Abstract Background The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In ...Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied. Objectives In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid. Methods A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units PRU), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed. Results Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose. Conclusions Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54.
Abstract Background The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in ...patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. Objectives The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets. Methods Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into “low-dose” (≤100 mg) and “high-dose” (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists. Results Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group. Conclusions Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial COGENT; NCT00557921 )
Early revascularization is the mainstay of treatment for cardiogenic shock (CS) complicating acute myocardial infarction. However, data on the contemporary trends in management and outcomes of CS ...complicating non–ST-elevation myocardial infarction (NSTEMI) are limited. We used the 2006 to 2012 Nationwide Inpatient Sample databases to identify patients aged ≥18 years with NSTEMI with or without CS. Temporal trends and differences in coronary angiography, revascularization, and outcomes were analyzed. Of 2,191,772 patients with NSTEMI, 53,800 (2.5%) had a diagnosis of CS. From 2006 to 2012, coronary angiography rates increased from 53.6% to 60.4% in patients with NSTEMI with CS (ptrend <0.001). Among patients who underwent coronary angiography, revascularization rates were significantly higher in patients with CS versus without CS (72.5% vs 62.6%, p <0.001). Patients with NSTEMI with CS had significantly higher risk-adjusted in-hospital mortality (odds ratio 10.09, 95% confidence interval 9.88 to 10.32) as compared to those without CS. In patients with CS, an invasive strategy was associated with lower risk-adjusted in-hospital mortality (odds ratio 0.43, 95% confidence interval 0.42 to 0.45). Risk-adjusted in-hospital mortality, length of stay, and total hospital costs decreased over the study period in patients with and without CS (ptrend <0.001). In conclusion, we observed an increasing trend in coronary angiography and decreasing trend in in-hospital mortality, length of stay, and total hospital costs in patients with NSTEMI with and without CS. Despite these positive trends, overall coronary angiography and revascularization rates remain less than optimal and in-hospital mortality unacceptably high in patients with NSTEMI and CS.
Background 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. Study Design 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. Conclusions 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.
Patients receiving dialysis are at high risk for sudden cardiac death. Although clinical trials have shown that implantable cardioverter-defibrillators (ICDs) are effective in improving survival in a ...variety of populations, dialysis patients have been routinely excluded from these analyses. The purpose of this meta-analysis was to synthesize the available evidence regarding the effectiveness of ICD therapy in patients receiving dialysis. Medline, EMBASE, Web of Science, and Google Scholar were searched for pertinent studies published from 1999 to 2008. In addition, hand searches of the relevant annual scientific sessions and major scientific meetings in North America and Europe from 2000 to 2008 were performed. All clinical reports describing outcomes of ICD therapy in relation to renal function were eligible. Four investigators independently extracted the data in a standardized manner. Seven studies were identified, with a total of 2,516 patients and 89 patients receiving dialysis. Despite having ICDs, patients receiving dialysis had a 2.7-fold higher mortality compared with those not receiving dialysis. The results were similar in fixed- and random-effects models. Comparing patients receiving dialysis and those with chronic kidney disease but not receiving dialysis, there was no significant difference in mortality (risk ratio 1.62, 95% confidence interval 0.84 to 3.14). No evidence of publication bias was found. In conclusion, this meta-analysis suggests that even in those with ICDs, there is still a 2.7-fold increased mortality risk in patients who receive dialysis compared with those who do not. Beta blockers may be less cardioprotective in patients with ICDs who are on dialysis.
Abstract Background The effect of saxagliptin on cardiovascular outcomes according to different hemoglobin A1c (HbA1c) levels has not been described. Thus, we analyzed the SAVOR-TIMI 53 trial to ...compare the cardiovascular effects of saxagliptin vs placebo according to baseline HbA1c. Methods A total of 16,492 patients with type 2 diabetes (HbA1c 6.5%-12.0% in the 6 months before randomization) and either a history of established cardiovascular disease or multiple risk factors for atherosclerosis were randomized to saxagliptin or placebo in addition to usual care. Patients were followed for a median of 2.1 years. The primary endpoint was cardiovascular death, myocardial infarction, or ischemic stroke. Results Patients were stratified by HbA1c at randomization into the following prespecified groups: <7%, 7%-<8%, 8%-<9%, and ≥9%. Baseline HbA1c ≥7% was associated with increased risk of cardiovascular death, myocardial infarction, or ischemic stroke (adjusted hazard ratio HRadj 1.35; 95% confidence interval CI, 1.17-1.58) but not hospitalization for heart failure (HRadj 1.09; 95% CI, 0.88-1.36). Saxagliptin neither increased nor decreased the risk of cardiovascular death, myocardial infarction, or ischemic stroke in patients with HbA1c <7% (HR 1.01; 95% CI, 0.78-1.31), 7%-<8% (HR 0.98; 95% CI, 0.80-1.20), 8%-<9% (HR 1.09; 95% CI, 0.85-1.39), ≥9% (HR 0.95; 95% CI, 0.77-1.18) ( P -interaction = .89). Conclusions Baseline HbA1c is associated with increased risk of macrovascular events but not hospitalization for heart failure. There was no heterogeneity in the effect of saxagliptin on cardiovascular events by baseline HbA1c, with cardiovascular death, myocardial infarction, or ischemic stroke neither increased nor decreased across the spectrum of baseline HbA1c values.
Objectives The purpose of this study is to develop a method for risk-standardizing hospital survival after cardiac arrest. Background A foundation with which hospitals can improve quality is to be ...able to benchmark their risk-adjusted performance against other hospitals, something that cannot currently be done for survival after in-hospital cardiac arrest. Methods Within the Get With The Guidelines (GWTG)-Resuscitation registry, we identified 48,841 patients admitted between 2007 and 2010 with an in-hospital cardiac arrest. Using hierarchical logistic regression, we derived and validated a model for survival to hospital discharge and calculated risk-standardized survival rates (RSSRs) for 272 hospitals with at least 10 cardiac arrest cases. Results The survival rate was 21.0% and 21.2% for the derivation and validation cohorts, respectively. The model had good discrimination (C-statistic 0.74) and excellent calibration. Eighteen variables were associated with survival to discharge, and a parsimonious model contained 9 variables with minimal change in model discrimination. Before risk adjustment, the median hospital survival rate was 20% (interquartile range: 14% to 26%), with a wide range (0% to 85%). After adjustment, the distribution of RSSRs was substantially narrower: median of 21% (interquartile range: 19% to 23%; range 11% to 35%). More than half (143 52.6%) of hospitals had at least a 10% positive or negative absolute change in percentile rank after risk standardization, and 50 (23.2%) had a ≥20% absolute change in percentile rank. Conclusions We have derived and validated a model to risk-standardize hospital rates of survival for in-hospital cardiac arrest. Use of this model can support efforts to compare hospitals in resuscitation outcomes as a foundation for quality assessment and improvement.
Background Studies on outcomes among patients with heart failure (HF) with preserved left ventricular ejection fraction (HF p EF), borderline left ventricular ejection fraction (HF b EF), and reduced ...left ventricular ejection fraction (HF r EF) remain limited. We sought to characterize mortality and readmission in patients with HF in the contemporary era. Methods Get With The Guidelines–HF was linked to Medicare data for longitudinal follow-up. Patients were grouped into HF p EF (left ventricular ejection fraction EF ≥50%), HF b EF (40% ≤ EF < 50%), and HF r EF (EF <40%). Multivariable models were constructed to examine the relationship between EF and outcomes at 30 days and 1 year and to study trends over time. Results A total of 40,239 patients from 220 hospitals between 2005 and 2011 were included in the study: 18,897 (47%) had HF p EF, 5,626 (14%) had HF b EF, and 15,716 (39%) had HF r EF. In crude survival analysis, patients with HF r EF had slightly increased mortality compared with HF b EF and HF p EF. After risk adjustment, mortality at 1 year was not significantly different for HF r EF, HF b EF, and HF p EF (HF r EF vs HF p EF, hazard ratio HR 1.040 95% CI 0.998-1.084, and HF b EF vs HF p EF, HR 0.967 95% CI 0.917-1.020). Patients with HF p EF had increased risk of all-cause readmission compared with HF r EF. Conversely, risk of cardiovascular and HF readmissions were higher in HF r EF and HF b EF compared with HF p EF. Conclusions Among patients hospitalized with HF, patients with HF p EF and HF b EF had slightly lower mortality and higher all-cause readmission risk than patients with HF r EF, although the mortality differences did not persist after risk adjustment. Irrespective of EF, these patients experience substantial mortality and readmission highlighting the need for new therapeutic strategies.
Objectives Saxagliptin, a dipeptidyl peptidase 4 inhibitor, improves glycemic control in patients with type 2 diabetes mellitus (T2DM) by increasing endogenous active, intact glucagon-like peptide 1 ...and glucose-dependent insulinotropic polypeptide in response to food, which augments insulin secretion and decreases glucagon release. Research Design and Methods SAVOR-TIMI 53 is a phase 4, randomized, double-blind, placebo-controlled trial conducted in 25 countries that is designed to evaluate the safety and efficacy of saxagliptin during long-term treatment of approximately 16,500 patients with T2DM. Eligible patients who are either treatment naive or on any background antidiabetic treatment (except incretin therapy) with history of established cardiovascular (CV) disease or multiple risk factors are randomized 1:1 to saxagliptin 5 mg QD (2.5 mg in subjects with moderate/severe renal impairment) or matching placebo, stratified by qualifying disease state. The primary end point is the composite of CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke. The trial will continue until approximately 1,040 primary end points accrue, providing 85% power to identify a 17% relative reduction of the primary end point with saxagliptin versus placebo and 98% power to test for noninferiority of saxagliptin versus placebo (reject the upper limit of 95% CI for a hazard ratio <1.3 at a 1-sided α of .025). Conclusion SAVOR-TIMI 53 is testing the hypothesis that treatment with saxagliptin is safe and reduces CV events in high-risk patients with T2DM.
Background Prior studies have suggested an association between higher heart rate and higher mortality, particularly in chronic heart failure (HF). Whether this relationship holds true in patients ...hospitalized with HF and differs between patients in sinus rhythm (SR) and atrial fibrillation (AF) has not been well studied. Methods We examined 145,221 admissions for HF from 295 hospitals enrolled in Get With The Guidelines-Heart Failure from January 2005 through September 2011. The associations of admission heart rate with in-hospital outcomes were evaluated overall and by heart rhythm. Results Patients presenting at higher heart rate tended to be younger and have less comorbidities. In-hospital mortality had a J-shaped relationship with heart rate, with the lowest mortality rate associated with heart rates between 70 and 75. However, the relationship differed between patients presenting in SR and AF: at heart rates above 100, the mortality curve for AF plateaued, whereas that for SR continued to rise. Higher heart rate was independently associated with higher mortality (SR adjusted OR 1.21, 95% CI 1.15-1.28 per 10 beat per minute increase in heart rate between 70-105; AF adjusted OR 1.20, 95% CI 1.14-1.27). Findings were similar when stratifying patients by ischemic etiology, diabetes, ejection fraction, blood pressure, and β-blocker use. Conclusions Higher admission heart rate is independently associated with worse outcomes in patients admitted for HF, including those in SR and AF. Whether early heart rate reduction improves outcomes in patients hospitalized with HF is worthy of investigation.
PDF
