Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study.

BACKGROUND: Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic profiles of these drugs in DM patients remains poorly explored and represented the aim of this study. METHODS: In this prospective, randomized, double-blind, double-dummy, crossover pharmacodynamic study, aspirin-treated DM patients (n=50) with coronary artery disease were randomly assigned to receive prasugrel (60 mg loading dose [LD]/10 mg maintenance dose once daily) or ticagrelor (180 mg LD/90 mg maintenance dose twice daily) for 1 week. Pharmacodynamic assessments were conducted using 4 different assays, including VerifyNow P2Y12, vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate, which allowed us to explore ADP- and non-ADP-induced (arachidonic acid-, collagen-, thrombin receptor-activating, peptide-induced) platelet signaling pathways. The acute (baseline, 30 minutes, and 2 hours post-LD) and maintenance (1 week) effects of therapy were assessed. The primary end point of the study was the comparison of P2Y12 reaction units determined by VerifyNow P2Y12 at 1 week between prasugrel and ticagrelor. RESULTS: ADP- and non-ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and maintenance dose. P2Y12 reaction units defined by VerifyNow were similar between prasugrel and ticagrelor at 30 minutes and 2 hours post-LD. At 1 week, P2Y12 reaction units were significantly lower with ticagrelor than with prasugrel (52 [32-72] versus 83 [63-103]; least-square means difference: -31; 95% confidence interval, -57 to -4; P=0.022; primary end point). Pharmacodynamic assessments measured by vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1 week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points. CONCLUSIONS: In DM patients with coronary artery disease, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity in comparison with prasugrel in the acute and chronic phases of treatment, whereas the inhibition of measures of non-ADP-induced platelet reactivity was not significantly different between the 2 agents. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01852214.

Frequency of Takotsubo Cardiomyopathy in Adult Patients Receiving Chemotherapy (from a 5-Year Nationwide Inpatient Study).

Takotsubo cardiomyopathy (TC) develops in patients who are under significant emotional, psychosocial, or sudden biochemical stress. However, the added burden of TC on the patients receiving chemotherapy has never been studied. We aimed to describe the additional clinical and economic burden, along with the potential predictors of TC and related in-hospital mortality in patients receiving chemotherapy using the largest inpatient cohort. We identified chemotherapy-related adult hospitalizations using the National Inpatient Sample databases (2010 to 2014). Primary end points were the incidence of TC and the odds of in-hospital mortality. Secondary end points were gender-based incidence differences, length of stay (LOS), hospital charges, and discharge disposition. We identified 1,067,977 chemotherapy-related hospitalizations, of which, 562 hospitalizations revealed TC incidence. Other co-morbidities were also significantly higher in the TC cohort. In unmatched analyses, the LOS (median 17 days vs 5 days) and total hospital charges (median $162,825 vs $46,335) were significantly higher in the TC group. A propensity-matched analysis confirmed the increased healthcare burden. Multivariate analysis revealed over 2-times higher odds (odds ratio [OR] 2.17) of in-hospital mortality in the TC group. Female gender (OR 2.48), and nonelective (OR 2.26), and nonfederal government hospital (OR 2.68) admissions had more than twice the odds of developing TC. An advanced age, Asian race, urban-teaching hospital, and complications such as septicemia, fluid-electrolyte disorders, cardiogenic shock, and respiratory failure independently raised mortality odds in the TC group. In conclusion, we observed an overall increasing nationwide trend in TC incidence in patients receiving chemotherapy, which adds to significantly increased in-hospital mortality, LOS, and healthcare charges.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and Its Inhibitors: a Review of Physiology, Biology, and Clinical Data.

OPINION STATEMENT: Atherosclerotic cardiovascular disease (ASCVD) remains the number one killer in the western world. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and ezetimibe has been shown to reduce the risk of cardiovascular events. Now, proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mabs) are available for high-risk individuals with ASCVD or familial hypercholesterolemia on maximally tolerated statin therapy but requiring greater LDL-C reduction. PCSK9 mab outcome trial results from the Further Cardiovascular Outcomes Research with PCSK9 Inhibitions in Subjects with Elevated Risk (FOURIER) study, which was presented at the American College of Cardiology in March 2017, which demonstrated a decrease of 15% in primary and 20% secondary end points over a 2-year period [1••]. These results firmly demonstrated additional benefit beyond maximally tolerated statin therapy in high-risk individuals. Thus, management of LDL-C will soon become more complex, as a new class of medication is added to our standard armamentarium. This review explores the discovery of PCSK9, its biology and physiology, and the development of the PCSK9 mabs.

Crushed Prasugrel Tablets in Patients With STEMI Undergoing Primary Percutaneous Coronary Intervention: The CRUSH Study.

BACKGROUND: Platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), which may be attributed to impaired absorption affecting drug pharmacokinetics (PK) and pharmacodynamics (PD). Crushing tablets has been suggested to lead to more favorable PK/PD profiles. To date, no studies have investigated the PK/PD effects of crushing prasugrel. OBJECTIVES: This study sought to determine whether crushing prasugrel is associated with more favorable drug bioavailability and platelet inhibitory effects compared with whole tablets in STEMI patients undergoing PPCI. METHODS: Our prospective, randomized, open-label study assessed STEMI patients undergoing PPCI (n = 52) who were treated with a prasugrel 60-mg loading dose (LD) either as whole or crushed tablets. PK/PD analyses were performed at 7 time points. PD effects were measured as P2Y12 reaction units and platelet reactivity index, and PK by plasma levels of prasugrel's active metabolite. RESULTS: Compared with whole tablets, crushed prasugrel led to reduced P2Y12 reaction units by 30 min post-LD, which persisted at 1, 2 (164 vs. 95; least square mean difference = 68; 95% confidence interval: 10 to 126; primary endpoint), and 4 h post-LD. Significant differences were no longer present at 6 h post-LD. Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with crushed prasugrel. PK analyses showed a >3-fold faster absorption with crushed compared with whole prasugrel. CONCLUSIONS: In STEMI patients undergoing PPCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. (Pharmacological Effects of Crushing Prasugrel in STEMI Patients; NCT02212028).

Pharmacodynamic Effects of Switching From Prasugrel to Ticagrelor: Results of the Prospective, Randomized SWAP-3 Study.

OBJECTIVES: This study sought to assess the pharmacodynamic (PD) effects of switching to ticagrelor patients who were treated with prasugrel after undergoing percutaneous coronary intervention in the setting of an acute coronary syndrome. BACKGROUND: In clinical practice, there is a frequent need to switch between P2Y12 receptor inhibitors. However, concerns on drug interactions have emerged when switching therapies. To date, the PD effects of switching from prasugrel to ticagrelor have yet to be investigated. METHODS: This was a prospective, randomized, open-label, 3-arm, parallel-design study conducted in patients (n = 82) on maintenance dual antiplatelet therapy with aspirin (81 mg QD) and prasugrel (10 mg QD). Patients were randomized to continue prasugrel 10 mg QD or switch to ticagrelor 90 mg bid, with or without a 180 mg loading dose (LD), for 1 week. PD assessments included P2Y12 reaction units (PRU) by VerifyNow, platelet reactivity index by vasodilator-stimulated phosphoprotein (VASP), and platelet aggregation by light transmittance aggregometry (LTA) at a total of 6 time points: baseline, 2 h, 4 h, 24 h, 48 h, and 1 week after randomization. RESULTS: After switching to ticagrelor, PRU levels decreased as early as 2 h after drug administration. Mean PRU levels remained low during the study time course, without evidence of drug interactions. The primary endpoint of noninferiority of ticagrelor (2 arms combined) versus prasugrel measured by PRU at 1 week was met (least squares mean difference: -18; 95% confidence interval: -41 to 5). There was no increase in rates of high on-treatment platelet reactivity (PRU >208), which were overall very low throughout the study time course. Similar levels of platelet reactivity were observed irrespective of the use of a ticagrelor LD. Parallel findings were observed with VASP and LTA. CONCLUSIONS: Switching from prasugrel to ticagrelor leads to transiently higher levels of platelet inhibition, irrespective of the use of a LD, without evidence of drug interactions. (Pharmacodynamic Evaluation of Switching From Prasugrel to Ticagrelor [SWAP3]; NCT02016170).