Deepak L. Bhatt, MD, MPH

Many clinicians are concerned about a possible interaction between the proton pump inhibitor omeprazole (Prilosec) and the antiplatelet drug clopidogrel (Plavix), which is often given to patients as part of dual antiplatelet therapy after an acute coronary syndrome or a percutaneous coronary intervention. Indeed, the US Food and Drug Administration (FDA) has warned that omeprazole reduces the antiplatelet effect of clopidogrel.

Although we should not take such warnings lightly, we also should not be alarmed. The data on which the FDA warning was based came mostly from laboratory assays of platelet function. Preliminary results from a randomized, controlled clinical trial with hard end points show that, for the time being, we should not change the way we manage patients.

PROTON PUMP INHIBITORS DECREASE GASTROINTESTINAL BLEEDING

Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after an acute coronary syndrome or a percutaneous coronary intervention compared with aspirin alone.¹ However, it also increases the risk of gastrointestinal bleeding. A recent analysis determined that dual antiplatelet therapy was the most significant risk factor associated with serious or fatal gastrointestinal bleeding in high-risk survivors of myocardial infarction.²

Given the risks of significant morbidity and death in patients on dual antiplatelet therapy who develop gastrointestinal bleeding, an expert consensus panel recommended the use of proton pump inhibitors in patients on dual antiplatelet therapy who have risk factors for gastrointestinal bleeding.³ Accordingly, these drugs are commonly used for gastrointestinal protection in patients requiring dual antiplatelet therapy.

A POSSIBLE CYP450 INTERACTION

Clopidogrel is metabolized from a prodrug to its active metabolite by the cytochrome P450 (CYP450) system. Proton pump inhibitors also are metabolized by the CYP450 system.⁴ Proton pump inhibitors are thought to diminish the activity of clopidogrel via inhibition of the CYP2C19 isoenzyme. However, the clinical significance of this inhibition is not clear. Different drugs of this class inhibit the CYP450 system to varying degrees.

The potential interaction between proton pump inhibitors and clopidogrel is worrisome for many physicians, since adverse cardiovascular outcomes are more common in patients in whom the antiplatelet response to clopidogrel is impaired.¹ This interaction led to the publication of numerous articles, and prompted the FDA to carefully analyze the potential clinical implications.

In several randomized trials, omeprazole diminished the response to clopidogrel (measured via platelet function assays).^5,6 It is unclear if this is a class effect, as proton pump inhibitors other than omeprazole have not consistently been shown to have this effect.^6,7 Observational studies of the effect of co-administration of a proton pump inhibitor and clopidogrel on cardiovascular outcomes following acute coronary syndromes have had conflicting findings.^8–11

THE FDA ISSUES AN ADVISORY

Given the reports of an impaired platelet response to clopidogrel with omeprazole, the FDA asked the manufacturer for data on this potential interaction. The data showed diminished platelet inhibition when clopidogrel was co-administered with omeprazole or when the two were taken 12 hours apart.

On November 17, 2009, the FDA issued a patient advisory and updated the patient safety information on the package insert for clopidogrel about this drug interaction.¹² Specifically, the FDA warns that omeprazole reduces the antiplatelet effect of clopidogrel by about 50%. The FDA warning sparked debate in the medical community, as the decision was based in part on ex vivo data.

POST HOC ANALYSES FROM RANDOMIZED CONTROLLED TRIALS

Several post hoc analyses of large randomized clinical trials have studied the potential interaction between proton pump inhibitors and clopidogrel.

In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor.¹³

In patients undergoing percutaneous coronary intervention, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial found that those taking a proton pump inhibitor had significantly less platelet inhibition with clopidogrel compared with those not on one.¹⁴ However, patients taking prasugrel (Effient) and a proton pump inhibitor only had a slight trend towards diminished platelet inhibition.¹⁴

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) found that proton pump inhibitors did not influence the long-term outcome of cardiovascular death, myocardial infarction, or stroke for patients on clopidogrel or prasugrel after an acute coronary syndrome.¹⁴ A subanalysis did not reveal any differences between omeprazole or other drugs of this class as to an effect on the primary outcome.

Though informative, the results of these post hoc analyses need to be validated with data from randomized clinical trials.

‘COGENT’ TRIAL HALTED EARLY, BUT PRELIMINARY RESULTS AVAILABLE

The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial was the first randomized clinical study of the effect of the interaction between clopidogrel and omeprazole on cardiovascular and gastrointestinal outcomes.¹⁵ In a double-blind fashion, patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dose combination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.

Unfortunately, the trial was stopped early because the sponsor declared bankruptcy. However, preliminary results revealed no significant difference in cardiovascular outcomes for patients on clopidogrel and omeprazole compared with clopidogrel alone.¹⁵ Furthermore, adverse gastrointestinal events were significantly fewer in patients on clopidogrel and omeprazole.

Thus, omeprazole appears to be safe and may offer gastrointestinal protection to patients on dual antiplatelet therapy, though we need to await publication of the full results.

‘SPICE ’ TRIAL TO EVALUATE POSSIBLE MECHANISMS OF INTERACTION

The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial is a mechanistic study that will evaluate platelet function and genetic polymorphisms in patients on clopidogrel and aspirin after a percutaneous coronary intervention. They will be randomized to statin therapy plus different proton pump inhibitors.¹⁶ Prior concerns about an ex vivo interaction between clopidogrel and certain statins were not validated by clinical data.¹⁷

OUR RECOMMENDATIONS

Based on the current evidence, patients on aspirin and clopidogrel who have an indication for a proton pump inhibitor or who are at risk of gastrointestinal bleeding can continue or start taking a proton pump inhibitor, including omeprazole.

Switching to another proton pump inhibitor is not currently supported by any randomized clinical trial, nor is changing to a histamine H₂-receptor antagonist. The effect of proton pump inhibitors other than omeprazole on clopidogrel is unclear, and it is not known if the interaction with clopidogrel is a class effect or specific to certain drugs of this class.¹⁸ On the other hand, we still have no compelling evidence of any major clinical interaction between alternative proton pump inhibitors and clopidogrel.¹⁸

Also, separating the dosing times of clopidogrel and omeprazole by 12 hours is not supported by any randomized clinical trial, and runs contrary to at least some ex vivo data.

It is important that all physicians assess the need for a proton pump inhibitor in their patients, as overuse of these drugs has been documented in certain settings.¹⁹

Clopidogrel and omeprazole share a common metabolic link via CYP2C19. Omeprazole, along with some other proton pump inhibitors, interacts with clopidogrel at the level of the CYP450 system. Platelet function studies show that platelet inhibition by clopidogrel is impaired, though the astute clinician should be aware of the wide variability associated with platelet function assays and clopidogrel.^1,20 However, what may appear to be an interaction at the enzymatic level does not necessarily translate into worse clinical outcomes. Additionally, reliance on nonrandomized studies rather than on randomized clinical trials can be misleading.

Many clinicians are concerned about a possible interaction between the proton pump inhibitor omeprazole (Prilosec) and the antiplatelet drug clopidogrel (Plavix), which is often given to patients as part of dual antiplatelet therapy after an acute coronary syndrome or a percutaneous coronary intervention. Indeed, the US Food and Drug Administration (FDA) has warned that omeprazole reduces the antiplatelet effect of clopidogrel.

Although we should not take such warnings lightly, we also should not be alarmed. The data on which the FDA warning was based came mostly from laboratory assays of platelet function. Preliminary results from a randomized, controlled clinical trial with hard end points show that, for the time being, we should not change the way we manage patients.

PROTON PUMP INHIBITORS DECREASE GASTROINTESTINAL BLEEDING

Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after an acute coronary syndrome or a percutaneous coronary intervention compared with aspirin alone.¹ However, it also increases the risk of gastrointestinal bleeding. A recent analysis determined that dual antiplatelet therapy was the most significant risk factor associated with serious or fatal gastrointestinal bleeding in high-risk survivors of myocardial infarction.²

Given the risks of significant morbidity and death in patients on dual antiplatelet therapy who develop gastrointestinal bleeding, an expert consensus panel recommended the use of proton pump inhibitors in patients on dual antiplatelet therapy who have risk factors for gastrointestinal bleeding.³ Accordingly, these drugs are commonly used for gastrointestinal protection in patients requiring dual antiplatelet therapy.

A POSSIBLE CYP450 INTERACTION

Clopidogrel is metabolized from a prodrug to its active metabolite by the cytochrome P450 (CYP450) system. Proton pump inhibitors also are metabolized by the CYP450 system.⁴ Proton pump inhibitors are thought to diminish the activity of clopidogrel via inhibition of the CYP2C19 isoenzyme. However, the clinical significance of this inhibition is not clear. Different drugs of this class inhibit the CYP450 system to varying degrees.

The potential interaction between proton pump inhibitors and clopidogrel is worrisome for many physicians, since adverse cardiovascular outcomes are more common in patients in whom the antiplatelet response to clopidogrel is impaired.¹ This interaction led to the publication of numerous articles, and prompted the FDA to carefully analyze the potential clinical implications.

In several randomized trials, omeprazole diminished the response to clopidogrel (measured via platelet function assays).^5,6 It is unclear if this is a class effect, as proton pump inhibitors other than omeprazole have not consistently been shown to have this effect.^6,7 Observational studies of the effect of co-administration of a proton pump inhibitor and clopidogrel on cardiovascular outcomes following acute coronary syndromes have had conflicting findings.^8–11

THE FDA ISSUES AN ADVISORY

Given the reports of an impaired platelet response to clopidogrel with omeprazole, the FDA asked the manufacturer for data on this potential interaction. The data showed diminished platelet inhibition when clopidogrel was co-administered with omeprazole or when the two were taken 12 hours apart.

On November 17, 2009, the FDA issued a patient advisory and updated the patient safety information on the package insert for clopidogrel about this drug interaction.¹² Specifically, the FDA warns that omeprazole reduces the antiplatelet effect of clopidogrel by about 50%. The FDA warning sparked debate in the medical community, as the decision was based in part on ex vivo data.

POST HOC ANALYSES FROM RANDOMIZED CONTROLLED TRIALS

Several post hoc analyses of large randomized clinical trials have studied the potential interaction between proton pump inhibitors and clopidogrel.

In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor.¹³

In patients undergoing percutaneous coronary intervention, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial found that those taking a proton pump inhibitor had significantly less platelet inhibition with clopidogrel compared with those not on one.¹⁴ However, patients taking prasugrel (Effient) and a proton pump inhibitor only had a slight trend towards diminished platelet inhibition.¹⁴

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) found that proton pump inhibitors did not influence the long-term outcome of cardiovascular death, myocardial infarction, or stroke for patients on clopidogrel or prasugrel after an acute coronary syndrome.¹⁴ A subanalysis did not reveal any differences between omeprazole or other drugs of this class as to an effect on the primary outcome.

Though informative, the results of these post hoc analyses need to be validated with data from randomized clinical trials.

‘COGENT’ TRIAL HALTED EARLY, BUT PRELIMINARY RESULTS AVAILABLE

The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial was the first randomized clinical study of the effect of the interaction between clopidogrel and omeprazole on cardiovascular and gastrointestinal outcomes.¹⁵ In a double-blind fashion, patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dose combination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.

Unfortunately, the trial was stopped early because the sponsor declared bankruptcy. However, preliminary results revealed no significant difference in cardiovascular outcomes for patients on clopidogrel and omeprazole compared with clopidogrel alone.¹⁵ Furthermore, adverse gastrointestinal events were significantly fewer in patients on clopidogrel and omeprazole.

Thus, omeprazole appears to be safe and may offer gastrointestinal protection to patients on dual antiplatelet therapy, though we need to await publication of the full results.

‘SPICE ’ TRIAL TO EVALUATE POSSIBLE MECHANISMS OF INTERACTION

The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial is a mechanistic study that will evaluate platelet function and genetic polymorphisms in patients on clopidogrel and aspirin after a percutaneous coronary intervention. They will be randomized to statin therapy plus different proton pump inhibitors.¹⁶ Prior concerns about an ex vivo interaction between clopidogrel and certain statins were not validated by clinical data.¹⁷

OUR RECOMMENDATIONS

Based on the current evidence, patients on aspirin and clopidogrel who have an indication for a proton pump inhibitor or who are at risk of gastrointestinal bleeding can continue or start taking a proton pump inhibitor, including omeprazole.

Switching to another proton pump inhibitor is not currently supported by any randomized clinical trial, nor is changing to a histamine H₂-receptor antagonist. The effect of proton pump inhibitors other than omeprazole on clopidogrel is unclear, and it is not known if the interaction with clopidogrel is a class effect or specific to certain drugs of this class.¹⁸ On the other hand, we still have no compelling evidence of any major clinical interaction between alternative proton pump inhibitors and clopidogrel.¹⁸

Also, separating the dosing times of clopidogrel and omeprazole by 12 hours is not supported by any randomized clinical trial, and runs contrary to at least some ex vivo data.

It is important that all physicians assess the need for a proton pump inhibitor in their patients, as overuse of these drugs has been documented in certain settings.¹⁹

Clopidogrel and omeprazole share a common metabolic link via CYP2C19. Omeprazole, along with some other proton pump inhibitors, interacts with clopidogrel at the level of the CYP450 system. Platelet function studies show that platelet inhibition by clopidogrel is impaired, though the astute clinician should be aware of the wide variability associated with platelet function assays and clopidogrel.^1,20 However, what may appear to be an interaction at the enzymatic level does not necessarily translate into worse clinical outcomes. Additionally, reliance on nonrandomized studies rather than on randomized clinical trials can be misleading.

Many clinicians are concerned about a possible interaction between the proton pump inhibitor omeprazole (Prilosec) and the antiplatelet drug clopidogrel (Plavix), which is often given to patients as part of dual antiplatelet therapy after an acute coronary syndrome or a percutaneous coronary intervention. Indeed, the US Food and Drug Administration (FDA) has warned that omeprazole reduces the antiplatelet effect of clopidogrel.

Although we should not take such warnings lightly, we also should not be alarmed. The data on which the FDA warning was based came mostly from laboratory assays of platelet function. Preliminary results from a randomized, controlled clinical trial with hard end points show that, for the time being, we should not change the way we manage patients.

PROTON PUMP INHIBITORS DECREASE GASTROINTESTINAL BLEEDING

Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after an acute coronary syndrome or a percutaneous coronary intervention compared with aspirin alone.¹ However, it also increases the risk of gastrointestinal bleeding. A recent analysis determined that dual antiplatelet therapy was the most significant risk factor associated with serious or fatal gastrointestinal bleeding in high-risk survivors of myocardial infarction.²

Given the risks of significant morbidity and death in patients on dual antiplatelet therapy who develop gastrointestinal bleeding, an expert consensus panel recommended the use of proton pump inhibitors in patients on dual antiplatelet therapy who have risk factors for gastrointestinal bleeding.³ Accordingly, these drugs are commonly used for gastrointestinal protection in patients requiring dual antiplatelet therapy.

A POSSIBLE CYP450 INTERACTION

Clopidogrel is metabolized from a prodrug to its active metabolite by the cytochrome P450 (CYP450) system. Proton pump inhibitors also are metabolized by the CYP450 system.⁴ Proton pump inhibitors are thought to diminish the activity of clopidogrel via inhibition of the CYP2C19 isoenzyme. However, the clinical significance of this inhibition is not clear. Different drugs of this class inhibit the CYP450 system to varying degrees.

The potential interaction between proton pump inhibitors and clopidogrel is worrisome for many physicians, since adverse cardiovascular outcomes are more common in patients in whom the antiplatelet response to clopidogrel is impaired.¹ This interaction led to the publication of numerous articles, and prompted the FDA to carefully analyze the potential clinical implications.

In several randomized trials, omeprazole diminished the response to clopidogrel (measured via platelet function assays).^5,6 It is unclear if this is a class effect, as proton pump inhibitors other than omeprazole have not consistently been shown to have this effect.^6,7 Observational studies of the effect of co-administration of a proton pump inhibitor and clopidogrel on cardiovascular outcomes following acute coronary syndromes have had conflicting findings.^8–11

THE FDA ISSUES AN ADVISORY

Given the reports of an impaired platelet response to clopidogrel with omeprazole, the FDA asked the manufacturer for data on this potential interaction. The data showed diminished platelet inhibition when clopidogrel was co-administered with omeprazole or when the two were taken 12 hours apart.

On November 17, 2009, the FDA issued a patient advisory and updated the patient safety information on the package insert for clopidogrel about this drug interaction.¹² Specifically, the FDA warns that omeprazole reduces the antiplatelet effect of clopidogrel by about 50%. The FDA warning sparked debate in the medical community, as the decision was based in part on ex vivo data.

POST HOC ANALYSES FROM RANDOMIZED CONTROLLED TRIALS

Several post hoc analyses of large randomized clinical trials have studied the potential interaction between proton pump inhibitors and clopidogrel.

In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor.¹³

In patients undergoing percutaneous coronary intervention, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial found that those taking a proton pump inhibitor had significantly less platelet inhibition with clopidogrel compared with those not on one.¹⁴ However, patients taking prasugrel (Effient) and a proton pump inhibitor only had a slight trend towards diminished platelet inhibition.¹⁴

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) found that proton pump inhibitors did not influence the long-term outcome of cardiovascular death, myocardial infarction, or stroke for patients on clopidogrel or prasugrel after an acute coronary syndrome.¹⁴ A subanalysis did not reveal any differences between omeprazole or other drugs of this class as to an effect on the primary outcome.

Though informative, the results of these post hoc analyses need to be validated with data from randomized clinical trials.

‘COGENT’ TRIAL HALTED EARLY, BUT PRELIMINARY RESULTS AVAILABLE

The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial was the first randomized clinical study of the effect of the interaction between clopidogrel and omeprazole on cardiovascular and gastrointestinal outcomes.¹⁵ In a double-blind fashion, patients with acute coronary syndromes or undergoing percutaneous coronary interventions were randomized to receive a fixed-dose combination pill containing either clopidogrel and delayed-release omeprazole or clopidogrel alone. All patients also received aspirin.

Unfortunately, the trial was stopped early because the sponsor declared bankruptcy. However, preliminary results revealed no significant difference in cardiovascular outcomes for patients on clopidogrel and omeprazole compared with clopidogrel alone.¹⁵ Furthermore, adverse gastrointestinal events were significantly fewer in patients on clopidogrel and omeprazole.

Thus, omeprazole appears to be safe and may offer gastrointestinal protection to patients on dual antiplatelet therapy, though we need to await publication of the full results.

‘SPICE ’ TRIAL TO EVALUATE POSSIBLE MECHANISMS OF INTERACTION

The Evaluation of the Influence of Statins and Proton Pump Inhibitors on Clopidogrel Antiplatelet Effects (SPICE) trial is a mechanistic study that will evaluate platelet function and genetic polymorphisms in patients on clopidogrel and aspirin after a percutaneous coronary intervention. They will be randomized to statin therapy plus different proton pump inhibitors.¹⁶ Prior concerns about an ex vivo interaction between clopidogrel and certain statins were not validated by clinical data.¹⁷

OUR RECOMMENDATIONS

Based on the current evidence, patients on aspirin and clopidogrel who have an indication for a proton pump inhibitor or who are at risk of gastrointestinal bleeding can continue or start taking a proton pump inhibitor, including omeprazole.

Switching to another proton pump inhibitor is not currently supported by any randomized clinical trial, nor is changing to a histamine H₂-receptor antagonist. The effect of proton pump inhibitors other than omeprazole on clopidogrel is unclear, and it is not known if the interaction with clopidogrel is a class effect or specific to certain drugs of this class.¹⁸ On the other hand, we still have no compelling evidence of any major clinical interaction between alternative proton pump inhibitors and clopidogrel.¹⁸

Also, separating the dosing times of clopidogrel and omeprazole by 12 hours is not supported by any randomized clinical trial, and runs contrary to at least some ex vivo data.

It is important that all physicians assess the need for a proton pump inhibitor in their patients, as overuse of these drugs has been documented in certain settings.¹⁹

Clopidogrel and omeprazole share a common metabolic link via CYP2C19. Omeprazole, along with some other proton pump inhibitors, interacts with clopidogrel at the level of the CYP450 system. Platelet function studies show that platelet inhibition by clopidogrel is impaired, though the astute clinician should be aware of the wide variability associated with platelet function assays and clopidogrel.^1,20 However, what may appear to be an interaction at the enzymatic level does not necessarily translate into worse clinical outcomes. Additionally, reliance on nonrandomized studies rather than on randomized clinical trials can be misleading.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

Despite all the attention paid to ST-segment-elevation myocardial infarction (MI), in terms of sheer numbers, non-ST-elevation MI and unstable angina are where the action is. Acute coronary syndromes account for 2.43 million hospital discharges per year. Of these, 0.46 million are for ST-elevation MI and 1.97 million are for non-ST-elevation MI and unstable angina.^1,2

A number of recent studies have begun to answer some of the pressing questions about treating these types of acute coronary syndromes. In this article, I update the reader on these studies, along with recent findings regarding stenting and antiplatelet agents. As you will see, they are all interconnected.

TO CATHETERIZE IS BETTER THAN NOT TO CATHETERIZE

In the 1990s, a topic of debate was whether patients presenting with unstable angina or non-ST-elevation MI should routinely undergo catheterization or whether they would do just as well with a conservative approach, ie, undergoing catheterization only if they developed recurrent, spontaneous, or stress-induced ischemia. Now, the data are reasonably clear and favor an aggressive strategy.³

Mehta et al⁴ performed a meta-analysis of seven randomized controlled trials (N = 9,212 patients) of aggressive vs conservative angiography and revascularization for non-ST-elevation MI or unstable angina. The results favored the aggressive strategy. At 17 months of follow-up, death or MI had occurred in 7.4% of patients who received the aggressive therapy compared with 11.0% of those who received the conservative therapy, for an odds ratio of 0.82 (P = .001).

The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implemention of the ACC/AHA Guidelines?) Quality Improvement Initiative⁵ analyzed data from a registry of 17,926 patients with non-ST-elevation acute coronary syndrome who were at high risk because of positive cardiac markers or ischemic electrocardiographic changes. Overall, 2.0% of patients who received early invasive care (catheterization within the first 48 hours) died in the hospital compared with 6.2% of those who got no early invasive care, for an adjusted odds ratio of 0.63 (95% confidence interval [CI] 0.52–0.77).

The investigators also stratified the patients into those at low, medium, and high risk, using the criteria of the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin [eptifibatide] Therapy) risk score. There were fewer deaths with early invasive therapy in each risk group, and the risk reduction was greatest in the high-risk group.⁵

Bavry et al⁶ performed an updated meta-analysis of randomized trials. At a mean follow-up of 24 months, the relative risk of death from any cause was 0.75 in patients who received early invasive therapy.

In another meta-analysis, O’Donoghue et al⁷ found that the odds ratio of death, MI, or rehospitalization with acute coronary syndromes was 0.73 (95% CI 0.55–0.98) in men who received invasive vs conservative therapy; in women it was 0.81 (95% CI 0.65–1.01). In women, the benefit was statistically significant in those who had elevations of creatine kinase MB or troponin but not in those who did not, though the benefit in men appeared to be less dependent on the presence of biomarker abnormalities.

MUST ANGIOGRAPHY BE DONE IN THE FIRST 24 HOURS?

Although a number of trials showed that a routine invasive strategy leads to better outcomes than a conservative strategy, until recently we had no information as to whether the catheterization needed to be done early (eg, within the first 24 hours) or if it could be delayed a day or two while the patient received medical therapy.

Mehta et al⁸ conducted a trial to find out: the Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial. Patients were included if they had unstable angina or non-ST-elevation MI, presented to a hospital within 24 hours of the onset of symptoms, and had two of three high-risk features: age 60 years or older, elevated cardiac biomarkers, or electrocardiographic findings compatible with ischemia. All received standard medical therapy, and 3,031 were randomly assigned to undergo angiography either within 24 hours after randomization or 36 or more hours after randomization.

At 6 months, the primary outcome of death, new MI, or stroke had occurred in 9.6% of the patients in the early-intervention group and in 11.3% of those in the delayed-intervention group, but the difference was not statistically significant. However, the difference in the rate of a secondary end point, death, MI, or refractory ischemia, was statistically significant: 9.5% vs 12.9%, P = .003, owing mainly to less refractory ischemia with early intervention.

The patients were also stratified into two groups by baseline risk. The rate of the primary outcome was significantly lower with early intervention in high-risk patients, but not in those at intermediate or low risk. Thus, early intervention may be beneficial in patients at high risk, such as those with ongoing chest pain, but not necessarily in those at low risk.

LEAVE NO LESION BEHIND?

Coronary artery disease often affects more than one segment. Until recently, it was not known whether we should stent all stenotic segments in patients presenting with non-ST-elevation MI or unstable angina, or only the “culprit lesion.”

Shishehbor et al⁹ examined data from a Cleveland Clinic registry of 1,240 patients with acute coronary syndrome and multivessel coronary artery disease who underwent bare-metal stenting. The median follow-up was 2.3 years. Using a propensity model to match patients in the two groups with similar baseline characteristics, they found that the rate of repeat revascularization was less with multivessel intervention than with culprit-only stenting, as was the rate of the combined end point of death, MI, or revascularization, but not that of all-cause mortality or the composite of death or MI.

BARE-METAL VS DRUG-ELUTING STENTS: BALANCING THE RISKS AND BENEFITS

After a patient receives a stent, two bad things can happen: the artery can close up again either gradually, in a process called restenosis, or suddenly, via thrombosis.

Drug-eluting stents were invented to solve the problem of restenosis, and they work very well. Stone et al¹⁰ pooled the data from four double-blind trials of sirolimus (Rapamune) stents and five double-blind trials of paclitaxel (Taxol) stents and found that, at 4 years, the rates of target-lesion revascularization (for restenosis) were 7.8% with sirolimus stents vs 23.6% with bare-metal stents (P < .001), and 10.1% with paclitaxel stents vs 20.0% with bare-metal stents (P < .001).

Thrombosis was much less common in these studies, occurring in 1.2% of the sirolimus stent groups vs 0.6% of the bare-metal stent groups (P = .20), and in 1.3% of the paclitaxel stent groups vs 0.9% of the bare-metal stent groups (P = .30).¹⁰

However, drug-eluting stents appear to increase the risk of thrombosis later on, ie, after 1 year. Bavry et al,¹¹ in a meta-analysis, calculated that when stent thrombosis occurred, the median time after implantation was 15.5 months with sirolimus stents vs 4 months with bare-metal stents (P = .0052), and 18 months with paclitaxel stents vs 3.5 months with bare-metal stents (P = .04). The absolute risk of very late stent thrombosis after 1 year was very low, with five events per 1,000 patients with drug-eluting stents vs no events with bare-metal stents (P = .02). Nevertheless, this finding has practical implications. How long must patients continue dual antiplatelet therapy? And what if a patient needs surgery a year later?

Restenosis is not always so gradual

Although stent thrombosis is serious and often fatal, bare-metal stent restenosis is not always benign either, despite the classic view that stent restenosis is a gradual process that results in exertional angina. Reviewing 1,186 cases of bare-metal stent restenosis in 984 patients at Cleveland Clinic, Chen et al¹² reported that 9.5% of cases presented as acute MI (2.2% as ST-elevation MI and 7.3% as non-ST-elevation MI), and 26.4% as unstable angina requiring hospitalization.

A Mayo Clinic study¹³ corroborated these findings. The 10-year incidence of clinical bare-metal stent restenosis was 18.1%, and the incidence of MI was 2.1%. The 10-year rate of bare-metal stent thrombosis was 2%. Off-label use, primarily in saphenous vein grafts, increased the incidence; other correlates were prior MI, peripheral arterial disease, and ulcerated lesions.

Furthermore, bare-metal stent thrombosis can also occur later. We saw a case that occurred 13 years after the procedure, 3 days after the patient stopped taking aspirin because he was experiencing flu-like symptoms, ran out of aspirin, and felt too sick to go out and buy more. The presentation was with ST-elevation MI. The patient recovered after treatment with intracoronary abciximab (ReoPro), percutaneous thrombectomy, balloon angioplasty, and, eventually, bypass surgery.¹⁴

No difference in risk of death with drug-eluting vs bare-metal stents

Even though drug-eluting stents pose a slightly higher risk of thrombosis than bare-metal stents, the risk of death is no higher.¹⁵

I believe the reason is that there are competing risks, and that the higher risk of thrombosis with first-generation drug-eluting stents and the higher risk of restenosis with bare-metal stents essentially cancel each other out. For most patients, there is an absolute benefit with drug-eluting stents, which reduce the need for revascularization with no effect in terms of either increasing or decreasing the risk of MI or death. Second-generation drug-eluting stents may have advantages in reducing rates of death or MI compared with first-generation drug-eluting stents, though this remains to be proven conclusively.

The right revascularization for the right patient

Bavry and I¹⁶ developed an algorithm for deciding on revascularization, posing a series of questions:

• Does the patient need any form of revascularization?
• Is he or she at higher risk of both stent thrombosis and restenosis, as in patients with diabetes, diffuse multivessel disease with bifurcation lesions, or chronic total occlusions? If so, coronary artery bypass grafting remains an excellent option.
• Does he or she have a low risk of restenosis, as in patients without diabetes with focal lesions in large vessels? If so, one could consider a bare-metal stent, which would probably be more cost-effective than a drug-eluting stent in this situation.
• Does the patient have relative contraindications to drug-eluting stents? Examples are a history of noncompliance with medical therapy, financial issues such as lack of insurance that would make buying clopidogrel (Plavix) a problem, long-term anticoagulation, or anticipated need for surgery in the next few years.

If a drug-eluting stent is used, certain measures can help ensure that it is used optimally. It should often be placed under high pressure with a noncompliant balloon so that it achieves contact with the artery wall all around. One should consider intravascular ultrasonographic guidance to make sure the stent is well opposed if it is in a very calcified lesion. Dual antiplatelet therapy with clopidogrel and aspirin should be given for at least 1 year, and if there is no bleeding, perhaps longer, pending further data.¹⁶

LEAVE NO PLATELET ACTIVATED?

Platelets have several types of receptors that, when bound by their respective ligands, lead to platelet activation and aggregation and, ultimately, thrombus formation. Antagonists to some of these receptors are available or are being developed.¹⁷

For long-term therapy, blocking the process “upstream,” ie, preventing platelet activation, is better than blocking it “downstream,” ie, preventing aggregation. For example, clopidogrel, ticlopipine (Ticlid), and prasugrel (Effient) have active metabolites that bind to a subtype of the adenosine diphosphate receptor and prevent platelet activation, whereas the glycoprotein IIb/IIIa inhibitors such as abciximab work downstream, binding to a different receptor and preventing aggregation.¹⁸

The evidence for using dual antiplatelet therapy (ie, aspirin plus clopidogrel) in patients with acute coronary syndromes without ST-elevation is very well established.

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial,¹⁹ published in 2001, found a 20% relative risk reduction and a 2% absolute risk reduction in the incidence of MI, stroke, or cardiovascular death in patients randomly assigned to receive clopidogrel plus aspirin for 1 year vs aspirin alone for 1 year (P < .001). In the subgroup of patients who underwent percutaneous coronary intervention, the relative risk reduction in the incidence of MI or cardiovascular death at 1 year of follow-up was 31% (P = .002).²⁰

As a result of these findings, the cardiology society guidelines²¹ recommend a year of dual antiplatelet therapy after acute coronary syndromes, regardless of whether the patient is treated medically, percutaneously, or surgically.

But what happens after clopidogrel is withdrawn? Ho et al²² retrospectively analyzed data from Veterans Affairs hospitals and found a spike in the incidence of death or MI in the first 90 days after stopping clopidogrel treatment. This was true in medically treated patients as well as in those treated with percutaneous coronary interventions, in those with or without diabetes mellitus, in those who received a drug-eluting stent or a bare-metal stent, and in those treated longer than 9 months.

The investigators concluded that there might be a “clopidogrel rebound effect.” However, I believe that a true rebound effect, such as after withdrawal of heparin or warfarin, is biologically unlikely with clopidogrel, since clopidogrel irreversibly binds to its receptor for the 7- to 10-day life span of the platelet. Rather, I believe the phenomenon must be due to withdrawal of protection in patients at risk.

In stable patients, dual therapy is not as beneficial

Would dual antiplatelet therapy with clopidogrel and aspirin also benefit patients at risk of atherothrombotic events but without acute coronary syndromes?

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial²³ included 15,603 patients with either clinically evident but stable cardiovascular disease or multiple risk factors for athero-thrombosis. They were randomly assigned to receive either clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin. At a median of 28 months, the groups did not differ significantly in the rate of MI, stroke, or death from cardiovascular causes.

However, the subgroup of patients who had documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease did appear to derive significant benefit from dual therapy.²⁴ In this subgroup, the rate of MI, stroke, or cardiovascular death at a median follow-up of 27.6 months was 8.8% with placebo plus aspirin compared with 7.3% with clopidogrel plus aspirin, for a hazard ratio of 0.83 (95% CI 0.72–0.96, P = .01). Unstented patients with stable coronary artery disease but without prior MI derived no benefit.

Bleeding and thrombosis: The Scylla and Charybdis of antiplatelet therapy

However, with dual antiplatelet therapy, we steer between the Scylla of bleeding and the Charybdis of thrombosis.²⁵

In the CHARISMA subgroup who had prior MI, ischemic stroke, or symptomatic peripheral arterial disease, the incidence of moderate or severe bleeding was higher with dual therapy than with aspirin alone, but the rates converged after about 1 year of treatment.²⁴ Further, there was no difference in fatal bleeding or intracranial bleeding, although the rate of moderate bleeding (defined as the need for transfusion) was higher with dual therapy (2.0% vs 1.3%, P = .004).

I believe the data indicate that if a patient can tolerate dual antiplatelet therapy for 9 to 12 months without any bleeding issues, he or she is unlikely to have a major bleeding episode if dual therapy is continued beyond this time.

About half of bleeding events in patients on chronic antiplatelet therapy are gastrointestinal. To address this risk, in 2008 an expert committee from the American College of Cardiology, American College of Gastroenterology, and American Heart Association issued a consensus document²⁶ in which they recommended assessing gastrointestinal risk factors in patients on antiplatelet therapy, such as history of ulcers (and testing for and treating Helicobacter pylori infection if present), history of gastrointestinal bleeding, concomitant anticoagulant therapy, and dual antiplatelet therapy. If any of these were present, the committee recommended considering a proton pump inhibitor. The committee also recommended a proton pump inhibitor for patients on antiplatelet therapy who have more than one of the following: age 60 years or more, corticosteroid use, or dyspepsia or gastroesophageal reflux symptoms.

Some ex vivo platelet studies and observational analyses have suggested that there might be an adverse interaction between clopidogrel and proton pump inhibitors due to a blunting of clopidogrel’s antiplatelet effect. A large randomized clinical trial was designed and launched to determine if a single-pill combination of the proton pump inhibitor omeprazole (Prilosec) and clopidogrel would be safer than clopidogrel alone when added to aspirin. Called COGENT-1 (Clopidogrel and the Optimization of GI Events Trial), it was halted early in 2009 when it lost its funding. However, preliminary data did not show an adverse interaction between clopidogrel and omeprazole.

What is the right dose of aspirin?

Steinhubl et al²⁷ performed a post hoc observational analysis of data from the CHARISMA trial. Their findings suggested that higher doses of aspirin are not more effective than lower doses for chronic therapy. Furthermore, in the group receiving clopidogrel plus aspirin, the incidence of severe or life-threatening bleeding was significantly greater with aspirin doses higher than 100 mg than with doses lower than 100 mg, 2.6% vs 1.7%, P = .040.

A randomized, controlled trial called Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT/OASIS 7)²⁸ recently reported that higher-dose aspirin (ie, 325 mg) may be better than lower dose aspirin (ie, 81 mg) in patients with acute coronary syndromes undergoing percutaneous coronary intervention and receiving clopidogrel. During this 30-day study, there was no increase in overall bleeding with the higher dose of aspirin, though gastrointestinal bleeding was slightly increased.²⁹ In a factorial design, the second part of this trial found that a higher-dose clopidogrel regimen reduced stent thrombosis.²⁹

In vitro, response to clopidogrel shows a normal bell-shaped distribution.³⁰ In theory, therefore, patients who are hyperresponders may be at higher risk of bleeding, and those who are hyporesponders may be at risk of ischemic events.

A clinical trial is under way to examine whether hyporesponders should get higher doses. Called GRAVITAS (Gauging Responsiveness With a VerifyNow Assay Impact on Thrombosis and Safety), it will use a point-of-care platelet assay and then allocate patients to receive either standard therapy or double the dose of clopidogrel. The primary end point will be the rate of cardiovascular death, nonfatal MI, or stent thrombosis at 6 months.

Is prasugrel better than clopidogrel?

Prasugrel (Effient) is a new drug of the same class as clopidogrel, ie, a thienopyridine, with its active metabolite binding to the same platelet receptor as clopidogrel and inhibiting platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. Prasugrel was recently approved by the Food and Drug Administration. But is it better?³¹

The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI 38) compared prasugrel and clopidogrel in 13,608 patients with moderate- to high-risk acute coronary syndromes who were scheduled to undergo percutaneous coronary intervention.³²

Overall, prasugrel was better. At 15 months, the incidence of the primary end point (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower with prasugrel therapy than with clopidogrel in the entire cohort (9.9% vs 12.1%, hazard ratio 0.81, 95% CI 0.73–0.90, P < .001), in the subgroup with ST-segment elevation MI, and in the subgroup with unstable angina or non-ST-elevation MI.

However, there was a price to pay. The rate of major bleeding was higher with prasugrel (2.4% vs 1.8%, hazard ratio 1.32, 95% CI 1.03–1.68, P = .03). Assessing the balance between the risk and the benefit, the investigators identified three subgroups who did not derive a net clinical benefit from prasugrel: patients who had had a previous stroke or transient ischemic attack (this group actually had a net harm from prasugrel), patients 75 years of age or older, and patients weighing less than 60 kg (132 pounds).

More work is needed to determine which patients are best served by standard-dose clopidogrel, higher doses of clopidogrel, platelet-assay-guided dosing of clopidogrel, or prasugrel.²⁴

Short-acting, potent intravenous platelet blockade with an agent such as cangrelor is theoretically appealing, but further research is necessary.^33,34 Ticagrelor, a reversible adenosine diphosphate receptor antagonist, provides yet another potential option in antiplatelet therapy for acute coronary syndromes. In the recent PLATO trial (Study of Platelet Inhibition and Patient Outcomes), compared with clopidogrel, ticagrelor reduced the risk of ischemic events, including death.^35,36 Here, too, there was more major bleeding (unrelated to coronary artery bypass grafting) with ticagrelor.

Thus, clinical assessment of an individual patient’s ischemic and bleeding risks will continue to be critical as therapeutic strategies evolve.

In patients at risk of myocardial infarction or stroke, two antiplatelet drugs are not always better than one. In a large recent trial,^1,2 adding clopidogrel (Plavix) to aspirin therapy did not offer much benefit to a cohort of patients at risk of cardiovascular events, although a subgroup did appear to benefit: those at even higher risk because they already had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

These were the principal findings in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study,^1,2 in which one of us (D.L.B.) was principal investigator.

These findings further our understanding of who should receive dual antiplatelet therapy, and who would be better served with aspirin therapy alone. In this article, we discuss important studies that led up to the CHARISMA trial, review CHARISMA’s purpose and study design, and interpret its results.

PREVENTING ATHEROTHROMBOSIS BY BLOCKING PLATELETS

Platelets are key players in the atherothrom-botic process.^3–5 The Antiplatelet Trialists’ Collaboration,⁶ in a meta-analysis of trials performed up to 1997, calculated that antiplatelet therapy (mostly with aspirin) reduced the vascular mortality rate by 15% in patients with acute or previous vascular disease or some other predisposing condition. Thus, aspirin has already been shown to be effective as primary prevention (ie, in patients at risk but without established vascular disease) and as secondary prevention (ie, in those with established disease).^7,8

Yet many patients have significant vascular events in spite of taking aspirin.⁶ Aspirin failure is thought to be multifactorial, with causes that include weak platelet inhibition, noncompliance, discontinuation due to adverse effects (including severe bleeding), and drug interactions. In addition, aspirin resistance has been linked to worse prognosis and may prove to be another cause of aspirin failure.^9–11

Clopidogrel, an adenosine diphosphate (ADP) receptor antagonist, has also been studied extensively as an antiplatelet agent.^5,12 Several studies have indicated that clopidogrel and ticlopidine (Ticlid, a related drug) may be more potent than aspirin, both in the test tube and in real patients.^13–15

KEY TRIALS LEADING TO CHARISMA

• Clopidogrel is more effective and slightly safer than aspirin as secondary prevention, as shown in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.^16–21
• The combination of clopidogrel plus aspirin is more beneficial than placebo plus aspirin in patients with acute coronary syndromes, as shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial,^22–24 the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myo-car-dial Infarction (CLARITY-TIMI 28) trial,²⁵ and the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT).²⁶
• The combination of clopidogrel plus aspirin is beneficial in patients undergoing percutaneous coronary interventions, with or without drug-eluting stent placement,^27–30 as shown in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial,²⁸ the Effect of Clopidogrel Pretreatment Before Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction With Fibrinolytics (PCI-CLARITY) study,²⁹ and the Effects of Pre-treatment With Clopidogrel and Aspirin Followed by Long-term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE) study.³⁰ In fact, most patients undergoing percutaneous interventions now receive a loading dose of clopidogrel before the procedure and continue to take it for up to 1 year afterward. However, the ideal long-term duration of clopidogrel treatment is still under debate.

In view of these previous studies, we wanted to test dual antiplatelet therapy in a broader population at high risk of atherothrombosis, ie, in patients with either established vascular disease or with multiple risk factors for it.

CHARISMA STUDY DESIGN

CHARISMA was a prospective, randomized, double-blind, placebo-controlled study of the efficacy and safety of clopidogrel plus aspirin vs placebo plus aspirin in patients at high risk of cardiovascular events.

A total of 15,603 patients, all older than 45 years, were randomly assigned to receive clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin, in addition to standard therapy as directed by individual clinicians (eg, statins, beta-blockers). Patients were followed up at 1, 3, and 6 months and every 6 months thereafter until study completion, which occurred after 1,040 primary efficacy end points. The median duration of follow-up was 28 months.¹

Patients had to have one of the following to be included: multiple atherothrombotic risk factors, documented coronary disease, documented cerebrovascular disease, or documented peripheral arterial disease (Table 2). Specific exclusion criteria included the use of oral antithrombotic or chronic nonsteroidal anti-inflammatory medications.¹

End points

The primary end point was the combined incidence of the first episode of myocardial infarction or stroke, or death from cardiovascular causes.

The secondary end point was the combined incidence of myocardial infarction, stroke, death from cardiovascular causes, or hospitalization for unstable angina, a transient ischemic attack, or revascularization procedure.

The primary safety end point was severe bleeding, as defined in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) study³¹ as intracranial hemorrhage, fatal bleeding, or bleeding leading to hemody-namic compromise. Moderate bleeding was defined as bleeding that required transfusion but did not meet the GUSTO definition of severe bleeding.

OVERALL, NO BENEFIT

The rates of the secondary end point were 16.7% vs 17.9% (absolute risk reduction 1.2%; relative risk reduction 8%; P = .04).

Possible benefit in symptomatic patients

In a prespecified analysis, patients were classified as being “symptomatic” (having documented cardiovascular disease, ie, coronary, cerebrovascular, or symptomatic peripheral arterial disease) or “asymptomatic” (having multiple risk factors without established cardiovascular disease).¹

In the symptomatic group (n = 12,153), the primary end point was reached in 6.9% of patients treated with clopidogrel vs 7.9% with placebo (absolute risk reduction 1.0%; relative risk reduction 13%; P = .046). The 3,284 asymptomatic patients showed no benefit; the rate of the primary end point for the clopido-grel group was 6.6% vs 5.5% in the placebo group (P = .20).

In a post hoc analysis, we examined the data from 9,478 patients who were similar to those in the CAPRIE study (ie, with documented prior myocardial infarction, prior ischemic stroke, or symptomatic peripheral arterial disease). The rate of cardiovascular death, myocardial infarction, or stroke was 8.8% in the placebo-plus-aspirin group and 7.3% in the clopidogrel-plus-aspirin group (absolute risk reduction 1.5%; relative risk reduction 17%; P = .01; Figure 1).²

HOW SHOULD WE INTERPRET THESE FINDINGS?

CHARISMA was the first trial to evaluate whether adding clopidogrel to aspirin therapy would reduce the rates of vascular events and death from cardiovascular causes in stable patients at risk of ischemic events. As in other trials, the benefit of clopidogrel-plus-aspirin therapy was weighed against the risk of bleeding with this regimen. How are we to interpret the findings?

• In the group with multiple risk factors but without clearly documented cardiovascular disease, there was no benefit—and there was an increase in moderate bleeding. Given these findings, physicians should not prescribe dual antiplatelet therapy for primary prevention in patients without known vascular disease.
• A potential benefit was seen in a prespecified subgroup who had documented cardiovascular disease. Given the limitations of subgroup analysis, however, and given the increased risk of moderate bleeding, this positive result should be interpreted with some degree of caution.
• CHARISMA suggests that there may be benefit of protracted dual antiplatelet therapy in stable patients with documented prior ischemic events.

A possible reason for the observed lack of benefit in the overall cohort but the positive results in the subgroups with established vascular disease is that plaque rupture and thrombosis may be a precondition for dual antiplatelet therapy to work.

Another possibility is that, although we have been saying that diabetes mellitus (one of the possible entry criteria in CHARISMA) is a “coronary risk equivalent,” this may not be absolutely true. Although it had been demonstrated that patients with certain risk factors, such as diabetes, have an incidence of ischemic events similar to that in patients with prior MI and should be considered for antiplatelet therapy to prevent vascular events,³² more recent data have shown that patients with prior ischemic events are at much higher risk than patients without ischemic events, even if the latter have diabetes.^33,34

• The observation in CHARISMA that the incremental bleeding risk of dual antiplatelet therapy vs aspirin does not persist beyond a year in patients who have tolerated therapy for a year without a bleeding event may affect the decision to continue clopidogrel beyond 1 year, such as in patients with acute coronary syndromes or patients who have received drug-eluting stents.^35,36
• Another important consideration is cost-effectiveness. Several studies have analyzed the impact of cost and found clopidogrel to be cost-effective by preventing ischemic events and adding years of life.^37,38 A recent analysis from CHARISMA also shows cost-effectiveness in the subgroup of patients enrolled with established cardiovascular disease.³⁹ Once clopidogrel becomes generic, the cost-effectiveness will become even better.

Further studies should better define which stable patients with cardiovascular disease should be on more than aspirin alone.

In patients at risk of myocardial infarction or stroke, two antiplatelet drugs are not always better than one. In a large recent trial,^1,2 adding clopidogrel (Plavix) to aspirin therapy did not offer much benefit to a cohort of patients at risk of cardiovascular events, although a subgroup did appear to benefit: those at even higher risk because they already had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

These were the principal findings in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study,^1,2 in which one of us (D.L.B.) was principal investigator.

These findings further our understanding of who should receive dual antiplatelet therapy, and who would be better served with aspirin therapy alone. In this article, we discuss important studies that led up to the CHARISMA trial, review CHARISMA’s purpose and study design, and interpret its results.

PREVENTING ATHEROTHROMBOSIS BY BLOCKING PLATELETS

Platelets are key players in the atherothrom-botic process.^3–5 The Antiplatelet Trialists’ Collaboration,⁶ in a meta-analysis of trials performed up to 1997, calculated that antiplatelet therapy (mostly with aspirin) reduced the vascular mortality rate by 15% in patients with acute or previous vascular disease or some other predisposing condition. Thus, aspirin has already been shown to be effective as primary prevention (ie, in patients at risk but without established vascular disease) and as secondary prevention (ie, in those with established disease).^7,8

Yet many patients have significant vascular events in spite of taking aspirin.⁶ Aspirin failure is thought to be multifactorial, with causes that include weak platelet inhibition, noncompliance, discontinuation due to adverse effects (including severe bleeding), and drug interactions. In addition, aspirin resistance has been linked to worse prognosis and may prove to be another cause of aspirin failure.^9–11

Clopidogrel, an adenosine diphosphate (ADP) receptor antagonist, has also been studied extensively as an antiplatelet agent.^5,12 Several studies have indicated that clopidogrel and ticlopidine (Ticlid, a related drug) may be more potent than aspirin, both in the test tube and in real patients.^13–15

KEY TRIALS LEADING TO CHARISMA

• Clopidogrel is more effective and slightly safer than aspirin as secondary prevention, as shown in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.^16–21
• The combination of clopidogrel plus aspirin is more beneficial than placebo plus aspirin in patients with acute coronary syndromes, as shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial,^22–24 the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myo-car-dial Infarction (CLARITY-TIMI 28) trial,²⁵ and the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT).²⁶
• The combination of clopidogrel plus aspirin is beneficial in patients undergoing percutaneous coronary interventions, with or without drug-eluting stent placement,^27–30 as shown in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial,²⁸ the Effect of Clopidogrel Pretreatment Before Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction With Fibrinolytics (PCI-CLARITY) study,²⁹ and the Effects of Pre-treatment With Clopidogrel and Aspirin Followed by Long-term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE) study.³⁰ In fact, most patients undergoing percutaneous interventions now receive a loading dose of clopidogrel before the procedure and continue to take it for up to 1 year afterward. However, the ideal long-term duration of clopidogrel treatment is still under debate.

In view of these previous studies, we wanted to test dual antiplatelet therapy in a broader population at high risk of atherothrombosis, ie, in patients with either established vascular disease or with multiple risk factors for it.

CHARISMA STUDY DESIGN

CHARISMA was a prospective, randomized, double-blind, placebo-controlled study of the efficacy and safety of clopidogrel plus aspirin vs placebo plus aspirin in patients at high risk of cardiovascular events.

A total of 15,603 patients, all older than 45 years, were randomly assigned to receive clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin, in addition to standard therapy as directed by individual clinicians (eg, statins, beta-blockers). Patients were followed up at 1, 3, and 6 months and every 6 months thereafter until study completion, which occurred after 1,040 primary efficacy end points. The median duration of follow-up was 28 months.¹

Patients had to have one of the following to be included: multiple atherothrombotic risk factors, documented coronary disease, documented cerebrovascular disease, or documented peripheral arterial disease (Table 2). Specific exclusion criteria included the use of oral antithrombotic or chronic nonsteroidal anti-inflammatory medications.¹

End points

The primary end point was the combined incidence of the first episode of myocardial infarction or stroke, or death from cardiovascular causes.

The secondary end point was the combined incidence of myocardial infarction, stroke, death from cardiovascular causes, or hospitalization for unstable angina, a transient ischemic attack, or revascularization procedure.

The primary safety end point was severe bleeding, as defined in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) study³¹ as intracranial hemorrhage, fatal bleeding, or bleeding leading to hemody-namic compromise. Moderate bleeding was defined as bleeding that required transfusion but did not meet the GUSTO definition of severe bleeding.

OVERALL, NO BENEFIT

The rates of the secondary end point were 16.7% vs 17.9% (absolute risk reduction 1.2%; relative risk reduction 8%; P = .04).

Possible benefit in symptomatic patients

In a prespecified analysis, patients were classified as being “symptomatic” (having documented cardiovascular disease, ie, coronary, cerebrovascular, or symptomatic peripheral arterial disease) or “asymptomatic” (having multiple risk factors without established cardiovascular disease).¹

In the symptomatic group (n = 12,153), the primary end point was reached in 6.9% of patients treated with clopidogrel vs 7.9% with placebo (absolute risk reduction 1.0%; relative risk reduction 13%; P = .046). The 3,284 asymptomatic patients showed no benefit; the rate of the primary end point for the clopido-grel group was 6.6% vs 5.5% in the placebo group (P = .20).

In a post hoc analysis, we examined the data from 9,478 patients who were similar to those in the CAPRIE study (ie, with documented prior myocardial infarction, prior ischemic stroke, or symptomatic peripheral arterial disease). The rate of cardiovascular death, myocardial infarction, or stroke was 8.8% in the placebo-plus-aspirin group and 7.3% in the clopidogrel-plus-aspirin group (absolute risk reduction 1.5%; relative risk reduction 17%; P = .01; Figure 1).²

HOW SHOULD WE INTERPRET THESE FINDINGS?

CHARISMA was the first trial to evaluate whether adding clopidogrel to aspirin therapy would reduce the rates of vascular events and death from cardiovascular causes in stable patients at risk of ischemic events. As in other trials, the benefit of clopidogrel-plus-aspirin therapy was weighed against the risk of bleeding with this regimen. How are we to interpret the findings?

• In the group with multiple risk factors but without clearly documented cardiovascular disease, there was no benefit—and there was an increase in moderate bleeding. Given these findings, physicians should not prescribe dual antiplatelet therapy for primary prevention in patients without known vascular disease.
• A potential benefit was seen in a prespecified subgroup who had documented cardiovascular disease. Given the limitations of subgroup analysis, however, and given the increased risk of moderate bleeding, this positive result should be interpreted with some degree of caution.
• CHARISMA suggests that there may be benefit of protracted dual antiplatelet therapy in stable patients with documented prior ischemic events.

A possible reason for the observed lack of benefit in the overall cohort but the positive results in the subgroups with established vascular disease is that plaque rupture and thrombosis may be a precondition for dual antiplatelet therapy to work.

Another possibility is that, although we have been saying that diabetes mellitus (one of the possible entry criteria in CHARISMA) is a “coronary risk equivalent,” this may not be absolutely true. Although it had been demonstrated that patients with certain risk factors, such as diabetes, have an incidence of ischemic events similar to that in patients with prior MI and should be considered for antiplatelet therapy to prevent vascular events,³² more recent data have shown that patients with prior ischemic events are at much higher risk than patients without ischemic events, even if the latter have diabetes.^33,34

• The observation in CHARISMA that the incremental bleeding risk of dual antiplatelet therapy vs aspirin does not persist beyond a year in patients who have tolerated therapy for a year without a bleeding event may affect the decision to continue clopidogrel beyond 1 year, such as in patients with acute coronary syndromes or patients who have received drug-eluting stents.^35,36
• Another important consideration is cost-effectiveness. Several studies have analyzed the impact of cost and found clopidogrel to be cost-effective by preventing ischemic events and adding years of life.^37,38 A recent analysis from CHARISMA also shows cost-effectiveness in the subgroup of patients enrolled with established cardiovascular disease.³⁹ Once clopidogrel becomes generic, the cost-effectiveness will become even better.

Further studies should better define which stable patients with cardiovascular disease should be on more than aspirin alone.

In patients at risk of myocardial infarction or stroke, two antiplatelet drugs are not always better than one. In a large recent trial,^1,2 adding clopidogrel (Plavix) to aspirin therapy did not offer much benefit to a cohort of patients at risk of cardiovascular events, although a subgroup did appear to benefit: those at even higher risk because they already had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease.

These were the principal findings in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study,^1,2 in which one of us (D.L.B.) was principal investigator.

These findings further our understanding of who should receive dual antiplatelet therapy, and who would be better served with aspirin therapy alone. In this article, we discuss important studies that led up to the CHARISMA trial, review CHARISMA’s purpose and study design, and interpret its results.

PREVENTING ATHEROTHROMBOSIS BY BLOCKING PLATELETS

Platelets are key players in the atherothrom-botic process.^3–5 The Antiplatelet Trialists’ Collaboration,⁶ in a meta-analysis of trials performed up to 1997, calculated that antiplatelet therapy (mostly with aspirin) reduced the vascular mortality rate by 15% in patients with acute or previous vascular disease or some other predisposing condition. Thus, aspirin has already been shown to be effective as primary prevention (ie, in patients at risk but without established vascular disease) and as secondary prevention (ie, in those with established disease).^7,8

Yet many patients have significant vascular events in spite of taking aspirin.⁶ Aspirin failure is thought to be multifactorial, with causes that include weak platelet inhibition, noncompliance, discontinuation due to adverse effects (including severe bleeding), and drug interactions. In addition, aspirin resistance has been linked to worse prognosis and may prove to be another cause of aspirin failure.^9–11

Clopidogrel, an adenosine diphosphate (ADP) receptor antagonist, has also been studied extensively as an antiplatelet agent.^5,12 Several studies have indicated that clopidogrel and ticlopidine (Ticlid, a related drug) may be more potent than aspirin, both in the test tube and in real patients.^13–15

KEY TRIALS LEADING TO CHARISMA

• Clopidogrel is more effective and slightly safer than aspirin as secondary prevention, as shown in the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.^16–21
• The combination of clopidogrel plus aspirin is more beneficial than placebo plus aspirin in patients with acute coronary syndromes, as shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial,^22–24 the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myo-car-dial Infarction (CLARITY-TIMI 28) trial,²⁵ and the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT).²⁶
• The combination of clopidogrel plus aspirin is beneficial in patients undergoing percutaneous coronary interventions, with or without drug-eluting stent placement,^27–30 as shown in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial,²⁸ the Effect of Clopidogrel Pretreatment Before Percutaneous Coronary Intervention in Patients With ST-Elevation Myocardial Infarction With Fibrinolytics (PCI-CLARITY) study,²⁹ and the Effects of Pre-treatment With Clopidogrel and Aspirin Followed by Long-term Therapy in Patients Undergoing Percutaneous Coronary Intervention (PCI-CURE) study.³⁰ In fact, most patients undergoing percutaneous interventions now receive a loading dose of clopidogrel before the procedure and continue to take it for up to 1 year afterward. However, the ideal long-term duration of clopidogrel treatment is still under debate.

In view of these previous studies, we wanted to test dual antiplatelet therapy in a broader population at high risk of atherothrombosis, ie, in patients with either established vascular disease or with multiple risk factors for it.

CHARISMA STUDY DESIGN

CHARISMA was a prospective, randomized, double-blind, placebo-controlled study of the efficacy and safety of clopidogrel plus aspirin vs placebo plus aspirin in patients at high risk of cardiovascular events.

A total of 15,603 patients, all older than 45 years, were randomly assigned to receive clopidogrel 75 mg/day plus aspirin 75 to 162 mg/day or placebo plus aspirin, in addition to standard therapy as directed by individual clinicians (eg, statins, beta-blockers). Patients were followed up at 1, 3, and 6 months and every 6 months thereafter until study completion, which occurred after 1,040 primary efficacy end points. The median duration of follow-up was 28 months.¹

Patients had to have one of the following to be included: multiple atherothrombotic risk factors, documented coronary disease, documented cerebrovascular disease, or documented peripheral arterial disease (Table 2). Specific exclusion criteria included the use of oral antithrombotic or chronic nonsteroidal anti-inflammatory medications.¹

End points

The primary end point was the combined incidence of the first episode of myocardial infarction or stroke, or death from cardiovascular causes.

The secondary end point was the combined incidence of myocardial infarction, stroke, death from cardiovascular causes, or hospitalization for unstable angina, a transient ischemic attack, or revascularization procedure.

The primary safety end point was severe bleeding, as defined in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) study³¹ as intracranial hemorrhage, fatal bleeding, or bleeding leading to hemody-namic compromise. Moderate bleeding was defined as bleeding that required transfusion but did not meet the GUSTO definition of severe bleeding.

OVERALL, NO BENEFIT

The rates of the secondary end point were 16.7% vs 17.9% (absolute risk reduction 1.2%; relative risk reduction 8%; P = .04).

Possible benefit in symptomatic patients

In a prespecified analysis, patients were classified as being “symptomatic” (having documented cardiovascular disease, ie, coronary, cerebrovascular, or symptomatic peripheral arterial disease) or “asymptomatic” (having multiple risk factors without established cardiovascular disease).¹

In the symptomatic group (n = 12,153), the primary end point was reached in 6.9% of patients treated with clopidogrel vs 7.9% with placebo (absolute risk reduction 1.0%; relative risk reduction 13%; P = .046). The 3,284 asymptomatic patients showed no benefit; the rate of the primary end point for the clopido-grel group was 6.6% vs 5.5% in the placebo group (P = .20).

In a post hoc analysis, we examined the data from 9,478 patients who were similar to those in the CAPRIE study (ie, with documented prior myocardial infarction, prior ischemic stroke, or symptomatic peripheral arterial disease). The rate of cardiovascular death, myocardial infarction, or stroke was 8.8% in the placebo-plus-aspirin group and 7.3% in the clopidogrel-plus-aspirin group (absolute risk reduction 1.5%; relative risk reduction 17%; P = .01; Figure 1).²

HOW SHOULD WE INTERPRET THESE FINDINGS?

CHARISMA was the first trial to evaluate whether adding clopidogrel to aspirin therapy would reduce the rates of vascular events and death from cardiovascular causes in stable patients at risk of ischemic events. As in other trials, the benefit of clopidogrel-plus-aspirin therapy was weighed against the risk of bleeding with this regimen. How are we to interpret the findings?

• In the group with multiple risk factors but without clearly documented cardiovascular disease, there was no benefit—and there was an increase in moderate bleeding. Given these findings, physicians should not prescribe dual antiplatelet therapy for primary prevention in patients without known vascular disease.
• A potential benefit was seen in a prespecified subgroup who had documented cardiovascular disease. Given the limitations of subgroup analysis, however, and given the increased risk of moderate bleeding, this positive result should be interpreted with some degree of caution.
• CHARISMA suggests that there may be benefit of protracted dual antiplatelet therapy in stable patients with documented prior ischemic events.

A possible reason for the observed lack of benefit in the overall cohort but the positive results in the subgroups with established vascular disease is that plaque rupture and thrombosis may be a precondition for dual antiplatelet therapy to work.

Another possibility is that, although we have been saying that diabetes mellitus (one of the possible entry criteria in CHARISMA) is a “coronary risk equivalent,” this may not be absolutely true. Although it had been demonstrated that patients with certain risk factors, such as diabetes, have an incidence of ischemic events similar to that in patients with prior MI and should be considered for antiplatelet therapy to prevent vascular events,³² more recent data have shown that patients with prior ischemic events are at much higher risk than patients without ischemic events, even if the latter have diabetes.^33,34

• The observation in CHARISMA that the incremental bleeding risk of dual antiplatelet therapy vs aspirin does not persist beyond a year in patients who have tolerated therapy for a year without a bleeding event may affect the decision to continue clopidogrel beyond 1 year, such as in patients with acute coronary syndromes or patients who have received drug-eluting stents.^35,36
• Another important consideration is cost-effectiveness. Several studies have analyzed the impact of cost and found clopidogrel to be cost-effective by preventing ischemic events and adding years of life.^37,38 A recent analysis from CHARISMA also shows cost-effectiveness in the subgroup of patients enrolled with established cardiovascular disease.³⁹ Once clopidogrel becomes generic, the cost-effectiveness will become even better.

Further studies should better define which stable patients with cardiovascular disease should be on more than aspirin alone.