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Stuart J Connolly,
A John Camm,
Jonathan L Halperin,
Campbell Joyner,
Marco Alings,
John Amerena,
Dan Atar,
Álvaro Avezum,
Per Blomström,
Martin Borggrefe, [......],
Denis Xavier,
Jun Zhu,
Jun-Ren Zhu,
Lydie Baret-Cormel,
Estelle Weinling,
Christoph Staiger,
Salim Yusuf,
Susan Chrolavicius,
Rizwan Afzal,
Stefan H Hohnloser
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ABSTRACT: 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.
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.
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).
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.).
New England Journal of Medicine 11/2011; 365(24):2268-76. · 53.30 Impact Factor
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Joshua I Barzilay,
Peggy Gao,
Lars Rydén,
Helmut Schumacher,
Jeffrey Probstfield, Patrick Commerford,
Antonio Dans,
Rafael Ferreira,
Mátyás Keltai,
Ernesto Paolasso,
Salim Yusuf,
Koon Teo
[show abstract]
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ABSTRACT: Several large clinical trials suggest that ACE inhibitors may reduce the incidence of diabetes. Less is known about the effects of angiotensin receptor blockers (ARBs) on reducing incident diabetes or leading to regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia.
Participants were 3,488 adults at high risk for cardiovascular disease but free from diabetes (mean age 67 years; 61% male) in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study. The participants were randomized to the ARB telmisartan 80 mg (n = 1,726) or placebo (n = 1,762) in addition to usual care.
During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83-1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo.
There was no evidence that addition of the ARB telmisartan to usual care prevents incident diabetes or leads to regression of IFG or IGT in people at high risk for cardiovascular disease but free from diabetes.
Diabetes care 07/2011; 34(9):1902-7. · 8.09 Impact Factor
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Stuart J Connolly,
John Eikelboom,
Campbell Joyner,
Hans-Christoph Diener,
Robert Hart,
Sergey Golitsyn,
Greg Flaker,
Alvaro Avezum,
Stefan H Hohnloser,
Rafael Diaz, [......],
Jae Hyung Kim,
Fernando Lanas-Zanetti,
Antonio Gonzalez-Hermosillo,
Antonio L Dans,
Muhammad Munawar,
Martin O'Donnell,
John Lawrence,
Gayle Lewis,
Rizwan Afzal,
Salim Yusuf
[show abstract]
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ABSTRACT: 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.
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.
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.
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.).
New England Journal of Medicine 02/2011; 364(9):806-17. · 53.30 Impact Factor
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Craig Anderson,
Koon Teo,
Peggy Gao,
Hisatomi Arima,
Antonio Dans,
Thomas Unger, Patrick Commerford,
Leanne Dyal,
Helmut Schumacher,
Janice Pogue,
Ernesto Paolasso,
Nicolaas Holwerda,
Irina Chazova,
Azan Binbrek,
James Young,
Salim Yusuf
[show abstract]
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ABSTRACT: cardiovascular risk factors are associated with dementia and cognitive decline. We investigated the effects of renin-angiotensin system blockade on cognitive function in patients aged 55 years and older with established atherosclerotic cardiovascular disease or diabetes with end-organ damage in two clinical trials.
in the main study, ONTARGET, a double-blind, double-dummy, randomised controlled trial, the effects on cardiovascular outcomes of standard doses of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), an angiotensin-receptor blocker (telmisartan), and a combination of the drugs were evaluated in 25 620 participants. In the parallel TRANSCEND trial, the effects of telmisartan were compared with those of placebo in 5926 participants intolerant to ACE inhibitors. Secondary outcomes included cognitive impairment (defined by investigator-reported diagnosis of dementia or significant cognitive dysfunction, or a score of ≤ 23 on the Mini-Mental State Examination [MMSE]) and cognitive decline (a decrease of ≤ 3 points on the MMSE from baseline during follow-up). Analyses were by intention to treat. We pooled data from these studies to identify baseline predictors of cognitive impairment and its frequency according to mean systolic blood pressure during follow-up. These studies were registered with ClinicalTrials.gov, number NCT00153101.
During a median duration of 56 months (IQR 51-64) of follow-up in ONTARGET, cognitive impairment occurred in 652 (8%) of 7865 patients allocated ramipril, 584 (7%) of 7797 allocated telmisartan, and 618 (8%) of 7807 allocated combination treatment (combination vs ramipril, odds ratio [OR] 0·95, 95% CI 0·85-1·07, p= 0·39; telmisartan vs ramipril, OR 0·90, 0·80-1·01, p = 0·06). Corresponding figures for cognitive decline were 1314 (17%), 1279 (17%), and 1240 (17%) in each of the groups, respectively (telmisartan vs ramipril, OR 0·97, 0·89-1·06, p= 0·53; combination vs ramipril, OR 0·95, 0·88-1·04, p=0·28). In TRANSCEND, cognitive impairment occurred in 239 (9%) of 2694 participants allocated telmisartan compared with 245 (9%) of 2689 allocated placebo (OR 0·97, 0·81-1·17, p= 0·76). The corresponding figures for cognitive decline were 454 (17%) and 412 (16%; OR 1·10, 0·95-1·27, p= 0·22).
In patients with cardiovascular disease or diabetes, different approaches to blocking of the renin-angiotensin system had no clear effects on cognitive outcomes. Although patients with the lowest systolic blood pressure had the greatest preservation of cognitive function, meta-regression analyses did not show any benefits of blood-pressure lowering on cognition over several years of treatment.
The Lancet Neurology 10/2010; 10(1):43-53. · 23.46 Impact Factor
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ABSTRACT: 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.
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.
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.
Circulation 11/2008; 118(20):2029-37. · 14.74 Impact Factor
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Heart (British Cardiac Society) 08/2008; 94(7):824-5. · 4.22 Impact Factor
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South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 08/2007; 97(7):500-3. · 2.04 Impact Factor
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The Lancet 07/2006; 367(9526):1884-6. · 38.28 Impact Factor
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Bongani Mayosi,
Kate Robertson,
Jimmy Volmink,
Wole Adebo,
Kingsley Akinyore,
Albert Amoah,
Charles Bannerman,
Shan Biesman-Simons,
Jonathan Carapetis,
Antoinette Cilliers, [......],
Tiny Mokone,
Elijah Ogola,
Samuel Omokhodion,
Chapman Palweni,
Adrian Pearce,
Avril Salo,
Baby Thomas,
Kathie Walker,
Charles Wiysonge,
Salah Zaher
South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde 04/2006; 96(3 Pt 2):246. · 2.04 Impact Factor
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[show abstract]
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ABSTRACT: 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.
First-time AMI patients (n=578) were matched to 785 controls by age and sex in 9 SSA countries, with South Africa contributing approximately 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.
Known CVD risk factors account for approximately 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.
Circulation 01/2006; 112(23):3554-61. · 14.74 Impact Factor
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Bongani Mayosi,
Charles Wiysonge,
Mpiko Ntsekhe,
Jimmy Volmink,
Freedom Gumedze,
Gary Maartens,
Akinyemi Aje,
Baby Thomas,
Kandathil Thomas,
Abolade Awotedu, [......],
Andy Parish,
Karen Sliwa,
Brian Vezi,
Nowshad Alam,
Basil Brown,
Trevor Gould,
Tim Visser,
Muki Shey,
Nombulelo Magula, Patrick Commerford
[show abstract]
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ABSTRACT: Abstract
Background
The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa.
Methods
Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status.
Results
A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs.
Conclusion
Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease.
BMC Infectious Diseases. 01/2006;
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Salim Yusuf,
Steven Hawken,
Stephanie Ounpuu,
Leonelo Bautista,
Maria Grazia Franzosi, Patrick Commerford,
Chim C Lang,
Zvonko Rumboldt,
Churchill L Onen,
Liu Lisheng,
Supachai Tanomsup,
Paul Wangai,
Fahad Razak,
Arya M Sharma,
Sonia S Anand
[show abstract]
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ABSTRACT: 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.
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.
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.
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.
The Lancet 11/2005; 366(9497):1640-9. · 38.28 Impact Factor
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Salim Yusuf,
Steven Hawken,
Stephanie Ôunpuu,
Leonelo Bautista,
Maria Grazia Franzosi, Patrick Commerford,
Chim Lang,
Zvonko Rumboldt,
Churchill L Onen,
Liu Lisheng,
Supachai Tanomsup,
Paul Wangai,
Fahad Razak,
Arya M Sharma,
Sonia S Anand
[show abstract]
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ABSTRACT: 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. The article references also includes three 'Web Extra material' PDF's : Webtable 1. Demographics and prevalence of risk factors in cases and controls in the INTERHEART study.; Webtable 2. Anthropometric measures by region.; INTERHEART Project Office Staff, National Coordinators, and Investigators.
