Aspirin increases nitric oxide formation in chronic stable coronary disease.

INTRODUCTION: There are no published randomized data on secondary prevention in humans about whether aspirin affects nitric oxide (NO) formation. In patients with chronic stable coronary disease, we tested whether aspirin at clinically relevant doses increases NO formation. MATERIALS AND METHODS: In a randomized, double-blind trial, 37 patients from 2 cardiology office practices were assigned to daily doses of 81, 162.5, 325, 650, or 1300 aspirin for 12 weeks. Primary prespecified outcome measures were changes in heme oxygenase (HO-1), a downstream target of NO formation, and asymmetrical dimethyl arginine (ADMA), a competitive inhibitor of NO synthase. RESULTS: There were no significant differences for HO-1 or ADMA between any of the clinically relevant doses of aspirin tested, so all were combined. For HO-1, there was a significant increase (10.29 ± 2.44, P < .001) from baseline (15.37 ± 1.85) to week 12 (25.66 ± 1.57). The mean ratio (MR) of week 12 to baseline for HO-1 was significantly higher than 1.0 (1.67, confidence interval [CI] from 1.60 to 1.74, P < .001). For ADMA, there was a significant decrease (-0.24 ± 0.11, P < .001) from baseline (0.78 ± 0.08) to week 12 (0.54 ± 0.07). The MR of week 12 to baseline for ADMA was significantly lower than 1.0 (0.69, CI from 0.66 to 0.73, P < .001). CONCLUSIONS: In patients with chronic stable coronary disease, all clinically relevant daily doses of aspirin tested, from 81 to 1300 mg, produce similar and statistically significant increases in HO-1 and decreases in ADMA. These are the first randomized data on secondary prevention patients. These data support the hypothesis that aspirin has additional beneficial effects mediated through NO formation. Further research, including direct randomized comparisons on atherosclerosis using noninvasive techniques as well as on occlusive vascular disease events, is necessary.

The need for increased utilization of statins after occlusive stroke.

In registry data, among patients who have survived an occlusive stroke, only about half are treated with statins despite a large and persuasive totality of evidence, which includes large-scale randomized trials. In a comprehensive worldwide meta-analysis of 90,056 participants, statins conferred statistically significant and clinically important reductions in stroke and myocardial infarction, as well as cardiovascular and total mortality. In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial of patients with prior stroke or transient ischemic attack, high-potency statins decreased risks of recurrent stroke and major cardiovascular events. In a nonrandomized subgroup analysis, patients who achieved a 50% or greater reduction in low-density lipoprotein cholesterol (LDL-C) compared to those who achieved <50% had a statistically significant 31% reduction in risk of stroke. Finally, in a comprehensive, worldwide meta-analysis of all trials of cardiovascular disease, patients treated with intensive compared with conventional statin therapy had significantly reduced risks of stroke and myocardial infarction as well as any cardiovascular event or death. Based on this totality of evidence the US federal guidelines as well as those of the American Heart Association/American Stroke Association have been revised to recommend that patients with a prior occlusive stroke should have an optional goal for LDL of 70 mg/dL. All these considerations pose important and timely clinical and public health challenges concerning the need for wider utilization of statins in the treatment of patients with stroke.

Control of health care-associated infections (HAI): winning both the battles and the war.

At present, the United States (US) experiences its greatest life expectancy due mainly to improvements in mortality from cardiovascular diseases, which include coronary heart disease and stroke. These, in turn, are due largely to decreases in cigarette smoking as well as earlier and more aggressive diagnoses and treatments. These advances in health care delivery are, not surprisingly, accompanied by increasing numbers of complicating health care-associated infections (HAI). HAIs are a major and increasing cause of morbidity and mortality in the US as well as around the world. To win both the battles and the war against HAI requires a multidisciplinary approach to the vigorous implementation and maintenance of proper infection control procedures. This should include continuous surveillance and reinforcement of guidelines to enhance evidence-based practices to prevent and control HAI. It will also be necessary to implement a new paradigm of early and formal education of future health care providers into the biology of infection as well as the principles of infection control in the classroom and subsequently, with translation into their clinical training. Finally, there must also be the incorporation and expansion of continuing medical education for established health care providers about prevention and control of HAI.

A randomized trial of aspirin at clinically relevant doses and nitric oxide formation in humans.

BACKGROUND: we performed the first test in humans of whether aspirin at clinically relevant doses increases nitric oxide (NO) formation. METHODS: seventy primary prevention patients with metabolic syndrome were randomly assigned to 81 mg, 162.5 mg, 325 mg, 650 mg, or 1300 mg aspirin daily for 12 weeks to test changes in heme oxygenase (HO-1), a downstream target of NO formation and asymmetrical dimethylarginine (ADMA), a competitive inhibitor of NO synthase. FINDINGS: for HO-1, the mean was 29.37 nanograms per milliliter at baseline and 57.45 at 12 weeks giving a mean ratio (MR) of 1.96 (P < .001) and 95% confidence interval (CI) from 1.91 to 2.00. There was no effect modification by dose or gender (P = .341). For ADMA, the mean was 1.70 micromoles per liter at baseline and 0.81 at 12 weeks, giving an MR of 0.48 (P < .001) and CI from 0.46 to 0.49. There was no effect modification by dose but a possible difference by gender (P = .055). INTERPRETATION: in high-risk primary prevention patients, aspirin significantly increases markers of NO formation. All doses produce similar increases in HO-1 and decreases in ADMA. The antiplatelet properties of aspirin to irreversibly inhibit platelet dependent cyclooxygenase are sufficient to explain benefits in patients with occlusive vascular diseases. Nonetheless, these data contribute to the formulation of the hypothesis that aspirin has additional beneficial effects mediated through NO formation. Further research, including direct randomized comparisons on atherosclerosis using noninvasive techniques as well as on occlusive vascular disease events, is necessary to test whether this hypothesis has clinical or public health relevance.

Academic perspectives on the United States Food and Drug Administration's guidance for industry on diabetes mellitus.

The United States Food and Drug Administration (FDA) has issued Guidance for Industry, subtitled Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. From an academic perspective, these regulatory requirements provide undue emphasis on the results of phase 2 trials not designed to test hypotheses about clinical cardiovascular events. Phase 2 trials should be considered hypothesis formulating either alone or in their meta-analyses. Thus, this FDA guidance for industry does not adequately emphasize the importance and necessity of well designed and conducted phase 3 trials of sufficient size, dose, and duration to test the hypothesis formulated from the meta-analysis of the phase 2 trials. We believe that the guiding principle about benefits and risks of drugs should be that rational decisions for individual patients and the health of the general public should be based on a sufficient totality of evidence. When that totality of evidence is incomplete, it is appropriate to remain uncertain. We believe phase 2 trials should be performed mainly for proof of concept and dose ranging. To detect reliably the most plausible small to moderate effects of drugs, the totality of evidence must include large scale randomized phase 3 trials. These individual trials must be of sufficient size, dose, and duration as well as achieve high adherence and follow-up. They must also achieve enough clinical endpoints to distinguish reliably between the null hypothesis of no effect and the most plausible alternative hypotheses of small benefit or harm.

Hypothesis formulation from subgroup analyses: nonadherence or nonsteroidal anti-inflammatory drug use explains the lack of clinical benefit of aspirin on first myocardial infarction attributed to "aspirin resistance".

BACKGROUND: "Aspirin resistance" has been defined as the occurrence of cardiovascular events despite regular intake of aspirin. One major analytic study suggesting that "aspirin resistance" is a clinical reality was unable to control for confounding by nonadherence or nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We formulated a hypothesis from subgroup analyses in the Physicians' Health Study, a randomized double-blind placebo-controlled trial testing 325 mg of aspirin every other day among 22,071 apparently healthy US male physicians. We classified participants by nonadherence or NSAIDs and used time-varying Cox proportional hazard models to adjust for confounding. RESULTS: After 5 years, the blinded aspirin component was terminated early based on the unanimous recommendation of the Data and Safety Monitoring Board. Of 378 confirmed first myocardial infarctions (139 aspirin and 239 placebo), the relative risk (RR) was 0.56 (95% CI 0.45-0.70, P < .00001). There was no statistically significant reduction among aspirin <150/180 pills/y (RR = 0.91, 95% CI 0.61-1.35, P = .62) or NSAID users >60 days per year (RR = 1.54, 95% CI 0.68-3.47, P = .31). There was a statistically significant reduction among aspirin >150/180 pills/y and NSAID users <60 days/y (RR = 0.55, 95% CI 0.44-0.70, P < or = .0001) and an increase among aspirin <150/180 pills/y and NSAID users >60 days/y (RR of 3.43, 95% CI 1.41-8.33, P = .007). CONCLUSIONS: In subgroup analyses useful to formulate hypotheses from a large randomized trial in apparently healthy men, aspirin nonadherence or NSAID use explained the lack of clinical benefit of aspirin on first myocardial infarction that has been attributed to "aspirin resistance." Direct randomized comparisons are necessary in trials designed a priori to test this hypothesis.

Use of aspirin among diabetics in the primary prevention of cardiovascular disease: need for reliable randomized evidence and astute clinical judgment.

BACKGROUND: The American Heart Association Guidelines recommend aspirin for all apparently healthy individuals whose 10-year risk of a first coronary heart disease (CHD) event is >10%. METHODS: The United States (US) Preventive Services Task Force (USPSTF) has recently updated its guidelines to encourage men 45 to 79 years and women 55 to 79 years to use aspirin when the potential benefit outweighs the potential harm. In addition, in some US guidelines, diabetes is considered to be a CHD risk equivalent. RESULTS: Two recently published trials, the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) and the Prevention of Progression of Arterial Disease and Diabetes (POPADAD), concluded that aspirin did not reduce risks of CHD. Both JPAD and POPADAD had inadequate statistical power. Reliable randomized evidence is necessary to provide a sufficient totality of evidence about benefits and risks among diabetics. CONCLUSION: At present, astute individual clinical judgments are necessary.

Modest dietary reductions in blood cholesterol have important public health benefits.

Large reductions in blood cholesterol produce major clinical and public health benefits. Based on extrapolations from randomized evidence, assuming no threshold, a 3% to 4% reduction in blood cholesterol would decrease risk of coronary heart disease (CHD) by 12%. If so, treating larger numbers of people at lower risk would yield greater reductions in CHD than treating smaller numbers at higher risk. High- and moderate-risk patients require evidence-based doses of high-potency statins, as adjuncts to dietary management and benefits to individuals are large and easily quantifiable in randomized trials. In low-risk patients, however, dietary modifications contribute to a public health benefit while that benefit to any individual is small. Thus, the hypothesis that modest dietary reductions in blood cholesterol have important public health benefits is easily quantifiable by extrapolation from existing data but impossible to test among randomized individuals, as the sample sizes and costs are prohibitively large.

Lumbar spinal stenosis: can positional therapy alleviate pain?

METHODS: We analyzed a retrospective case series of 52 patients with spinal stenosis confirmed by spinal imaging and walking limitations treated with a wheeled walker set to induce lumbosacral flexion. RESULTS: Of the 52 patients, improvement in ambulation was classified as excellent for 30 (58%), good for 7 (13%), moderate for 8 (16%), and poor for 7 (13%). Among 48 patients with neurogenic pain, pain relief was classified as excellent for 22 (46%), good for 11 (23%), moderate for 7 (14.5%), and poor for 8 (16.5%). CONCLUSIONS: These retrospective data from a case series support the hypothesis that positional therapy with a wheeled walker set to induce lumbosacral flexion relieves lower extremity symptoms of spinal stenosis. However, an adequate test of this hypothesis will require randomized trials of sufficient size and duration that include objective clinical endpoints such as quality-of-life measures, immobility complications and need for drugs, physical therapy, procedures including epidural injections, and spinal surgery. In the meantime, this conservative strategy is an option for patients following the recommendations of the North American Spine Society, or for those who have contraindications (or aversions) to surgery or epidural injections, or who have found these options ineffective. Positional therapy with a wheeled walker offers the possibility of short-term benefits for ambulation and pain, with minimal risks and costs.

The need for wider and appropriate utilization of aspirin and statins in the treatment and prevention of cardiovascular disease.

There is an increasing burden of occlusive cardiovascular disease (CVD) in developed, as well as in developing, countries. In fact, the WHO has projected that CVD will become the leading cause of death in the world in the next 10 years. The proximate cause of virtually all occlusive vascular events is thrombosis and the principal underlying cause is atherosclerosis. Aspirin, which inhibits platelet-dependent cyclooxygenase for the entire life of the platelet, has clinically important antithrombotic effects. Statins, which principally decrease low-density lipoprotein cholesterol, triglycerides and increase high-density lipoprotein cholesterol, have clinically important antiatherogenic effects. In secondary prevention, in a wide range of patients who have survived a prior myocardial infarction (MI), occlusive stroke, transient ischemic attack, as well as other high-risk conditions, long-term use of aspirin confers statistically significant and clinically important reductions in MI, stroke and CVD death. In addition, aspirin confers similar benefits when administered during acute MI or acute occlusive stroke. In primary prevention, aspirin confers a statistically significant and clinically important reduction in risk of a first MI but the data on stroke and CVD death remain inconclusive, so aspirin should be prescribed on an individual basis by the healthcare provider who weighs this clear benefit against long-term side effects. In a meta-analysis of 14 randomized trials of 90,056 subjects treated for 5 years, statins confer statistically significant and clinically important reductions in MI, stroke, CVD death and total mortality. In a meta-analysis of randomized trials of statins, in which aspirin was used in varying frequencies, the combination of aspirin and statins conferred greater clinical benefits than either agent alone on MI, occlusive stroke and CVD death. At present, the wider and more appropriate use of aspirin and statins will reduce premature MI, stroke and CVD death.

Guidelines for management of high-risk African Americans with multiple cardiovascular risk factors: recommendations of an expert consensus panel.

African Americans have higher rates of cardiovascular disease (CVD) than do Caucasians, which contributes significantly to their reduced life expectancy. Most African American adults have at least one major risk factor for CVD. Nonetheless, African Americans are often underdiagnosed and undertreated, despite presenting to the healthcare system late in their course, often after a CVD event. Patients with multiple risk factors have a CVD risk far greater than the sum of their individual risks. Metabolic syndrome tends to be clustered to a greater degree in African American women. Aggressive management of African Americans is necessary. In this report, we provide guidelines for the management of high-risk African Americans. For each individual risk factor, we address existing data and guidelines in the general population, existing data in African Americans, and proposed guidelines for African Americans based on evidence or extrapolation. In particular, for elevated cholesterol and blood pressure, evidence is emerging that lower is better, so aggressive management strategies are necessary. For dyslipidemia, statins alone will generally reach the goal, but for hypertension, multiple drugs are usually necessary. We conclude that further research in African Americans is necessary to complete the totality of evidence.