The optimal duration of dual antiplatelet therapy remains unclear, despite being proven efficacious for roughly 2 decades.
The optimal duration of dual antiplatelet therapy (DAPT), a combination of aspirin and a P2Y12 receptor inhibitor (Clopidogrel, Prasugrel, or Ticagrelor), remains unclear, despite being proven efficacious for roughly 2 decades. Although recent randomized control trials have found that a course of at least 12 months of DAPT after drug-eluding stent (DES) implantation succeeds in reduction of adverse thrombotic events, this is offset by the risk of major bleeding.
The American Heart Association (AHA) and American College of Cardiology (ACC) recommend that DAPT should be extended beyond 12 months after implantation of DES, as long as the patient is not at high risk of bleeding. In 2014, Mauri et al. found that 1 year of DAPT “significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding.”
Fewer trials have sought to determine the optimal duration of DAPT for populations with type 2 diabetes, for whom management with DAPT is made more challenging by the pro-thrombotic and hyper-coagulation state typically found in this population. Patients with compromised glucose metabolism are also considered to be “resistant” to aspirin, a mainstay of DAPT.
“One of the major issues when dealing with aspirin and diabetics is whether aspirin is less effective in diabetics than in non-diabetics,” Juan Badimon, PhD, the director of the Atherothrombosis Research Unit and a professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai, told MD Magazine. “The lower effectivity may be the consequence of the weak antiplatelet activity that is not enough to inhibit the hyper-reactivity in diabetic patients. When prescribing aspirin, as with any other antithrombotic agent, you should always evaluate the benefits, [such as reduced thrombotic events,] and the adverse risks, [such as bleeding complications]. This evaluation depends on the intrinsic characteristic of each individual patient.”
Jean-Francois Tanguay, MD, a professor of Medicine and Director of The Interventional Cardiology Program at the University of Montreal, told MD Magazine that even when exploring simple aspirin for patients with diabetes, it is vague as to whether it has benefit in primary prevention.
“First, there’s a question about the agent: is aspirin strong enough? Is clopidogrel better? Is ticagrelor or prasugrel better? Again, they have not been clearly proven to be superior to aspirin alone in patients,” he said. “It’s always [the result of] subgroup analysis of different trials—some being positive, some being negative. When you’re faced with treating a patient with diabetes and there are other criteria of a high risk of event—multiple lesions, multiple stents, or prior bypass— there’s a suggestion to give longer-term DAPT to these patients.”
Improving the efficacy and bioavailability of aspirin in patients with diabetes is being investigated in ongoing trials, based on the higher platelet turnover of diabetics versus non-diabetics. The hypothesis is that altering the timing of dosage may promote antithrombotic protection while reducing risk of gastrointestinal bleeding.
“A new, but still not totally demonstrated possibility, is to administrate aspirin twice a day,” said Badimon. “One of the possibilities that is currently under investigation in 2 randomized clinical trials is the administration of the same dose of aspirin in 2 pills; for instance, in the morning and at night. But as per today, it is a hypothesis that [remains] to be demonstrated by the ongoing clinical trials. Furthermore, if the hypothesis is shown to be correct, the same approach could be used for diabetics and also for non-diabetic subjects.”
Calculating the risk of DAPT and aspirin alone relies on individual patient risk factors such as diabetes, prior myocardial infarction (MI), hypertension, smoking history, and renal insufficiency. The ACC’s DAPT Risk Calculator is an app that easily generates a “DAPT Score” to evaluate safety of usage on the basis of these risk factors. These factors can also be used to calculate risk and benefits of aspirin.
“A very knowledgeable epidemiologic group at Harvard and Brigham & Women’s Hospital has developed a phone app called the Aspirin-Guide for looking at the potential for harm versus the potential for good,” Donald Smith, MD, a professor of medicine and cardiology at the Icahn School of Medicine and the director of Lipids and Metabolism at the Zena and Michael A. Weiner Cardiovascular Institute and the Mari-Jose and Henry R. Kravis Center for Cardiovascular Health at Mount Sinai, told MD Magazine. “This helps determine whether to use aspirin or not in any patient, including those with diabetes, and other risk factors in the calculation.”
The Aspirin-Guide app utilizes an algorithm to calculate the patient’s 10-year atherosclerotic cardiovascular disease score (ACC/AHA ASCVD score) as well as their bleeding risk score. The app also factors in the patient’s age, sex, race, smoking status, and whether they have diabetes. It will then advise a recommended dosage of aspirin.
“What we have said in the Canadian guidelines for antiplatelet therapy is that we have to go with the risk of an ischemic event and the risk of a bleeding event,” said Tanguay, who also serves as the director of Coronary Care Unit, as well as a cardiologist and research scientist at the Montreal Heart Institute. “Diabetics are more pro-thrombogenic and have more ischemic events, and some have risk factors for bleeding. But in general, they benefit from the more powerful agents, like ticagrelor and prasugrel, when they have a stent or had an MI.”
Tanguay added that if a physician felt that their patient was at high risk for an ischemic event but had a low risk of bleeding, then longer-term DAPT is most likely safe. “If the patient has a DAPT Score of greater than or equal to 2, it appears there may be benefit for continuing DAPT up to 3 years,” he said. “We have some patients that we keep on DAPT because they have some recurrent event like stent thrombosis, and we are always balancing the risk of bleeding.”
Patients with diabetes on DAPT who develop further complications of metabolic syndrome may eventually require additional intervention. Those who are hypertensive and have atrial fibrillation may require an anticoagulant, in addition to being on the DAPT. Triple therapy of aspirin, a P2Y12 receptor inhibitor, and a powerful anticoagulant like a NOAC (New Oral Anticoagulant)— namely rivaroxaban, apixaban, or dabigatran—significantly increases the risk of bleeding and therefore require discontinuation of 1 or 2 agents to manage the bleeding risk while still maintaining antithrombotic benefits.
“If you’d like to stop 1 of the 2 antiplatelet drugs, continue for a while with 1 antiplatelet drug with the anticoagulant. If, after 1 year , [there are] no adverse events, then you could consider stopping the single antiplatelet and just continuing the full dose NOAC,” said Tanguay.
Mauri L, Kereiakes DJ, Yeh, RW, et al. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med. 2014; 371: 2155-2166.