Exploring PLATO-USA paradox and CURRENT-OASIS 7 trials reveals the benefit of higher aspirin dose.

Ticagrelor was compared with clopidogrel in the PLATO trial, which randomized 18,624 patients with acute coronary syndromes (ACS) to either ticagrelor (180 mg loading dose plus 90 mg twice daily maintenance dose) plus aspirin or clopidogrel (300–600 mg loading dose plus 75 mg once daily maintenance dose) plus aspirin. Ticagrelor led to a significant reduction in the primary end point [a composite of death from vascular causes, myocaridal infarction (MI), or stroke] compared to clopidogrel [9.8% vs. 11.7%, 95% confidence interval (CI), 0.77–0.92, P , 0.001, respectively]. The CURRENT-OASIS 7 trial was a 232 factorial design, randomizing 25,086 patients with an ACS to either double-dose clopidogrel (a 600 mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300 mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300–325 mg daily) or lower-dose aspirin (75–100 mg daily). The primary outcome was not significantly reduced in patients assigned to double-dose clopidogrel compared with standard-dose clopidogrel [4.2% vs. 4.4%; hazard ratio (HR), 0.94; 95% CI, 0.983–1.06; P 5 0.30]. However, major bleeding was significantly increased with the double-dose versus standard-dose clopidogrel (2.5% vs. 2.0%, HR, 1.24; 95% CI, 1.05–1.46; P 5 0.01). Among patients who underwent percutaneous coronary intervention (PCI) (17,263 patients), the primary end point (death from cardiovascular causes, MI, or stroke) and stent thrombosis were significantly reduced with double-dose clopidogrel compared with standard-dose clopidogrel (3.9% vs. 4.5%, P 5 0.04% and 1.6% vs. 2.3%; HR, 0.68; 95% CI, 0.55–0.85; P 5 0.001). A post hoc analysis from the Platelet Inhibition and Patient Outcomes (PLATO) trial was undertaken to suggest that the increased use of aspirin 300–325 mg (53.6%) in the United States compared with the rest of the world (RW) (1.7%) was the only factor to explain (out of 37 factors explored) the regional interaction; that ticagrelor was less effective and potentially more harmful versus clopidogrel. However, this seems to be smoke and mirrors to distract clinicians from the more plausible reasons for ticagrelor failure in PLATO-USA; that (1) USA sites were monitored by a third party contract research organization, whereas other regions were monitored by the sponsors of PLATO (AstraZeneca) and (2) that a more appropriate dose (.300 mg) of aspirin was more commonly given in US sites versus other geographical regions, allowing the “clopidogrel” arm to have better mortality reduction compared with sites that used low-dose aspirin (75–100 mg). The latter will be discussed in greater detail. The explanation for ticagrelor’s failure in the PLATOUSA cohort as being a result of increased use of aspirin . 300 mg is inherently flawed from the saying “correlation does not equal causation. ” Almost all post hoc analyses from trials using aspirin [CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events), BRAVO (Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion), CHARISMA (The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance), and WHS (Women Health Study)] have shown that low-dose aspirin (75–100 mg) causes less bleeding and similar if not greater efficacy compared with high-dose aspirin (300–325 mg). However, post hoc subgroup analyses are not randomized, but observational data are subject to hidden confounding between highand low-dose aspirin groups. Thus, a randomized controlled trial (RCT) must be performed to prove causation. To prove causation, that aspirin 75–100 mg is as effective as 300–325 mg, investigators must undertake an RCT. This was partly the reason for the undertaking Wegmans Pharmacy, Ithaca, NY; HeartDrug Research, Johns Hopkins University, Towson, MD. V. L. Serebruany is listed as an inventor for the US patent application: Treating Cardiac Arrhythmias, Heart Failure, Peripheral Artery Disease and Stroke with Cyclopentyl-Triazolo-Pyrimidine or Derivative Thereof (USN 61/253,829) assigned to HeartDrug Research. He received funding for research studies with clopidogrel, and consultant fees from both clopidogrel and ticagrelor manufacturers. *Address for correspondence: 500 South Meadow Street, Ithaca, New York. E-mail: jjdinicol@gmail.com American Journal of Therapeutics 22, 85–86 (2015)