Author + information
- Michael J. Domanski, MD∗ ()
- Peter Munk Cardiac Centre/Mount Sinai Hospital and the University of Toronto, Toronto, Ontario, Canada
- ↵∗Reprint requests and correspondence:
Dr. Michael J. Domanski, Division of Cardiology Peter Munk Cardiac Centre, University Health Network/Mount Sinai Hospital, University of Toronto, 4N-484, 585 University Avenue, Toronto, ON M5G 2N2, Canada.
Patients with coronary artery disease (CAD) who have a history of myocardial infarction (MI) are at increased risk of MI compared to patients with CAD and no such history (1). This results, at least in part, from increased platelet activation of uncertain, but prolonged, duration. The effectiveness of aspirin in preventing recurrent MI is well established (2). However, aspirin inhibition of cyclo-oxygenase results in suppression of only 1 of several pathways by which platelets participate in thrombosis, and so the demonstrated enhanced efficacy of dual antiplatelet therapy (3) is not surprising.
Whereas the role of dual antiplatelet therapy after MI is clear, until recently few data have been available to guide the duration of therapy. Common practice has been movement to monotherapy with aspirin after 12 months. Recently reported studies now suggest benefit of longer duration dual antiplatelet therapy.
The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) study examined a group of stable patients with a history of either known atherothrombotic disease or multiple risk factors for atherothrombotic events (4). Bhatt et al. (4) studied 9,478 patients who had a history of MI, ischemic stroke, or documented peripheral arterial disease, comparing outcomes in patients treated with aspirin and clopidogrel to those of patients treated with aspirin alone for a median duration of 27.6 months. The composite of death, MI, or stroke was significantly lower in dual-antiplatelet-therapy treated patients than in those treated with aspirin alone over this extended period.
The DAPT (Dual Antiplatelet Therapy) trial enrolled 9,961 patients who had a history of a drug- eluting coronary stent placement (5). After 12 months of treatment with aspirin and either clopidogrel or prasugrel, patients were randomly assigned to continuation of their thienopyridine drug in addition to aspirin or to monotherapy with aspirin alone. Over the follow-up period of 18 months, the rate of MI was reduced from 4.1% in the aspirin-plus-placebo group to 2.1% (p <0.001) in patients treated with both aspirin and thienopyridine. Death from any cause was 2.0% in the aspirin-plus-placebo-treated patients versus 1.5% in the aspirin-plus-thienopyridine-treated group (hazard ratio [HR]: 1.36; 95% confidence interval [CI]: 1.00 to 1.85; p = 0.05). Stent thrombosis was also reduced with dual antiplatelet therapy compared to treatment with aspirin and placebo (0.4% vs. 1.4%; p = 0.001). Additionally, an elevated risk of stent thrombosis and MI was observed 3 months after discontinuation of thienopyridine treatment. Importantly, the benefit of dual antiplatelet therapy was present in patients whether or not they had prior MI. This differs from the subgroup analysis of CHARISMA that showed benefit for dual antiplatelet therapy in the prior MI patients but not in those with CAD and no prior MI. The apparent difference may be the result of all patients in the DAPT trial having received a stent, an event that would be expected to result in platelet activation analogous to the activation that attends the post-MI state.
The PEGASUS-TIMI 54 (Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial examined the potential benefit of dual antiplatelet therapy beyond 1 year after an MI comparing the treatment with aspirin to treatment with aspirin and ticagrelor, a P2Y12 receptor antagonist (6). The study consisted of 21,162 subjects who had had a spontaneous MI 1 to 3 years before enrollment, were at least 50 years of age, and had 1 additional high-risk feature: age of 65 years or older, diabetes mellitus requiring medication, a second prior spontaneous MI, multivessel CAD, or chronic renal dysfunction. Patients were randomly assigned to aspirin and placebo or to aspirin and ticagrelor in 1 of 2 doses. Compared to addition of placebo, both ticagrelor doses resulted in an absolute reduction in the primary endpoint of cardiovascular death, MI, or stroke of 1% to 2% at 3 years of follow-up. The 2 ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, compared with 9.04% in the placebo group (HR for 90 mg of ticagrelor vs. placebo: 0.85; 95% CI: 0.75 to 0.96; p = 0.008; HR for 60 mg of ticagrelor vs. placebo: 0.84; 95% CI: 0.74 to 0.95; p = 0.004). The results of this study are consistent across subgroups, including patients with diabetes.
The data available to the clinician, principally the studies cited above, but also smaller studies, are examined in a structured review by Udell et al. (7). As would be expected, this study concluded that dual antiplatelet therapy beyond 1 year is more effective than aspirin alone in reducing occurrence of cardiovascular death, recurrent MI, and stroke.
An important insight highlighted by this paper is the nature and import of the increased bleeding that is the price that the clinician would expect to pay for enhanced antiplatelet efficacy. Although significant bleeding complications were, indeed, slightly more frequent (1.85% vs. 1.09%; that is, <1% difference) there was no statistically significant increase in intracranial hemorrhage or death attributed to bleeding.
So, how do these data inform clinical decision-making, and what questions remain? The studies discussed earlier make clear that there is a therapeutic benefit to continuing dual antiplatelet therapy, compared to monotherapy with aspirin, in patients at elevated risk of MI consequent upon a history of MI. The PEGASUS-TIMI 54 study adds the additional insight that even for patients who had dual antiplatelet therapy stopped (doing so at 1 year being a common practice), restarting dual antiplatelet therapy is indicated. We also know that although significant bleeding is more common with dual antiplatelet therapy than with aspirin monotherapy, intracranial hemorrhage and hemorrhagic death are not statistically significantly increased. So, although there is a bleeding price to be paid for efficacy, catastrophic complications are not increased and even the increase is, numerically, strikingly modest.
So, continuation of dual antiplatelet therapy beyond 1 year is indicated to prevent recurrent infarction in patients tolerating the treatment. What we do not know is whether there is a time beyond which there is an attenuation of the treatment difference between monotherapy with aspirin and dual antiplatelet therapy such that dual antiplatelet therapy is no longer needed.
In this issue of the Journal, Bhatt et al. (8) explore the PEGASUS-TIMI 54 results in the 6,806 diabetic patients in that study. The relative efficacy of dual antiplatelet therapy in this pre-specified subgroup (HR: 0.84; CI: 0.74 to 0.96; p = 0.013) was essentially identical to that of the cohort as whole (HR: 0.84; 95% CI: 0.72 to 0.96; p = 0.035) suggesting operation of the protective mechanism of antiplatelet therapy operates similarly in diabetic patients and in nondiabetic patients. The enhanced reduction in absolute risk in patients with diabetes, compared to patients without diabetes, results from the high absolute event risk in these patients.
There is a huge population of patients with diabetes and prior infarction and the report of Bhatt et al. (8) extends the reassurance of data reported with the main study that this pre-specified subgroup of patients with diabetes derive benefit that is similar (in relative terms) to that enjoyed by other groups. Other high-risk subgroups could be explored in addition to this one (such as the patients with renal insufficiency). More pertinent is whether there is any time threshold beyond which dual antiplatelet therapy does not provide additional benefit beyond that offered by aspirin monotherapy. Also of importance is whether there are lower-risk populations than those with prior MI that can be identified who do not now receive dual antiplatelet therapy but who would benefit from such treatment.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Domanski holds the Pfizer Chair in cardiovascular research.
- American College of Cardiology Foundation
- Fanaroff A.C.,
- Roe M.T.
- Amsterdam E.A.,
- Wenger N.K.,
- Brindis R.G.,
- et al.
- Bhatt D.L.,
- Flather M.D.,
- Hacke W.,
- et al.
- Udell J.A.,
- Bonaca M.P.,
- Collet J.P.,
- et al.
- Bhatt D.L.,
- Bonaca M.P.,
- Bansilal S.,
- et al.