So often in modern medicine we mistake science for truth. In doing so we have become enamored with the p-value and view it as the major determinant of relevance in scientific inquiry. An almost arbitrary selected value of 0.05 is independently responsible for defining what is considered beneficial, and what will be discarded as medical quackery. The p-value was first proposed by Ronald Fisher as a novel method of defining the probability that the results observed had occurred by chance alone. Or stated more formally, “the probability, under the assumption of no effect or no difference (the null hypothesis), of obtaining a result equal to or more extreme than what was actually observed” (1). Originally intended as a tool for clinicians to assess whether the results from a trial were due to the treatment effect in question or merely random chance, its meaning has transformed into something far more divine. Despite its overwhelming acceptance, the p-value has many flaws. It is incapable of distinguishing clinical relevance, rather only denotes the probability of equivalence. In addition, its faculties are easily overwhelmed when multiple observations are performed. Finally, the mathematical assumptions it is built upon do not take into account prior evidence and provide no guidance for future endeavors (1).
Our romance with the p-value has not gone unnoticed by many pharmaceutical companies who have learned that they need not manufacture a drug that produces clinical benefits, but rather fabricate a trial that demonstrates statistical significance. Since the p-value does not take into account prior evidence, trialists are not required to justify results as they relate to the entirety of an evidentiary body but rather demonstrate singular mathematical significance in a statistical vacuum. As such we are asked to live in the evidentiary present with only selective access to past knowledge. Even when we are granted a privileged glimpse at results from prior trials, it is often comprised of incomplete and limited data intended to sway our opinion in a deliberate manner. This phenomenon, known as publication bias, allows pharmaceutical companies to preferentially publish trials with p-values that suit their interests while suppressing others that do not support their claims. By prospectively highlighting a would-be therapy’s more flattering features and bullying Frequentist statistics with sample sizes that would make even negligible differences significant, it is easy to snatch statistical victory from the grasp of clinical obscurity. This is likely what the makers of ticagrelor hoped for when they designed the PEGASUS Trial.
PEGASUS Trial’s intentions were to extend ticagrelor’s temporal indication beyond the 12-month window, testing the hypothesis that long-term therapy of ticagrelor in conjunction with low-dose aspirin reduces the risk of major adverse cardiovascular events among stable patients with a history of myocardial infarction. Bonaca et al randomized 21,162 patients who experienced a myocardial infarction within the past 1-3 years to either 90 mg or 60 mg of ticagrelor twice daily or placebo. This is not the first time such a hypothesis has been investigated (2). Multiple trials have studied whether prolonged use of P2Y12 inhibitors possess any value other than augmenting the pharmaceutical industries’ coffers. The largest of these investigations, the DAPT trial, was published in 2014 by Mauri et al in NEJM (3). This trial examined patients 12 months after a cardiovascular event and considered whether the continuation of either clopidogrel or prasugrel was beneficial. The authors randomized 9,961 patients to either a P2Y12 inhibitor or an appropriate placebo. The DAPT Trial demonstrated that prolonged use of dual-antiplatelet therapy decreased the rate of cardiovascular events (4.3% vs. 5.9%) and stent restenosis (0.4% vs 1.4%) in exchange for an increased rate of severe bleeding (2.5% vs. 1.6%). There was also a small increase in overall mortality (2% vs 1.5%) in patients randomized to prolonged P2Y12 inhibition (3). Multiple recent meta-analyses confirm these findings (4,5). These results should come as no surprise as the bulk of the literature examining P2Y12 inhibitors has highlighted their benefit primarily as a means of reducing type 4a peri-procedural infarctions of questionable clinical relevance. And so this was the landscape AstraZeneca faced when designing the PEGASUS Trial. Every prior trial examining the question of prolonged dual-antiplatelet therapy has demonstrated that the small reductions in ischemic endpoints are easily overshadowed by the excessive increase in the rate of severe bleeding events. Fortunately in the modern era of Frequentist statistics none of these failures matter. Because the p-value does not account for prior evidence, the authors of the PEGASUS Trial did not have to account for this less-than-stellar history. Success by modern standards is simply the ability to contrive a primary endpoint that will demonstrate an appreciably low enough p-value to be considered significant.
Bonaca et al’s primary outcome was the composite rate of cardiovascular death, MI and stroke over the follow up period (3-years). The absolute rate of primary events were 7.85%, 7.77%, and 9.02% in the 90 mg, 60 mg and placebo groups respectively. This small (approximately 1.20% absolute difference) was found to be impressively statistically significant (p-values of 0.008 and 0.004 in the 90 mg vs placebo and 60 mg vs placebo comparisons respectively). Its clinical significance is far more questionable, and unlike its statistical counterpart cannot be bullied by the mass and size of the sample population. The effect size of this composite outpoint is diminutively small. The effect sizes of each respective component of this composite outcome are even smaller. The only measure that maintained its statistical significance consistently across all treatment comparisons was the reduction in myocardial infarction, which boasts a 0.85% and 0.72% absolute reduction in the 90 mg and 60 mg groups respectively.
Conversely the rates of bleeding in the patients randomized to receive the active agent were impressively high, especially given the previous studies examining ticagrelor demonstrated a more reasonable safety profile. The rate of TIMI major bleeding was 2.6%, 2.3% and 1.06% in the 90 mg, 60 mg and placebo groups respectively. Since both the rate of intracranial hemorrhage and fatal hemorrhage were statistically similar, most of this excess bleeding seems to be in the form of “clinically overt hemorrhage associated with a drop in hemoglobin of ?5 g/dL or a ?15% absolute decrease in hematocrit.” (2) These results are not too dissimilar from those of the DAPT Trial(3). Patients taking P2Y12 inhibitors will benefit from a slight decrease in the risk of non-fatal myocardial infarctions and stent restenosis while experiencing an increased risk of clinically significant bleeding.
Despite the positive spin of this trial, it is far from a success. The investigators enrolled the more infirmed spectrum of patients with CAD, so as to include a cohort more likely to benefit from additional anti-platelet inhibition. They also excluded the patients most at risk for hemorrhagic complications so as to limit the appearance of adversity. Investigators excluded patients with a history of ischemic stroke or intracranial hemorrhage, a central nervous system tumor, an intracranial vascular abnormality, with a history of gastrointestinal bleeding within the previous 6 months or major surgery within the previous 30 days (2). This of course in itself is not a concern, was it not for the likely application of prolonged dual-antiplatelet therapy to a far broader patient population.
Our current version of evidence-based medicine has left us susceptible to mistaking mathematical manipulations as scientific truth. It is short sighted and allows for the linguistic error of misinterpreting statistical significance for clinical relevance. The PEGASUS Trial boasts p-values far below what is traditionally considered significant, and yet p-values below 0.05 hold little intrinsic value to our patients’ well being. Yes, from a Frequentist’s perspective we are capable of concluding with relative certainty that the use of ticagrelor decreases the composite endpoint of myocardial death, MI, or stroke. The clinical relevance of which, is far from certain as its weight is powered exclusively by a decrease in myocardial infarctions. It is unlikely this small benefit is worth the impressive increase in serious hemorrhagic events. From the very earliest trials examining P2Y12 inhibitors, their benefits have been primarily due to the manipulation of statistical constructs rather than any inherent efficacy (6,7). The PEGASUS Trial is no different. These trials are not landmark demonstrations of P2Y12 inhibitors’ benefits, but rather statistical manipulations of clinical insignificant differences stacked one on top of the other to give the appearance of height when none is present. It is the statistical equivalent of an eyespot meant to keep the scorn of the medical skeptics at bay. Know that we are not scared or confused by your statistical mimicry. We see these trials for what they are, pharmaceutical advertisements poorly hidden behind the guise of scientific inquiry.
- Goodman SN. Toward evidence-based medical statistics. 1: The P value fallacy. Ann Intern Med. 1999;130(12):995-1004.
- Bonaca MP, Bhatt DL, Cohen M, et al. Long-Term Use of Ticagrelor in Patients with Prior Myocardial Infarction. N Engl J Med. 2015
- 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(23):2155-66.
- Palmerini T, Sangiorgi D, Valgimigli M, et al. Short- versus long-term dual antiplatelet therapy after drug-eluting stent implantation: an individual patient data pairwise and network meta-analysis. J Am Coll Cardiol. 2015;65(11):1092-102.
- Giustino G, Baber U, Sartori S, et al. Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Coll Cardiol. 2015;65:(13)1298-310
- 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.
University of Maryland
Resuscitation Fellowship Graduate