Dual Antiplatelet Therapy Duration Warrants Individualization for ACS
The optimal duration of dual antiplatelet therapy (DAPT) for patients with acute coronary syndrome (ACS) should be customized based on individual patient characteristics, particularly ischemic/bleeding risk, presence of diabetes, and type of stent, according to a presentation at the 2017 Multidisciplinary Cardio-Endo Renal Collaborative (CERC) meeting.
Patients with ACS and diabetes or a first-generation drugeluting stent who are not at risk for bleeding could benefit from DAPT for ≥12 months, according to Deepak L. Bhatt, MD, MPH. However, those with coronary artery disease, a bleeding history, limited disease, and a second-generation stent should receive ≤12 months of treatment, he added.
“In a patient who is not bleeding with ACS, in general, I prefer going for more than 12 months, especially if they’ve got things like diabetes, renal failure, heart failure, or previous stent thrombosis or symptomatic peripheral artery disease,” Bhatt, executive director of Interventional Cardiovascular Programs, Brigham and Women’s Hospital's Heart & Vascular Center, said during his talk at the CERC meeting.
“There’s also coronary anatomy-related factors, if they’ve got long lesions, small vessels, bifurcated lesions, complex anatomy, or left main disease that’s being treated. If there’s a first-generation stent, long stents, or multiple stents, in those situations, in an ACS patient, I tend to go longer,” he added.
DAPT is a mainstay of the treatment of ACS, typically consisting of a P2Y12 inhibitor plus low-dose aspirin. The first agent approved in this setting was clopidogrel (Plavix), which was followed by other P2Y12 inhibitors, namely prasugrel (Effient) and ticagrelor (Brilinta). Prasugrel, which is indicated for ACS with aspirin only following stenting, is a more efficient irreversible P2Y12 inhibitor than clopidogrel, Bhatt noted, and ticagrelor inhibits P2Y12 directly and is reversible.
In the phase 3 PCI-CURE study,1 clopidogrel combined with aspirin resulted in a 31% relative risk reduction compared with aspirin and placebo for patients with ACS (8.8% clopidogrel vs 12.6% placebo; HR, 0.69; P = .002). In the CHARISMA subgroup analysis of those with a prior myocardial infarction (MI),2 the addition of clopidogrel to aspirin reduced the relative risk of an adverse cardiovascular (CV) event by 23% versus aspirin and placebo (HR, 0.774; P = .031).
In the phase 3 TRITON-TMI 38 trial,3 there were fewer deaths from CV causes, nonfatal MIs, or nonfatal strokes with prasugrel (9.9%) versus clopidogrel (12.1%), representing a 19% reduction in risk (HR, 0.81; 95% CI, 0.73-0.90; P <.001). A second study, the TRILOGY ACS trial,4 looked at prasugrel in those <75 years with ACS. After 30 months, death from CV, MI, or stroke occurred in 13.9% versus 16.0% of patients for aspirin plus prasugrel versus clopidogrel, respectively. Interestingly, those treated for ≤12 months did not have a benefit with prasugrel compared with >12 months of therapy.
Several subgroup analyses of the TRILOGY trial were conducted. In those who did not receive prior coronary angiography, there was no difference between the groups (HR, 1.01; P = .954); however, those receiving angiography had a meaningful improvement with prasugrel versus clopidogrel (10.7% vs 14.9%; HR, 0.77; P = .031).5
“The patients who got the angiogram before randomization might be a proxy for ACS; they had the real thing,” said Bhatt. “The no-angiograms were probably those with heart failure with a positive troponin who enrolled in the trial, but the positive troponin is probably from the heart failure and not plaque rupture.”
For ticagrelor, findings from the PLATO trial demonstrated superiority at a variety of doses.6 In this phase 3 trial, 11.7% of patients in the clopidogrel/aspirin group had an event versus 9.8% in the ticagrelor/aspirin arm (HR, 0.84; P = .0003). This improvement with ticagrelor versus clopidogrel was also seen specifically for MI (HR, 0.84; P = .005) and CV deaths (HR, 0.79; P = .001). Moreover, in the phase 3 PEGASUS-TIMI 54 trial,7 significantly more patients treated with placebo had a ST-elevation MI compared with ticagrelor, with risk reductions of approximately 40% seen with the P2Y12 inhibitor.
The PEGASUS-TIMI 54 trial also sought to uncover an optimal dose for ticagrelor. In this trial, a 90-mg twice-daily dose was compared with 60 mg or placebo. Both doses showed similar efficacy (major adverse cardiac event [MACE], 7.8% ticagrelor vs 9.0% placebo). “PEGASUS showed a significant reduction in CV death, MI, and stroke,” said Bhatt. “PEGASUS also showed an increase in nonfatal bleeding.”
Overall, the heightened inhibition of P2Y12 with ticagrelor was associated with more bleeding events compared with clopidogrel. However, in the setting of coronary artery bypass grafting (CABG), there were fewer bleeding adverse events with ticagrelor compared with clopidogrel. This could be related to the reversible P2Y12 inhibition of ticagrelor, suggesting the drug had exited the system prior to the procedure taking place, Bhatt suggested.
EXTENDED THERAPY IDEAL FOR SOME
Across trials exploring DAPT, patients were frequently treated beyond 12 months. In a combined analysis of studies that included 33,435 patients,8 extended DAPT was associated with improvements in CV death, MI, or stroke compared with aspirin alone. Overall, an event occurred in 6.4% of those treated with ≥12 months of DAPT versus 7.5% with aspirin (HR, 0.78; 95% CI, 0.67-0.90). For CV death specifically, there was also a benefit favoring DAPT (2.3% events with DAPT vs 2.6% for aspirin; HR, 0.85; 95% CI, 0.74-0.98).
Bleeding events were more common in the extended DAPT arm across the analysis. The risk of major bleeding was 73% higher with DAPT versus aspirin alone, warranting careful use of extended therapy, Bhatt noted (1.9% vs 1.1%; HR, 1.73; 95% CI, 1.19-2.50).
In analyses of the available data,9 the benefits of extended DAPT increased with the level of percutaneous coronary intervention (PCI) complexity, Bhatt noted. The characteristics to consider, he said, were prior bleeding, white blood count, age, creatinine clearance, and hemoglobin levels.
For those with no high-risk characteristics, a benefit for extended DAPT was not seen versus 3 or 6 months of treatment (HR, 1.01; 95% CI, 0.75-1.35). However, for those with ≥3 high-risk features, there was a 78% reduction in the risk of a MACE with extended therapy (HR, 0.22; 95% CI, 0.05-1.06).
In addition to these characteristics, the presence of underlying diabetes amplified the benefits of clopidogrel in the phase 3 CAPRIE study.10 In patients without diabetes, those taking aspirin alone had an event rate of 12.7% versus 11.8% with clopidogrel/aspirin. CV events occurred in 17.7% and 15.6% for patients with diabetes treated with aspirin alone or DAPT, respectively. Additionally, those with diabetes being treated with insulin had CV rates of 21.5% and 17.7%, for aspirin alone and DAPT, respectively.
Similar improvements in MACE were also seen with ticagrelor versus placebo when looking at diabetes status in the phase 3 PEGASUS-TIMI 54 trial.11 In those with diabetes, the MACE rate was 11.6% with placebo versus 10.1% with ticagrelor (HR, 0.84; P = .03). For those without diabetes, the MACE rates were 7.8% and 6.7% in the placebo and ticagrelor arms, respectively (HR, 0.84; P = .01).
In addition to MACE improvements, ticagrelor also reduced the risk of death by 34% versus placebo in patients with diabetes (HR, 0.66; P = .01). In those without diabetes, the risk of death was reduced by 12% with ticagrelor versus placebo (HR, 0.88; P = .39). Coronary death in those with diabetes occurred in 3.4% of those with placebo versus 2.3% with DAPT (HR, 0.66; P = .01) and was not statistically different between the groups for those without diabetes.
“In the diabetic patients, the combination DAPT with ticagrelor and aspirin was also associated with a reduction in coronary deaths,” Bhatt noted. “In the diabetic patients with previous MI, in this trial at least, there is a benefit for extended DAPT with aspirin and ticagrelor.”
The prospective phase 3 THEMIS trial is currently exploring the impact of 60-mg ticagrelor on cardiovascular events compared with placebo for patients with type 2 diabetes at high risk for a CV event, defined as a history of PCI or CABG. Those with a prior MI or stroke were excluded from the trial. The trial enrolled 19,349 patients, with primary results anticipated in November 2018 (NCT01991795).
“Probably sometime in the next couple years, this study will report, and we will find out whether this large universe of those with diabetes and angiographic coronary disease should all be on dual antiplatelet therapy,” said Bhatt. “If the answer is yes, then of course that will be practice changing. If the answer is no, though, it is still interesting and important. It tells us the floor for which we would never want to use dual antiplatelet therapy. The results will be informative either way.”
1. Mehta SR, Yusuf S, Peters RJG, et al. 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(9281):527-533.
2. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49(19):1982-1988. doi: 10.1016/j.jacc.2007.03.025.
3. Wiviott SD,Brauwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001- 2015. doi: 10.1056/NEJMoa0706482.
4. Roe MT, Armstrong PW, Fox KAA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297-1309. doi: 10.1056/NEJMoa1205512.
5. Wiviott SD, White HD, Ohman EM, et al. Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial. Lancet. 2013;382(9892):605-613. doi: 10.1016/S0140-6736(13)61451-8.
6. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045- 1057. doi: 10.1056/NEJMoa0904327.
7. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800. doi: 10.1056/NEJMoa1500857.
8. Udell JA, Bonaca MP, Collet JP, et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J. 2016;37(4):390-399. doi: 10.1093/eurheartj/ehv443.
9. Giustino G, Chieffo A, Palmerini T, et al. Efficacy and safety of dual antiplatelet therapy after complex PCI. J Am Coll Cardiol. 2016;68(17):1851- 1864. doi: 10.1016/j.jacc.2016.07.760.
10. Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ.Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol. 2002;90(6):625-628.
11. Bhatt DL, Bonaca MP, Bansilal S, et al. Reduction in ischemic events with ticagrelor in diabetic patients with prior myocardial infarction in PEGASUS-TIMI 54. J Am Coll Cardiol. 2016;67(23):2732-2740. doi: 10.1016/j.jacc.2016.03.529.