[Show abstract][Hide abstract] ABSTRACT: Clopidogrel and prasugrel are antiplatelet therapies commonly used to treat patients with cardiovascular disease. They are both pro-drugs requiring biotransformation into active metabolites. It has been proposed that a genetic variant Q192R (rs662 A>G) in PON1 significantly alters the biotransformation of clopidogrel and affects clinical outcomes; however, this assertion has limited support. The relationship between this variant and clinical outcomes with prasugrel has not been studied. We genotyped PON1 Q192R in 275 healthy subjects treated with clopidogrel or prasugrel and 2922 patients with an ACS undergoing PCI randomized to treatment with clopidogrel or prasugrel in the TRITON-TIMI 38 trial. A meta-analysis was performed including 13 studies and 16,760 clopidogrel-treated patients. Among clopidogrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.62) or change in platelet aggregation (P = 0.51). Consistent with these results, in clopidogrel-treated patients in TRITON-TIMI 38, there was no association between Q192R and the rates of CV death, myocardial infarction, or stroke (RR 11.2 %, QR 8.6 %, and QQ 9.3 %; P = 0.66) or stent thrombosis (RR 2.4 %, QR 0.7 %, and QQ 1.6 %, P = 0.30), with patients with the putative at-risk Q variant having numerically lower event rates. Likewise, among prasugrel-treated subjects, there were no associations between Q192R and active drug metabolite levels (P = 0.88), change in platelet aggregation (P = 0.97), or clinical outcomes (P = 0.72). In a meta-analysis, the Q variant was not significantly associated with MACE (QQ vs. RR 1.22, 95 % CI 0.84-1.76) or stent thrombosis (QQ vs. RR OR 1.36, 95 % CI 0.77-2.38). Furthermore, when restricted to the validation studies, the OR (95 % CI) for MACE and stent thrombosis were 0.99 (0.77-1.27) and 1.23 (0.74-2.03), respectively. In the present study, the Q192R genetic variant in PON1 was not associated with the pharmacologic or clinical response to clopidogrel, nor was it associated with the response to prasugrel. The meta-analysis reinforced a lack of a significant association between Q192R and cardiovascular outcomes in clopidogrel-treated patients.
Journal of Thrombosis and Thrombolysis 11/2015; DOI:10.1007/s11239-015-1264-9 · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non-vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking.
Methods and results:
We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarin-controlled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01).
Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin.
American heart journal 09/2015; 170(4):669-74. DOI:10.1016/j.ahj.2015.06.020 · 4.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -Vorapaxar antagonizes protease-activated receptor (PAR)-1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a prior myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with vorapaxar was modified by concurrent thienopyridine use.
-TRA 2°P-TIMI 50 was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26,449 patients with prior atherothrombosis. This pre-specified analysis included 16,897 patients who qualified with a MI in the preceding 2 weeks to 12 months and was restricted to patients without a history of stroke or TIA given its contraindication in that population. Randomization was stratified on the basis of planned thienopyridine use. Thienopyridine was planned at randomization in 12,410 (73%). Vorapaxar significantly reduced the composite of cardiovascular death, MI and stroke when compared to placebo regardless of planned thienopyridine therapy (planned thienopyridine HR 0.80, 0.70-0.91, p<0.001; no planned thienopyridine HR 0.75, 0.60-0.94, p=0.011; p-interaction=0.67). Findings were similar when patients were stratified by actual thienopyridine use at baseline (p-interaction=0.82) and through 18 months (p-interaction=0.44). GUSTO moderate or severe bleeding risk was increased with vorapaxar and was not significantly altered by planned thienopyridine (planned HR 1.50, 1.18-1.89, p<0.001; no planned HR 1.90, 1.17-3.07, p=0.009; p-interaction=0.37) or actual thienopyridine use (p-interaction=0.24).
-Vorapaxar reduced cardiovascular death, MI, or stroke in stable patients with a history of prior MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use. Clinical Trial Registration Information-http://www.clinicaltrials.gov. Identifier: NCT00526474.
[Show abstract][Hide abstract] ABSTRACT: Statins lower low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP); addition of ezetimibe to statins further reduces LDL-C and hs-CRP. An analysis of the relationship between achieved LDL-C and hs-CRP targets and outcomes for simvastatin and ezetimibe/simvastatin was prespecified in Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT).
The IMPROVE-IT trial randomly assigned 18 144 patients stabilized after acute coronary syndrome to simvastatin or ezetimibe/simvastatin. LDL-C and hs-CRP were measured at baseline and 1 month after randomization. Outcomes were assessed in those achieving one or both of the prespecified targets of LDL-C<70 mg/dL and hs-CRP<2 mg/L versus achieving neither target, adjusting for differences in baseline characteristics. An exploratory analysis examined targets of LDL-C<50 mg/dL and hs-CRP<1 mg/L. Patients meeting both targets at baseline, with no 1-month values, or with end points before 1 month were excluded. Of 15 179 patients, 39% achieved the dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) targets at 1 month, 14% met neither target, 14% met only the hs-CRP target, and 33% met only the LDL-C target. Those achieving dual targets had lower primary end point rates than those meeting neither target (cardiovascular death, major coronary event, or stroke; 38.9% versus 28.0%; adjusted hazard ratio, 0.73; 0.66-0.81; P<0.001). More patients treated with ezetimibe/simvastatin met dual targets than those treated with simvastatin alone (50% versus 29%, P<0.001). The association of dual-target attainment with improved outcomes was similar irrespective of treatment assignment (P-interaction=0.65). Similar findings were observed using the exploratory targets.
Significantly more patients treated with ezetimibe/simvastatin met prespecified and exploratory dual LDL-C and hs-CRP targets than patients treated with simvastatin alone. Reaching both LDL-C and hs-CRP targets was associated with improved outcomes after multivariable adjustment. Clinical Trial Registration-URL: http://www.clinicaltrials.gov; Unique identifier: NCT00202878.
[Show abstract][Hide abstract] ABSTRACT: Background:
The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established. We investigated the efficacy and safety of ticagrelor, a P2Y12 receptor antagonist with established efficacy after an acute coronary syndrome, in this context.
We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding.
The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively.
In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.).
New England Journal of Medicine 03/2015; 372(19). DOI:10.1056/NEJMoa1500857 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events.
The Lancet 03/2015; 385(9984). DOI:10.1016/S0140-6736(14)61943-7 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -Vorapaxar reduces cardiovascular death (CVD), myocardial infarction (MI), or stroke in patients with prior MI while increasing bleeding. Patients with diabetes mellitus (DM) are at high risk of recurrent thrombotic events despite standard therapy and may derive particular benefit from antithrombotic therapies. TRA 2°P-TIMI 50 was a randomized, double-blind, placebo-controlled trial of vorapaxar in patients with stable atherosclerosis.
-We examined the efficacy of vorapaxar in patients with and without DM who qualified for the trial with a prior MI. Because vorapaxar is contraindicated in patients with a history of stroke or transient ischemic attack, the analysis (n=16,896) excluded such patients. The primary endpoint of CVD, MI, or stroke occurred more frequently in patients with DM than in patients without DM (Rates in placebo-group: 14.3% vs. 7.6%, adjusted-HR 1.47, p<0.001). In patients with DM (n=3,623), vorapaxar significantly reduced the primary endpoint (11.4% vs. 14.3%, HR 0.73, 95% CI 0.60-0.89; p=0.002) with a number needed to treat to avoid 1 major CV event of 29. The incidence of GUSTO moderate/severe bleeding was increased with vorapaxar in patients with DM (4.4% vs. 2.6%, HR 1.60, 95% CI 1.07-2.40). However, net clinical outcome integrating these 2 endpoints (efficacy and safety) was improved with vorapaxar (HR 0.79; 95% CI 0.67-0.93).
-In patients with prior MI and DM, the addition of vorapaxar to standard therapy significantly reduced the risk of major vascular events with greater potential for absolute benefit in this group at high risk of recurrent ischemic events. Clinical Trial Registration Information-www.clinicaltrials.gov. Identifier: NCT00526474.
[Show abstract][Hide abstract] ABSTRACT: Aims:
Rivaroxaban reduces cardiovascular death, myocardial infarction (MI), or stroke in patients following acute coronary syndrome (ACS). We aimed to characterize the specific effects of rivaroxaban on the size and type of MI.
The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) study randomized 15,526 patients with a recent ACS to rivaroxaban 2.5 mg BID, rivaroxaban 5 mg BID, or placebo. An independent clinical events committee adjudicated each MI that occurred during the study and further classified them based on type. Data are presented as two-year Kaplan-Meier event rates and hazard ratios (HRs) and 95% confidence intervals (CI).
In total, 665 patients experienced a post-randomization MI. The majority (n=535, 80.5%) were spontaneous (Type 1) events. Rivaroxaban reduced spontaneous MI when compared with placebo (4.4% vs 5.7%, HR 0.80, 95% 0.67-0.95, p=0.01), and there were directionally consistent reductions with both the 2.5 mg BID (4.7% vs 5.7%, HR 0.84, 95% 0.68-1.02, p=0.08) and 5 mg BID doses (4.1% vs 5.7%, HR 0.77, 95% 0.62-0.94, p=0.01) as compared with placebo. Rivaroxaban reduced MI with large elevations in troponin or creatine kinase-MB (CK-MB) fraction (1.8% vs 2.4%, HR 0.73, 95% CI 0.56-0.96, p=0.03) and STEMI events (1.7% vs 2.5%, HR 0.74, 95% CI 0.56-0.99, p=0.04).
In patients stabilized and followed after ACS, the majority of MIs that occur are spontaneous and rivaroxaban significantly reduced the incidence of these events. Notably, rivaroxaban reduced MIs with extensive biomarker release and ST-segment elevation.
European Heart Journal: Acute Cardiovascular Care 10/2014; 4(5). DOI:10.1177/2048872614554109
[Show abstract][Hide abstract] ABSTRACT: To determine the effect of ranolazine, an anti-ischaemic agent with anti-arrhythmic properties, on the overall burden of atrial fibrillation (AF) in acute coronary syndromes (ACS) and determine whether ranolazine reduces the long-term incidence of clinical AF after ACS.
[Show abstract][Hide abstract] ABSTRACT: Importance
Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme.Objective
To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event.Design, Setting, and Participants
SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13 026 participants within 30 days of hospitalization with an ACS (non–ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries.Interventions
Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013.Main Outcomes and Measures
The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years.Results
During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).Conclusions and Relevance
In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events.Trial Registration
clinicaltrials.gov Identifier: NCT01000727
JAMA The Journal of the American Medical Association 08/2014; 312(10). DOI:10.1001/jama.2014.11061 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
At the end of 2 previous trials, an excess of stroke and bleeding was observed in patients with AF randomized to a new oral anticoagulant (NOAC) who transitioned to a vitamin K antagonist (VKA).
The ENGAGE AF–TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48) trial compared once-daily edoxaban to warfarin for stroke prevention in patients with AF. An end-of-trial transition plan was developed to minimize the risks of stroke due to inadequate anticoagulation and bleeding from excessive anticoagulation during this critical period.
All patients on the blinded study drug at the trial’s conclusion were included in this analysis. In pre-specified analyses, stroke, bleeding, and death that occurred through 30 days after the end-of-trial visit were stratified by randomized treatment allocation and open-label anticoagulant selected post-trial.
Of the 13,642 patients taking the blinded study drug at the end of the trial, 9,304 (68.2%) were transitioned to open-label VKA and 4,258 patients (31.2%) to an NOAC. There were 21 strokes evenly distributed across the 3 randomized treatment arms: warfarin 7 (1.90%/year), edoxaban high dose 7 (1.89%/year), edoxaban low dose 7 (1.85%/year). Major bleeding was also similar across the 3 treatment arms: warfarin 11 (2.98%/year), edoxaban high dose 10 (2.69%/year), edoxaban low dose 18 (4.76%/year). In patients transitioned to VKA, 85% of patients had at least 1 INR ≥2 by day 14 after the transition and 99% by day 30.
The ENGAGE AF–TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants. (Global Study to Assess the Safety and Effectiveness of Edoxaban [DU-176b] vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [EngageAFTIMI48]; NCT00781391)
Journal of the American College of Cardiology 08/2014; 64(6):576–584. DOI:10.1016/j.jacc.2014.05.028 · 16.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate-high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously.