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

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

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Meghana Halkar, MD

A. Michael Lincoff, MD

Percutaneous coronary intervention for acute coronary syndromes has evolved, and so, hand in hand, has antiplatelet therapy. With the advent of clopidogrel and newer agents, several studies demonstrated the benefits of dual antiplatelet therapy in preventing major vascular ischemic complications. The findings culminated in a guideline recommendation for at least 12 months of dual antiplatelet therapy after placement of a drug-eluting stent, when feasible—a class I recommendation (treatment should be given), level of evidence B (limited populations evaluated).^1,2 But extending dual antiplatelet therapy beyond 12 months had no strong favorable evidence until the recent Dual Antiplatelet Therapy (DAPT) study³ shed light on this topic.

Here, we review the evidence thus far on the optimal duration of dual antiplatelet therapy in the secondary prevention of coronary artery disease.

PLATELETS IN ACUTE CORONARY SYNDROMES AND STENT THROMBOSIS

Figure 1. The platelet aggregation cascade. Exposure of subendo-thelial matrix leads to adhesion of platelets to the vessel wall, activation, and aggregation. ADP = adenosine diphosphate; GP = glycoprotein; TxA2 = thromboxane A2; vWF = von Willebrand factor

Acute coronary syndromes begin with fissuring or ulceration of a vulnerable atherosclerotic plaque, followed by thrombosis and occlusion, mediated by platelet adhesion, activation, and aggregation (Figure 1). Transient occlusion results in unstable angina or non-ST-elevation myocardial infarction, while total occlusion usually results in ST-elevation myocardial infarction.

Platelet aggregation is prominent among the mechanisms leading to stent thrombosis and vaso-occlusive ischemic complications after percutaneous coronary intervention. Thus, antiplatelet agents play a vital role in both primary and secondary prevention of cardiovascular events.^4–6

Adhesion, activation, and aggregation

Adhesion. Disruption of the vascular endothelium as a result of vulnerable plaque fissuring or ulceration exposes subendothelial thrombogenic collagen and von Willebrand factor to blood. Collagen engages platelets through their glycoprotein (GP) Ia, IIa, and VI receptors, and von Willebrand factor binds platelets through the GP Ib-IX-V receptor.

Activation. Once platelets adhere to the subendothelium, they undergo a conformational change and become activated. Simultaneous release of various autocrine and paracrine mediators including adenosine diphosphate, serotonin, epinephrine, thromboxane, and various ligand-receptor interactions all contribute to the activation cascade. Adenosine diphosphate binds to the platelet receptor P2Y₁, leading to an increase in intracellular calcium, and it binds to P2Y₁₂, leading to a decrease in cyclic adenosine monophosphate, both of which cause GP IIb/IIIa receptor activation. Thromboxane A₂ released by platelets by cyclo-oxygenase 1 binds to alpha or beta variant receptors and contributes to GP IIb/IIIa activation through elevation of intracellular calcium levels.

Aggregation and thrombosis. Exposure of tissue factor to plasma following plaque rupture activates the coagulation cascade via the extrinsic pathway, which generates thrombin, a powerful platelet activator that causes thrombus formation via fibrin. Thrombin binds to protease-activated receptors PAR-1 and PAR-4 on platelets, causing an increase in intracellular calcium and a decrease in cyclic adenosine monophosphate with subsequent GP IIb/IIIa activation. GP IIb/IIIa facilitates platelet aggregation by binding to fibrinogen and forming a stable platelet thrombus.

In the early stages of thrombus formation, platelets predominate (“white” thrombi); further organization with fibrin results in older “red” thrombi. The stages of thrombi vary in non-ST-elevation and ST-elevation myocardial infarction and are prognostic markers of death.^4–8

PERCUTANEOUS INTERVENTION, RESTENOSIS, AND STENT THROMBOSIS

Percutaneous coronary intervention, the preferred means of revascularization for many patients, is performed emergently in patients with ST-elevation myocardial infarction, urgently in those with acute coronary syndromes without ST elevation, and electively in those with stable ischemic symptoms.

Percutaneous revascularization techniques have evolved from balloon angioplasty to bare-metal stents to drug-eluting stents, but each of these procedures has been associated with a periprocedural and postprocedural risk of thrombosis.

Balloon angioplasty was associated with vascular intimal injury, inciting elastic vascular recoil and smooth muscle cell proliferation leading to restenosis.

Bare-metal stents reduced the restenosis rate by eliminating vascular recoil, although restenosis still occurred within the stent because of neointimal proliferation of vascular smooth muscle cells. This was an important limitation, as both acute and subacute stent thrombosis were refractory to aggressive anticoagulation regimens that were associated with major bleeding complications and longer hospital length of stay. Stenting became mainstream practice only after the ISAR⁹ and STARS¹⁰trials showed that dual antiplatelet therapy controlled stent thrombosis.

Drug-eluting stents coated with anti-proliferative and anti-inflammatory polymers markedly reduced in-stent restenosis rates by suppressing the initial vascular smooth-muscle proliferative response. However, they were still associated with late and very late stent thrombosis with incomplete endothelialization, even up to 40 months after implantation. Proposed mechanisms include incomplete stent apposition and inflammatory hypersensitivity reactions to the polymer coating. Incomplete stent apposition associated with low-velocity blood flow at the junction of the stent strut and vessel wall, together with delayed endothelialization, promotes platelet adhesion and aggregation, followed by thrombus formation.¹¹

Second-generation drug-eluting stents have thinner struts and more biocompatible polymers and are thought to favor more complete re-endothelialization, reducing the rates of stent thrombosis.^8,12,13

Predictors of early stent thrombosis

The Dutch Stent Thrombosis Registry and other studies looked at risk factors for stent thrombosis.^14,15

Procedure-related factors included:

Stent undersizing
Residual uncovered dissections after angioplasty
Longer stents
Low flow after angioplasty (< 3 on the 0–3 Thrombolysis in Myocardial Infarction [TIMI] scale).

Lesion-related factors included:

Intermediate coronary artery disease both proximal and distal to the culprit lesions
Bifurcation lesions.

Patient-related factors included:

Low left ventricular ejection fraction
Diabetes mellitus
Peripheral arterial disease Premature discontinuation of clopidogrel.

ANTIPLATELET AGENTS: MECHANISM OF ACTION

Figure 2. Mechanism of action of antiplatelet agents. AC = adenyl cyclase; cAMP = cyclic adenosine monophosphate; Ca = calcium; CYP = cytochrome P450; Gs, Gi, Gq = G proteins; PDEIII = phosphodiesterase III, PGR, P2Y12, P2Y1, P2X1 = platelet receptors; PKA = protein kinase A; VASP = vasodilator-stimulated phosphoprotein; VASP-P = phosphorylated VASP

Various pathways play synergistic roles in platelet activation and aggregation and thrombus formation, and different antiplatelet agents inhibit these specific pathways, thus complementing each other and having additive effects (Figure 2, Table 1).^5,16–21

Aspirin inhibits cyclo-oxygenase 1

Cyclo-oxygenase 1, found in platelets, endothelial cells, and other cells, catalyzes the conversion of arachidonic acid to thromboxane A₂. Aspirin irreversibly inhibits cyclo-oxygenase 1 by acetylating its serine residue, preventing formation of thromboxane A₂ and preventing platelet activation and aggregation.

P2Y₁₂ ADP receptor antagonists

Clopidogrel and prasugrel are thienopyridine agents that irreversibly inhibit the P2Y₁₂ receptor, thereby preventing binding of adenosine diphosphate and the subsequent platelet activation-aggregation cascade. They are both prodrugs and require conversion by cytochrome P450 enzymes to active metabolites. Prasugrel is 10 times more potent than clopidogrel due to more efficient formation of its active metabolite, and it achieves a comparable effect on platelet inhibition 30 minutes faster than the peak effect of clopidogrel at 6 hours. The overall peak inhibitory effect of prasugrel is twice that of clopidogrel.²²

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, directly and reversibly inhibits the P2Y₁₂ ADP receptor. Unlike clopidogrel and prasugrel, it does not need to be converted to an active metabolite, and it noncompetitively inhibits P2Y₁₂ at a site different from the adenosine diphosphate binding site.²³ Like prasugrel, ticagrelor inhibits platelet function more rapidly and more completely than clopidogrel.

Cangrelor, an intravenously administered analogue of adenosine triphosphate, reversibly inhibits the P2Y₁₂ receptor. It has undergone phase 3 trials but is not yet approved for clinical use.²⁴

WHY DUAL ANTIPLATELET THERAPY?

Aspirin is good, clopidogrel is better

Aspirin has a well-validated role in both primary and secondary prevention of coronary and noncoronary atherosclerotic vascular disease.

The CAPRIE trial found clopidogrel monotherapy to be superior to aspirin monotherapy in patients with established atherosclerotic vascular disease.²⁵

After stenting, short-term dual therapy is better than short-term warfarin

Thrombotic complications in the early postprocedural period were a major limitation of stenting, and existing anticoagulation regimens were ineffective in preventing them.^26,27

The ISAR trial studied the benefit of combined antiplatelet vs anticoagulant therapy after stent placement. Patients randomized to receive combined aspirin plus ticlopidine (an early P2Y₁₂ inhibitor) had significantly lower rates of primary cardiac, hemorrhagic, and vascular events at 30 days.⁹ Two other trials confirmed this finding.^28,29

STARS¹⁰ also confirmed the benefit of aspirin and ticlopidine after stenting. Patients were randomly assigned to aspirin alone, aspirin plus warfarin, or aspirin plus ticlopidine after stent placement. The rate of stent thrombosis at 30 days was significantly lower in the dual antiplatelet group than in the other two groups. The dual antiplatelet group had a higher rate of bleeding than the aspirin-alone group, but the rate was similar to that of the aspirin-plus-warfarin group.

Long-term dual antiplatelet therapy is beneficial in several situations

ISAR and STARS were landmark trials that showed stent thrombosis could be reduced by dual antiplatelet therapy for a 30-day period. However, the long-term role of dual antiplatelet therapy was still unknown.

The CURE trial^30–32 randomized patients presenting with acute coronary syndromes without ST elevation to receive clopidogrel plus aspirin or placebo plus aspirin for 3 to 12 months. The rate of the primary end point (cardiac death, nonfatal myocardial infarction, or stroke) was significantly lower in the clopidogrel-plus-aspirin group. A similar benefit of dual antiplatelet therapy was seen in the subgroup of patients who underwent percutaneous coronary intervention. Both pretreatment with clopidogrel plus aspirin for a median of 10 days prior to percutaneous intervention and continuing it for a mean of 9 months reduced major adverse cardiovascular events.

The CREDO trial²⁰ found that the combination of clopidogrel and aspirin significantly reduced the incidence of death, myocardial infarction, or stroke at 1 year after percutaneous coronary intervention. A subgroup of patients in this trial who had a longer pretreatment interval with a loading clopidogrel dose showed a benefit at 28 days, which was not as evident with a shorter loading dose interval.

The CLARITY-TIMI 28 trial^33,34 showed the advantage of adding clopidogrel to aspirin in patients receiving fibrinolytic therapy for ST-elevation myocardial infarction. Adding clopidogrel both improved the patency of the infarct-related artery and reduced ischemic complications. In patients who subsequently underwent percutaneous coronary intervention and stenting, clopidogrel pretreatment was associated with a significant decrease in ischemic complications before and after the procedure. There was no significant increase in bleeding complications in either group.

COMMIT/CCS 2³⁵ also showed the benefit of dual antiplatelet therapy in patients with ST-elevation myocardial infarction. Clopidogrel added to aspirin during the short-term in-hospital or postdischarge treatment period significantly reduced a composite end point of reinfarction, death, or stroke as well as death from any cause.

The CHARISMA trial^36–38 aimed to determine if patients who were more stable (ie, no recent acute coronary syndrome event or percutaneous coronary intervention) would benefit. Overall, CHARISMA showed no benefit of adding clopidogrel to aspirin compared with aspirin alone in a broad population of patients with established vascular disease (secondary prevention) or risk factors for vascular disease (primary prevention).

But importantly, though no benefit was seen in the primary prevention group, the large subgroup of patients with established atherosclerotic vascular disease (12,153 of the 15,603 patients in the trial) did benefit from dual antiplatelet therapy.^36,37 This subgroup showed an overall reduction in absolute risk of 1.5% (relative risk 0.88, P = .046) over a median follow-up of 27.6 months. This benefit was even more apparent in the 9,478 patients with prior myocardial infarction, stroke, or peripheral artery disease, for whom the relative risk reduction was 17.1% (P = .01) and the reduction in absolute risk 1.5%.³⁸

These results are comparable to the 2% absolute risk reduction in the CURE trial for similar end points over 9 months. In both studies, there was no significant increase in the risk of major bleeding or intracranial bleeding in the clopidogrel-plus-aspirin groups, although minor bleeding was increased by dual antiplatelet therapy.

The rate of severe bleeding, which was the primary safety end point in CHARISMA, was not significantly different in the clopidogrel-plus-aspirin group compared with the placebo-plus-aspirin group (relative risk 1.25, 95% CI 0.97–1.61, P = .09).

Thus, although the CHARISMA findings were negative overall, the positive finding observed in the predominant subgroup of patients with established vascular disease can therefore be considered supportive of the results of the subsequent trials discussed below.

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.⁴³All of them showed that short-duration therapy was not inferior to standard-duration therapy.⁴⁴These 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.

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Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001; 358:527–533.
Morais J. Insights from CURE: using clopidogrel on top of standard therapy. Cerebrovasc Dis 2002; 13(suppl 1):17–21.
Ferguson JJ. Clopidogrel plus aspirin in patients with acute myocardial infarction treated with fibrinolytic therapy—CLARITY-TIMI 28. Future Cardiol 2005; 1:605–610.
Sabatine MS, Cannon CP, Gibson CM, et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005; 294:1224–1232.
Chen ZM, Jiang LX, Chen YP, et al; COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366:1607–1621.
Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
Bhatt DL, Fox KA, Hacke W, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706–1717.
Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372:1791–1800.
Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014; 64:2086–2097.
Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125:505–513.
Feres F, Costa RA, Abizaid A, et al; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013; 310:2510–2522.
Kim BK, Hong MK, Shin DH, et al; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60:1340–1348.
El-Hayek G, Messerli F, Bangalore S, et al. Meta-analysis of randomized clinical trials comparing short-term versus long-term dual antiplatelet therapy following drug-eluting stents. Am J Cardiol 2014; 114:236–242.
Valgimigli M, Campo G, Monti M, et al; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012; 125:2015–2026.
Collet JP, Silvain J, Barthelemy O, et al; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014; 384:1577–1585.
Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129:304–312.
Kwok CS, Bulluck H, Ryding AD, Loke YK. Benefits and harms of extending the duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents: a meta-analysis. ScientificWorldJournal 2014; 2014:794078.
Dewilde WJ, Oirbans T, Verheugt FW, et al; WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107–1115.

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Meghana Halkar, MD
Department of Cardiovascular Medicine, MedStar Washington Hospital Center, Washington, DC

A. Michael Lincoff, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Meghana Halkar, MD, FACP, MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, 106 Irving Street, Washington, DC 20010; [email protected]

Dr. Lincoff has disclosed research support from AstraZeneca, CSL Behring, Edwards LifeSciences, Eli Lilly, Esperion, Medtronic, Pfizer, Regado, Roche, and Takeda and consulting and membership on advisory committees or review panels for Roche.

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Cleveland Clinic Journal of Medicine - 83(9)

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Cleveland Clinic Journal of Medicine

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acute coronary syndrome, ACS, myocardial infarction, MI, stent, drug-eluting stent, DES, platelets, antiplatelet drugs, dual antiplatelet therapy, DAPT, aspirin, clopidogrel, prasugrel, cilostazol, ticagrelor, cangrelor, Meghana Halkar, A Michael Lincoff

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Current Drug Therapy

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Meghana Halkar, MD

A. Michael Lincoff, MD

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Meghana Halkar, MD

A. Michael Lincoff, MD

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Meghana Halkar, MD
Department of Cardiovascular Medicine, MedStar Washington Hospital Center, Washington, DC

A. Michael Lincoff, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Meghana Halkar, MD, FACP, MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, 106 Irving Street, Washington, DC 20010; [email protected]

Dr. Lincoff has disclosed research support from AstraZeneca, CSL Behring, Edwards LifeSciences, Eli Lilly, Esperion, Medtronic, Pfizer, Regado, Roche, and Takeda and consulting and membership on advisory committees or review panels for Roche.

Author and Disclosure Information

Meghana Halkar, MD
Department of Cardiovascular Medicine, MedStar Washington Hospital Center, Washington, DC

A. Michael Lincoff, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Meghana Halkar, MD, FACP, MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, 106 Irving Street, Washington, DC 20010; [email protected]

Dr. Lincoff has disclosed research support from AstraZeneca, CSL Behring, Edwards LifeSciences, Eli Lilly, Esperion, Medtronic, Pfizer, Regado, Roche, and Takeda and consulting and membership on advisory committees or review panels for Roche.

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Halkar_DualAntiplateletTherapy.pdf

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Halkar_DualAntiplateletTherapy.pdf

Percutaneous coronary intervention for acute coronary syndromes has evolved, and so, hand in hand, has antiplatelet therapy. With the advent of clopidogrel and newer agents, several studies demonstrated the benefits of dual antiplatelet therapy in preventing major vascular ischemic complications. The findings culminated in a guideline recommendation for at least 12 months of dual antiplatelet therapy after placement of a drug-eluting stent, when feasible—a class I recommendation (treatment should be given), level of evidence B (limited populations evaluated).^1,2 But extending dual antiplatelet therapy beyond 12 months had no strong favorable evidence until the recent Dual Antiplatelet Therapy (DAPT) study³ shed light on this topic.

Here, we review the evidence thus far on the optimal duration of dual antiplatelet therapy in the secondary prevention of coronary artery disease.

PLATELETS IN ACUTE CORONARY SYNDROMES AND STENT THROMBOSIS

Figure 1. The platelet aggregation cascade. Exposure of subendo-thelial matrix leads to adhesion of platelets to the vessel wall, activation, and aggregation. ADP = adenosine diphosphate; GP = glycoprotein; TxA2 = thromboxane A2; vWF = von Willebrand factor

Acute coronary syndromes begin with fissuring or ulceration of a vulnerable atherosclerotic plaque, followed by thrombosis and occlusion, mediated by platelet adhesion, activation, and aggregation (Figure 1). Transient occlusion results in unstable angina or non-ST-elevation myocardial infarction, while total occlusion usually results in ST-elevation myocardial infarction.

Platelet aggregation is prominent among the mechanisms leading to stent thrombosis and vaso-occlusive ischemic complications after percutaneous coronary intervention. Thus, antiplatelet agents play a vital role in both primary and secondary prevention of cardiovascular events.^4–6

Adhesion, activation, and aggregation

Adhesion. Disruption of the vascular endothelium as a result of vulnerable plaque fissuring or ulceration exposes subendothelial thrombogenic collagen and von Willebrand factor to blood. Collagen engages platelets through their glycoprotein (GP) Ia, IIa, and VI receptors, and von Willebrand factor binds platelets through the GP Ib-IX-V receptor.

Activation. Once platelets adhere to the subendothelium, they undergo a conformational change and become activated. Simultaneous release of various autocrine and paracrine mediators including adenosine diphosphate, serotonin, epinephrine, thromboxane, and various ligand-receptor interactions all contribute to the activation cascade. Adenosine diphosphate binds to the platelet receptor P2Y₁, leading to an increase in intracellular calcium, and it binds to P2Y₁₂, leading to a decrease in cyclic adenosine monophosphate, both of which cause GP IIb/IIIa receptor activation. Thromboxane A₂ released by platelets by cyclo-oxygenase 1 binds to alpha or beta variant receptors and contributes to GP IIb/IIIa activation through elevation of intracellular calcium levels.

Aggregation and thrombosis. Exposure of tissue factor to plasma following plaque rupture activates the coagulation cascade via the extrinsic pathway, which generates thrombin, a powerful platelet activator that causes thrombus formation via fibrin. Thrombin binds to protease-activated receptors PAR-1 and PAR-4 on platelets, causing an increase in intracellular calcium and a decrease in cyclic adenosine monophosphate with subsequent GP IIb/IIIa activation. GP IIb/IIIa facilitates platelet aggregation by binding to fibrinogen and forming a stable platelet thrombus.

In the early stages of thrombus formation, platelets predominate (“white” thrombi); further organization with fibrin results in older “red” thrombi. The stages of thrombi vary in non-ST-elevation and ST-elevation myocardial infarction and are prognostic markers of death.^4–8

PERCUTANEOUS INTERVENTION, RESTENOSIS, AND STENT THROMBOSIS

Percutaneous coronary intervention, the preferred means of revascularization for many patients, is performed emergently in patients with ST-elevation myocardial infarction, urgently in those with acute coronary syndromes without ST elevation, and electively in those with stable ischemic symptoms.

Percutaneous revascularization techniques have evolved from balloon angioplasty to bare-metal stents to drug-eluting stents, but each of these procedures has been associated with a periprocedural and postprocedural risk of thrombosis.

Balloon angioplasty was associated with vascular intimal injury, inciting elastic vascular recoil and smooth muscle cell proliferation leading to restenosis.

Bare-metal stents reduced the restenosis rate by eliminating vascular recoil, although restenosis still occurred within the stent because of neointimal proliferation of vascular smooth muscle cells. This was an important limitation, as both acute and subacute stent thrombosis were refractory to aggressive anticoagulation regimens that were associated with major bleeding complications and longer hospital length of stay. Stenting became mainstream practice only after the ISAR⁹ and STARS¹⁰trials showed that dual antiplatelet therapy controlled stent thrombosis.

Drug-eluting stents coated with anti-proliferative and anti-inflammatory polymers markedly reduced in-stent restenosis rates by suppressing the initial vascular smooth-muscle proliferative response. However, they were still associated with late and very late stent thrombosis with incomplete endothelialization, even up to 40 months after implantation. Proposed mechanisms include incomplete stent apposition and inflammatory hypersensitivity reactions to the polymer coating. Incomplete stent apposition associated with low-velocity blood flow at the junction of the stent strut and vessel wall, together with delayed endothelialization, promotes platelet adhesion and aggregation, followed by thrombus formation.¹¹

Second-generation drug-eluting stents have thinner struts and more biocompatible polymers and are thought to favor more complete re-endothelialization, reducing the rates of stent thrombosis.^8,12,13

Predictors of early stent thrombosis

The Dutch Stent Thrombosis Registry and other studies looked at risk factors for stent thrombosis.^14,15

Procedure-related factors included:

Stent undersizing
Residual uncovered dissections after angioplasty
Longer stents
Low flow after angioplasty (< 3 on the 0–3 Thrombolysis in Myocardial Infarction [TIMI] scale).

Lesion-related factors included:

Intermediate coronary artery disease both proximal and distal to the culprit lesions
Bifurcation lesions.

Patient-related factors included:

Low left ventricular ejection fraction
Diabetes mellitus
Peripheral arterial disease Premature discontinuation of clopidogrel.

ANTIPLATELET AGENTS: MECHANISM OF ACTION

Figure 2. Mechanism of action of antiplatelet agents. AC = adenyl cyclase; cAMP = cyclic adenosine monophosphate; Ca = calcium; CYP = cytochrome P450; Gs, Gi, Gq = G proteins; PDEIII = phosphodiesterase III, PGR, P2Y12, P2Y1, P2X1 = platelet receptors; PKA = protein kinase A; VASP = vasodilator-stimulated phosphoprotein; VASP-P = phosphorylated VASP

Various pathways play synergistic roles in platelet activation and aggregation and thrombus formation, and different antiplatelet agents inhibit these specific pathways, thus complementing each other and having additive effects (Figure 2, Table 1).^5,16–21

Aspirin inhibits cyclo-oxygenase 1

Cyclo-oxygenase 1, found in platelets, endothelial cells, and other cells, catalyzes the conversion of arachidonic acid to thromboxane A₂. Aspirin irreversibly inhibits cyclo-oxygenase 1 by acetylating its serine residue, preventing formation of thromboxane A₂ and preventing platelet activation and aggregation.

P2Y₁₂ ADP receptor antagonists

Clopidogrel and prasugrel are thienopyridine agents that irreversibly inhibit the P2Y₁₂ receptor, thereby preventing binding of adenosine diphosphate and the subsequent platelet activation-aggregation cascade. They are both prodrugs and require conversion by cytochrome P450 enzymes to active metabolites. Prasugrel is 10 times more potent than clopidogrel due to more efficient formation of its active metabolite, and it achieves a comparable effect on platelet inhibition 30 minutes faster than the peak effect of clopidogrel at 6 hours. The overall peak inhibitory effect of prasugrel is twice that of clopidogrel.²²

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, directly and reversibly inhibits the P2Y₁₂ ADP receptor. Unlike clopidogrel and prasugrel, it does not need to be converted to an active metabolite, and it noncompetitively inhibits P2Y₁₂ at a site different from the adenosine diphosphate binding site.²³ Like prasugrel, ticagrelor inhibits platelet function more rapidly and more completely than clopidogrel.

Cangrelor, an intravenously administered analogue of adenosine triphosphate, reversibly inhibits the P2Y₁₂ receptor. It has undergone phase 3 trials but is not yet approved for clinical use.²⁴

WHY DUAL ANTIPLATELET THERAPY?

Aspirin is good, clopidogrel is better

Aspirin has a well-validated role in both primary and secondary prevention of coronary and noncoronary atherosclerotic vascular disease.

The CAPRIE trial found clopidogrel monotherapy to be superior to aspirin monotherapy in patients with established atherosclerotic vascular disease.²⁵

After stenting, short-term dual therapy is better than short-term warfarin

Thrombotic complications in the early postprocedural period were a major limitation of stenting, and existing anticoagulation regimens were ineffective in preventing them.^26,27

The ISAR trial studied the benefit of combined antiplatelet vs anticoagulant therapy after stent placement. Patients randomized to receive combined aspirin plus ticlopidine (an early P2Y₁₂ inhibitor) had significantly lower rates of primary cardiac, hemorrhagic, and vascular events at 30 days.⁹ Two other trials confirmed this finding.^28,29

STARS¹⁰ also confirmed the benefit of aspirin and ticlopidine after stenting. Patients were randomly assigned to aspirin alone, aspirin plus warfarin, or aspirin plus ticlopidine after stent placement. The rate of stent thrombosis at 30 days was significantly lower in the dual antiplatelet group than in the other two groups. The dual antiplatelet group had a higher rate of bleeding than the aspirin-alone group, but the rate was similar to that of the aspirin-plus-warfarin group.

Long-term dual antiplatelet therapy is beneficial in several situations

ISAR and STARS were landmark trials that showed stent thrombosis could be reduced by dual antiplatelet therapy for a 30-day period. However, the long-term role of dual antiplatelet therapy was still unknown.

The CURE trial^30–32 randomized patients presenting with acute coronary syndromes without ST elevation to receive clopidogrel plus aspirin or placebo plus aspirin for 3 to 12 months. The rate of the primary end point (cardiac death, nonfatal myocardial infarction, or stroke) was significantly lower in the clopidogrel-plus-aspirin group. A similar benefit of dual antiplatelet therapy was seen in the subgroup of patients who underwent percutaneous coronary intervention. Both pretreatment with clopidogrel plus aspirin for a median of 10 days prior to percutaneous intervention and continuing it for a mean of 9 months reduced major adverse cardiovascular events.

The CREDO trial²⁰ found that the combination of clopidogrel and aspirin significantly reduced the incidence of death, myocardial infarction, or stroke at 1 year after percutaneous coronary intervention. A subgroup of patients in this trial who had a longer pretreatment interval with a loading clopidogrel dose showed a benefit at 28 days, which was not as evident with a shorter loading dose interval.

The CLARITY-TIMI 28 trial^33,34 showed the advantage of adding clopidogrel to aspirin in patients receiving fibrinolytic therapy for ST-elevation myocardial infarction. Adding clopidogrel both improved the patency of the infarct-related artery and reduced ischemic complications. In patients who subsequently underwent percutaneous coronary intervention and stenting, clopidogrel pretreatment was associated with a significant decrease in ischemic complications before and after the procedure. There was no significant increase in bleeding complications in either group.

COMMIT/CCS 2³⁵ also showed the benefit of dual antiplatelet therapy in patients with ST-elevation myocardial infarction. Clopidogrel added to aspirin during the short-term in-hospital or postdischarge treatment period significantly reduced a composite end point of reinfarction, death, or stroke as well as death from any cause.

The CHARISMA trial^36–38 aimed to determine if patients who were more stable (ie, no recent acute coronary syndrome event or percutaneous coronary intervention) would benefit. Overall, CHARISMA showed no benefit of adding clopidogrel to aspirin compared with aspirin alone in a broad population of patients with established vascular disease (secondary prevention) or risk factors for vascular disease (primary prevention).

But importantly, though no benefit was seen in the primary prevention group, the large subgroup of patients with established atherosclerotic vascular disease (12,153 of the 15,603 patients in the trial) did benefit from dual antiplatelet therapy.^36,37 This subgroup showed an overall reduction in absolute risk of 1.5% (relative risk 0.88, P = .046) over a median follow-up of 27.6 months. This benefit was even more apparent in the 9,478 patients with prior myocardial infarction, stroke, or peripheral artery disease, for whom the relative risk reduction was 17.1% (P = .01) and the reduction in absolute risk 1.5%.³⁸

These results are comparable to the 2% absolute risk reduction in the CURE trial for similar end points over 9 months. In both studies, there was no significant increase in the risk of major bleeding or intracranial bleeding in the clopidogrel-plus-aspirin groups, although minor bleeding was increased by dual antiplatelet therapy.

The rate of severe bleeding, which was the primary safety end point in CHARISMA, was not significantly different in the clopidogrel-plus-aspirin group compared with the placebo-plus-aspirin group (relative risk 1.25, 95% CI 0.97–1.61, P = .09).

Thus, although the CHARISMA findings were negative overall, the positive finding observed in the predominant subgroup of patients with established vascular disease can therefore be considered supportive of the results of the subsequent trials discussed below.

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.⁴³All of them showed that short-duration therapy was not inferior to standard-duration therapy.⁴⁴These 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.

Percutaneous coronary intervention for acute coronary syndromes has evolved, and so, hand in hand, has antiplatelet therapy. With the advent of clopidogrel and newer agents, several studies demonstrated the benefits of dual antiplatelet therapy in preventing major vascular ischemic complications. The findings culminated in a guideline recommendation for at least 12 months of dual antiplatelet therapy after placement of a drug-eluting stent, when feasible—a class I recommendation (treatment should be given), level of evidence B (limited populations evaluated).^1,2 But extending dual antiplatelet therapy beyond 12 months had no strong favorable evidence until the recent Dual Antiplatelet Therapy (DAPT) study³ shed light on this topic.

Here, we review the evidence thus far on the optimal duration of dual antiplatelet therapy in the secondary prevention of coronary artery disease.

PLATELETS IN ACUTE CORONARY SYNDROMES AND STENT THROMBOSIS

Figure 1. The platelet aggregation cascade. Exposure of subendo-thelial matrix leads to adhesion of platelets to the vessel wall, activation, and aggregation. ADP = adenosine diphosphate; GP = glycoprotein; TxA2 = thromboxane A2; vWF = von Willebrand factor

Acute coronary syndromes begin with fissuring or ulceration of a vulnerable atherosclerotic plaque, followed by thrombosis and occlusion, mediated by platelet adhesion, activation, and aggregation (Figure 1). Transient occlusion results in unstable angina or non-ST-elevation myocardial infarction, while total occlusion usually results in ST-elevation myocardial infarction.

Platelet aggregation is prominent among the mechanisms leading to stent thrombosis and vaso-occlusive ischemic complications after percutaneous coronary intervention. Thus, antiplatelet agents play a vital role in both primary and secondary prevention of cardiovascular events.^4–6

Adhesion, activation, and aggregation

Adhesion. Disruption of the vascular endothelium as a result of vulnerable plaque fissuring or ulceration exposes subendothelial thrombogenic collagen and von Willebrand factor to blood. Collagen engages platelets through their glycoprotein (GP) Ia, IIa, and VI receptors, and von Willebrand factor binds platelets through the GP Ib-IX-V receptor.

Activation. Once platelets adhere to the subendothelium, they undergo a conformational change and become activated. Simultaneous release of various autocrine and paracrine mediators including adenosine diphosphate, serotonin, epinephrine, thromboxane, and various ligand-receptor interactions all contribute to the activation cascade. Adenosine diphosphate binds to the platelet receptor P2Y₁, leading to an increase in intracellular calcium, and it binds to P2Y₁₂, leading to a decrease in cyclic adenosine monophosphate, both of which cause GP IIb/IIIa receptor activation. Thromboxane A₂ released by platelets by cyclo-oxygenase 1 binds to alpha or beta variant receptors and contributes to GP IIb/IIIa activation through elevation of intracellular calcium levels.

Aggregation and thrombosis. Exposure of tissue factor to plasma following plaque rupture activates the coagulation cascade via the extrinsic pathway, which generates thrombin, a powerful platelet activator that causes thrombus formation via fibrin. Thrombin binds to protease-activated receptors PAR-1 and PAR-4 on platelets, causing an increase in intracellular calcium and a decrease in cyclic adenosine monophosphate with subsequent GP IIb/IIIa activation. GP IIb/IIIa facilitates platelet aggregation by binding to fibrinogen and forming a stable platelet thrombus.

In the early stages of thrombus formation, platelets predominate (“white” thrombi); further organization with fibrin results in older “red” thrombi. The stages of thrombi vary in non-ST-elevation and ST-elevation myocardial infarction and are prognostic markers of death.^4–8

PERCUTANEOUS INTERVENTION, RESTENOSIS, AND STENT THROMBOSIS

Percutaneous coronary intervention, the preferred means of revascularization for many patients, is performed emergently in patients with ST-elevation myocardial infarction, urgently in those with acute coronary syndromes without ST elevation, and electively in those with stable ischemic symptoms.

Percutaneous revascularization techniques have evolved from balloon angioplasty to bare-metal stents to drug-eluting stents, but each of these procedures has been associated with a periprocedural and postprocedural risk of thrombosis.

Balloon angioplasty was associated with vascular intimal injury, inciting elastic vascular recoil and smooth muscle cell proliferation leading to restenosis.

Bare-metal stents reduced the restenosis rate by eliminating vascular recoil, although restenosis still occurred within the stent because of neointimal proliferation of vascular smooth muscle cells. This was an important limitation, as both acute and subacute stent thrombosis were refractory to aggressive anticoagulation regimens that were associated with major bleeding complications and longer hospital length of stay. Stenting became mainstream practice only after the ISAR⁹ and STARS¹⁰trials showed that dual antiplatelet therapy controlled stent thrombosis.

Drug-eluting stents coated with anti-proliferative and anti-inflammatory polymers markedly reduced in-stent restenosis rates by suppressing the initial vascular smooth-muscle proliferative response. However, they were still associated with late and very late stent thrombosis with incomplete endothelialization, even up to 40 months after implantation. Proposed mechanisms include incomplete stent apposition and inflammatory hypersensitivity reactions to the polymer coating. Incomplete stent apposition associated with low-velocity blood flow at the junction of the stent strut and vessel wall, together with delayed endothelialization, promotes platelet adhesion and aggregation, followed by thrombus formation.¹¹

Second-generation drug-eluting stents have thinner struts and more biocompatible polymers and are thought to favor more complete re-endothelialization, reducing the rates of stent thrombosis.^8,12,13

Predictors of early stent thrombosis

The Dutch Stent Thrombosis Registry and other studies looked at risk factors for stent thrombosis.^14,15

Procedure-related factors included:

Stent undersizing
Residual uncovered dissections after angioplasty
Longer stents
Low flow after angioplasty (< 3 on the 0–3 Thrombolysis in Myocardial Infarction [TIMI] scale).

Lesion-related factors included:

Intermediate coronary artery disease both proximal and distal to the culprit lesions
Bifurcation lesions.

Patient-related factors included:

Low left ventricular ejection fraction
Diabetes mellitus
Peripheral arterial disease Premature discontinuation of clopidogrel.

ANTIPLATELET AGENTS: MECHANISM OF ACTION

Figure 2. Mechanism of action of antiplatelet agents. AC = adenyl cyclase; cAMP = cyclic adenosine monophosphate; Ca = calcium; CYP = cytochrome P450; Gs, Gi, Gq = G proteins; PDEIII = phosphodiesterase III, PGR, P2Y12, P2Y1, P2X1 = platelet receptors; PKA = protein kinase A; VASP = vasodilator-stimulated phosphoprotein; VASP-P = phosphorylated VASP

Various pathways play synergistic roles in platelet activation and aggregation and thrombus formation, and different antiplatelet agents inhibit these specific pathways, thus complementing each other and having additive effects (Figure 2, Table 1).^5,16–21

Aspirin inhibits cyclo-oxygenase 1

Cyclo-oxygenase 1, found in platelets, endothelial cells, and other cells, catalyzes the conversion of arachidonic acid to thromboxane A₂. Aspirin irreversibly inhibits cyclo-oxygenase 1 by acetylating its serine residue, preventing formation of thromboxane A₂ and preventing platelet activation and aggregation.

P2Y₁₂ ADP receptor antagonists

Clopidogrel and prasugrel are thienopyridine agents that irreversibly inhibit the P2Y₁₂ receptor, thereby preventing binding of adenosine diphosphate and the subsequent platelet activation-aggregation cascade. They are both prodrugs and require conversion by cytochrome P450 enzymes to active metabolites. Prasugrel is 10 times more potent than clopidogrel due to more efficient formation of its active metabolite, and it achieves a comparable effect on platelet inhibition 30 minutes faster than the peak effect of clopidogrel at 6 hours. The overall peak inhibitory effect of prasugrel is twice that of clopidogrel.²²

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, directly and reversibly inhibits the P2Y₁₂ ADP receptor. Unlike clopidogrel and prasugrel, it does not need to be converted to an active metabolite, and it noncompetitively inhibits P2Y₁₂ at a site different from the adenosine diphosphate binding site.²³ Like prasugrel, ticagrelor inhibits platelet function more rapidly and more completely than clopidogrel.

Cangrelor, an intravenously administered analogue of adenosine triphosphate, reversibly inhibits the P2Y₁₂ receptor. It has undergone phase 3 trials but is not yet approved for clinical use.²⁴

WHY DUAL ANTIPLATELET THERAPY?

Aspirin is good, clopidogrel is better

Aspirin has a well-validated role in both primary and secondary prevention of coronary and noncoronary atherosclerotic vascular disease.

The CAPRIE trial found clopidogrel monotherapy to be superior to aspirin monotherapy in patients with established atherosclerotic vascular disease.²⁵

After stenting, short-term dual therapy is better than short-term warfarin

Thrombotic complications in the early postprocedural period were a major limitation of stenting, and existing anticoagulation regimens were ineffective in preventing them.^26,27

The ISAR trial studied the benefit of combined antiplatelet vs anticoagulant therapy after stent placement. Patients randomized to receive combined aspirin plus ticlopidine (an early P2Y₁₂ inhibitor) had significantly lower rates of primary cardiac, hemorrhagic, and vascular events at 30 days.⁹ Two other trials confirmed this finding.^28,29

STARS¹⁰ also confirmed the benefit of aspirin and ticlopidine after stenting. Patients were randomly assigned to aspirin alone, aspirin plus warfarin, or aspirin plus ticlopidine after stent placement. The rate of stent thrombosis at 30 days was significantly lower in the dual antiplatelet group than in the other two groups. The dual antiplatelet group had a higher rate of bleeding than the aspirin-alone group, but the rate was similar to that of the aspirin-plus-warfarin group.

Long-term dual antiplatelet therapy is beneficial in several situations

ISAR and STARS were landmark trials that showed stent thrombosis could be reduced by dual antiplatelet therapy for a 30-day period. However, the long-term role of dual antiplatelet therapy was still unknown.

The CURE trial^30–32 randomized patients presenting with acute coronary syndromes without ST elevation to receive clopidogrel plus aspirin or placebo plus aspirin for 3 to 12 months. The rate of the primary end point (cardiac death, nonfatal myocardial infarction, or stroke) was significantly lower in the clopidogrel-plus-aspirin group. A similar benefit of dual antiplatelet therapy was seen in the subgroup of patients who underwent percutaneous coronary intervention. Both pretreatment with clopidogrel plus aspirin for a median of 10 days prior to percutaneous intervention and continuing it for a mean of 9 months reduced major adverse cardiovascular events.

The CREDO trial²⁰ found that the combination of clopidogrel and aspirin significantly reduced the incidence of death, myocardial infarction, or stroke at 1 year after percutaneous coronary intervention. A subgroup of patients in this trial who had a longer pretreatment interval with a loading clopidogrel dose showed a benefit at 28 days, which was not as evident with a shorter loading dose interval.

The CLARITY-TIMI 28 trial^33,34 showed the advantage of adding clopidogrel to aspirin in patients receiving fibrinolytic therapy for ST-elevation myocardial infarction. Adding clopidogrel both improved the patency of the infarct-related artery and reduced ischemic complications. In patients who subsequently underwent percutaneous coronary intervention and stenting, clopidogrel pretreatment was associated with a significant decrease in ischemic complications before and after the procedure. There was no significant increase in bleeding complications in either group.

COMMIT/CCS 2³⁵ also showed the benefit of dual antiplatelet therapy in patients with ST-elevation myocardial infarction. Clopidogrel added to aspirin during the short-term in-hospital or postdischarge treatment period significantly reduced a composite end point of reinfarction, death, or stroke as well as death from any cause.

The CHARISMA trial^36–38 aimed to determine if patients who were more stable (ie, no recent acute coronary syndrome event or percutaneous coronary intervention) would benefit. Overall, CHARISMA showed no benefit of adding clopidogrel to aspirin compared with aspirin alone in a broad population of patients with established vascular disease (secondary prevention) or risk factors for vascular disease (primary prevention).

But importantly, though no benefit was seen in the primary prevention group, the large subgroup of patients with established atherosclerotic vascular disease (12,153 of the 15,603 patients in the trial) did benefit from dual antiplatelet therapy.^36,37 This subgroup showed an overall reduction in absolute risk of 1.5% (relative risk 0.88, P = .046) over a median follow-up of 27.6 months. This benefit was even more apparent in the 9,478 patients with prior myocardial infarction, stroke, or peripheral artery disease, for whom the relative risk reduction was 17.1% (P = .01) and the reduction in absolute risk 1.5%.³⁸

These results are comparable to the 2% absolute risk reduction in the CURE trial for similar end points over 9 months. In both studies, there was no significant increase in the risk of major bleeding or intracranial bleeding in the clopidogrel-plus-aspirin groups, although minor bleeding was increased by dual antiplatelet therapy.

The rate of severe bleeding, which was the primary safety end point in CHARISMA, was not significantly different in the clopidogrel-plus-aspirin group compared with the placebo-plus-aspirin group (relative risk 1.25, 95% CI 0.97–1.61, P = .09).

Thus, although the CHARISMA findings were negative overall, the positive finding observed in the predominant subgroup of patients with established vascular disease can therefore be considered supportive of the results of the subsequent trials discussed below.

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.⁴³All of them showed that short-duration therapy was not inferior to standard-duration therapy.⁴⁴These 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.

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Steinhubl SR, Berger PB, Mann JT 3rd, et al; CREDO Investigators. Clopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288:2411–2420.
Nusca A, Patti G. Platelet function and inhibition in ischemic heart disease. Curr Cardiol Rep 2012; 14:457–467.
Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015.
Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045–1057.
Genereux P, Stone GW, Harrington RA, et al; CHAMPION PHOENIX Investigators. Impact of intraprocedural stent thrombosis during percutaneous coronary intervention: Insights from the CHAMPION PHOENIX Trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). J Am Coll Cardiol 2014; 63:619–629.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348:1329–1339.
Brilakis ES, Patel VG, Banerjee S. Medical management after coronary stent implantation: a review. JAMA 2013; 310:189–198.
Warren J, Baber U, Mehran R. Antiplatelet therapy after drug-eluting stent implantation. J Cardiol 2015; 65:98–104.
Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial After Intracoronary Stenting (MATTIS). Circulation 1998; 98:2126–2132.
Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The Full Anticoagulation versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation 1998; 98:1597–1603.
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502.
Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001; 358:527–533.
Morais J. Insights from CURE: using clopidogrel on top of standard therapy. Cerebrovasc Dis 2002; 13(suppl 1):17–21.
Ferguson JJ. Clopidogrel plus aspirin in patients with acute myocardial infarction treated with fibrinolytic therapy—CLARITY-TIMI 28. Future Cardiol 2005; 1:605–610.
Sabatine MS, Cannon CP, Gibson CM, et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005; 294:1224–1232.
Chen ZM, Jiang LX, Chen YP, et al; COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366:1607–1621.
Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
Bhatt DL, Fox KA, Hacke W, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706–1717.
Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372:1791–1800.
Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014; 64:2086–2097.
Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125:505–513.
Feres F, Costa RA, Abizaid A, et al; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013; 310:2510–2522.
Kim BK, Hong MK, Shin DH, et al; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60:1340–1348.
El-Hayek G, Messerli F, Bangalore S, et al. Meta-analysis of randomized clinical trials comparing short-term versus long-term dual antiplatelet therapy following drug-eluting stents. Am J Cardiol 2014; 114:236–242.
Valgimigli M, Campo G, Monti M, et al; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012; 125:2015–2026.
Collet JP, Silvain J, Barthelemy O, et al; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014; 384:1577–1585.
Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129:304–312.
Kwok CS, Bulluck H, Ryding AD, Loke YK. Benefits and harms of extending the duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents: a meta-analysis. ScientificWorldJournal 2014; 2014:794078.
Dewilde WJ, Oirbans T, Verheugt FW, et al; WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107–1115.

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Mauri L, Kereiakes DJ, Yeh RW, et al; DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371:2155–2166.
Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J 2010; 74:597–607.
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Showkathali R, Natarajan A. Antiplatelet and antithrombin strategies in acute coronary syndrome: state-of-the-art review. Curr Cardiol Rev 2012; 8:239–249.
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Claessen BE, Henriques JP, Jaffer FA, Mehran R, Piek JJ, Dangas GD. Stent thrombosis: a clinical perspective. JACC Cardiovasc Interv 2014; 7:1081–1092.
Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334:1084–1089.
Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339:1665–1671.
Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48:193–202.
Nikam N, Steinberg TB, Steinberg DH. Advances in stent technologies and their effect on clinical efficacy and safety. Med Devices (Auckl) 2014; 7:165–178.
Simard T, Hibbert B, Ramirez FD, Froeschl M, Chen YX, O’Brien ER. The evolution of coronary stents: a brief review. Can J Cardiol 2014; 30:35–45.
Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and where are we going? The Andreas Gruntzig Lecture ESC 2014. Eur Heart J 2015; 36:3320–3331.
van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent thrombosis: the Dutch Stent Thrombosis Registry. J Am Coll Cardiol 2009; 53:1399–1409.
Berger JS. Aspirin, clopidogrel, and ticagrelor in acute coronary syndromes. Am J Cardiol 2013; 112:737–745.
Franchi F, Angiolillo DJ. Novel antiplatelet agents in acute coronary syndrome. Nat Rev Cardiol 2015; 12:30–47.
Patrono C, Rocca B. The future of antiplatelet therapy in cardiovascular disease. Annu Rev Med 2010; 61:49–61.
Park SJ, Kang SM, Park DW. Dual antiplatelet therapy after drug-eluting stents: defining the proper duration. Coron Artery Dis 2014; 25:83–89.
Steinhubl SR, Berger PB, Mann JT 3rd, et al; CREDO Investigators. Clopidogrel for the reduction of events during observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288:2411–2420.
Nusca A, Patti G. Platelet function and inhibition in ischemic heart disease. Curr Cardiol Rep 2012; 14:457–467.
Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357:2001–2015.
Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361:1045–1057.
Genereux P, Stone GW, Harrington RA, et al; CHAMPION PHOENIX Investigators. Impact of intraprocedural stent thrombosis during percutaneous coronary intervention: Insights from the CHAMPION PHOENIX Trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). J Am Coll Cardiol 2014; 63:619–629.
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348:1329–1339.
Brilakis ES, Patel VG, Banerjee S. Medical management after coronary stent implantation: a review. JAMA 2013; 310:189–198.
Warren J, Baber U, Mehran R. Antiplatelet therapy after drug-eluting stent implantation. J Cardiol 2015; 65:98–104.
Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial After Intracoronary Stenting (MATTIS). Circulation 1998; 98:2126–2132.
Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The Full Anticoagulation versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation 1998; 98:1597–1603.
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345:494–502.
Mehta SR, Yusuf S, Peters RJ, et al; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 2001; 358:527–533.
Morais J. Insights from CURE: using clopidogrel on top of standard therapy. Cerebrovasc Dis 2002; 13(suppl 1):17–21.
Ferguson JJ. Clopidogrel plus aspirin in patients with acute myocardial infarction treated with fibrinolytic therapy—CLARITY-TIMI 28. Future Cardiol 2005; 1:605–610.
Sabatine MS, Cannon CP, Gibson CM, et al; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005; 294:1224–1232.
Chen ZM, Jiang LX, Chen YP, et al; COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005; 366:1607–1621.
Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
Bhatt DL, Fox KA, Hacke W, et al; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354:1706–1717.
Bhatt DL, Flather MD, Hacke W, et al; CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:1982–1988.
Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372:1791–1800.
Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 2014; 64:2086–2097.
Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study. Circulation 2012; 125:505–513.
Feres F, Costa RA, Abizaid A, et al; OPTIMIZE Trial Investigators. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA 2013; 310:2510–2522.
Kim BK, Hong MK, Shin DH, et al; RESET Investigators. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; 60:1340–1348.
El-Hayek G, Messerli F, Bangalore S, et al. Meta-analysis of randomized clinical trials comparing short-term versus long-term dual antiplatelet therapy following drug-eluting stents. Am J Cardiol 2014; 114:236–242.
Valgimigli M, Campo G, Monti M, et al; Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) Investigators. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012; 125:2015–2026.
Collet JP, Silvain J, Barthelemy O, et al; ARCTIC investigators. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet 2014; 384:1577–1585.
Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation 2014; 129:304–312.
Kwok CS, Bulluck H, Ryding AD, Loke YK. Benefits and harms of extending the duration of dual antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents: a meta-analysis. ScientificWorldJournal 2014; 2014:794078.
Dewilde WJ, Oirbans T, Verheugt FW, et al; WOEST study investigators. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381:1107–1115.

Issue

Cleveland Clinic Journal of Medicine - 83(9)

Issue

Cleveland Clinic Journal of Medicine - 83(9)

Page Number

675-688

Page Number

675-688

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Cleveland Clinic Journal of Medicine

Publications

Cleveland Clinic Journal of Medicine

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

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

Legacy Keywords

acute coronary syndrome, ACS, myocardial infarction, MI, stent, drug-eluting stent, DES, platelets, antiplatelet drugs, dual antiplatelet therapy, DAPT, aspirin, clopidogrel, prasugrel, cilostazol, ticagrelor, cangrelor, Meghana Halkar, A Michael Lincoff

Legacy Keywords

acute coronary syndrome, ACS, myocardial infarction, MI, stent, drug-eluting stent, DES, platelets, antiplatelet drugs, dual antiplatelet therapy, DAPT, aspirin, clopidogrel, prasugrel, cilostazol, ticagrelor, cangrelor, Meghana Halkar, A Michael Lincoff

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The outcomes of patients with acute coronary syndrome events have been improving as percutaneous coronary intervention and its accompanying medical therapy have evolved.
Newer, more potent antiplatelet agents are preferred over clopidogrel when possible.
Two earlier studies showed no advantage of extended dual antiplatelet therapy over the standard 12-month duration, but the recent Dual Antiplatelet Therapy trial did.
The protection against ischemia afforded by dual antiplatelet therapy comes at the price of increased risk of bleeding.

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