripiprazole initiation does not necessarily imply causation. As in Mr. N’s case, it is not always possible to determine whether worsening psychosis is the natural disease course or a treatment effect. In addition, it is not possible to differentiate lack of efficacy from a true propensity for aripiprazole to worsen psychosis.

It also is conceivable discontinuation or dosage reduction of a previous antipsychotic would worsen psychotic symptoms or cause side effects. When significant changes in psychopathology or side effects develop during the transition from 1 antipsychotic to another, it is difficult to determine etiology. Specifically, rapid transition from a medication with significant anticholinergic and antihistaminic properties—such as quetiapine or olanzapine—to 1 without these properties—such as aripiprazole—may result in symptoms of activation, including restlessness, insomnia, and anxiety. Consequently, these symptoms could be mistaken for worsening psychosis.²⁸ Only 1 patient in this series was reported to abruptly discontinue an antipsychotic with significant anticholinergic properties (clozapine) before initiating aripiprazole.²⁴ Studies by Takeuchi et al¹⁴ and Pae et al²⁵ did not report the relative baseline use of antipsychotic medication with anticholinergic properties.

In a pooled analysis of treatment-emergent adverse events in 5 randomized clinical trials of patients receiving aripiprazole for acute relapse of schizophrenia, the incidence of akathisia was 10%, although it is not clear if this is a dose-related adverse effect.²⁹ Because akathisia may be confused for worsening psychosis,³⁰ it is possible akathisia was mistakenly identified as worsening psychotic symptoms in Mr. N’s case, as well as several reports from our literature review.

Covert akathisia is unlikely to explain worsening psychopathology observed in all patients in our literature review because confusion of akathisia and worsening psychosis is not a widespread phenomenon. In a post hoc analysis of pooled safety data from aripiprazole trials, Kane et al³¹ did not find a correlation between presence of akathisia and aripiprazole efficacy as measured by the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS negative, Clinical Global Impressions-Severity, Clinical Global Impressions-Improvement, and percentage of responders. Pae et al²⁵ also noted there was no correlation between scores on the Barnes Akathisia Rating Scale and worsening psychopathology in patients switched to aripiprazole.

An antagonist always is an antagonist and clinicians have appreciated this concept since the days of chlorpromazine. The activity of aripiprazole, however, is on a pharmacologic continuum between a neutral antagonist and full agonist and currently there is no way to precisely determine the level of D2 receptor agonist action in a patient.

Although it is interesting to speculate that aripiprazole’s D2 receptor agonist action may contribute to worsening psychosis,^32-34 there are other plausible explanations to consider. Rapid transition from a drug with significant anticholinergic properties and aripiprazole-associated akathisia may contribute to worsening psychopathology in patients starting aripiprazole. Because covert side effects may be incorrectly identified as psychotic agitation, we cannot exclude this as a possible etiologic factor in Mr. N’s case as well as the cases in our literature review.

Related Resource

• Abilify [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Biperiden • Akineton
• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Divalproex • Depakote
• Duloxetine • Cymbalta
• Fluphenazine • Permitil, Prolixin
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid
• Lorazepam • Ativan
• Nortriptyline • Aventyl, Pamelor
• Methylphenidate • Concerta
• Molindone • Moban
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Propranolol • Inderal
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Thyroxine • Synthroid
• Valproic acid • Depakene
• Ziprasidone • Geodon

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. N, age 29, presents to the emergency department at the urging of his family because of poor self-care, bizarre behavior, and disturbed sleep. He first experienced psychiatric symptoms 10 years ago after his mother died. He became dysphoric and paranoid, displaying bizarre responses and behaviors with poor self-care and a gradual functional decline. He has been taking sertraline, 100 mg/d, for 10 years.

Upon arrival at the hospital’s inpatient unit, Mr. N is unkempt, oddly related, and paranoid. His affect is constricted. Mr. N displays thought blocking and possibly is responding to internal stimuli. Sertraline is continued and haloperidol, 1 mg/d, is initiated. For the next 2 weeks, Mr. N continues to be oddly related, irritable, and paranoid, and experiences disturbed sleep and thought blocking. After an episode of impulsive aggression, the treatment team initiates aripiprazole, which is titrated to 30 mg/d for 1 week. Mr. N’s clinical status worsens; he is menacing toward other patients and his thinking is more disorganized, with loose associations and ideas of reference. He requires 4 injections of IM haloperidol, 5 mg, and several visits to the seclusion room over the next week. Haloperidol is increased to 30 mg/d over the next 10 days, then aripiprazole is discontinued because of a putative drug interaction with haloperidol. Following the medication changes Mr. N demonstrates better behavioral control, but still is grossly psychotic. While awaiting transfer to a state hospital, Mr. N receives a trial of olanzapine, 20 to 40 mg/d, for 2 weeks without significant benefit.

Several clinical trials demonstrate a significant reduction in intensity of psychotic symptoms with aripiprazole, which has a unique mechanism of action.¹ However, since its FDA approval in 2002, several case reports have described treatment-emergent psychotic symptoms associated with aripiprazole initiation. Over the past 40 years, reports of worsening psychosis associated with antipsychotics have been limited to patients with schizophrenia who were taking high dosages or who had high plasma concentrations, when anticholinergic delirium may have explained increased psychotic symptoms.^2-4

How can a drug effectively treat psychotic symptoms and occasionally worsen them? In this article, we discuss the relevant pharmacology and clinical literature on aripiprazole and try to make sense of this apparent paradox.

Unique pharmacologic profile

Antipsychotics have been reported to be either neutral antagonists or inverse agonists at the D2 receptor, based on in vitro data.⁵ Aripiprazole and its main metabolite, dehydroaripiprazole, originally were described as partial agonists at D2 dopamine receptors.^6,7 However, it appears aripiprazole’s pharmacologic action is better explained by the concept of functional selectivity. Aripiprazole may interact preferentially with distinct conformations of the D2 receptor, leading to a spectrum of pharmacologic effects, including acting as a full agonist, partial agonist, or antagonistic.⁵

Researchers have hypothesized that the pathophysiology of schizophrenia may, in part, be caused by dysfunction of mesocorticolimbic dopaminergic neurons characterized by an enhanced sensitivity of postsynaptic D2 receptors and increased sensitivity to dopaminergic drugs.^8,9 In addition, chronic treatment with a D2 receptor antagonist is associated with increases in postsynaptic dopamine receptor density (ie, an increase in receptor reserve).^10,11 Upregulation of D2 receptors may explain several features seen in patients chronically treated with antipsychotics, including tardive dyskinesia¹² and rapid psychotic relapse after discontinuing an antipsychotic (supersensitivity psychosis).¹³ Because chronic antipsychotic treatment leads to high postsynaptic receptor reserve, aripiprazole initiation may produce overactivation of D2 receptors, which might worsen a patient’s condition.¹⁴ In vitro data^15-18 and clinical observations indicate that aripiprazole has intrinsic efficacy at D2 receptors, as do clinical observations, such as:

• its propensity to reduce serum prolactin¹⁹
• a decreased likelihood of producing extrapyramidal side effects despite >80% occupancy of D2 receptors⁶
• case reports documenting aripiprazole-associated mania,²⁰ improvement of risperidone-associated cognitive impairment,²¹ and pathologic gambling.²²

Emergence or worsening of psychotic symptoms or a marginal antipsychotic effect may occur if aripiprazole is indeed a postsynaptic D2 receptor agonist. An individual patient’s outcome likely would depend on his or her sensitivity to psychosis and concurrent or previous exposure to a D2 receptor antagonist. For example, stimulation of postsynaptic D2 receptors may be further augmented if the dosage of the previous antipsychotic was reduced or withdrawn before initiating aripiprazole because additional receptors would be available for interaction with aripiprazole.

Case reports

A literature review revealed 23 reports of treatment-emergent psychosis associated with aripiprazole initiation (Table). The mean age of the patients was 47 (range: 17 to 69) and 57% were men. Most patients (87%) were diagnosed with a schizophrenia-spectrum illness before aripiprazole initiation. Most (57%) had mild, stable, or no psychotic symptoms before aripiprazole initiation. Most were receiving relatively high doses of antipsychotics (average chlorpromazine equivalents [CPZE]: 648 mg/d) before aripiprazole initiation. This medication was either decreased or discontinued in 70% of patients.

Emergence or worsening of psychotic symptoms included agitation, aggressive behavior, and increased psychomotor activity. However, akathisia evaluation was described in only 2 reports: 1 author identified akathisia symptoms, but attributed them to a concomitant antipsychotic (fluphenazine)²³ and the other report specifically excluded the possibility of akathisia.²⁴ Two systematic studies have attempted to establish risk factors for aripiprazole-associated worsening psychosis (Box).^14,25

In our literature review, the mean final dose of aripiprazole was 21.5 mg/d (range: 2 to 60 mg/d). In the cases describing subsequent treatment, all but 1 patient were switched to another antipsychotic, including 2 whose psychotic symptoms stabilized with continuation of aripiprazole and addition of a second antipsychotic. Interestingly, in the case reported by Adan-Manes et al,²⁶ initial treatment with aripiprazole monotherapy was efficacious, but a subsequent trial of adjunctive aripiprazole resulted in worsening psychosis.

Table

Case reports: Treatment-emergent psychosis associated with aripiprazole