30 research outputs found
1084-176 Efficacy of ezetimibe coadministered with simvastatin versus atorvastatin in patients with hypercholesterolemia
Acute Decline in Renal Function, Inflammation, and Cardiovascular Risk after an Acute Coronary Syndrome
Background and objectives: Chronic kidney disease is associated with a higher risk of cardiovascular outcomes. The prognostic significance of worsening renal function has also been shown in various cohorts of cardiac disease; however, the predictors of worsening renal function and the contribution of inflammation remains to be established. Design, setting, participants, & measurements: Worsening renal function was defined as a 25% or more decrease in estimated GFR (eGFR) over a 1-mo period in patients after a non-ST or ST elevation acute coronary syndromes participating in the Aggrastat-to-Zocor Trial; this occurred in 5% of the 3795 participants. Results: A baseline C-reactive protein (CRP) in the fourth quartile was a significant predictor of developing worsening renal function (odds ratio, 2.48; 95% confidence interval, 1.49, 4.14). After adjusting for baseline CRP and eGFR, worsening renal function remained a strong multivariate predictor for the combined cardiovascular composite of CV death, recurrent myocardial infarction (MI), heart failure or stroke (hazard ratio, 1.6; 95% confidence interval, 1.1, 2.3). Conclusions: Patients with an early decline in renal function after an acute coronary syndrome are at a significant increased risk for recurrent cardiovascular events. CRP is an independent predictor for subsequent decline in renal function and reinforces the idea that inflammation may be related to the pathophysiology of progressive renal disease
Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome The IMPROVE-IT Trial
AbstractBackgroundIntensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin.ObjectivesThis analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy.MethodsAll PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization â„30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis.ResultsAmong 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005).ConclusionsLipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878
Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial
Background CSL112 is a new formulation of human apolipoprotein AâI (apoAâI) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, doubleâblind, multicenter, doseâranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease. Methods and Results Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2âhour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations \u3e3Ă upper limits of normal and study drugârelated adverse events. Pharmacokinetic/pharmacodynamic assessments included apoAâI plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7â, 3.4â, and 6.8âg CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (\u3e3Ă upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7â, 3.4â, and 6.8âg groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusionâsite bruising. CSL112 resulted in rapid (Tmaxâ2 hours) and doseâdependent increases in apoAâI (145% increase in the 6.8âg group) and total cholesterol efflux (up to 3.1âfold higher than placebo) (P\u3c0.001). Conclusions CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoAâI levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420
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Competing Risks of Cardiovascular Versus Noncardiovascular Death During LongâTerm FollowâUp After Acute Coronary Syndromes
Background: Understanding the relative risk of cardiovascular versus noncardiovascular death is important for designing clinical trials. These risks may differ depending on patient age, sex, and type of acute coronary syndrome (ACS). Methods and Results: IMPROVEâIT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized controlled trial of simvastatin plus either ezetimibe or placebo following stabilized ACS. Cause of death was adjudicated by an independent committee. We compared the cumulative incidence of cardiovascular and noncardiovascular death for patients with unstable angina/nonâSTâsegment elevation myocardial infarction (UA/NSTEMI) and STâsegment elevation myocardial infarction (STEMI), in those <65 and â„65 years old, and males and females, over 7 years of followâup. Of 18 131 patients, the presenting event was STEMI for 5190 (29%) and UA/NSTEMI for 12 941 (71%); 10 173 (56%) patients were <65 years old and 7971 (44%) were â„65 years old at presentation. UA/NSTEMI patients were older than STEMI patients, with more cardiovascular and noncardiovascular risk factors. In STEMI patients, the cumulative incidence of cardiovascular death was higher for âŒ4 years following the index event, after which noncardiovascular death predominated. In UA/NSTEMI patients, the cumulative incidence of cardiovascular death remained higher than noncardiovascular death over the full followâup period. Patients â„65 years old and <65 years old had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of followâup. Female patients had a higher incidence of cardiovascular death than noncardiovascular death for âŒ6 years following the index event; male patients had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of followâup. Conclusions: Among postâACS patients enrolled in a longâterm clinical trial, the relative incidence of cardiovascular and noncardiovascular death differed based on type of ACS presentation and sex, but not age. These findings further delineate longâterm prognosis after ACS and should inform the design of future cardiovascular outcomes trials
Cardiovascular Events and LongâTerm Risk of Sudden Death Among Stabilized Patients After Acute Coronary Syndrome: Insights From IMPROVEâIT
Background Unlike patients with low ejection fraction after an acute coronary syndrome (ACS), little is known about the longâterm incidence and influence of cardiovascular events before sudden death among stabilized patients after ACS. Methods and Results A total of 18 144 patients stabilized within 10 days after ACS in IMPROVEâIT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) were studied. Cumulative incidence rates (IRs) and IRs per 100 patientâyears of sudden death were calculated. Using Cox proportional hazards, the association of â„1 additional postrandomization cardiovascular events (myocardial infarction, stroke, and hospitalization for unstable angina or heart failure) with sudden death was examined. Early (â€1 year after ACS) and late sudden deaths (>1 year) were compared. Of 2446 total deaths, 402 (16%) were sudden. The median time to sudden death was 2.7 years, with 109 early and 293 late sudden deaths. The cumulative IR was 2.47% (95% CI, 2.23%â2.73%) at 7 years of followâup. The risk of sudden death following a postrandomization cardiovascular event (150/402 [37%] sudden deaths; median 1.4 years) was greater (IR/100 patientâyears, 1.45 [95% CI, 1.23â1.69]) than the risk with no postrandomization cardiovascular event (IR/100 patientâyears, 0.27 [95% CI, 0.24â0.30]). Postrandomization myocardial infarction (hazard ratio [HR], 3.64 [95% CI, 2.85â4.66]) and heart failure (HR, 4.55 [95% CI, 3.33â6.22]) significantly increased future risk of sudden death. Conclusions Patients stabilized within 10 days of an ACS remain at longâterm risk of sudden death with the greatest risk in those with an additional cardiovascular event. These results refine the longâterm risk and risk effectors of sudden death, which may help clinicians identify opportunities to improve care. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878
Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVEâIT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)
Background: IMPROVEâIT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex. Methods and Results: In IMPROVEâIT, patients with acute coronary syndrome and lowâdensity lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization â„30 days, and stroke. Among 18 144 patients in IMPROVEâIT, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced lowâdensity lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79â0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90â1.01; P=0.26 for interaction). When the total number of primary events was considered, women had an 18% reduction with the addition of ezetimibe (relative risk, 95% confidence interval, 0.81; 0.71â0.94) and men had a 6% reduction (relative risk, 0.94; 95% confidence interval, 0.87â1.02; P=0.08 for interaction). The addition of ezetimibe did not increase the rates of safety events in either women or men. Conclusions: IMPROVEâIT demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipidâlowering therapy to optimize cardiovascular outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878