Marc S Sabatine

Harvard Medical School, Boston, Massachusetts, United States

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Publications (246)2509.76 Total impact

  • Matthew A Cavender, Marc S Sabatine
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    ABSTRACT: Background Bivalirudin is an alternative to heparin in patients undergoing percutaneous coronary intervention (PCI). We aimed to define the effects of a bivalirudin-based anticoagulation regimen compared with a heparin-based anticoagulation regimen on ischaemic and bleeding outcomes. Methods We searched Medline, the Cochrane Library, and relevant meeting abstracts (search done on April 9, 2014) for randomised trials that assessed bivalirudin versus heparin in patients planned for PCI. The primary efficacy endpoint was the incidence of major adverse cardiac events (MACE) up to 30 days. Secondary efficacy endpoints were death, myocardial infarction, ischaemia-driven revascularisation, and stent thrombosis. The primary safety endpoint was major bleeding up to 30 days. We calculated pooled risk ratios and 95% CIs using random-effects models. Findings We included data from 16 trials involving 33 958 patients, of whom 2422 experienced MACE and 1406 had a major bleed. There was an increase in the risk of MACE with bivalirudin-based regimens compared with heparin-based regimens (risk ratio 1·09, 95% CI 1·01–1·17; p=0·0204), which was largely driven by increases in myocardial infarction (1·12, 1·03–1·23) and seemingly also by ischaemia-driven revascularisation (1·16, 0·997–1·34) with bivalirudin compared with heparin, with no effect on mortality (0·99, 0·82–1·18). Bivalirudin increased the risk of stent thrombosis (risk ratio 1·38, 95% CI 1·09–1·74; p=0·0074), which was primarily due to an increase in acute cases in ST-segment elevation myocardial infarction (4·27, 2·28–8·00; p<0·0001). Overall, bivalirudin-based regimens lowered the risk of major bleeding (risk ratio 0·62, 95% CI 0·49–0·78; p<0·0001), but the magnitude of this effect varied greatly (p<0·0001) depending on whether glycoprotein IIb/IIIa inhibitors were used predominantly in the heparin arm only (0·53, 0·47–0·61; p<0·0001), provisionally in both arms (0·78, 0·51–1·19; p=0·25), or planned in both arms (1·07, 0·87–1·31; p=0·53). Interpretation Compared with a heparin-based regimen, a bivalirudin-based regimen increases the risk of myocardial infarction and stent thrombosis, but decreases the risk of bleeding, with the magnitude of the reduction depending on concomitant glycoprotein IIb/IIIa inhibitor use. Physicians should weigh the trade-off between ischaemic and bleeding events when choosing between different anticoagulant regimens. Funding None.
    08/2014; 384(9943):599–606.
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    ABSTRACT: The degree of antiplatelet response to clopidogrel has been associated with clinical outcomes. Studies have investigated whether adjustment of antiplatelet therapies based on a single platelet function test is beneficial.
    Journal of the American College of Cardiology 07/2014; 64(4):361-8. · 14.09 Impact Factor
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    ABSTRACT: P2Y12 receptor antagonist therapy is recommended in addition to ASA for up to 1 year after acute coronary syndrome to reduce ischemic events. In contrast, the benefit of long-term dual antiplatelet therapy beyond 1 year remains unclear. Ticagrelor is a potent, reversibly binding P2Y12 receptor-antagonist that has been shown to be superior to clopidogrel in patients with acute coronary syndromes for up to 1 year. PEGASUS-TIMI 54 is a randomized, double-blind, placebo-controlled, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor in addition to aspirin (75-150 mg) for the prevention of major adverse cardiovascular events in patients with a history of myocardial infarction and risk factors. Patients with a history of spontaneous myocardial infarction within 1 to 3 years are randomized in a 1:1:1 fashion to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or matching placebo, all with low dose ASA, until the end of the study. The primary endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. Recruitment began in October 2010 and completed in April 2013 with a sample size of over 21,000 patients. The trial is planned to continue until the latest of either 1,360 adjudicated primary end points are accrued or the last patient randomized has been followed for at least 12 months. PEGASUS-TIMI 54 is investigating whether the addition of intensive antiplatelet therapy with ticagrelor to low-dose aspirin reduces major adverse cardiovascular events in high-risk patients with a history of myocardial infarction.
    American heart journal 04/2014; 167(4):437-444.e5. · 4.65 Impact Factor
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    ABSTRACT: Prior trials with monoclonal antibodies to proprotein convertase subtilizin/kexin type 9 (PCSK9) reported robust low density lipoprotein cholesterol (LDL-C) reductions. However, the ability to detect potentially beneficial changes in other lipoproteins such as lipoprotein (a), triglycerides, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein (Apo) A1, and adverse events (AEs) was limited by sample sizes of individual trials. We report a pooled analysis from four phase 2 studies of evolocumab (AMG 145), a monoclonal antibody to PCSK9. The trials randomized 1359 patients to various doses of subcutaneous evolocumab every 2 weeks (Q2W) or 4 weeks (Q4W), placebo, or ezetimibe for 12 weeks; 1252 patients contributed to efficacy and 1314, to safety analyses. Mean percentage (95% CI) reductions in LDL-C vs. placebo ranged from 40.2% (44.6%, 35.8%) to 59.3% (63.7%, 54.8%) among the evolocumab groups (all P < 0.001). Statistically significant reductions in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides and lipoprotein (a) [Lp(a)], and increases in HDL-C were also observed. Adverse events (AEs) and serious AEs with evolocumab were reported in 56.8 and 2.0% of patients, compared with 49.2% and 1.2% with placebo. Adjudicated cardiac and cerebrovascular events were reported in 0.3 and 0% in the placebo and 0.9 and 0.3% in the evolocumab arms, respectively. In addition to LDL-C reduction, evolocumab, dosed either Q2W or Q4W, demonstrated significant and favourable changes in other atherogenic and anti-atherogenic lipoproteins, and was well tolerated over the 12-week treatment period.
    European Heart Journal 03/2014; · 14.10 Impact Factor
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    ABSTRACT: The relationships between Q waves that appear during the acute phase of ST-elevation myocardial infarction (STEMI), clinical characteristics, ST-segment resolution (STRes), and clopidogrel therapy in patients treated with fibrinolysis are not well described. We hypothesized that Q waves would be associated with less successful reperfusion and increased cardiovascular events. In the CLARITY-TIMI 28 trial, 3491 STEMI patients treated with fibrinolysis were randomized to clopidogrel or placebo. Electrocardiograms were evaluated for STRes post-fibrinolysis and the presence of pathologic Q waves during the index hospitalization in 3322 patients. Q waves were identified in 2045 patients (61.6%) prior to discharge and were associated with increased odds of congestive heart failure (CHF) (adjusted odds ratio [ORadj ]: 2.10, P = 0.002) or the composite of cardiovascular death/CHF at 30 days (ORadj : 2.08, P ≤ 0.001). Q waves were associated with lower odds of Thrombolysis in Myocardial Infarction [TIMI] flow grade 2 to 3 (ORadj : 0.78, P = 0.028), TIMI myocardial perfusion grade 3 (ORadj : 0.83, P = 0.029), and complete STRes at 90 minutes (ORadj : 0.80, P = 0.030). Patients with both a Q wave and incomplete STRes 90 minutes after fibrinolysis were at higher risk for cardiovascular death or CHF (11.1%) than patients with no Q wave and at least partial STRes (1.9%). Overall, clopidogrel tended to be equally or more effective in patients without Q waves compared to those with Q waves. Among STEMI patients treated with fibrinolysis, evaluating for Q waves prior to discharge is a simple method of assessing for less successful reperfusion and an increased risk of adverse 30-day cardiovascular outcomes. The combination of Q waves and 90-minute STRes allows additional risk refinement.
    Clinical Cardiology 01/2014; · 1.83 Impact Factor
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    ABSTRACT: Arginine-vasopressin (AVP) is an acute marker of physiologic stress. Copeptin is the C-terminal fragment of vasopressin precursor hormone that is more easily measured than AVP. Studies assessing the utility of copeptin in the diagnosis of myocardial infarction (MI) have demonstrated mixed results. The aim of this study was to test the hypothesis that copeptin improves diagnostic performance when added to troponin for detecting MI in patients presenting to the emergency department with nontraumatic chest pain. We measured copeptin, local cardiac troponin I (local cTnI), and a contemporary sensitive cardiac troponin I (sensitive cTnI) at presentation and serially in patients who presented with acute chest pain. A copeptin cutoff of 14 pmol/L was utilized. MI was diagnosed in 25.7% of patients. Noncoronary acute cardiopulmonary causes of chest pain occurred in 12.8%. Patients with MI had significantly higher copeptin levels than patients with noncardiac chest pain (P < 0.001). The area under the receiver operating characteristic curve (AUC) for copeptin was 0.60 (95% confidence interval: 0.54-0.66), significantly less than the AUC for local cTnI (0.92) or sensitive cTnI (0.96). The combination of copeptin with either the local or sensitive troponin assay (c-statistics 0.92 and 0.95, respectively) did not significantly improve the AUC as compared to either troponin assay alone. This finding persisted in the subgroup of early presenters (≤6 hours from symptom onset). Copeptin did not improve the diagnostic performance for detecting MI when used alone or in combination with a contemporary sensitive cTnI assay, though our cohort had relatively few early presenters.
    Clinical Cardiology 01/2014; · 1.83 Impact Factor
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    ABSTRACT: Observational studies have raised concerns that high-potency statins increase the risk of acute kidney injury. We therefore examined the incidence of kidney injury across 2 randomized trials of statin therapy. PROVE IT-TIMI 22 enrolled 4162 subjects after an acute coronary syndrome (ACS) and randomized them to atorvastatin 80 mg/day versus pravastatin 40 mg/day. A-to-Z enrolled 4497 subjects after ACS and randomized them to a high-potency (simvastatin 40 mg/day×1 months, then simvastatin 80 mg/day) versus a delayed moderate-potency statin strategy (placebo×4 months, then simvastatin 20 mg/day). Serum creatinine was assessed centrally at serial time points. Adverse events (AEs) relating to kidney injury were identified through database review. Across both trials, mean serum creatinine was similar between treatment arms at baseline and throughout follow-up. In A-to-Z, the incidence of a 1.5-fold or ≥0.3 mg/dL rise in serum creatinine was 11.4% for subjects randomized to a high-potency statin regimen versus 12.4% for those on a delayed moderate-potency regimen (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.76 to 1.10; P=0.33). In PROVE IT-TIMI 22, the incidence was 9.4% for subjects randomized to atorvastatin 80 mg/day and 10.6% for subjects randomized to pravastatin 40 mg/day (OR, 0.88; 95% CI, 0.71 to 1.09; P=0.25). Consistent results were observed for different kidney injury thresholds and in individuals with diabetes mellitus or with moderate renal dysfunction. The incidence of kidney injury-related adverse events (AEs) was not statistically different for patients on a high-potency versus moderate-potency statin regimen (OR, 1.06; 95% CI, 0.68 to 1.67; P=0.78). For patients enrolled in 2 large randomized trials of statin therapy after ACS, the use of a high-potency statin regimen did not increase the risk of kidney injury.
    Journal of the American Heart Association. 01/2014; 3(3):e000784.
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    ABSTRACT: Objectives This study sought to define the ability of AMG 145, a monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), to enable subjects at high risk for major adverse cardiovascular events to achieve National Cholesterol Education Program–Adult Treatment Panel III (NCEP-ATP III) parameters for low-density lipoprotein cholesterol (LDL-C) and other lipid goals. Background Many patients at high risk for adverse cardiovascular events are unable to achieve the NCEP-ATP III LDL-C goal of <70 mg/dl, even with high-potency statin therapy. Methods In 282 subjects from the LAPLACE–TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy–Thrombolysis In Myocardial Infarction 57) trial at high risk according to NCEP-ATP III criteria, we compared the proportion of subjects achieving the NCEP-ATP III recommended LDL-C goal of <70 mg/dl across treatment arms. Other outcomes included the triple goals of LDL-C <70 mg/dl, non–high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and apolipoprotein B (ApoB) <80 mg/dl. Results During the dosing interval, more than 90% of subjects in both of the top dose groups every 2 weeks and every 4 weeks attained this lipid target over the dosing interval, with similar success rates for the triple lipid goal. Conclusions PCSK9 inhibition with AMG 145 enables high-risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing cardiovascular events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications.
    Journal of the American College of Cardiology 01/2014; 63(5):430–433. · 14.09 Impact Factor
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    ABSTRACT: Objectives To assess the effect of evolocumab (AMG 145) on lipoprotein (a) (Lp(a)) from a pooled analysis of four phase 2 trials. Background Lipoprotein (a), a low-density lipoprotein (LDL) particle linked to the plasminogen-like glycoprotein apolipoprotein (a), shows a consistent and independent positive association with cardiovascular disease risk in epidemiological studies. Current therapeutic options to reduce Lp(a) are limited. Methods A pooled analysis of data from 1359 patients in 4 phase 2 trials assessed the effects of evolocumab, a fully human monoclonal antibody to PCSK9, on lipoprotein (a), the relation between Lp(a) and lowering of LDL cholesterol (LDL-C) and apolipoprotein B, and the influence of background statin therapy. Lipoprotein (a) was measured by a standardized isoform-independent method. Results Evolocumab treatment for 12 weeks resulted in significant (p<0.001) mean (95% confidence interval) dose-related reductions in Lp(a) compared to control; 29.5 (23.3 to 35.7)% and 24.5 (20.4 to 28.7)% with 140 mg and 420 mg dosed every 2 and 4 weeks, respectively with no plateau of effect. Lipoprotein (a) reductions were significantly correlated with percentage reductions in LDL-C (Spearman’s correlation coefficient 0.5134, p<0.001) and apolipoprotein B (Spearman’s correlation coefficient 0.5203, p<0. 001). Mean percentage reductions did not differ based on age or gender, but trended greater in those on statins. Conclusions Inhibition of PCSK9 with evolocumab resulted in significant dose-related reductions in Lp(a). While the mean percentage reduction was significantly greater in those with baseline Lp(a) ≤125 nmol/L, the absolute reduction was substantially larger in those >125 nmol/L.
    Journal of the American College of Cardiology 01/2014; · 14.09 Impact Factor
  • Journal of the American College of Cardiology 01/2014; 63(12):A20. · 14.09 Impact Factor
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    ABSTRACT: To determine whether increases in cardiac work lead to alterations in the plasma metabolome and whether such changes arise from the heart or peripheral organs.
    PLoS ONE 01/2014; 9(6):e99058. · 3.73 Impact Factor
  • Journal of the American College of Cardiology 01/2014; 63(9):943. · 14.09 Impact Factor
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    ABSTRACT: Objective To assess the prognostic performance of C-terminal provasopressin (copeptin), midregional-pro-adrenomedullin (MR-proADM), and midregional-pro-atrial natriuretic peptide (MR-proANP) in a large prospective cohort of patients with NSTE-ACS. Background Copeptin, MR-proADM, and MR-proANP are emerging biomarkers of hemodynamic stress that have been associated with adverse cardiovascular (CV) outcomes in heart failure (HF) and stable ischemic disease. Methods We measured copeptin, MR-proADM, and MR-proANP in 4,432 patients with non-ST-elevation ACS (NSTE-ACS) randomized to ranolazine or placebo in the MERLIN-TIMI 36 trial and followed for 1 year. Results High concentration (Q4 v. Q1-3) of each biomarker identified an increased risk of CV death or HF (copeptin 13.2% v. 5.0%, p>0.001; MR-proADM 15.8% v. 4.1%, p>0.001; MR-proANP 17.7% v. 3.5%, p>0.001), as well as CV death, HF, and MI individually (all p≤0.001). After adjustment for important covariates, each biomarker remained associated with CV death or HF at 1 year (adjusted hazard ratios: copeptin 1.71, MR-proADM 1.96, MR-proANP 2.20; all p≤0.001). These biomarkers improved prognostic discrimination and patient re-classification for CV death or HF at 1 year (all categorical NRI <10%, p>0.001), and maintained independent association with composite CV death or HF when concurrently assessed in a model with clinical indicators plus BNP, cTnI, ST2, PAPP-A, and MPO (each p≤0.01). Conclusions Copeptin, MR-proADM, and MR-proANP are complementary prognostic markers for CV death and HF in patients with NSTE-ACS, that perform as well as or better than established and other emerging biomarkers, and warrant further investigation of applications for therapeutic decision-making. Clinical trial info NCT00099788
    Journal of the American College of Cardiology 01/2014; · 14.09 Impact Factor
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    ABSTRACT: Objectives To test two hypotheses: 1) Fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of renal function, clinical factors, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from ACE inhibitor therapy. Background FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in SIHD are more sparse. Methods FGF-23 levels were measured in 3,627 SIHD patients randomized to trandolapril or placebo within the Prevention of Events With Angiotensin-Converting Enzyme (PEACE) trial and followed for a median of 5.2 years. Results After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, the top quartile FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (HR, 1.73; 95% CI, 1.09-2.74; P=0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (HR, 0.45; 95% CI, 0.28-0.72), whereas there was no clinical benefit in the remaining patients (HR, 1.07; 95% CI, 0.75-1.52; P-interaction=0.0039). This interaction was independent of and additive to stratification based on renal function. Conclusions Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in SIHD patients and identify patients who derive significant clinical benefit from ACE inhibitor therapy regardless of renal function. Clinical Trial Registration http://www.clinicaltrials.gov; Identifier: NCT00000558
    Journal of the American College of Cardiology 01/2014; · 14.09 Impact Factor
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    ABSTRACT: We sought to describe real-world patterns of care in NSTEMI patients across different risk profiles for bleeding and mortality. The NCDR ACTION Registry-GWTG in-hospital mortality and major bleeding risk scores were developed to assess patient risk and optimize treatment decisions. However, little is known about the alignment of contemporary clinical management patterns with these risk estimates. We studied 61,366 NSTEMI patients in the NCDR ACTION-Registry-GWTG from January 2007 to March 2009, stratifying them into four groups based on estimated risk of mortality and major bleeding. There were 24,709 (40.3%) patients in each of the concordant risk groups (low:low; high:high) and 5974 (9.7%) in each of the discordant risk groups (low:high; high:low). Subjects at high estimated risk for both mortality and major bleeding were least likely to receive guideline-based adjunctive pharmacotherapy or to undergo angiography within 48 hours but most likely to receive an excess dose of an antithrombotic agent. Patients at low estimated risk for mortality and bleeding received the most intensive adjunctive therapy and were most likely to undergo invasive angiography. There are significant differences in contemporary patterns of care across varying risk profiles of mortality and major bleeding. Despite practice patterns which seem to emphasize avoiding harm with reduced use of antithrombotic therapy, patients at high risk for major bleeding continue to receive excess doses of antithrombotic therapy. Additional performance improvement efforts are needed to optimize outcomes in NSTEMI patients with high risk for both bleeding and mortality.
    American heart journal 12/2013; 166(6):1043-1049.e1. · 4.65 Impact Factor
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    ABSTRACT: Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined. Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively. Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date. http://clinicaltrials.gov. Unique identifier: NCT01439880.
    Circulation 11/2013; · 15.20 Impact Factor
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    ABSTRACT: This study sought to evaluate the clinical relevance of potential clopidogrel drug-drug interactions. Some studies have demonstrated that statins and calcium channel blockers (CCBs) may attenuate the pharmacodynamic effects of clopidogrel. The TRITON-TIMI 38 trial enrolled 13,608 patients with an acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), and randomized them to clopidogrel or prasugrel. Use of a statin or CCB was left to the discretion of the treating physician. A multivariable Cox model with propensity score was employed to evaluate the association between statin or CCB use and clinical outcomes. Of the 6,795 subjects assigned to clopidogrel, 4,794 (70.6%) were on a CYP3A4-metabolized statin, and 966 (14.2%) were on a CCB at randomization. The risk of cardiovascular (CV) death, myocardial infarction (MI), or stroke was similar regardless of baseline use of statins (adjusted hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 0.85 to 1.22) or CCBs (adjusted HR: 1.16; 95% CI: 0.94 to 1.43) in clopidogrel-treated patients. Further, the combined use of a CCB and atorvastatin 80 mg daily (adjusted HR: 0.82; 95% CI: 0.37 to 1.84), or a CCB, statin, and proton pump inhibitor (adjusted HR: 1.04; 95% CI: 0.70 to 1.54) were not associated with an increased risk of CV death, MI, or stroke. The use of statins or CCBs did not modify the relative efficacy of prasugrel versus clopidogrel for the primary endpoint (p for interaction = 0.43, 0.55, respectively). In patients with ACS undergoing PCI, the use of statins or CCBs was not associated with an increased risk of CV events in clopidogrel-treated patients. Consistent results were observed when the drugs were administered alone, together, or in combination with proton pump inhibitors.
    JACC. Cardiovascular Interventions 11/2013; · 1.07 Impact Factor
  • Sameer Bansilal, Marc P Bonaca, Marc S Sabatine
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    ABSTRACT: Ticagrelor is a potent P2Y12 adenosine diphosphate receptor antagonist characterized by a rapid onset, consistent and reversible antiplatelet effect, and an acceptable safety profile compared with existing adenosine diphosphate receptor blockers. In the large Phase III trial, PLATO, ticagrelor significantly reduced the composite of cardiovascular death, myocardial infarction, or stroke as well as cardiovascular and all-cause mortality compared with clopidogrel in patients presenting with acute coronary syndromes. With its favorable impact on mortality, ticagrelor changes the landscape of anti-thrombotic therapy for patients with acute coronary syndromes.
    Expert Review of Cardiovascular Therapy 10/2013;
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    ABSTRACT: To define the ability of AMG 145, a monoclonal antibody directed against PCSK9, to enable subjects at high risk for major adverse cardiovascular events to achieve NCEP-ATP III LDL-C and other lipid parameter goals. Many patients at high risk for adverse CV events are unable to achieve NCEP-ATP III LDL-C goal of <70mg/dL, even with high potency statin therapy. In 282 subjects from the LAPLACE-TIMI 57 trial at high risk by NCEP-ATP III, we compared across treatment arms the proportion of subjects achieving NCEP-ATP III recommended LDL-C <70 mg/dL. Other outcomes included the triple goal of LDL-C <70 mg/dL, non-HDL-C <100 mg/dL, and ApoB <80 mg/dL. Each dose of AMG 145 significantly increased the proportion of the patients achieving an LDL-C of <70 mg/dL, with ≥90% of subjects in both the top doses every 2 weeks and every 4 weeks attaining this lipid target over the dosing interval, with similar success rates for the triple lipid goal. PCSK9 inhibition with AMG 145 enables high risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing CV events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications.
    Journal of the American College of Cardiology 10/2013; · 14.09 Impact Factor
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    ABSTRACT: To assess the prognostic utility of lipoprotein (a) [Lp(a)] in individuals with coronary artery disease (CAD). Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. Plasma Lp(a) was measured in 6762 subjects with CAD from three studies; data were then combined with eight previously published studies for a total of 18,979 subjects. Across the three studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (OR 1.03 per log-transformed SD, 95% CI 0.96-1.11) or by quintile (OR Q5:Q1 1.05, 95% CI, 0.83-1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR 1.40, 95% CI 1.15-1.71), but with significant between-study heterogeneity (P=0.001). When stratified on the basis of LDL cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was ≥130 mg/dl (OR 1.46, 95% CI 1.23-1.73, P<0.001), whereas this relationship was not significant for studies with an average LDL cholesterol <130 mg/dl (OR 1.20, 95 CI 0.90-1.60, P=0.21). Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.
    Journal of the American College of Cardiology 10/2013; · 14.09 Impact Factor

Publication Stats

10k Citations
2,509.76 Total Impact Points

Institutions

  • 2003–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2012–2013
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 2007–2013
    • University of Oslo
      • Division of Medicine
      Kristiania (historical), Oslo County, Norway
    • University of Cambridge
      • Department of Public Health and Primary Care
      Cambridge, ENG, United Kingdom
    • Radboud University Medical Centre (Radboudumc)
      Nymegen, Gelderland, Netherlands
  • 2002–2013
    • Partners HealthCare
      Boston, Massachusetts, United States
    • University of Texas Southwestern Medical Center
      • • Division of Cardiology
      • • Medical School
      Dallas, TX, United States
    • Brigham and Women's Hospital
      • • TIMI Study Group
      • • Department of Medicine
      • • Center for Brain Mind Medicine
      Boston, Massachusetts, United States
  • 2009–2012
    • Akershus universitetssykehus
      Kristiania (historical), Oslo County, Norway
    • Massachusetts Institute of Technology
      Cambridge, Massachusetts, United States
  • 2011
    • The University of Western Ontario
      London, Ontario, Canada
  • 2008–2011
    • Broad Institute of MIT and Harvard
      Cambridge, Massachusetts, United States
  • 1999–2011
    • Massachusetts General Hospital
      • • Division of Cardiology
      • • Cardiovascular Research Center
      • • Department of Medicine
      Boston, Massachusetts, United States
  • 2010
    • Harvard University
      • Department of Economics
      Cambridge, MA, United States
  • 2008–2010
    • Celera
      Alameda, California, United States
  • 2006–2009
    • Beth Israel Deaconess Medical Center
      • Department of Medicine
      Boston, MA, United States
  • 2005
    • Rochester General Hospital
      Rochester, New York, United States