Objective To determine the effects of antiplatelet therapy among patients at high risk of occlusive vascular events. Design Collaborative meta-analyses (systematic overviews). Inclusion criteria Randomised trials of an antiplatelet regimen versus control or of one antiplatelet regimen versus another in high risk patients (with acute or previous vascular disease or some other predisposing condition) from which results were available before September 1997. Trials had to use a method of randomisation that precluded prior knowledge of the next treatment to be allocated and comparisons had to be unconfounded-that is, have study groups that differed only in terms of antiplatelet regimen. Studies reviewed 287 studies involving 135 000 patients in comparisons of antiplatelet therapy versus control and 77 000 in comparisons of different antiplatelet regimens. Main outcome measure "Serious vascular event": non-fatal myocardial infarction, non-fatal stroke, or vascular death. Results Overall, among these High risk patients, allocation to antiplatelet therapy reduced the combined outcome of any serious vascular event by about one quarter; non-fatal myocardial infarction was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). Absolute reductions in the risk of having a serious vascular event were 36 (SE 5) per 1000 treated for two years among patients with previous myocardial infarction; 38 (5) per 1000 patients treated for one month among patients with acute myocardial infarction; 36 (6) per 1000 treated for two years among those with previous stroke or transient ischaemic attack; 9 (3) per 1000 treated for three weeks among those with acute stroke; and 22 (3) per 1000 treated for two years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01)). In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extracranial bleeding. Aspirin was the most widely studied antiplatelet drug, with doses of 75-150 mg daily at least as effective as higher daily doses. The effects of doses lower than 75 mg daily were less certain. Clopidogrel reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 (4) vascular events per 1000 (P <0.0001) but caused 23 major (but rarely fatal) extracranial bleeds per 1000. Conclusions Aspirin (or another oral antiplatelet drug) is protective in most types of patient at increased risk of occlusive vascular events, including those with an acute myocardial infarction or ischaemic stroke, unstable or stable angina, previous myocardial infarction, stroke or cerebral ischaemia, peripheral arterial disease, or atrial fibrillation, Low dose aspirin (75-150 mg daily) is an effective antiplatelet regimen for long term use, but in acute settings an initial loading dose of at least 150 mg aspirin may be required. Adding a second antiplatelet drug to aspirin may produce additional benefits in some clinical circumstances, but more research into this strategy is needed.

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Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients

Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.

ContextComplications of atherosclerosis cause most morbidity and mortality
in patients with diabetes mellitus. Despite the frequency and severity of
disease, proven medical therapy remains incompletely understood and underused.ObjectiveTo review the epidemiology, pathophysiology, and medical and invasive
treatment of atherosclerosis in patients with diabetes mellitus.Data SourcesUsing the index terms diabetes mellitus, myocardial infarction, peripheral vascular
diseases, cerebrovascular accident, endothelium, vascular smooth muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we
searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data
sources included bibliographies of identified articles and preliminary data
presented at recent cardiology conferences.Study SelectionWe selected original investigations and reviews of the epidemiology,
pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized,
double-blind, controlled studies, when available, to support therapeutic recommendations.
Criteria for data inclusion (168 of 396) included publication in a peer-reviewed
journal or presentation at a national cardiovascular society–sponsored
meeting.Data ExtractionData quality was determined by publication in peer-reviewed literature.
Data extraction was performed by one of the authors.Data SynthesisDiabetes mellitus markedly increases the risk of myocardial infarction,
stroke, amputation, and death. The metabolic abnormalities caused by diabetes
induce vascular dysfunction that predisposes this patient population to atherosclerosis.
Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme
inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular
events. Although diabetic patients undergo revascularization procedures because
of acute coronary syndromes or critical limb ischemia, the outcomes are less
favorable than in nondiabetic cohorts.ConclusionsSince most patients with diabetes die from complications of atherosclerosis,
they should receive intensive preventive interventions proven to reduce their
cardiovascular risk.

Diabetes and atherosclerosis: epidemiology, pathophysiology, and management.

Diabetes mellitus affects approximately 100 million persons worldwide.1 Five to ten percent have type 1 (formerly known as insulin-dependent) and 90% to 95% have type 2 (non–insulin-dependent) diabetes mellitus. It is likely that the incidence of type 2 diabetes will rise as a consequence of lifestyle patterns contributing to obesity.2 Cardiovascular physicians are encountering many of these patients because vascular diseases are the principal causes of death and disability in people with diabetes. The macrovascular manifestations include atherosclerosis and medial calcification. The microvascular consequences, retinopathy and nephropathy, are major causes of blindness and end-stage renal failure. Physicians must be cognizant of the salient features of diabetic vascular disease in order to treat these patients most effectively. The present review will focus on the relationship of diabetes mellitus and atherosclerotic vascular disease, highlighting pathophysiology and molecular mechanisms (Part I) and clinical manifestations and management strategies (Part II).

Abnormalities in endothelial and vascular smooth muscle cell function, as well as a propensity to thrombosis, contribute to atherosclerosis and its complications. Endothelial cells, because of their strategic anatomic position between the circulating blood and the vessel wall, regulate vascular function and structure. In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis.3 Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of l-arginine.4 The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells.4 In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with …

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Diabetes and Vascular Disease Pathophysiology, Clinical Consequences, and Medical Therapy: Part I

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)62110-1.pdf

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.

Objectives. —This report presents information on the effects of aspirin on mortality, the occurrence of cardiovascular events, and the incidence of kidney disease in the patients enrolled in the Early Treatment Diabetic Retinopathy Study (ETDRS). Study Design. —This multicenter, randomized clinical trial of aspirin vs placebo was sponsored by the National Eye Institute. Patients. —Patients (N=3711) were enrolled in 22 clinical centers between April 1980 and July 1985. Men and women between the ages of 18 and 70 years with a clinical diagnosis of diabetes mellitus were eligible. Approximately 30% of all patients were considered to have type I diabetes mellitus, 31% type II, and in 39% type I or II could not be determined definitely. Intervention. —Patients were randomly assigned to aspirin or placebo (two 325-mg tablets once per day). Main Outcome Measures. —Mortality from all causes was specified as the primary outcome measure for assessing the systemic effects of aspirin. Other outcome variables included cause-specific mortality and cardiovascular events. Results. —The estimate of relative risk for total mortality for aspirin-treated patients compared with placebo-treated patients for the entire study period was 0.91 (99% confidence interval, 0.75 to 1.11). Larger differences were noted for the occurrence of fatal and nonfatal myocardial infarction; the estimate of relative risk was 0.83 for the entire follow-up period (99% confidence interval, 0.66 to 1.04). Conclusions. —The effects of aspirin on any of the cardiovascular events considered in the ETDRS were not substantially different from the effects observed in other studies that included mainly nondiabetic persons. Furthermore, there was no evidence of harmful effects of aspirin. Aspirin has been recommended previously for persons at risk for cardiovascular disease. The ETDRS results support application of this recommendation to those persons with diabetes at increased risk of cardiovascular disease. (JAMA. 1992;268:1292-1300)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=399755&pdfFileName=jama_268_10_033.pdf

Robert Sorenson

Papers

Aspirin Effects on Mortality and Morbidity in Patients With Diabetes Mellitus: Early Treatment Diabetic Retinopathy Study Report 14