Editorial Mortality after clopidogrel in the non-invasive PLATO cohort and TRILOGY ACS trial: Another mismatched death paradox Victor L. Serebruany a, ⁎, James J. DiNicolantonio b , Mehmet Mustafa Can c , Alexander Dukhanin d , Ales Tomek e a HeartDrug Research Laboratories, Johns Hopkins University, Osler Medical Building, 7600 Osler Drive, Suite 307, Towson, MD, 21204, United States b Wegmans Pharmacy, Ithaca, NY, United States c Bagcılar Research and Education Hospital, Cardiology Department, Bagcılar, Istanbul, Turkey d Department of Molecular Pharmacology & Radiobiology, Pirogov Russian National Research Medical University, Moscow, Russia e Neurology Department, Charles University, 2nd School of Medicine, Prague, Czech Republic abstract article info Article history: Received 30 November 2012 Received in revised form 22 January 2013 Accepted 4 May 2013 Available online 2 June 2013 Keywords: Mortality Acute coronary syndromes Non invasive strategy Clinical trials Background: Excess mortality especially in the clopidogrel arm of the PLATO trial raise concerns of data integrity, and call for independent verification of vital records in the national death registries. Recently published data focused on outcomes in patients after non-invasive strategies yielded from the PLATO (PLATO-NIS) and TRILOGY ACS trials allowing comparison of all cause mortality (ACM) between trials. Methods: To compare the prorated over follow-up duration rates of ACM in the clopidogrel arms of PLATO-NIS cohort and TRILOGY ACS trial. Results: The background clinical characteristics indicate similar if not higher mortality should be expected in TRILOGY ACS. PLATO trial was almost half the duration with a mean follow-up of 277 days compared to TRILOGY ACS (513 days). Matching prorated over follow-up duration of ACM rates in the clopidogrel arm revealed 0.027/day or 9.86% yearly mortality in PLATO-NIS cohort (195 fatalities among 2615 patients enrolled). The ACM rates in TRILOGY ACS (409/4663) were only 0.017/day or 6.2% annually after clopidogrel, suggesting that the risk to die in the control PLATO-NIS group was 63% higher and barely missed significance (p = 0.051) compared to TRILOGY ACS. Conclusions: Prorated over length of follow-up PLATO-NIS mortality rates after clopidogrel far exceeded those observed in a similar medically managed patients in a TRILOGY ACS trial. The background clinical differences between trials are not responsible for the elevated PLATO-NIS mortality numbers. These data further challenge the death paradox reported in the overall PLATO trial and call for the urgent independent verification of vital records. © 2013 Elsevier Ireland Ltd. All rights reserved. There is an unsolved yet controversy regarding the extreme death rates reported in the PLATO trial [1]. The unusually high all-cause and vascular mortality, especially in the clopidogrel arm, initiate a public debate with the opinions ranging from the call for independent veri- fication of vital records in the national death registries to the argu- ments that it is impossible to extrapolate mortality rates among different trials, play of chance considerations, or a call for a second confirmatory ACS ticagrelor study [2–4]. Since only about 64% of PLATO patients underwent PCI for qualifying vascular event, the out- comes in the non-invasive PLATO cohort are of particular importance. Two recently published papers revealed vascular outcomes including all cause mortality in medically managed non-invasive patients, while therapy with 75 mg/daily clopidogrel served as a control arm for both PLATO [5] and TRILOGY ACS [6]. A brief description of both discussed studies are outlined below. The overall PLATelet Inhibition and Clinical Outcomes (PLATO) trial was a phase 3, randomized, double blind, parallel-group, multi- national, clinical study, comparing the efficacy of ticagrelor (formerly known as AZD6140, to be marketing as Brilinta®) versus standard care treatment with clopidogrel. Patients (n = 18,624) with moder- ate to high-risk ACS undergoing coronary intervention were random- ized to ticagrelor 180 mg loading dose followed by 90 mg twice daily thereafter, or clopidogrel 300-600 mg loading dose followed by 75 mg once daily for 6 to 12 months. The primary end point was the time of the first event of death from vascular causes, myocardial infarction (MI) or stroke, and occurred in 11.7% of patients treated with clopidogrel, versus 9.8% of patients randomized to ticagrelor, representing a highly significant benefit (HR = 0.84; CI = 0.77–0.92; p b 0.001) of the experimental agent [1]. Importantly, the benefit of ticagrelor was driven equally by the reduction of vascular death (p b 0.001), and MI (p b 0.005) with 89 events favoring ticagrelor International Journal of Cardiology 168 (2013) 640–642 ⁎ Corresponding author. Tel.: +1 410 847 9490; fax: +1 443 583 0205. E-mail address: heartdrug@aol.com (V.L. Serebruany). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.05.066 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard