Dual antiplatelet therapy for acute coronary syndromes: How long to continue?

The PEGASUS-TIMI 54 trial³⁹ studied the benefit of adding ticagrelor (60 or 90 mg) to low-dose aspirin in patients with stable coronary artery disease who had had a myocardial infarction 1 to 3 years earlier.

Confirming the results of the CHARISMA subgroup analysis, the incidence of the ischemic primary efficacy end point (a composite of cardiovascular death, myocardial infarction, and stroke) was significantly lower in both groups receiving ticagrelor plus aspirin compared with those receiving placebo plus aspirin. The Kaplan-Meier rate at 3 years for the ticagrelor 90 mg-plus-aspirin group was 7.85% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.85, 95% confidence interval [CI] 0.75–0.96, P = .008). The rate for the ticagrelor 60 mg-plus-aspirin group was 7.77% vs 9.04% for the placebo-plus-aspirin group (hazard ratio 0.84, 95% CI 0.74–0.95, P = .004).

The rates of all TIMI major and minor bleeding, as well as bleeding requiring transfusion or discontinuation of the study drug, were significantly higher in both ticagrelor dosing groups than in the placebo group (P < .01 for both groups vs placebo). The rates of fatal bleeding and nonfatal intracranial hemorrhage were not significantly higher. Although there was an overall reduction in ischemic end points with the addition of ticagrelor, there was also a significantly higher incidence of bleeding in this group.

Comment. Thus, with or without percutaneous coronary intervention in acute coronary syndrome as well as in stable coronary artery disease, dual antiplatelet therapy was shown to improve outcomes and decrease ischemic complications compared with aspirin alone. It provided benefit in the setting of acute coronary syndrome (in the CURE trial) and percutaneous coronary intervention (in the CREDO trial) for up to 1 year.

Major questions remained to be addressed:

• Do the results of CREDO, which was performed before the current interventional era and the use of drug-eluting stents, reflect outcomes after current interventional practice?
• Could shorter periods of dual antiplatelet therapy be sufficient, especially with newer stents with less risk of late thrombosis?
• Does the benefit of dual antiplatelet therapy extend beyond the 1-year time period tested in those trials to date?

RECOMMENDATIONS FOR DOSING

The American College of Cardiology Foundation/American Heart Association guidelines for dosing of antiplatelet agents for non-ST-elevation myocardial infarction are summarized in Table 2, and those for ST-elevation myocardial infarction are summarized in Table 3.^1,2

WOULD SHORTER THERAPY AFTER STENTING WORK AS WELL?

The American College of Cardiology Foundation/American Heart Association currently recommend dual antiplatelet therapy for at least 12 months after drug-eluting stent placement, with shorter courses appropriate for patients who develop excessive bleeding complications or who are at high risk of bleeding.

Four trials (Table 4) evaluated whether shorter durations of dual antiplatelet therapy would suffice: SECURITY,⁴⁰ EXCELLENT,⁴¹ OPTIMIZE,⁴² and RESET.⁴³ All of them showed that short-duration therapy was not inferior to standard-duration therapy.⁴⁴ These studies were comparable in that:

• Patients were randomized at the time of percutaneous coronary intervention or within 24 hours of it.
• Most patients received a second-generation drug-eluting stent, with the following exceptions: in EXCELLENT,⁴¹ one-fourth of patients received a Cypher first-generation drug-eluting stent, and in RESET,⁴³ approximately one-fourth of the patients received a sirolimus-eluting stent in the standard-duration group for short lesions. Those patients with longer lesions in the RESET standard-duration group received an evero­limus drug-eluting stent.
• The second antiplatelet added to aspirin in all studies was clopidogrel, with the exception of the SECURITY trial, in which fewer than 2% of patients received ticagrelor or prasugrel.⁴⁰
• All the trials except RESET excluded patients who had had a myocardial infarction within 72 hours, and thus most patients studied had a lower risk profile.
• All of the trials sought to study noninferiority of short- vs standard-duration dual antiplatelet therapy, defined as the occurrence of a primary end point at 1 year (a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, target vessel failure or revascularization, or bleeding).

Their low-risk patient populations and infrequent end points rendered these studies underpowered to make definitive conclusions about the relative efficacy of 6-months vs 12-months of dual antiplatelet therapy.

WOULD LONGER THERAPY BE BETTER?

The PRODIGY trial⁴⁵ assessed durations of dual antiplatelet therapy both shorter and longer than the conventional 1 year, randomizing patients undergoing placement of a bare-metal stent, first-generation drug-eluting stent, or second-generation drug-eluting stent to receive aspirin and clopidogrel for either 6 months or 24 months. The study showed no significant difference in primary outcomes in the short- or long-duration groups.

Other trials that compared the standard 12 months of dual antiplatelet therapy with extended duration beyond 12 months were DAPT,³ ARCTIC-Interruption,⁴⁶ and DES-LATE.⁴⁷ The trials were comparable in that:

• All patients were randomized after completing 12 months of dual antiplatelet therapy following drug-eluting stent placement.
• All patients who were included had been free of major cardiac ischemic events or bleeding during the 12 months following stent placement.
• The primary aim of all three studies was to compare primary end points in groups receiving aspirin alone vs extended dual antiplatelet therapy. The primary end point was a composite of death due to a cardiovascular cause, nonfatal myocardial infarction, stroke, or stent thrombosis.
• The principal safety end point was bleeding.

Although the two earlier studies (ARCTIC-Interruption and DES-LATE) did not show any benefit of extended dual antiplatelet therapy compared with the standard 12-month duration, the recent DAPT study did.

The DAPT study

The DAPT study³ was an international, multicenter, placebo-controlled, double-blind randomized trial designed to examine the benefit of dual antiplatelet therapy beyond 1 year in a patient population large enough to provide definitive assessment of benefit and risk.

A total of 9,961 patients who received drug-eluting stents were randomized after 12 months of dual antiplatelet therapy to receive either a thienopyridine (clopidogrel or prasugrel) plus aspirin or placebo plus aspirin. They were followed for an additional 18 months. The coprimary efficacy end points were stent thrombosis and a composite of death, myocardial infarction, or stroke, while the primary safety end point was moderate or severe bleeding. The patients were also observed from months 30 to 33 on aspirin alone after stopping the thienopyridine.

Results. Longer therapy substantially reduced the risks of stent thrombosis (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.17–0.48) and the composite ischemic end point (HR 0.71, 95% CI 0.59–0.85). Follow-up during the 3-month thienopyridine discontinuation phase starting at 30 months revealed convergence of the ischemic event-rate curves in the two groups, which suggested that continuing dual antiplatelet therapy beyond 30 months might have been beneficial. Myocardial infarction unrelated to stent thrombosis accounted for 55% of the treatment benefit of dual antiplatelet therapy.

The risk of bleeding was higher in the thienopyridine group during the treatment period (2.5% vs 1.6%, P = .001). There was also a higher rate of noncardiovascular mortality in the thienopyridine group, although this difference may have been due to chance.^3,48

Why were the results different?

All three trials included first- and second-generation drug-eluting stents, with different proportions in different trials. In ARCTIC-Interruption,⁴⁶ 43% of the patients in the continuation group had a first-generation stent, as did 64% of the patients in the dual antiplatelet group of DES-LATE.⁴⁷ In the DAPT trial,³ 38% of the patients in the longer-duration arm had a first-generation stent, and in 26% of cases it was a paclitaxel-eluting stent.

Only clopidogrel was used as the second antiplatelet agent in DES-LATE, whereas prasugrel was used in 10% of patients in ARCTIC-Interruption and 35% in DAPT.

Yet none of these differences seem to explain the differences in outcome among the studies. ARCTIC-Interruption and DES-LATE did not show any benefit of continued dual antiplatelet therapy beyond 12 months. DAPT showed benefit of extended therapy with prasugrel or with clopidogrel, and with first-generation or second-generation drug-eluting stents. The most likely explanation for the different results was that DAPT was the only trial sufficiently powered to definitively assess the end points, including stent thrombosis.

A balance between ischemic efficacy and bleeding risk is the major consideration with any antithrombotic and antiplatelet therapy. In the three largest trials we discussed (the vascular disease subgroups of CHARISMA,³⁸ PEGASUS,³⁹ and DAPT³), comparison of the prespecified efficacy and safety end points of each trial suggests that dual antiplatelet therapy has a net benefit, particularly given the irreversible nature of ischemic end points.

In CHARISMA,³⁸ 60 cardiovascular deaths, myocardial infarctions, or strokes were prevented per year per 10,000 patients treated, at the cost of 28 excess moderate bleeding events.

In PEGASUS,³⁹ 42 cardiovascular deaths, myocardial infarctions, or strokes were prevented, at the cost of 79 excess bleeding events requiring transfusion.

In DAPT (a selected population who had tolerated dual antiplatelet therapy for 1 year), 106 deaths, myocardial infarctions, or stroke events were prevented, at the cost of 47 excess moderate bleeding events^.3

Indirect comparisons between trials are problematic, given different end point definitions, populations, and background therapies. But their results suggest that less-intensive inhibition with clopidogrel as the second antiplatelet long-term (as in CHARISMA) may provide the best balance of benefit vs risk.

BALANCING RISK AND BENEFIT

The evidence is unequivocal that dual antiplatelet therapy suppresses coronary ischemic complications resulting from thrombosis at sites of spontaneous plaque rupture following acute coronary syndromes or mechanical plaque disruption and foreign body implantation associated with percutaneous coronary intervention.

Three large-scale trials (DAPT,³ PEGASUS,³⁹ and the secondary prevention subgroup of CHARISMA³⁸) showed that the protective effect of dual antiplatelet therapy continues with prolonged therapy in patients who have experienced an acute coronary syndrome event or have received a drug-eluting stent. That benefit seems to be due to the action of these therapies on the culprit vessel (the one that caused the acute coronary syndrome or the site of stenting), as well as nonculprit arteries, emphasizing that dual antiplatelet therapy protects against atherosclerosis progression and future plaque rupture events.

For the durations studied in the longest trials thus far, 30 months (DAPT³) and 36 months (PEGASUS³⁹), event curves continue to diverge, indicating that the advantage of dual antiplatelet therapy may persist for an indefinite period of time. Thus, indefinite therapy with dual antiplatelet agents can be supported, particularly in patients with advanced coronary artery disease or those who have had multiple coronary events.

We believe that the balance of evidence suggests that smaller studies that failed to show a benefit of longer-term therapy were underpowered to do so.

The ischemic protection is associated with the adverse effect of increased bleeding risk. Unfortunately, there has been little success in guiding dual antiplatelet therapy based on ischemic vs bleeding risk, in part because the same factors that predict risk of ischemic complications seem to predict increased susceptibility to bleeding. Nevertheless, indirect comparisons between studies suggest that for longer-term therapy clopidogrel may be superior to ticagrelor or prasugrel: the absolute excess bleeding risk with dual antiplatelet therapy vs aspirin in the CHARISMA secondary prevention subgroup was less than that in PEGASUS, with similar absolute reductions in ischemic events. So while the TRITON-TIMI 38²² and PLATO²³ trials support the superiority of prasugrel or ticagrelor over clopidogrel for the first year after acute coronary syndrome, subsequent years of therapy may best be provided with clopidogrel.

Some patients may have identifiable factors that place them at very high risk of bleeding—need for surgical procedures, need for anticoagulation, or occurrence of bleeding complications or excessive “nuisance bleeding.” In those patients, the data suggest that dual antiplatelet therapy could be discontinued after 6 months, or perhaps even 3 months in the highest bleeding risk circumstances after second-generation drug-eluting stent placement.

WOEST⁴⁹ was an open-label randomized controlled trial that studied the safety of antiplatelet regimens in patients on anticoagulation requiring percutaneous coronary interventions. Patients were randomized to double therapy with anticoagulant and clopidogrel vs triple therapy with additional aspirin following percutaneous coronary intervention. The primary end point was bleeding events within 1 year. Clopidogrel without aspirin was associated with significantly fewer bleeding events compared with triple therapy, with no increase in adverse ischemic events. The strategy tested in the WOEST trial seems reasonable in the specific group of patients who require ongoing anticoagulant therapy after drug-eluting stent placement, recognizing that the trial was somewhat underpowered to make definitive conclusions, particularly in patients at high risk for stent thrombosis.

Based on the results of PEGASUS and the CHARISMA subgroup with established ischemic burden, in which dual antiplatelet therapy was started after an interruption following the index coronary event, it is also reasonable to restart long-term dual antiplatelet therapy in patients who require interruption for short-term indications such as a surgical procedure.