Patrick Commerford

Obesity and the risk of myocardial infarction in 27 000 participants from 52 countries: a case-control study

BACKGROUND Obesity is a major risk factor for cardiovascular disease, but the most predictive measure for different ethnic populations is not clear. We aimed to assess whether markers of obesity, especially waist-to-hip ratio, would be stronger indicators of myocardial infarction than body-mass index (BMI), the conventional measure. METHODS We did a standardised case-control study of acute myocardial infarction with 27 098 participants in 52 countries (12,461 cases and 14,637 controls) representing several major ethnic groups. We assessed the relation between BMI, waist and hip circumferences, and waist-to-hip ratio to myocardial infarction overall and for each group. FINDINGS BMI showed a modest and graded association with myocardial infarction (OR 1.44, 95% CI 1.32-1.57 top quintile vs bottom quintile before adjustment), which was substantially reduced after adjustment for waist-to-hip ratio (1.12, 1.03-1.22), and non-significant after adjustment for other risk factors (0.98, 0.88-1.09). For waist-to-hip ratio, the odds ratios for every successive quintile were significantly greater than that of the previous one (2nd quintile: 1.15, 1.05-1.26; 3rd quintile: 1.39; 1.28-1.52; 4th quintile: 1.90, 1.74-2.07; and 5th quintiles: 2.52, 2.31-2.74 [adjusted for age, sex, region, and smoking]). Waist (adjusted OR 1.77; 1.59-1.97) and hip (0.73; 0.66-0.80) circumferences were both highly significant after adjustment for BMI (p<0.0001 top vs bottom quintiles). Waist-to-hip ratio and waist and hip circumferences were closely (p<0.0001) associated with risk of myocardial infarction even after adjustment for other risk factors (ORs for top quintile vs lowest quintiles were 1.75, 1.33, and 0.76, respectively). The population-attributable risks of myocardial infarction for increased waist-to-hip ratio in the top two quintiles was 24.3% (95% CI 22.5-26.2) compared with only 7.7% (6.0-10.0) for the top two quintiles of BMI. INTERPRETATION Waist-to-hip ratio shows a graded and highly significant association with myocardial infarction risk worldwide. Redefinition of obesity based on waist-to-hip ratio instead of BMI increases the estimate of myocardial infarction attributable to obesity in most ethnic groups.

Apixaban in Patients with Atrial Fibrillation

BACKGROUND Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. METHODS In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. RESULTS Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. CONCLUSIONS In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).

Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes Observations From the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study

Background—We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome (ACS). Methods and Results—In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, 12 562 patients with ACS using aspirin, 75 to 325 mg daily, were randomized to clopidogrel or placebo for up to 1 year. In this analysis, patients were divided into the following 3 aspirin dose groups: ≤100 mg, 101 through 199 mg, and ≥200 mg. The combined incidence of cardiovascular death, myocardial infarction, or stroke was reduced by clopidogrel regardless of aspirin dose, as follows: ≤100 mg, 10.5% versus 8.6% (relative risk [RR], 0.81 [95% CI, 0.68 to 0.97]); 101 to 199 mg, 9.8% versus 9.5% (RR, 0.97 [95% CI 0.77 to 1.22]); and ≥200 mg, 13.6% versus 9.8% (RR, 0.71 [95% CI, 0.59 to 0.85]). The incidence of major bleeding increased with increasing aspirin dose both in the placebo group (1.9%, 2.8%, and 3.7%, respectively; P =0.0001) and the clopidogrel group (3.0%, 3.4%, and 4.9%, respectively; P =0.0009); thus, the excess risk with clopidogrel was 1.1%, 1.2%, and 1.2%, respectively. The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 (95% CI 1.29 to 2.72) in the placebo group, 1.6 (95% CI 1.19 to 2.23) in the clopidogrel group, and 1.7 (95% CI 1.36 to 2.20) in the combined group. Conclusions—In patients with ACS, adding clopidogrel to aspirin is beneficial regardless of aspirin dose. Bleeding risks increase with increasing aspirin dose, with or without clopidogrel, without any increase in efficacy. Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg, with or without clopidogrel.

Benefit of Oral Anticoagulant Over Antiplatelet Therapy in Atrial Fibrillation Depends on the Quality of International Normalized Ratio Control Achieved by Centers and Countries as Measured by Time in Therapeutic Range

Background— Oral anticoagulation (OAC) therapy is effective in atrial fibrillation but requires vigilance to maintain the international normalized ratio in the therapeutic range. This report examines how differences in time in therapeutic range (TTR) between centers and between countries affect the outcomes of OAC therapy. Methods and Results— In a posthoc analysis, the TTRs of patients on OAC in a randomized trial of OAC versus clopidogrel plus aspirin (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ACTIVE W]) were used to calculate the mean TTR for each of 526 centers and 15 countries. Proportional-hazards analysis, with and without adjustment for baseline variables, was performed, with patients stratified by TTR quartile and country. A wide variation in TTRs was found between centers, with mean TTRs for centers in the 4 quartiles of 44%, 60%, 69%, and 78%. For patients at centers below the median TTR (65%), no treatment benefit was demonstrated as measured by relative risk for vascular events of clopidogrel plus aspirin versus OAC (relative risk, 0.93; 95% confidence interval, 0.70 to 1.24; P=0.61). However, for patients at centers with a TTR above the study median, OAC had a marked benefit, reducing vascular events by >2-fold (relative risk, 2.14; 95% confidence interval, 1.61 to 2.85; P<0.0001). Mean TTR also varied between countries from 46% to 78%; relative risk (clopidogrel plus aspirin versus OAC) varied from 0.6 to 3.6 (a 5-fold difference). A population-average model predicted that a TTR of 58% would be needed to be confident that patients would benefit from being on OAC. Conclusions— A wide variation exists in international normalized ratio control, as measured by TTR, between clinical centers and between countries, which has a major impact on the treatment benefit of OAC therapy. For centers and countries, a target threshold TTR exists (estimated between 58% and 65%) below which there appears to be little benefit of OAC over antiplatelet therapy.

Controversies in ventricular remodelling

Ventricular remodelling describes structural changes in the left ventricle in response to chronic alterations in loading conditions, with three major patterns: concentric remodelling, when a pressure load leads to growth in cardiomyocyte thickness; eccentric hypertrophy, when a volume load produces myocyte lengthening; and myocardial infarction, an amalgam of patterns in which stretched and dilated infarcted tissue increases left-ventricular volume with a combined volume and pressure load on non-infarcted areas. Whether left-ventricular hypertrophy is adaptive or maladaptive is controversial, as suggested by patterns of signalling pathways, transgenic models, and clinical findings in aortic stenosis. The transition from apparently compensated hypertrophy to the failing heart indicates a changing balance between metalloproteinases and their inhibitors, effects of reactive oxygen species, and death-promoting and profibrotic neurohumoral responses. These processes are evasive therapeutic targets. Here, we discuss potential novel therapies for these disorders, including: sildenafil, an unexpected option for anti-transition therapy; surgery for increased sphericity caused by chronic volume overload of mitral regurgitation; an antifibrotic peptide to inhibit the fibrogenic effects of transforming growth factor beta; mechanical intervention in advanced heart failure; and stem-cell therapy.

Dronedarone in high-risk permanent atrial fibrillation

BACKGROUND Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation. METHODS We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death. RESULTS After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02). CONCLUSIONS Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.).

Risk Factors Associated With Myocardial Infarction in Africa The INTERHEART Africa Study

Background— Cardiovascular disease (CVD) is rising in low-income countries. However, the impact of modifiable CVD risk factors on myocardial infarction (MI) has not been studied in sub-Saharan Africa (SSA). Therefore, we conducted a case-control study among patients with acute MI (AMI) in SSA to explore its association with known CVD risk factors. Methods and Results— First-time AMI patients (n=578) were matched to 785 controls by age and sex in 9 SSA countries, with South Africa contributing ≈80% of the participants. The relationships between risk factors and AMI were investigated in the African population and in 3 ethnic subgroups (black, colored, and European/other Africans) and compared with those found in the overall INTERHEART study. Relationships between common CVD risk factors and AMI were found to be similar to those in the overall INTERHEART study. Modeling of 5 risk factors (smoking history, diabetes history, hypertension history, abdominal obesity, and ratio of apolipoprotein B to apolipoprotein A-1) provided a population attributable risk of 89.2% for AMI. The risk for AMI increased with higher income and education in the black African group in contrast to findings in the other African groups. A history of hypertension revealed higher MI risk in the black African group than in the overall INTERHEART group. Conclusions— Known CVD risk factors account for ≈90% of MI observed in African populations, which is consistent with the overall INTERHEART study. Contrasting gradients found in socioeconomic class, risk factor patterns, and AMI risk in the ethnic groups suggest that they are at different stages of the epidemiological transition.

Fibrin and Fibrinogen-Related Antigens in Patients with Stable and Unstable Coronary Artery Disease

Coronary-artery thrombosis may be important in the pathogenesis of unstable angina at rest. To study this possibility, we measured the serum concentrations of fibrin-related antigen, D dimer (the principal breakdown fragment of fibrin), and fibrin monomer (an intermediate product of fibrin formation) in the serum of five groups of subjects. These included 10 healthy controls, 10 controls with noncardiac pain, and three groups of 10 patients each with chronic stable angina, unstable angina at rest, or acute myocardial infarction. The concentration of fibrin-related antigen (normal range, 48 to 184 ng per milliliter) was normal in the control patients with noncardiac pain (63 to 202 ng per milliliter) and in patients with chronic stable angina (95 to 186), but it was increased in patients with unstable angina (401 to 2507) or acute myocardial infarction (470 to 1930) (P less than 0.001). D dimer concentrations in patients with unstable angina (178.3 to 310.6 ng per milliliter) or acute myocardial infarction (103.9 to 321.6) were higher than those in patients with chronic stable angina (28.6 to 52.1), in controls with noncardiac pain (44.7 to 53.1), and in healthy controls (40.4 to 50.3) (P less than 0.001). Concentrations of fibrin monomer were highest in patients with acute myocardial infarction (247.5 to 571.3 ng per milliliter) (P less than 0.001), intermediate in those with unstable angina (54.7 to 241.7) (P less than 0.001), and normal (normal range, 14.5 to 19.8 ng per milliliter) in controls with noncardiac pain (12.0 to 18.4). and patients with chronic stable angina (10.7 to 17.6). These findings suggest the presence of an active thrombotic process in patients with unstable angina at rest or acute myocardial infarction. The data do not prove that the coronary arteries were the site of the thrombotic process, but the observations are consistent with the hypothesis that thrombus formation may have an important role in the pathogenesis of these conditions.

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

BACKGROUND We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS In this double‐blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban‐plus‐aspirin group after a mean follow‐up of 23 months. RESULTS The primary outcome occurred in fewer patients in the rivaroxaban‐plus‐aspirin group than in the aspirin‐alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=‐4.126), but major bleeding events occurred in more patients in the rivaroxaban‐plus‐aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban‐plus‐aspirin group as compared with 378 (4.1%) in the aspirin‐alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban‐alone group than in the aspirin‐alone group, but major bleeding events occurred in more patients in the rivaroxaban‐alone group. CONCLUSIONS Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424.)

Health care-associated native valve endocarditis: importance of non-nosocomial acquisition.

BACKGROUND The clinical profile and outcome of nosocomial and non-nosocomial health care-associated native valve endocarditis are not well defined. OBJECTIVE To compare the characteristics and outcomes of community-associated and nosocomial and non-nosocomial health care-associated native valve endocarditis. DESIGN Prospective cohort study. SETTING 61 hospitals in 28 countries. PATIENTS Patients with definite native valve endocarditis and no history of injection drug use who were enrolled in the ICE-PCS (International Collaboration on Endocarditis Prospective Cohort Study) from June 2000 to August 2005. MEASUREMENTS Clinical and echocardiographic findings, microbiology, complications, and mortality. RESULTS Health care-associated native valve endocarditis was present in 557 (34%) of 1622 patients (303 with nosocomial infection [54%] and 254 with non-nosocomial infection [46%]). Staphylococcus aureus was the most common cause of health care-associated infection (nosocomial, 47%; non-nosocomial, 42%; P = 0.30); a high proportion of patients had methicillin-resistant S. aureus (nosocomial, 57%; non-nosocomial, 41%; P = 0.014). Fewer patients with health care-associated native valve endocarditis had cardiac surgery (41% vs. 51% of community-associated cases; P < 0.001), but more of the former patients died (25% vs. 13%; P < 0.001). Multivariable analysis confirmed greater mortality associated with health care-associated native valve endocarditis (incidence risk ratio, 1.28 [95% CI, 1.02 to 1.59]). LIMITATIONS Patients were treated at hospitals with cardiac surgery programs. The results may not be generalizable to patients receiving care in other types of facilities or to those with prosthetic valves or past injection drug use. CONCLUSION More than one third of cases of native valve endocarditis in non-injection drug users involve contact with health care, and non-nosocomial infection is common, especially in the United States. Clinicians should recognize that outpatients with extensive out-of-hospital health care contacts who develop endocarditis have clinical characteristics and outcomes similar to those of patients with nosocomial infection. PRIMARY FUNDING SOURCE None.