By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco, Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
Bellemain-Appaix A, et al. Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: A systematic review and meta-analysis. BMJ 2014;349:g6269 (Published 24 October 2014).
Each year when I lecture the incoming cardiology fellows on the management of non-ST elevation acute coronary syndromes (NSTE-ACS), we embark on a discussion of optimal guideline-driven treatment vs real-world practicalities. Current ACC/AHA guidelines assign a class I recommendation to the administration of dual antiplatelet therapy to unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI) patients at the time of presentation. This applies whether an initial invasive or conservative strategy is planned, and it emerged more than a decade ago based primarily on the results of the 2001 Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study. In our hospital system, however, the reality is that such pretreatment — giving thienopyridine before coronary angiography — may adversely affect the subset of patients who are later found to have surgical anatomy. I say good luck finding a surgeon willing to operate on your clopidogrel-loaded patient. Cardiothoracic surgeons generally prefer that thienopyridines be withheld until after cardiac catheterization.
Now, it seems the surgeons have more support for their point of view. In their recent meta-analysis, Bellemain-Appaix and colleagues looked at thienopyridine (P2Y12 inhibitor) pretreatment in seven studies that included primarily NSTEACS patients, including four randomized, controlled trials and three registries. In the overall cohort, pretreatment did not reduce the risk of all-cause mortality or cardiovascular death. Major adverse cardiovascular events were reduced in the pretreatment group (odds ratio [OR], 0.84; 95% confidence interval [CI] 0.72 to 0.98; P = 0.02), but individual endpoints, such as myocardial infarction, were not significantly affected. Among the subset of patients who underwent percutaneous coronary intervention (PCI), which represented a minority of the total cohort, there was likewise no reduction in death or cardiovascular death, but pretreatment with P2Y12 inhibitors was associated only with a non-significant trend toward a reduction of major adverse cardiac events (MACE). Within the PCI group, pretreatment was associated with a reduction of urgent revascularization (OR, 0.72; 95% CI, 0.52 to 1.00); however, this result was driven primarily by the results of the PCI subset of the CURE, in which the delay from admission to revascularization averaged a relatively long 10 days.
By contrast, pretreatment with thienopyridine showed a consistent and significant effect on the primary safety endpoints in this study. Major bleeding was increased in the overall cohort (odds ratio 1.32 [1.16 to 1.49], P < 0.0001), as well as in the subset undergoing PCI (odds ratio 1.23 [1.00 to 1.50], P = 0.048). Minor bleeding was increased significantly only in the unselected group of patients with NSTEACS. The authors concluded that the risk-benefit ratio of thienopyridine pretreatment is not favorable in unselected patients with NSTEACS.
COMMENTARY
In the patients studied as part of this meta-analysis, pretreatment with thienopyridine had a relatively modest effect on MACE in the overall cohort, with no effect on mortality, but a consistent hazard with regard to bleeding. The authors’ conclusion, that the risk-benefit ratio of thienopyridine pretreatment is not favorable in unselected patients with NSTEACS, seems to be a reasonable one. That is not to say that pretreatment is never beneficial or warranted in these patients. For a more nuanced conclusion, we should look more closely at the studies included in this analysis.
Only the ACCOAST (a comparison of prasugrel at PCI or time of diagnosis of non-ST elevation myocardial infarction) trial, which was the sole dataset in the analysis to use prasugrel, looked specifically at the question of pretreatment prior to coronary angiography in NSTEMI patients. In ACCOAST, treating patients upfront with antithrombotic therapy and aspirin, but delaying prasugrel administration until the time of coronary angiography, did not alter ischemic outcomes, but reduced by one-half the incidence of major bleeding compared with early administration of prasugrel. It is worth noting that even before ACCOAST, prasugrel was the only P2Y12 inhibitor specifically not recommended for administration prior to coronary angiography, based on its specific bleeding profile.
With the exception of ACUITY (acute catheterization and urgent intervention triage strategy), most of the included clopidogrel trials were older and were performed in a clinical environment that had important differences from today. Compared with that time period, contemporary practice has seen more widespread adoption of an early invasive strategy, the use of a higher loading dose for clopidogrel (600 vs 300 mg), and the availability of newer and more potent P2Y12 receptor antagonists. In CURE, the clopidogrel group showed ischemic benefit within hours, and the event curves for clopidogrel- and placebo-treated patients continued to separate throughout the study. Patients who fit the CURE paradigm of longer waiting times to angiography would seem to be appropriate beneficiaries of early thienopyridine treatment.
What, then, should we do with this information? As always, the right course of action will depend heavily on individual patient- and environment-specific factors. In intermediate-risk patients with a short expected interval from admission to cardiac catheterization, pretreatment has little recommendation and should be avoided. However, for higher-risk patients in whom there is an expected delay to angiography of longer than 24 to 48 hours, pretreatment with either clopidogrel or ticagrelor should be considered on a case-by-case basis.
