A Case of Identity Part Two

Our standards for acceptable benefit of antiplatelet agents in the management of ACS have become deplorably low. When ISIS-2 was first published we defined success only by aspirin’s ability to affect mortality. The number commonly cited, 2.4%, only describes aspirin’s absolute benefit to decrease death (1). In the one trial that examined its properties to prevent further infarction, published in the NEJM in 1988, aspirin demonstrated additional capabilities to decrease myocardial infarction as well as save lives (2). If in ISIS-2, aspirin had performed as poorly as clopidogrel did in its efficacy defining study, the CURE trial, it may have never gained the stature it currently holds in the management of ACS (3). To date aspirin has been the only antiplatelet agent that has demonstrated a consistent and clinically relevant mortality benefit. Despite the obvious benefits, it was not long before we turned towards other agents in an attempt to supplement aspirin’s antiplatelet properties. The concept of dual antiplatelet therapy so appealing, its theoretical basis so believable, it soon became a perfunctory part of our management strategy for patients presenting to the Emergency Department with ACS.

Our current concept of dual antiplatelet therapy was first defined in 1996 with the publication of the CAPRIE trial. Published in The Lancet in November of 1996, this trial was the first of many to indicate clopidogrel’s efficacy in finding clinically irrelevant reductions of methodologically deceitful composite endpoints (4). So began the era of dual antiplatelet therapy in which, based off weak endpoints and statistical chicanery, clopidogrel and its post-patent clones have bullied and fibbed their way to success.

Throughout the literature examining clopidogrel in a multitude of ACS cohorts of varying degrees of severity, its vaulted dual anti-platelet capabilities have never demonstrated a clinically relevant mortality benefit. Its success has been powered by the reduction of non-fatal MIs, the majority of which are peri-procedural troponin leaks of questionable clinical significance. The only clinically relevant endpoint clopidogrel has consistently demonstrated is a 1% absolute increase in serious bleeding. Despite these mediocre capabilities, Bristol-Meyer, through sheer force of will and marketing prowess, catapulted their drug to the forefront of pharmaceutical sales for over a decade. The true level of clopidogrel’s mundanity has been discussed in a previous post. The more important question for Emergency Physicians is, does the upstream administration of P2Y12 inhibitors provide added benefit over only administering these medications after confirming appropriate coronary anatomy during catherization?

Upstream use of P2Y12 inhibitors in ACS is commonly believed to be beneficial as it deters thrombus formation through additional inhibition of platelet adherence vs the singular capabilities of aspirin alone. Despite a dearth of evidence validating this claim and reasonable data stating otherwise, this practice has been routinely implemented since the publication of the CURE trial over a decade ago.

So is there a role for dual antiplatelet therapy in today’s Emergency Department?

Two recent publications sought to address this very question. The more methodologically ambitious of these trials was a systematic review and meta-analysis published in the BMJ in October of 2014 in which Bellemain-Appaix et al attempted to examine all the literature addressing the potential benefit of upstream use of P2Y12 inhibitors in NSTEMI patients undergoing PCI (5). Much to the chagrin of the authors, only one trial included (the recently published ACCOAST trial) specifically examines this specific inquiry. The authors, not to be dissuaded, attempted a piecemeal collection of various subgroups from a number of trials that seemed to meet their entry criteria. This resulted in a statistically and clinically heterogeneous cohort whose subsequent data should probably not have been combined into a single analysis. Nevertheless the authors plunged ahead examining the NSTEMI patients in both the CREDO and CURE trials, as well as the subset of patients in the ACUITY trial who were pre-treated with clopidogrel. Also including the entire cohort from the ACCOAST trial, the only trial included examining prasugrel. Combining these trials with the data from three observational cohorts, the authors collected information on 32,838 patients.

Contrary to most trials attempting to examine potential benefit in the use of P2Y12 inhibitors, these authors set aside the traditional composite endpoint (stroke, MI, or cardiovascular death) and looked exclusively at mortality and major bleeding. The authors found no mortality benefit in either the entire cohort, the subgroup of patients from the RCTs, or in the group that underwent PCI. Conversely, an increased risk of bleeding was observed in patients treated with upstream P2Y12 inhibitors. No difference was seen in the rate of stroke, myocardial infarction or urgent revascularization. However when a composite outcome the authors termed “adverse cardiac outcomes” was measured, they found a small reduction in risk (odds ratio 0.84, CI 0.72-098). As with all individual trials examined, this composite benefit is powered by a small increase in myocardial infarctions, that when examined alone did not reach statistical significance (odds ratio of 0.81, CI 0.64- 1.03). When the subgroup of patients who underwent PCI was isolated this decrease in “adverse cardiac events” was no longer significant (odds ratio 0.83, CI 0.99-0.1.03). This speaks more to the drastic decrease in sample size (32,383 to 17,545), decreasing the statistical power to detect clinically irrelevant differences, than a meaningful difference between those who undergo PCI compared to those who do not (5).

Unfortunately the clinical heterogeneity between the trials included in this meta-analysis is quite high. The trials included span different eras and different strategies in the overall management of patients experiencing NSTEMIs. It is questionable whether they should have been included in a formal analysis at all. Fortunately one does not require the above stated statistical manipulations to reach the same conclusions garnered by the authors. Each trial that examined the efficacy of upstream use of P2Y12 inhibitors failed to identify any clinically meaningful benefit.

The CURE trial was the earliest trial included in this analysis. This trial paved the way for clopidogrel’s use in the Emergency Department simply by utilizing composite endpoints of questionable clinical significance and a sample size large enough to bully even the smallest deviation from placebo towards statistical relevance. Published in NEJM in 2001, the authors claimed a statistically significant 2.1% absolute decrease in cardiovascular death and myocardial infarction (MI). This difference was completely powered by the 1.5% absolute difference in MIs, the majority of which were type IV MIs (peri-procedural). This small reduction is of questionable clinical consequence as the mortality rate between groups was identical at 30 days (1.0% vs 1.1%) as well as at the end of follow up (2.3% vs 2.4%)(mean of 8 months)(3).

The CREDO trial sought to answer the question of whether treatment with clopidogrel prior to angiography was beneficial, examined patients scheduled for urgent cardiac cathertization. Patients were randomized to upstream administration of clopidogrel or placebo 3-24 hours prior to cath. All patients received daily clopidogrel following PCI. Like CURE before it, the CREDO authors found no clinically important benefit to the upstream use of clopidogrel. No statistical difference was recorded in the rates of death, stroke or MI at 28 days between the placebo and upstream clopidogrel groups. The authors claim success in the statistical significance of a secondary endpoint, the per-protocol analysis of the 1-year outcomes, noting a 2% absolute reduction in the rate of death, MI, and stroke. Similar to CURE, this difference was powered by the 1.9% reduction of MIs. Interestingly, statistical significance is lost upon examining any of the three endpoints individually, or when the same composite endpoint is analyzed using the authors’ primary outcome and more statistically appropriate methodology, the intention-to-treat analysis. As is typical with all P2Y12 inhibitor trials there was a 1% increase in major bleeding events in both the CURE and CREDO trials, the vast majority of which were related to subsequent CABG procedures after coronary anatomy revealed less than ideal conditions for stent placement (6).

Neither of these trials are methodologically ideal to address the question, in the modern Emergency Department does the upstream use of P2Y12 inhibitors result in improved patient oriented benefits? In the CURE trial less than half the patients (43.8%) underwent coronary angiography and only 21.2% received PCI. In the CREDO trial only 67% of the patients were actually having an enzyme defined NSTEMI (3,6)

The final RCT included in the Bellemain-Appaix et al meta-analysis, the ACCOAST trial, is far more relevant. Using modern PCI techniques and standards, Montalescot et al specifically examined whether upstream administration of prasugrel was beneficial when compared to its administration in the cath lab after visualizing the coronary anatomy. The recent marketing disaster that was the publication of the TRILOGY trial, a completely negative study comparing prasugrel to clopidogrel in patients with ACS, was the first obstacle in prasugrel’s race to fill the post-patent void at the top of the antiplatelet hierarchy. ACCOAST was an attempt to regain the momentum lost with TRILOGY’s failure. Authors randomized 4,033 patients with NSTEMI in the Emergency Department to either 30 mg of prasugrel 2-48 hours prior to PCI or placebo. Following visualization of the anatomy during angiography and stent placement when appropriate, the prasugrel group received the remaining 30 mg of the 60 mg loading dose that is recommended by Eli Lilly. The placebo group received the full 60 mg dose of prasugrel at the time of PCI if stent placement was thought to be beneficial. The authors failed to demonstrate a benefit in upstream administration of prasugrel when compared to its administration in the cath lab, with no difference in cardiovascular death, myocardial infarct, stroke, urgent revascularization or glycoprotein IIb/IIIa bailout (10.8% vs 10.8%). As is consistent with the rest of the literature examining the use of P2Y12 inhibitors, the pretreatment group was found to have approximately 1% increase in major bleeding. Most due to an increase in bleeding during CABG (20.7% vs 13.7%)(7).

Finally, what about the added benefit of dual antiplatelet therapy in the hyperacute patient? What is the benefit of P2Y12 inhibitors in patients with a time dependent lesion? In an article published in September 2014 in the NEJM, Montalescot et al examined this very question. The authors of the “Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC)” trial randomized patients to a 180 mg loading dose of ticagrelor in either the ambulance on the way to the hospital or in the cath lab prior to angiography. The authors and their benefactors, AstraZeneca, hoped to demonstrate that upstream use of ticagrelor was an important addition to the management of these hyperacute patients. Though they included patients with ST-elevation MIs up to 6 hours after symptom onset, the majority of patients were identified within 70 minutes of symptom onset (well within the time dependent portion of STEMI pathology)(8).

A total of 1,862 patients were randomized to either pre-hospital or in-hospital treatment. The authors selected the unfortunate clinically irrelevant measures of the proportion of patients who did not have 70% or greater resolution of ST-segment elevation before PCI, and the proportion of patients who did not meet the criteria for TIMI flow grade 3 in the infarct-related artery at angiography before PCI as their co-primary endpoints. Thankfully we were saved the discussion of why neither of these metrics translated into patient oriented outcomes as the authors failed to find a difference between the pre-hospital and in-hospital groups. Nor was there a difference in the more traditional composite endpoint (rate of cardiovascular deaths, MIs, strokes, urgent revascularizations, or definitive stent thrombosis) so commonly used in P2Y12 inhibitor trials (4.5% vs 4.4%). In an altogether unsurprising twist, the authors claim this trial a success after dredging up a single secondary endpoint from the many measured that achieved a p-value of significance. Patients who received pre-hospital administration of ticagrelor experienced a smaller rate of definitive stent thrombosis when compared to patients receiving the drug in the cath lab (0.2% vs 1.2%). This difference seemed to have no clinical relevance as there was no difference in the rate of myocardial infarction or death at 30 days between the groups. In fact the mortality rate in the pre-hospital group was alarmingly higher, though the 1.3% absolute difference (3.3% vs 2.0%) in 30-mortality failed to reach statistical significance(8).

As is the case with any in depth examination of the literature supporting the use of P2Y12 inhibitors we are left entirely underwhelmed. From as far back as the CURE trial the theoretical benefits of dual antiplatelet therapy have consistently lacked evidentiary support of clinically relevant patient oriented outcomes. Even the small industry manipulated advantages seemingly evaporate when drugs are compared to their own administration downstream in the cath lab once suitable anatomy has been defined. Recently published trials examining long-term use of P2Y12 inhibitors after stent placement have been far from stellar (9,10). Both a meta-analysis and large RCT demonstrated that even in cases of anatomically confirmed disease with stent placement, these medications offer very limited benefits over aspirin therapy alone and in some cases even demonstrate a small increase in mortality (0.5% increase in all-cause mortality). This is not a case where more evidence is required. It is time we reexamine the utility of dual anti-platelet therapy in the Emergency Department. Clearly we now have convincing data that upstream use of P2Y12 inhibitors whether administered pre-hospital or in the Emergency Department do not provide any patient oriented benefits and can only lead to harm. In fact the only benefit that can be gained by maintaining this dual anti-platelet delusion is to ensure the well being of the pharmaceutical companies whose lies and manipulation have led us down this fool’s path in the first place.

Sources Cited:

Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2(8607):349-60.Heparin, Aspirin or Both NEJM
Théroux P, Ouimet H, Mccans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319(17):1105-11.
Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-39.
Bellemain-Appaix Anne, Kerneis Mathieu, O’Connor Stephen A, Silvain Johanne, Cucherat Michel, Beygui Farzin 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
Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-20.
Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999-1010.
Montalescot G, Hof AW, Lapostolle F, et al. Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction. N Engl J Med. 2014
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
Sammy Elmariah MD,Laura Mauri MD,Gheorghe Doros PhD,Benjamin Z Galper MD,Kelly E O'Neill BS,Prof Philippe Gabriel Steg MD,Prof Dean J Kereiakes MD,Dr Robert W Yeh MD. Extended duration dual antiplatelet therapy and mortality: a systematic review and meta-analysis. The Lancet – 16 November 2014