Jackie Bosch - Academia.edu (original) (raw)

Papers by Jackie Bosch

Thrombosis and Haemostasis, Jan 31, 2019

The most common causes of ischaemic stroke are represented by carotid artery atherosclerotic dise... more The most common causes of ischaemic stroke are represented by carotid artery atherosclerotic disease (CAAD) and atrial fibrillation. While oral anticoagulants substantially reduce the incidence of thromboembolic stroke (< 1%/year), the rate of ischaemic stroke and other cardiovascular disease events in patients with CAAD remains high, ranging from 8.4 to 18.1 events per 100 patient-years. Similar to any other atherosclerotic disease, anti-thrombotic therapies are proposed for CAAD to reduce stroke and other cardiovascular events. The 2017 European Society of Cardiology (ESC)/European Society for Vascular Surgery (ESVS) guidelines recommend for patients with asymptomatic CAAD 60% the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily at the exception of patient at very high bleeding risk. For patients with symptomatic CAAD 50%, the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily is recommended. New perspectives for anti-thrombotic therapy for the treatment of patients with CAAD come from the novel dual pathway strategy combining a low-dose anticoagulant (i.e. rivaroxaban) and aspirin that may help reduce longterm ischaemic complications in patients with CAAD. This review summarizes current evidence and recommendations for the anti-thrombotic management of patients with symptomatic or asymptomatic CAAD or those undergoing carotid revascularization.

Diabetes Care, Feb 4, 2020

To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomiz... more To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n 5 31,200). RESULTS Genetically lower ACE concentrations were associated with a lower risk of type 2 diabetes (odds ratio [OR] per SD 0.92 [95% CI 0.89-0.95]; P 5 1.79 3 10 27). This result was replicated in the UK Biobank (OR per SD 0.97 [0.96-0.99]; P 5 8.73 3 10 24). After standardization, the ACE GRS was associated with a larger decrease in type 2 diabetes risk per 2.4-mmHg lower mean arterial pressure (MAP) compared with that obtained from an RCT meta-analysis (OR per 2.4-mmHg lower MAP 0.19 [0.07-0.51] vs. 0.76 [0.60-0.97], respectively; P 5 0.007 for difference). CONCLUSIONS These results support the causal protective effect of ACE inhibitors on type 2 diabetes risk and may guide therapeutic decision making in clinical practice. Diabetes is a leading cause of death worldwide (1) and an important risk factor for cardiovascular and kidney diseases (2). The global prevalence of diabetes has doubled over the past 25 years (3), and, thus, policies to slow its incidence are urgently required. Exercise, dieting, and some glucose-lowering drugs can prevent or delay the onset of type 2 diabetes (4). Moreover, three (5-7) of five (5-9) large randomized controlled trials (RCTs) have suggested that ACE inhibitors may reduce the risk of type 2 diabetes compared with placebo in people at high risk for cardiovascular outcomes. However, one large RCT in people at low risk for cardiovascular diseases, who also had impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), reported a nonsignificantly lower effect of ACE inhibitors on incident type 2 diabetes (10). Thus, the causal relationship between ACE inhibition and protection from type 2 diabetes remains questionable.

European Heart Journal, Sep 1, 2019

Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurre... more Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease.

Circulation, Mar 11, 2003

Background-Previous trials in the prevention of heart failure have been restricted to patients wi... more Background-Previous trials in the prevention of heart failure have been restricted to patients with low ejection fraction or hypertension. We assessed an angiotensin-converting enzyme (ACE) inhibitor, ramipril, to prevent the development of heart failure in high-risk patients without known low ejection fraction or heart failure. Methods and Results-We randomly assigned 9297 patients to receive double-blind ramipril (10 mg daily) or matching placebo for 4.5 years. Death attributable to heart failure, hospitalization for heart failure, initiation of open-label ACE inhibitor for heart failure, or development of typical signs or symptoms of heart failure developed in 951 patients and was associated with a 4.01-fold increase in the risk of death (PϽ0.0001). The rate of developing heart failure was significantly increased with coronary disease (risk ratio, 2.17), microalbuminuria (1.82), left ventricular hypertrophy (1.47), increasing age (by decade, 1.37), and diabetes (1.36). Ramipril reduced new-onset heart failure rate from 11.5% to 9.0% (relative risk, 0.77; 95% CI, 0.68 to 0.87; PϽ0.0001). Ramipril consistently reduced heart failure rate both in those with (relative risk, 0.87) and those without an interim myocardial infarction (relative risk, 0.78). Ramipril also reduced the heart failure rate more in patients with baseline systolic pressure above the median (139 mm Hg) (relative risk, 0.67) compared with those below the median (relative risk, 0.91; Pϭ0.024 for interaction of group by treatment). Conclusion-Ramipril significantly reduces the rate of development of heart failure in patients at high risk of cardiovascular events. (Circulation. 2003;107:1284-1290.) Key Words: heart failure Ⅲ prevention Ⅲ drugs Ⅲ atherosclerosis Ⅲ trials H eart failure is presently the commonest cause of hospital admission in patients older than 65 years of age in the United States, 1,2 where it has a prevalence of 2 million and an annual incidence of 400 000. 3 Globally, atherosclerosis and coronary artery disease are expected to increase across the world in the next 2 decades 4,5 as the levels of obesity, diabetes, and hypertension increase. In addition, more patients are surviving acute myocardial infarction but with damaged hearts, and life expectancy is predicted to increase. 4 Therefore, the individual, community, health care, and economic burden of heart failure will continue to rise.

Circulation, Sep 14, 2004

Background-ACE inhibitor therapy reduces the risk of cardiovascular death, myocardial infarction,... more Background-ACE inhibitor therapy reduces the risk of cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, and need for revascularization in high-risk patients with clinical heart failure, overt left ventricular systolic dysfunction, or vascular disease. In patients with clinical heart failure or overt left ventricular systolic dysfunction, ACE inhibitor therapy also reduces the risk of sudden or arrhythmia-related cardiac death. The objective of this study was to assess the effect of the ACE inhibitor ramipril on sudden unexpected death or resuscitated cardiac arrest among the 9297 individuals without clinical heart failure or overt left ventricular dysfunction enrolled in the Heart Outcomes Prevention Evaluation (HOPE) trial. Methods and Results-During the median follow-up of 4.5 years, the composite outcome of unexpected death, documented arrhythmic death, or resuscitated cardiac arrest was reduced by 21% in patients randomized to ramipril therapy compared with those randomized to placebo. There were 155 (3.3%) composite outcome events in patients randomized to ramipril therapy compared with 195 (4.2%) such events in patients randomized to placebo (RR 0.79, 95% CI 0.64 to 0.98, Pϭ0.028). There were trends toward reductions in fatal primary outcome events (unexpected death or documented arrhythmic death; RR 0.81, 95% CI 0.64 to 1.02, Pϭ0.072) and in nonfatal primary outcome events (resuscitated cardiac arrest; RR 0.65, 95% CI 0.38 to 1.13, Pϭ0.127) in the ramipril treatment group. Conclusions-Ramipril reduces the risk of fatal and nonfatal serious arrhythmic events in high-risk patients without clinical heart failure or overt left ventricular systolic dysfunction. (Circulation. 2004;110:1413-1417.

European Heart Journal - Quality of Care and Clinical Outcomes

Aims The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial demo... more Aims The Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial demonstrated that rivaroxaban 2.5 mg BID with aspirin 100 mg was more effective than aspirin 100 mg daily alone for the prevention of cardiovascular (CV) death, stroke, or myocardial infarction in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD). We aimed to examine the cost-effectiveness of rivaroxaban using patient-level data from the COMPASS trial. Methods and results We performed an in-trial analysis and extrapolated our results for 33 years using a two-state Markov model with a 1-year cycle length. Hospitalization events, procedures, and study drugs were documented for patients. We applied country-specific (Canada, France, and Germany) direct healthcare system costs (in USD) to healthcare resources consumed by patients. Average cost per patient during the trial (mean follow-up of 23 months), quality-adjusted life years (QALYs), and lifetime cost-effe...

European Heart Journal, 2021

Aims Rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV)... more Aims Rosuvastatin (10 mg per day) compared with placebo reduced major adverse cardiovascular (CV) events by 24% in 12 705 participants at intermediate CV risk after 5.6 years. There was no benefit of blood pressure (BP) lowering treatment in the overall group, but a reduction in events in the third of participants with elevated systolic BP. After cessation of all the trial medications, we examined whether the benefits observed during the active treatment phase were sustained, enhanced, or attenuated. Methods and results After the randomized treatment period (5.6 years), participants were invited to participate in 3.1 further years of observation (total 8.7 years). The first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2). In total, 9326 (78%) of 11 994 sur...

Heart, 2021

ObjectiveIn patients with chronic coronary or peripheral artery disease enrolled in the Cardiovas... more ObjectiveIn patients with chronic coronary or peripheral artery disease enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, randomised antithrombotic treatments were stopped after a median follow-up of 23 months because of benefits of the combination of rivaroxaban 2.5 mg two times per day and aspirin 100 mg once daily compared with aspirin 100 mg once daily. We assessed the effect of switching to non-study aspirin at the time of early stopping.MethodsIncident composite of myocardial infarction, stroke or cardiovascular death was estimated per 100 person-years (py) during randomised treatment (n=18 278) and after study treatment discontinuation to non-study aspirin (n=14 068).ResultsDuring randomised treatment, the combination compared with aspirin reduced the composite (2.2 vs 2.9/100 py, HR: 0.76, 95% CI 0.66 to 0.86), stroke (0.5 vs 0.8/100 py, HR: 0.58, 95% CI 0.44 to 0.76) and cardiovascular death (0.9 vs 1.2/100 py, HR: 0.78, 95% CI 0.64 ...

New England Journal of Medicine, 2021

BACKGROUND A polypill comprising statins, multiple blood-pressure-lowering drugs, and aspirin has... more BACKGROUND A polypill comprising statins, multiple blood-pressure-lowering drugs, and aspirin has been proposed to reduce the risk of cardiovascular disease. METHODS Using a 2-by-2-by-2 factorial design, we randomly assigned participants without cardiovascular disease who had an elevated INTERHEART Risk Score to receive a polypill (containing 40 mg of simvastatin, 100 mg of atenolol, 25 mg of hydrochlorothiazide, and 10 mg of ramipril) or placebo daily, aspirin (75 mg) or placebo daily, and vitamin D or placebo monthly. We report here the outcomes for the polypill alone as compared with matching placebo, for aspirin alone as compared with matching placebo, and for the polypill plus aspirin as compared with double placebo. For the polypill-alone and polypill-plus-aspirin comparisons, the primary outcome was death from cardiovascular causes, myocardial infarction, stroke, resuscitated cardiac arrest, heart failure, or revascularization. For the aspirin comparison, the primary outcome was death from cardiovascular causes, myocardial infarction, or stroke. Safety was also assessed. RESULTS A total of 5713 participants underwent randomization, and the mean follow-up was 4.6 years. The low-density lipoprotein cholesterol level was lower by approximately 19 mg per deciliter and systolic blood pressure was lower by approximately 5.8 mm Hg with the polypill and with combination therapy than with placebo. The primary outcome for the polypill comparison occurred in 126 participants (4.4%) in the polypill group and in 157 (5.5%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.63 to 1.00). The primary outcome for the aspirin comparison occurred in 116 participants (4.1%) in the aspirin group and in 134 (4.7%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.67 to 1.10). The primary outcome for the polypill-plus-aspirin comparison occurred in 59 participants (4.1%) in the combined-treatment group and in 83 (5.8%) in the doubleplacebo group (hazard ratio, 0.69; 95% CI, 0.50 to 0.97). The incidence of hypotension or dizziness was higher in groups that received the polypill than in their respective placebo groups. CONCLUSIONS Combined treatment with a polypill plus aspirin led to a lower incidence of cardiovascular events than did placebo among participants without cardiovascular disease who were at intermediate cardiovascular risk. (Funded by the Wellcome Trust and others; TIPS-3 ClinicalTrials.gov number, NCT01646437.

Cardiovascular Research, 2020

Aims To examine the rates of venous thromboembolism (VTE) in high-income, upper middle-income, an... more Aims To examine the rates of venous thromboembolism (VTE) in high-income, upper middle-income, and lower middle/low-income countries (World Bank Classification). Methods and results We examined the rates of VTE in high-income, upper middle-income, and lower middle/low-income countries (World Bank Classification) in a cohort derived from four prospective international studies (PURE, HOPE-3, ORIGIN, and COMPASS). The primary outcome was a composite of pulmonary embolism, deep vein thrombosis, and thrombophlebitis. We calculated age- and sex-standardized incidence rates (per 1000 person-years) and used a Cox frailty model adjusted for covariates to examine associations between the incidence of VTE and country income level. A total of 215 307 individuals (1.5 million person-years of follow-up) from high-income (n = 60 403), upper middle-income (n = 42 066), and lower middle/low-income (n = 112 838) countries were included. The age- and sex-standardized incidence rates of VTE per 1000 pe...

Diabetes Care, 2020

OBJECTIVE To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelia... more OBJECTIVE To determine whether ACE inhibitors reduce the risk of type 2 diabetes using a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS A two-sample MR analysis included 17 independent genetic variants associated with ACE serum concentration in 4,147 participants from the Outcome Reduction with Initial Glargine INtervention (ORIGIN) (clinical trial reg. no. NCT00069784) trial, and their effects on type 2 diabetes risk were estimated from 18 studies of the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. A genetic risk score (GRS) underpinning lower ACE concentration was then tested for association with type 2 diabetes prevalence in 341,872 participants, including 16,320 with type 2 diabetes, from the UK Biobank. MR estimates were compared after standardization for blood pressure change, with the estimate obtained from a randomized controlled trial (RCT) meta-analysis of ACE inhibitors versus placebo (n = 31,200). RESULTS Genetically lower ACE...

Circulation, 2019

Background: Strokes were significantly reduced by the combination of rivaroxaban plus aspirin in ... more Background: Strokes were significantly reduced by the combination of rivaroxaban plus aspirin in comparison with aspirin in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies). We present detailed analyses of stroke by type, predictors, and antithrombotic effects in key subgroups. Methods: Participants had stable coronary artery or peripheral artery disease and were randomly assigned to receive aspirin 100 mg once daily (n=9126), rivaroxaban 5 mg twice daily (n=9117), or rivaroxaban 2.5 mg twice daily plus aspirin (n=9152). Patients who required anticoagulation or had a stroke within 1 month, previous lacunar stroke, or intracerebral hemorrhage were excluded. Results: During a mean follow-up of 23 months, fewer patients had strokes in the rivaroxaban plus aspirin group than in the aspirin group (83 [0.9% per year] versus 142 [1.6% per year]; hazard ratio [HR], 0.58; 95% CI, 0.44–0.76; P <0.0001). Ischemic/uncertain strokes were reduced by nearl...

European Heart Journal - Quality of Care and Clinical Outcomes, 2019

Aims The Heart Outcomes Prevention Evaluation-3 (HOPE-3) found that rosuvastatin alone or with ca... more Aims The Heart Outcomes Prevention Evaluation-3 (HOPE-3) found that rosuvastatin alone or with candesartan and hydrochlorothiazide (HCT) (in a subgroup with hypertension) significantly lowered cardiovascular events compared with placebo in 12 705 individuals from 21 countries at intermediate risk and without cardiovascular disease. We assessed the costs implications of implementation in primary prevention in countries at different economic levels. Methods and results Hospitalizations, procedures, study and non-study medications were documented. We applied country-specific costs to the healthcare resources consumed for each patient. We calculated the average cost per patient in US dollars for the duration of the study (5.6 years). Sensitivity analyses were also performed with cheapest equivalent substitutes. The combination of rosuvastatin with candesartan/HCT reduced total costs and was a cost-saving strategy in United States, Canada, Europe, and Australia. In contrast, the treatmen...

New England Journal of Medicine, 2000

Background Observational and experimental studies suggest that the amount of vitamin E ingested i... more Background Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis. Methods We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer. Results A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E. Conclusions In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years has no apparent effect on cardiovascular outcomes.

New England Journal of Medicine, 2012

The Lancet, 2006

Background Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserv... more Background Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The aim of this study was to assess prospectively the drug's ability to prevent type 2 diabetes in individuals at high risk of developing the condition. Methods 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. Findings At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11•6%) individuals given rosiglitazone and 686 (26•0%) given placebo developed the composite primary outcome (hazard ratio 0•40, 95% CI 0•35-0•46; p<0•0001); 1330 (50•5%) individuals in the rosiglitazone group and 798 (30•3%) in the placebo group became normoglycaemic (1•71, 1•57-1•87; p<0•0001). Cardiovascular event rates were much the same in both groups, although 14 (0•5%) participants in the rosiglitazone group and two (0•1%) in the placebo group developed heart failure (p=0•01). Interpretation Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

Kidney International, 2004

Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficien... more Effects of vitamin E on cardiovascular outcomes in people with mild-to-moderate renal insufficiency: Results of the HOPE Study. Background. A controlled trial reported cardiovascular benefits of vitamin E in terminal renal insufficiency. There are no data for renal insufficiency before the stage of terminal renal failure. We evaluated effects of vitamin E supplementation on cardiovascular and renal outcomes in 993 people with a serum creatinine ≥1.4 to 2.3 mg/dL. Methods. Post-hoc analysis of a randomized trial that compared treatment with natural source vitamin E (400 IU/day) to placebo in 9541 people, 993 of which had renal insufficiency. Participants had either known cardiovascular disease or diabetes and at least one additional coronary risk factor. Exclusion criteria included a serum creatinine >2.3 mg/dL and dipstickpositive proteinuria. The primary study outcome after an average of 4.5 years was the composite of myocardial infarction, stroke, or cardiovascular death. Secondary outcomes included revascularizations, total mortality, and clinical proteinuria. Results. In renal insufficiency, vitamin E supplementation had a neutral effect on the primary study outcome, on each component of the composite primary outcome, and on all secondary outcomes. Two hundred twenty-four primary outcomes, 23% of the vitamin E group and 22.1% of the placebo group, relative risk 1.03 (95% CI, 0.79-1.34; P = 0.82), were observed, and 585 secondary outcomes, including death in 17% and 18.8% of the vitamin E and placebo groups, respectively (RR 0.88, 95% CI, 0.66-1.18; P = 0.40). There was no effect of vitamin E on progression of proteinuria. Conclusion. In people with mild-to-moderate renal insufficiency at high cardiovascular risk, vitamin E at a dose of 400 IU/ day had no apparent effect on cardiovascular outcomes. A full listing of the HOPE Investigators has been previously published (see reference 13).

Journal of the American College of Cardiology, 2002

OBJECTIVES We evaluated the effects of long-term therapy with the angiotensin-converting enzyme (... more OBJECTIVES We evaluated the effects of long-term therapy with the angiotensin-converting enzyme (ACE) inhibitor ramipril on major cardiovascular (CV) outcomes in high-risk women. BACKGROUND The effect of long-term ACE inhibitor therapy in high-risk women without heart failure and with preserved left ventricular (LV) systolic function has not been previously reported. METHODS The Heart Outcomes Prevention Evaluation (HOPE) trial is a large, randomized clinical trial that evaluated ramipril and vitamin E in high-risk patients. We present the preplanned analysis of the effects of ramipril in women in the HOPE study. The study randomized 2,480 women aged Ն55 years with vascular disease or diabetes and at least one additional CV risk factor and without heart failure or a known low LV ejection fraction to ramipril (10 mg/day) or placebo. The primary outcome was the composite of myocardial infarction, stroke or CV death. Average follow-up was 4.5 years. RESULTS Treatment with ramipril resulted in reduced primary end point rates (11.3% vs. 14.9% in the placebo arm; relative risk [RR] 0.77, 95% confidence interval [CI] 0.62 to 0.96; p ϭ 0.019), fewer strokes (3.1% vs. 4.8%; RR 0.64, 95% CI 0.43 to 0.96; p ϭ 0.029) and fewer CV deaths (4.2% vs. 6.9%; RR 0.62, 95% CI 0.44 to 0.88; p ϭ 0.0068). There were trends toward reduced rates of myocardial infarction, heart failure and all-cause death. The beneficial effect of ramipril was similar in women and men. CONCLUSIONS Treatment with ramipril reduces the CV risk in high-risk women without heart failure and with preserved LV systolic function.

JAMA, 2005

Context Experimental and epidemiological data suggest that vitamin E supplementation may prevent ... more Context Experimental and epidemiological data suggest that vitamin E supplementation may prevent cancer and cardiovascular events. Clinical trials have generally failed to confirm benefits, possibly due to their relatively short duration. Objective To evaluate whether long-term supplementation with vitamin E decreases the risk of cancer, cancer death, and major cardiovascular events. Design, Setting, and Patients A randomized, double-blind, placebo-controlled international trial (the initial Heart Outcomes Prevention Evaluation [HOPE] trial conducted between December 21, 1993, and April 15, 1999) of patients at least 55 years old with vascular disease or diabetes mellitus was extended (HOPE-The Ongoing Outcomes [HOPE-TOO]) between April 16, 1999, and May 26, 2003. Of the initial 267 HOPE centers that had enrolled 9541 patients, 174 centers participated in the HOPE-TOO trial. Of 7030 patients enrolled at these centers, 916 were deceased at the beginning of the extension, 1382 refused participation, 3994 continued to take the study intervention, and 738 agreed to passive follow-up. Median duration of follow-up was 7.0 years. Intervention Daily dose of natural source vitamin E (400 IU) or matching placebo. Main Outcome Measures Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. Results Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs 586 (12.3%) in the placebo group (relative risk [RR], 0.94; 95% confidence interval [CI], 0.84-1.06; P=.30); for cancer deaths, 156 (3.3%) vs 178 (3.7%), respectively (RR, 0.88; 95% CI, 0.71-1.09; P=.24); and for major cardiovascular events, 1022 (21.5%) vs 985 (20.6%), respectively (RR, 1.04; 95% CI, 0.96-1.14; P=.34). Patients in the vitamin E group had a higher risk of heart failure (RR, 1.13; 95% CI, 1.01-1.26; P=.03) and hospitalization for heart failure (RR, 1.21; 95% CI, 1.00-1.47; P=.045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. Conclusion In patients with vascular disease or diabetes mellitus, long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk for heart failure.

JAMA, 2001

Context Type 2 diabetes is a growing clinical and public health problem. Preventive efforts relat... more Context Type 2 diabetes is a growing clinical and public health problem. Preventive efforts related to lifestyle modification are not always successful; therefore, alternative prevention strategies need to be studied. Objective To investigate the effectiveness of ramipril, an angiotensin-converting enzyme inhibitor, in preventing diabetes among high-risk persons. Design, Setting, and Participants The randomized, controlled Heart Outcomes Prevention Evaluation trial of 5720 patients older than 55 years without known diabetes but with vascular disease who were followed up for a mean of 4.5 years. The study included 267 hospitals in 19 countries and was conducted between 1994 and 1999. Intervention Patients were randomly assigned to receive ramipril, up to 10 mg/d (n=2837), or placebo (n=2883). Main Outcome Measure Diagnosis of diabetes determined from self-report at follow-up visits every 6 months, compared between the 2 groups. Results One hundred and two individuals (3.6%) in the ramipril group developed diabetes compared with 155 (5.4%) in the placebo group (relative risk [RR], 0.66; 95% confidence interval [CI], 0.51-0.85, PϽ.001). Similar results were noted when different diagnostic criteria were used; in the ramipril group, the RR for diagnosis of diabetes and hemoglobin A 1c greater than 110% was 0.60 (95% CI, 0.43-0.85), for initiation of glucoselowering therapy, 0.56 (95% CI, 0.41-0.77), and for both, 0.51 (95% CI, 0.34-0.76). These effects were also consistently seen in several subgroups examined. Conclusions Ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals. Because these results have important clinical and public health implications, this hypothesis requires prospective confirmation.