Sharif Halim

Conflicting Results Between Randomized Trials and Observational Studies on the Impact of Proton Pump Inhibitors on Cardiovascular Events When Coadministered With Dual Antiplatelet Therapy Systematic Review

Background— Discordant results have been reported on the effects of concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) for cardiovascular outcomes. We conducted a systematic review comparing the effectiveness and safety of concomitant use of PPIs and DAPT in the postdischarge treatment of unstable angina/non–ST-segment–elevation myocardial infarction patients. Methods and Results— We searched for clinical studies in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, from 1995 to 2012. Reviewers screened and extracted data, assessed applicability and quality, and graded the strength of evidence. We performed meta-analyses of direct comparisons when outcomes and follow-up periods were comparable. Thirty-five studies were eligible. Five (4 randomized controlled trials and 1 observational) assessed the effect of omeprazole when added to DAPT; the other 30 (observational) assessed the effect of PPIs as a class when compared with no PPIs. Random-effects meta-analyses of the studies assessing PPIs as a class consistently reported higher event rates in patients receiving PPIs for various clinical outcomes at 1 year (composite ischemic end points, all-cause mortality, nonfatal MI, stroke, revascularization, and stent thrombosis). However, the results from randomized controlled trials evaluating omeprazole compared with placebo showed no difference in ischemic outcomes, despite a reduction in upper gastrointestinal bleeding with omeprazole. Conclusions— Large, well-conducted observational studies of PPIs and randomized controlled trials of omeprazole seem to provide conflicting results for the effect of PPIs on cardiovascular outcomes when coadministered with DAPT. Prospective trials that directly compare pharmacodynamic parameters and clinical events among specific PPI agents in patients with unstable angina/non–ST-segment–elevation myocardial infarction treated with DAPT are warranted.

Biomarkers in Cardiovascular Clinical Trials: Past, Present, Future

BACKGROUND Cardiovascular (CV) clinical trials are instrumental in understanding treatment effects and offer insights into the natural progression of CV disease. Biomarkers are a critical component of patient selection, end point definition, and safety monitoring, and clinical trials provide a platform for the discovery and validation of new biomarkers that may augment the understanding of disease mechanisms, risk stratification, and/or clinical decision-making. CONTENT We review the roles that biomarkers have played in CV clinical trials and roles that CV clinical trials have played and will continue to play in the discovery and validation of biomarkers and their implementation in clinical practice. Large biobanks containing multiple specimen types are increasingly being created from patients enrolled in clinical trials, and such biobanks, when coupled with advances in molecular techniques and bioinformatics, promise to accelerate our understanding of CV disease mechanisms and to help fuel the discovery and development of novel therapeutic targets and biomarkers of risk and treatment response. SUMMARY The past, present, and future of biomarkers and clinical trials have been and will remain intertwined. Biomarkers were once the workhorses of patient selection and end point definition in clinical trials; more recently, clinical trials have been the proving ground for individual biomarkers. Attention to biobanking and the application of modern informatics and molecular techniques to samples collected within clinical trials will usher in the era of stratified and personalized medicine.

Use of Guidelines-Recommended Management and Outcomes Among Women and Men With Low-Level Troponin Elevation: Insights From CRUSADE

Background—Troponin elevation above the upper limit of normal (ULN) is diagnostic of myocardial infarction, but interpretation of “gray-zone” troponin elevations (1 to 1.5× ULN) remains uncertain. Using the CRUSADE database, we explored relationships between sex and treatment and outcomes among patients with troponin 1 to 1.5× ULN. Methods and Results—We compared treatment and outcomes among women and men using logistic generalized estimating equation method. Overall, 5049 of 85 671 (5.9%) non-ST-segment elevation acute coronary syndromes patients (2156 women, 2893 men) had troponin 1 to 1.5× ULN within 24 hours of presentation. Compared with troponin >1.5× ULN, “gray-zone” patients less often received all guidelines-indicated acute (mean composite score, 63% versus 72%) and discharge therapies (mean composite score, 73% versus 78%), but received them more frequently than patients with troponin <1× ULN (mean composite scores, 58% acute and 67% discharge). Among “gray-zone” patients, acute and discharge therapy use was similar between women and men, except acute aspirin (adjusted odds ratio, 0.80 [95% CI, 0.65 to 0.98]) and discharge angiotensin-converting enzyme inhibitors (adjusted odds ratio, 0.77 [95% CI, 0.67 to 0.88]). “Gray-zone” patients had lower mortality (2.3%) than the >1.5× ULN (4.5%) group but higher than the <1× ULN group (1.1%). Outcomes were similar among “gray-zone” women and men (adjusted odds ratios: death, 0.88 [95% CI, 0.58 to 1.35]; death/myocardial infarction, 0.77 [95% CI, 0.55 to 1.06]; transfusion, 1.04 [95% CI, 0.85 to 1.27]). Conclusions—Patients with non-ST-segment elevation acute coronary syndromes and low-level troponin elevations had lower overall risk and received less aggressive guidelines-based treatment than those with greater troponin elevations, but treatment patterns were largely similar by sex across troponin elevation groups.

Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients: Insights From Clinical Trials Over 17 Years

Background—Adequate representation by sex in trials allows generalizability of results. We examined representation of women in clinical trials during a 17-year period in which inclusion criteria were broadened and federal mandates for representativeness were launched. Methods and Results—Using mixed models, we studied sex-stratified temporal trends in enrollment, clinical characteristics, treatment, and outcomes among 76 148 non–ST-segment elevation acute coronary syndrome patients using patient-level data merged from 11 phase III trials conducted from 1994 to 2010. Overall, 33.3% of patients were women, which changed minimally over time. Women were consistently 4 to 5 years older than men (median age 68 [interquartile range 61–75] versus 64 [interquartile range 56–72] years) and more frequently had diabetes mellitus, hypertension, and heart failure; men more frequently had prior myocardial infarction and revascularization. GRACE risk scores increased over time for both sexes with the inclusion of older patients with more comorbidities. Use of percutaneous coronary intervention, in-hospital and discharge angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, &bgr;-blockers, and lipid-lowering drugs also increased among both sexes. Kaplan–Meier estimates of 6-month mortality declined from 7.0% [95% confidence interval 6.5%–7.6%] to 4.5% [95% confidence interval 4.0%–5.0%] among women and 6.3% [95% confidence interval 6.0%–6.7%] to 3.1% [95% confidence interval 2.9%–3.4%] among men during the 17-year period. Conclusions—The relative proportion of women in non–ST-segment elevation acute coronary syndrome trials changed minimally over time. Nevertheless, in parallel with men, use of evidence-based care and outcomes improved significantly over time among women.

Simultaneous consideration of multiple candidate protein biomarkers for long-term risk for cardiovascular events.

Background—Although individual protein biomarkers are associated with cardiovascular risk, rarely have multiple proteins been considered simultaneously to identify which set of proteins best predicts risk. Methods and Results—In a nested case–control study of 273 death/myocardial infarction (MI) cases and 273 age- (within 10 years), sex-, and race-matched and event-free controls from among 2023 consecutive patients (median follow-up 2.5 years) with suspected coronary disease, plasma levels of 53 previously reported biomarkers of cardiovascular risk were determined in a core laboratory. Three penalized logistic regression models were fit using the elastic net to identify panels of proteins independently associated with death/MI: proteins alone (Model 1); proteins in a model constrained to retain clinical variables (Model 2); and proteins and clinical variables available for selection (Model 3). Model 1 identified 6 biomarkers strongly associated with death/MI: intercellular adhesion molecule-1, matrix metalloproteinase-3, N-terminal pro-B-type natriuretic peptide, interleukin-6, soluble CD40 ligand, and insulin-like growth factor binding protein-2. In Model 2, only soluble CD40 ligand remained strongly associated with death/MI when all clinical risk predictors were retained. Model 3 identified a set of 6 biomarkers (intercellular adhesion molecule-1, matrix metalloproteinase-3, N-terminal pro-B-type natriuretic peptide, interleukin-6, soluble CD40 ligand, and insulin-like growth factor binding protein-2) and 5 clinical variables (age, red-cell distribution width, diabetes mellitus, hemoglobin, and New York Heart Association class) strongly associated with death/MI. Conclusions—Simultaneously assessing the association between multiple putative protein biomarkers of cardiovascular risk and clinical outcomes is useful in identifying relevant biomarker panels for further assessment.

Prognostic biomarkers in individuals with prevalent coronary heart disease

Coronary disease is the leading killer of individuals worldwide and a leading cause of healthcare expenditure. On a global scale, ischemic heart disease kills over 6 million individuals each year and is projected by the World Health Organization to be the greatest single-disease cause of death worldwide by an increasing margin into 2030. Nearly 17 million Americans (7.6% of the population) have prevalent coronary heart disease, 8 million of whom have had a prior myocardial infarction. It is estimated that in 2009, 550,000 will die from coronary heart disease in the United States and that the direct and indirect costs from treating coronary heart disease will exceed

Training in Structural Heart Interventions

165 billion. Although patients with known coronary artery disease are among the highest risk patients for future cardiac events, not all patients with coronary disease will have an ischemic event (first or recurrent). Determining which of these patients will have an ischemic event is critical to the concept of personalized cardiovascular care. Increasingly, biomarkers that can be readily assayed from blood or other body fluids will be critical to risk stratification and effective application of secondary prevention strategies, just as they have played an increasingly prominent role in risk stratification of acute coronary syndrome patients.

Current Status of Percutaneous PFO Closure

Over the last decade, there have been tremendous advances in our ability to treat valvular heart disease and anatomic cardiac defects utilizing catheter-based approaches. At the same time, the number of patients with acquired valvular heart disease or adult congenital heart disease who may benefit

Review: Omega-3 fatty acid supplements provide no protective benefit in cardiovascular disease

The clinical significance of persistent patent foramen ovale (PFO) is not well defined. Empirically, PFO has been associated with many clinical conditions. In cryptogenic stroke, migraine, and orthodeoxia/platypnea, a plausible biologic mechanism exists to support PFO closure as a possible treatment. Although transcatheter closure of PFO has been available for over 2 decades, it has remained controversial due to a paucity of evidence to guide patient and device selection. Contemporary studies investigating PFO closure as treatment for patients with these conditions have been published recently and longitudinal data regarding the safety and efficacy of the devices is now available. In this review, we aim to describe the potential clinical significance of a patent foramen in the adult, appraise the newest additions to the body of evidence, and discuss the safety, benefit, patient selection, and future of transcatheter treatment of PFO.

Frequency, clinical and angiographic characteristics, and outcomes of high-risk non-ST-segment elevation acute coronary syndromes patients with left circumflex culprit lesions

Source Citation Kwak SM, Myung SK, Lee YJ, Seo HG; Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary pre...