SNOWMASS, COLORADO – The hypothesis that long-term dual antiplatelet therapy is beneficial for secondary prevention of thrombotic events in an identifiable subset of patients with stable atherosclerosis is now being put to the test in a definitive 24,000-subject megatrial.
Results of the ongoing PEGASUS TIMI 54 trial, conducted in more than 30 countries, are anticipated next year.
Current ACC/American Heart Association/Society for Cardiovascular Angiography and Interventions guidelines recommend 1 year of dual antiplatelet therapy (DAPT) following stenting for acute coronary syndrome in order to protect against late stent thrombosis. Beyond 1 year, however, the risk of stent thrombosis is so low that it’s believed to be outweighed by the bleeding risks associated with DAPT.
The idea that intensified long-term antiplatelet therapy might be superior to aspirin alone for secondary cardiovascular prevention in certain vulnerable patients with stable ischemic heart disease was initially raised in a post hoc analysis of the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, Dr. Patrick T. O’Gara noted at the annual cardiovascular conference at Snowmass sponsored by the American College of Cardiology.
CHARISMA randomized 15,603 subjects with a broad range of cardiovascular risk to 28 months of clopidogrel plus aspirin or aspirin plus placebo. The overall trial was negative, that is, DAPT provided no significant advantage over aspirin alone in terms of the primary endpoint of cardiovascular death, MI, or stroke in this diverse population (N. Engl. J. Med. 2006;354:1706-17).
However, when the CHARISMA investigators conducted a post hoc analysis restricted to the 9,478 participants with baseline documented prior MI, ischemic stroke, or symptomatic peripheral arterial disease, they found a significantly lower rate of the composite primary endpoint in the DAPT group: 7.3%, compared with 8.8% with aspirin alone. This translated to a 17% relative risk reduction. Reassuringly, there was no significant difference in the rate of severe bleeding in the two study arms.
“Such patients may benefit from intensification of antithrombotic therapy beyond aspirin alone, a concept that future trials will need to validate,” the investigators noted (J. Am. Coll. Cardiol. 2007;49:1982-8).
The benefit of DAPT was particularly robust in the 3,846 CHARISMA participants with a history of prior MI. In this subgroup, the rate of the primary composite endpoint was 6.6% with DAPT and 8.3% with aspirin alone, for a 23% reduction in relative risk.
That signal of long-term DAPT having its greatest benefit in stable patients with a history of MI has since been noted repeatedly in secondary analyses of other large trials, observed Dr. O’Gara, executive medical director of the cardiovascular center at Brigham and Women’s Hospital, and professor of medicine at Harvard Medical School, both in Boston.
“Such a history is possibly indicative of a heavier burden of atherosclerotic disease,” mused Dr. O’Gara, the incoming ACC president.
The CHARISMA post hoc analysis was a major impetus for the TRA 2°P- (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) TIMI 50 trial, in which 26,449 patients with a history of MI, ischemic stroke, or peripheral arterial disease were randomized to the novel investigational thrombin-receptor antagonist vorapaxar or placebo on top of background daily aspirin.
In TRA 2°P–TIMI 50, the rate of the same primary composite endpoint used in CHARISMA was 9.3% during a median follow-up of 2.5 years in the group on DAPT with vorapaxar, for a highly statistically significant 13% relative risk reduction, compared with the 10.5% rate with standard therapy. However, this benefit came at the cost of significantly increased rates of moderate or severe bleeding – 4.2%, compared with 2.5% – and intracranial hemorrhage – 1.0% vs. 0.5% (N. Engl. J. Med. 2012;366:1404-13).
Based largely on the findings seen in the CHARISMA post hoc analysis, the TRA 2°P TIMI 50 investigators conducted a prespecified subgroup analysis restricted to the 17,779 patients who qualified for the study on the basis of an acute MI within the past year. Again, as in CHARISMA, the benefit of DAPT appeared to be greatest in patients with a history of MI. Their rate of the primary endpoint was 8.1% compared to 9.7% with standard therapy, for a 20% relative risk reduction (Lancet 2012;380:1317-24).
Because of this consistent signal that the benefit of DAPT is greatest in the setting of a history of MI, the PEGASUS TIMI 54 trial is restricted to stable patients with a history of acute MI 1-3 years prior to enrollment. In addition, they need to have one or more of the following atherothrombosis risk factors: aged 65 years or older, a second prior MI, diabetes, multivessel coronary artery disease, or non–end-stage chronic kidney disease.