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Dinicolantonio J.J.,Wegmans Pharmacy | Dinicolantonio J.J.,Charles University
International Journal of Cardiology | Year: 2013

Objective Ascertain platelet inhibition and patient outcomes (PLATO) trial conduct. Methods We examined information from the FDA complete response review. Results FDA Medical Review indicated that (1) patients on ticagrelor monitored by the study sponsor had a lower odds ratio for the primary endpoint (p = 0.0004) versus ticagrelor patients monitored by a third party Clinical Research Organisation (CRO) independent of the study sponsor, (2) a significant interaction existed between ticagrelor and regions monitored by the study sponsor for all cause mortality through study end in favor of ticagrelor (p = 0.006), (3) ticagrelor faired worse than clopidogrel when regions were monitored independent of the study sponsor by a third party Contract Research Organisation (United States, Russia and Georgia), (OR = 1.21, 95% CI: 0.91 to 1.59, p = 0.2022), (4) 46% of all primary endpoint events favoring ticagrelor came from just two countries (Poland and Hungary), (5) PLATO was easy to unblind by breaking open a clopidogrel/dummy clopidogrel tablet with at least 452 patients being unblinded prior to the database lock, (6) significantly more cardiac events submitted for clopidogrel counted in the primary analysis as a myocardial infarction (MI) compared to those submitted for ticagrelor (p < 0.0001), (7) significantly more ticagrelor subjects hospitalized after an index event/hospitalization were not being reported as having a primary event compared to clopidogrel (p = 0.002 in favor of ticagrelor), (8) site-reported MI was not significantly reduced with ticagrelor versus clopidogrel, (9) an estimated 23 definite or possible cardiovascular events or deaths on ticagrelor were either not submitted for adjudication, inactivated, deleted or were downgraded to "softer" endpoints (this was not shown in the FDA review for clopidogrel), and (10) four FDA reviewers voted for non-approval of ticagrelor. Discussion The FDA report highlights what appear to be multiple serious deficiencies in the reporting of the PLATO results, which clinicians will not have gleaned from the primary publication alone. Individual clinicians may therefore wish to carefully reconsider their practice of ticagrelor prescription for this indication. Guideline bodies should also evaluate the information in its totality. © 2013 Elsevier Ireland Ltd. Source

DiNicolantonio J.J.,Wegmans Pharmacy | Hackam D.G.,University of Western Ontario
Expert Review of Cardiovascular Therapy | Year: 2012

β-blockers are a standard of care in many clinical settings such as acute myocardial infarction, heart failure and patients at risk for a coronary event. However, not all β-blockers are the same and they vary in properties such as lipophilicity, metabolic profile, receptor inhibition, hemodynamics, tolerability and antioxidant/anti-inflammatory effects. It has been unclear whether these differences affect outcomes or if one β-blocker should be preferred over another. This review will summarize the properties of metoprolol, atenolol and carvedilol, as well as comparative experimental and clinical trials between these agents. We will provide compelling evidence of why carvedilol should be a first-line β-blocker and why it offers many advantages over the β1-selective β-blockers. Source

Dinicolantonio J.J.,Wegmans Pharmacy
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: In the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, dabigatran 150 mg was shown to be superior to warfarin for the prevention of stroke or systemic embolism. However, there are some concerns with the RE-LY trial, such as its open-label design, potential unblinding of "blinded" adjudicators, the use of concomitant warfarinaspirin (ASA), the disparity between baseline use of nonselective NSAIDs; the high unequal rate of drop-outs; unaccounted drop-ins; high rates of major bleeds in warfarin-treated patients, despite being a low risk population; and rates of major bleeds that do not match historic warfarin trials. Furthermore, although dabigatran offers potential advantages versus warfarin, there are disadvantages that must be taken into consideration before a patient is switched from the latter to the former. This review will summarize the flaws of the RE-LY trial as well as the clinically important advantages and disadvantages of dabigatran and warfarin. Areas covered: This review examines the differences between dabigatran and warfarin in terms of side effects, drugdrug interactions, drugfood interactions, and potential reasons for using one anticoagulant rather than the other. The main focus of this review is a discussion of the design, procedures and results of the RE-LY trial. Expert opinion: There seem to be major flaws with the RE-LY trial. A double-blinded trial should be performed testing dabigatran against warfarin to verify the results of the RE-LY trial. © 2012 Informa UK, Ltd. Source

Serebruany V.L.,Johns Hopkins University | Dinicolantonio J.J.,Wegmans Pharmacy
Thrombosis and Haemostasis | Year: 2013

Recent European Society of Cardiology (ESC) Guidelines declare superiority of prasugrel and ticagrelor over clopidogrel in non-ST segment elevation myocardial infarction (NSTEMI) and STEMI patients with acute coronary syndromes (ACS). The recommendations for NSTEMI and especially STEMI are based on a subgroup analyses yielded from a single trial with either prasugrel (TRITON), or ticagrelor (PLATO). In contrast, the United States (US) Guidelines present a more balanced, conservative, and evidence-based outlook suggesting no proven extra benefit of one P2Y12 antagonist over the other(s). It was the purpose of this study to scrutinise the evidence leading to the current ESC ACS Guidelines on oral antiplatelet agents and compare them with US recommendations. Matching the evidence from TRITON and PLATO primary publications with the data reported in the Food and Drug Administration (FDA) official reviews in light of their impact on current regional ACS Guidelines on antiplatelet P2Y12 inhibitors. The available body of evidence on the efficacy and safety of the new oral P2Y12 inhibitors challenge the ESC Guidelines, and supports the US recommendations. Some of the pivotal data with regard to the newer P2Y12 inhibitors (prasugrel and ticagrelor) on event definition, adjudication, questionable efficacy, and serious safety concerns were ignored by the European Task Force Members, while the other "beneficial" findings were exaggerated to a disproportional extent. We conclude that current ESC Guidelines, with regard to their recommendation of superiority of prasugrel or ticagrelor over clopidogrel, in contrast to the US, are overoptimistic, and not evidence based. Low clinical utilisation of prasugrel and especially ticagrelor worldwide in general, and Europe in particular suggests mismatch of prescription habits with issued ESC recommendations. © Schattauer 2013. Source

Dinicolantonio J.J.,Wegmans Pharmacy
Future Cardiology | Year: 2012

Furosemide is the most widely prescribed loop diuretic in the setting of systolic heart failure (HF), yet torsemide has been shown to have less inter- and intra-individual variation in bioavailability and a longer duration of action compared with furosemide. Thus, a systematic review and meta-analysis of randomized controlled trials comparing torsemide versus furosemide in patients with systolic HF using OVID MEDLINE, Excerpta Medica (Embase), Web of Science, PubMed and Google Scholar was performed. Extracted data included study design, sample characteristics, intervention, outcomes and control for potential confounding factors. A DerSimonian and Laird random-effects model was used to compute summary risk ratios for HF and cardiovascular (CV) readmission outcomes. Two randomized trials comparing furosemide with torsemide in 471 patients with systolic HF were identified. Compared to furosemide, torsemide significantly reduced total HF readmissions (relative risk [RR]: 0.41, 95% CI: 0.28-0.61, p < 0.0001) and HF readmissions (RR: 0.53, 95% CI: 0.33-0.84, p = 0.008) as well as CV readmissions (RR: 0.77, 95% CI: 0.60-0.98, p = 0.03) in patients with "at least 1 readmission." Moreover, compared with furosemide, torsemide caused a 14% reduction in all-cause mortality (RR: 0.86 [0.53-1.39], p = 0.54). Compared with furosemide, torsemide significantly reduces HF and CV-related hospital readmissions in systolic HF. Furthermore, torsemide is associated with a trend in reducing all-cause mortality. © 2012 Future Medicine Ltd. Source

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