Diabetes mellitus: an example of a well-considered disease. Introduction

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Prevention of cardiovascular diseases using a combined pharmacological approach: is there any place for a polypill"?"

peer reviewedIn the June 28, 2003 issue of the British Medical Journal, an extensive literature survey based on various large meta-analyses of the efficacy and safety of the reduction of four cardiovascular risk factors (cholesterol, arterial blood pressure, platelet aggregation, homocysteine) leads to the conclusion that a combined pharmacological intervention should reduce ischaemic heart disease events by 88% and strokes by 80% in at risk individuals. Therefore, a new paradigm is proposed for the prevention of cardiovascular diseases. This new strategy would consist in the systematic prescription to people with a history of heart attack or stroke, those with any form of obliterative atherosclerotic vascular disease or diabetes, and everyone aged 55 and older of a fixed combination of 6 pharmacological agents independently of initial risk factor profile.... Such pharmacological formulation, called "polypill", should contain a statin, three blood pressure lowering drugs (each at half standard dose), aspirin (75 mg/day) and folic acid (0.8 mg/day). We discuss the pros and cons of this new paradigm. However, the efficacy of such "polypill" remains to be demonstrated in a large controlled clinical trial as well as its superiority as compared to a classical approach of cardiovascular prevention based upon the individual optimal correction of each risk factor thanks a dose titration of each pharmacological compound

Experience collecting interim data on mortality: an example from the RALES study

INTRODUCTION: The Randomized Aldactone Evaluation Study (RALES) randomized 822 patients to receive 25 mg spironolactone daily and 841 to receive placebo. The primary endpoint was death from all causes. Randomization began on March 24, 1995; recruitment was completed on December 31, 1996; follow-up was scheduled to continue through December 31, 1999. Evidence of a sizeable benefit on mortality emerged early in the RALES. The RALES data safety monitoring board (DSMB), which met semiannually throughout the trial, used a prespecified statistical guideline to recommend stopping for efficacy. At the DSMB's request, its meetings were preceded by an 'endpoint sweep', that is, a census of all participants to confirm their vital status. METHODS: We used computer simulation to evaluate the effect of the sweeps. RESULTS: The sweeps led to an estimated 5 to 8% increase in the number of reported deaths at the fourth and fifth interim analyses. The data crossed the statistical boundary at the fifth interim analysis. If investigators had reported all deaths within the protocol-required 24-h window, the DSMB might have recommended stopping after the fourth interim analysis. DISCUSSION: Although endpoint sweeps can cause practical problems at the clinical centers, sweeps are very useful if the intervals between patient visits or contact are long or if endpoints require adjudication by committee, reading center, or central laboratory. CONCLUSION: We recommend that trials with interim analyses institute active reporting of the primary endpoints and endpoint sweeps

Prospects for Creation of Cardioprotective and Antiarrhythmic Drugs Based on Opioid Receptor Agonists

It has now been demonstrated that the μ, δ(1), δ(2), and κ(1) opioid receptor (OR) agonists represent the most promising group of opioids for the creation of drugs enhancing cardiac tolerance to the detrimental effects of ischemia/reperfusion (I/R). Opioids are able to prevent necrosis and apoptosis of cardiomyocytes during I/R and improve cardiac contractility in the reperfusion period. The OR agonists exert an infarct‐reducing effect with prophylactic administration and prevent reperfusion‐induced cardiomyocyte death when ischemic injury of heart has already occurred; that is, opioids can mimic preconditioning and postconditioning phenomena. Furthermore, opioids are also effective in preventing ischemia‐induced arrhythmias

The PROSPER Study (PROspective study of pravastatin in the elderly at risk)

peer reviewedStatins reduce coronary and cerebrovascular mortality and morbidity in middle-aged individuals. Until recently, their efficacy and safety in elderly people had not yet been firmly established. PROSPER was a controlled, randomised study involving 2,804 men and 3,000 women aged 70-82, with a history of, or risk factors for cardiovascular disease. Their baseline cholesterol level was 135-350 mg/dl; they were randomised to either 40 mg pravastatin per day, or matching placebo. Average follow-up was 3.2 years. The primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Pravastatin lowered LDL-cholesterol (-34%), and reduced the incidence of the primary endpoint (-15%; CI 95%: 3-26%; p = 0.014). Coronary death and non-fatal myocardial infarction risk was also reduced (-19%; p = 0.006), and mortality from coronary disease fell by 24% (p = 0.043). The risk for stroke, however, was unaffected (p = 0.8), whereas the incidence of transient ischemic attacks was reduced by 25%, which was (marginally) insignificant (p = 0.051). Pravastatin had no effect on cognitive functions or incapacity. New cancers were more frequent amongst pravastatin-treated individuals (+25%; p = 0.020). However incorporation of this new data in a meta-analysis of all pravastatin and all statin trials revealed no overall increase of cancer risk

Interheart: nine risk factors predict nine out of ten myocardial infarctions

peer reviewedINTERHEART is a standardised case-control study of acute myocardial infarction in 52 countries representing every inhabited continent. 15152 cases and 14820 controls were enrolled. Collectively, 9 factors accounted for 90% of myocardial infarctions in men and 94% in women. These factors were 6 risk factors (dyslipidaemia characterized by high apoB/apoA1 ratio, smoking, hypertension, diabetes mellitus, abdominal obesity and stressful psychosocial factors) and 3 protective factors (daily consumption of fruits and vegetables, regular alcohol consumption, and regular physical activity). These findings suggest that interventions targeting these 9 factors have the potential to prevent most premature cases of myocardial infarction and that these strategies should be implemented worldwide

Cardiovascular prevention: could the polypill reduce the risk of clinical inertia and poor compliance?

peer reviewedThe concept of "polypill" for cardiovascular prevention was introduced in 2003 in a landmark paper of the British Medical Journal. A model based on results provided by evidence-based medicine suggested that a "polypill", that contains a statin, three blood pressure lowering drugs (each at half standard dose), aspirin and folic acid, would result in an 80% reduction in the incidence of coronary and cerebrovascular events, while being associated with a good tolerance profile and offering a favourable cost-effectiveness ratio. The present paper aims at presenting the new advances dealing with this new paradigm in cardiovascular prevention. We will present the progresses of the "polypill" concept since 2003, the results of a first controlled clinical trial, the pharmaceutical feasibility for routine clinical use and the potential pharmaco-economical impacts of such a strategy. The "polypill" may offer a solution to avoid physician's clinical inertia and reduce patients's lack of compliance, two drawbacks in the field of cardiovascular prevention.Le concept de la «polypill» pour la prévention des maladies cardio-vasculaires a été mis en exergue en 2003 dans le British Medical Journal. Une analyse modélisée des données de la médecine factuelle suggérait que la prescription d’une combinaison de six médicaments – une statine, trois anti-hypertenseurs à faibles doses, de l’aspirine et de l’acide folique – permettrait de réduire d’environ 80 % les accidents coronariens et cérébro-vasculaires, sans entraîner de manifestations indésirables notables et avec un rapport coût-efficacité favorable. Le présent article vise à faire le point, quelques années plus tard, sur les avancées concernant ce nouveau paradigme en prévention cardio-vasculaire. Nous envisagerons successivement les progrès conceptuels concernant la «polypill» depuis 2003, les résultats d’un premier essai clinique contrôlé, la faisabilité pharmaceutique dans une perspective de routine clinique et les impacts pharmaco-économiques possibles d’une telle stratégie. La « polypill » pourrait offrir une solution pour limiter l’inertie clinique du médecin et remédier au manque d’observance du patient, deux fléaux dans le domaine de la prévention cardio-vasculaire

Physical exercise and sports: from the best to the worst

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Info-Congress. Bisoprolol in Congestive Heart Failure

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