Browsing by Author "White, Jennifer"

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    Benefit of Ezetimibe Added to Simvastatin in Reduced Kidney Function.
    (J Am Soc Nephrol, 2017-10) Stanifer, John W; Charytan, David M; White, Jennifer; Lokhnygina, Yuliya; Cannon, Christopher P; Roe, Matthew T; Blazing, Michael A
    Efficacy of statin-based therapies in reducing cardiovascular mortality in individuals with CKD seems to diminish as eGFR declines. The strongest evidence supporting the cardiovascular benefit of statins in individuals with CKD was shown with ezetimibe plus simvastatin versus placebo. However, whether combination therapy or statin alone resulted in cardiovascular benefit is uncertain. Therefore, we estimated GFR in 18,015 individuals from the IMPROVE-IT (ezetimibe plus simvastatin versus simvastatin alone in individuals with cardiovascular disease and creatinine clearance >30 ml/min) and examined post hoc the relationship of eGFR with end points across treatment arms. For the primary end point of cardiovascular death, major coronary event, or nonfatal stroke, the relative risk reduction of combination therapy compared with monotherapy differed by eGFR (P=0.04). The difference in treatment effect was observed at eGFR≤75 ml/min per 1.73 m2 and most apparent at levels ≤60 ml/min per 1.73 m2 Compared with individuals receiving monotherapy, individuals receiving combination therapy with a baseline eGFR of 60 ml/min per 1.73 m2 experienced a 12% risk reduction (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.82 to 0.95); those with a baseline eGFR of 45 ml/min per 1.73 m2 had a 13% risk reduction (HR, 0.87; 95% CI, 0.78 to 0.98). In stabilized individuals within 10 days of acute coronary syndrome, combination therapy seemed to be more effective than monotherapy in individuals with moderately reduced eGFR (30-60 ml/min per 1.73 m2). Further studies examining potential benefits of combination lipid-lowering therapy in individuals with CKD are needed.
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    Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial.
    (Lancet, 2017-05-06) Ohman, E Magnus; Roe, Matthew T; Steg, P Gabriel; James, Stefan K; Povsic, Thomas J; White, Jennifer; Rockhold, Frank; Plotnikov, Alexei; Mundl, Hardi; Strony, John; Sun, Xiang; Husted, Steen; Tendera, Michal; Montalescot, Gilles; Bahit, M Cecilia; Ardissino, Diego; Bueno, Héctor; Claeys, Marc J; Nicolau, Jose C; Cornel, Jan H; Goto, Shinya; Kiss, Róbert Gábor; Güray, Ümit; Park, Duk-Woo; Bode, Christoph; Welsh, Robert C; Gibson, C Michael
    BACKGROUND: Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months. METHODS: In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395. FINDINGS: Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840). INTERPRETATION: A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. FUNDING: Janssen Research & Development and Bayer AG.
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    P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes.
    (JAMA cardiology, 2019-07) Povsic, Thomas J; Ohman, E Magnus; Roe, Matthew T; White, Jennifer; Rockhold, Frank W; Montalescot, Gilles; Cornel, Jan H; Nicolau, Jose C; Steg, P Gabriel; James, Stefan; Bode, Christoph; Welsh, Robert C; Plotnikov, Alexei N; Mundl, Hardi; Gibson, C Michael
    Importance:Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown. Objective:To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial. Design, Setting, and Participants:The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019. Interventions:Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization. Main Outcomes and Measures:Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected. Results:Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated. Conclusions and Relevance:Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach. Clinical Trial Registration:ClinicalTrials.gov identifier: NCT02293395.