The role of warfarin and aspirin in secondary prevention of stroke

Antithrombotic therapy plays a central role in secondary prevention after ischemic stroke and transient ischemic attack. The choice among warfarin, aspirin, and other antiplatelet agents, however, depends on the cause of stroke and other individual patient characteristics. The use of warfarin anticoagulation in patients with atrial fibrillation and ischemic stroke has demonstrated robust reductions in risk of recurrent events, comparable with those achieved in primary prevention. Warfarin may also be recommended for patients with other high-risk cardioembolic sources of stroke. The role of warfarin in noncardioembolic ischemic stroke is more controversial. The Warfarin Aspirin Recurrent Stroke Study found no evidence of superiority of warfarin over aspirin in stroke patients overall, nor in any major stroke subtype, including those patients with patent foramen ovale. In post-hoc analyses, there was some evidence of benefit with warfarin in patients with cryptogenic stroke without hypertension. Risks of major bleeding did not differ significantly between warfarin and aspirin groups. For most patients with noncardioembolic strokes, therefore, antiplatelet therapy is the preferred option, although clinician experience still dictates practice in individual situations. Newer antiplatelet agents, and the combination of novel agents with aspirin, are also finding a role in stroke prevention as clinical trial data become available.     

The role of fibric acid derivatives in the secondary prevention of coronary heart disease

Fibric acid derivatives effectively lower triglycerides and raise high-density lipoprotein (HDL) cholesterol, but their effect on low-density lipoprotein (LDL) cholesterol is weakly beneficial (small decreases) to adverse (small increases) and varies according to the triglyceride level. Early primary prevention studies of atherosclerosis using the fibric acid derivative clofibrate showed only modest effects on atherosclerosis and an alarming increase in mortality in the intervention group. Although the Helsinki Heart Study later demonstrated that gemfibrozil decreased cardiac endpoints in primary prevention without increasing total mortality, the efficacy of fibric acid derivatives in both primary and secondary prevention of atherosclerosis has remained widely in doubt. Nevertheless, many patients with atherosclerosis have normal or even low LDL cholesterol, but elevated triglyceride, and low HDL cholesterol; furthermore, even aggressive LDL cholesterol lowering with HMG Co-A (3-hydroxy 3-methylglutaryl coenzyme A) reductase inhibitors (statins) fails to prevent the majority of atherosclerotic events. These findings have kindled increased interest in the use of fibric acid derivatives in atherosclerosis prevention, especially through treatment of non-LDL dyslipidemias. Recent studies with angiographic and clinical end-points have now provided evidence for a beneficial effect of at least some drugs in this class in the secondary prevention of atherosclerosis.     

Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study)

Summary Nicotinamide has been recently introduced, in addition to intensive insulin therapy for patients with recent-onset insulin-dependent diabetes mellitus (IDDM) to protect beta cells from end-stage destruction. However, available data are conflicting. A double blind trial in 56 newly-diagnosed IDDM patients receiving nicotinamide for 12 months at a dose of 25 mg/kg body weight or placebo was designed in order to determine whether this treatment could improve the integrated parameters of metabolic control (insulin dose, glycated haemoglobin and C-peptide secretion) in the year after diagnosis. In addition to nicotinamide or placebo, patients received three to four insulin injections daily to optimize blood glucose levels. Patients treated with nicotinamide or placebo received similar doses of insulin during follow-up and 1 year after diagnosis with comparable glycated haemoglobin levels (6.7 ± 1.8 % nicotinamide vs 7.1 ± 0.6 % placebo). Basal and glucagon stimulated C-peptide secretion detectable at diagnosis were similarly preserved in the course of 12 months follow-up both in nicotinamide and placebo treated patients. No adverse effects were observed in patients receiving nicotinamide. When age at diagnosis was taken into account, nicotinamide treated older patients ( > 15 years of age) showed significantly higher stimulated C-peptide secretion than placebo treated patients (p < 0.02). These results suggest that nicotinamide can preserve and improve stimulated beta-cell function only in patients diagnosed after puberty. We conclude that in these patients nicotinamide can be added to insulin at the time of disease diagnosis to maintain and possibly improve residual beta-cell function. However, further studies on patients diagnosed after puberty are needed to confirm whether nicotinamide can be considered an additional tool to insulin in early-onset IDDM. [Diabetologia (1995) 38: 848–852] Received: 20 June 1994 and in final revised form: 20 January 1995     

Clinical relevance of statins: their role in secondary prevention

Five large randomized clinical trials show the benefits of lipid lowering with statins on cardiac morbidity and mortality. Three of these were secondary-prevention trials--the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, Cholesterol and Recurrent Events (CARE), and Scandinavian Simvastatin Survival Study (4S). The CARE and LIPID studies, performed with pravastatin, comprise populations that are representative of the majority of patients with coronary disease in that they included subjects with 'average' cholesterol levels. The 4S study, using simvastatin, comprised a patient population with elevated lipid levels. Pooled data from three trials, CARE, LIPID, and the West of Scotland Coronary Prevention Study (WOSCOPS), were examined in the Pravastatin Pooling Project (PPP). Individual patient data from these three event trials were pooled into a single database, permitting subgroup analyses and providing increased power. In the PPP, pravastatin-treated patients had significantly lower all-cause mortality (7.9, vs. 9.8% in those receiving placebo, a relative risk reduction of 20%). Pravastatin treatment was associated with a significant 24% reduction in CHD mortality and a nonsignificant difference in other vascular deaths (17%) and noncardiovascular deaths (12%). However, the reductions in absolute risk were much larger in those with a history of coronary heart disease than in those without. In the combined analysis of CARE and LIPID, there was also a uniform relative risk reduction in both men and women. In high-risk groups such as diabetics, smokers, hypertensives, and the elderly, there were also significant risk reductions in clinical end points. Finally, in the 598 participants, who had a stroke (90% of which were non-fatal), CARE and LIPID individually demonstrated reductions in non-fatal and total stroke. These data confirm that benefits of treatment in secondary prevention of coronary heart disease encompasses prevention of stroke as well as coronary heart disease events. The benefits are found in those who have had unstable angina as well as myocardial infarction. These findings strengthen even further the case for much more widespread use of statins in secondary prevention.     

The potential role of AT(1)-receptor blockade in the prevention and reversal of atherosclerosis

The renin-angiotensin system may contribute to the development and progression of atherosclerosis both by increasing blood pressure and by direct effects on all phases of the atherogenic process. Genetic determinants of renin-angiotensin system activation, notably the DD genotype of angiotensin converting enzyme (ACE), are associated with an increased risk of cardiovascular events, as is increased plasma renin activity. In addition, angiotensin II has been shown to increase the uptake and oxidation of low density lipoprotein (LDL) by macrophages and endothelial cells. Angiotensin II also stimulates the production of interleukin 6 and activates the pro-inflammatory factor nuclear factor kappa(B), leading to expression of adhesion molecules and recruitment of monocytes and macrophages, and increases the production of pro-coagulatory factors. In animal experiments, treatment with ACE inhibitors or angiotensin AT(1)-receptor blockers has been shown to have anti-atherogenic effects. Studies with candesartan have shown that this agent produces a dose-dependent reduction in uptake of oxidised LDL by mouse macrophages in vitro, and reduces cholesterol accumulation and atherosclerosis development in the aorta of Watanabe rabbits. These effects were independent of changes in blood pressure. Such findings suggest that AT(1)-receptor blockers may be beneficial in reducing mortality and morbidity resulting from atherosclerotic disease, and are consistent with the findings from large outcome trials with ACE inhibitors in patients at risk of cardiovascular events.     

Milk in the prevention and management of type 2 diabetes: The potential role of milk proteins

Globally, diabetes mellitus is not only considered a leading cause of mortality and morbidities but has also created a substantial economic burden. There is growing evidence that foods and their components can be implemented in the prevention and management of type 2 diabetes mellitus (T2DM). Increased dairy consumption has been linked to a lower risk of T2DM. The protective role of dairy foods in the development of T2DM is thought to be largely attributable to dairy nutrients, one of them being dairy protein. There is considerable evidence that milk proteins increase the postprandial insulin response and lower the postprandial blood glucose response in both healthy subjects and patients with T2DM. The exact mechanisms by which milk proteins lower postprandial glucose levels are yet to established; however, the amino acids and bioactive peptides derived from milk proteins are thought to modify a physiological milieu, which includes delayed gastric emptying and the enhancement of incretin and insulin responses, consequently leading to lower postprandial glucose levels. The present review will focus on providing a clear presentation of the potential implementation of milk proteins as a dietary supplement in the prevention and management of T2DM by summarizing the relevant supporting evidence for this particular topic.     

Do calcium inhibitors have any role in secondary prevention of myocardial infarction?]

The value of using calcium blockers in post-infarction secondary prevention is controversial. The HELD meta-analysis (1989) involving 17,759 patients concluded that they made no contribution in this indication (9.8% mortality rate vs 9.3% in the control group). The findings of the DAVIT II study with verapamil demonstrate a significant reduction in the infarction recurrence rate (18% vs 21.6%) in the treatment group. In the patients without heart failure, there was some benefit in terms of reduced mortality (7.7% vs 11.8%). The true contribution of calcium channel inhibitors, relative to that of beta-blockers in post-infarction medication should be analyzed in function of the various infarction sub-groups (no Q-wave, thrombolytic, with or without left ventricular dysfunction), of the calcium channel inhibitor being investigated and of the administration regimen.     

The physician's role in tuberculosis prevention

Tuberculosis is not only treatable but preventable as well. A number of options exist for reducing the transmission of tubercle bacilli. Practitioners are in a position to intervene directly on behalf of their patients and indirectly by promptly reporting infectious patients to local public health authorities. A considerable body of information supports the use of isoniazid in persons who are infected by Mycobacterium tuberculosis and who also have readily identifiable characteristics that place them at increased risk for developing tuberculosis.     

Diet and prevention of coronary heart disease: the potential role of phytochemicals

Epidemiological studies, and some clinical trials, demonstrate that a proper diet reduces the rate of occurrence of cardiovascular disorders. Several in vitro studies suggest that some components of plant foods, most of which sharing a phenolic structure, are endowed with interesting 'pharmacological activities'. This article reviews the evidence that links a high dietary intake of phytochemicals from various sources with a reduced incidence of coronary heart disease.