David T. Nash

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Influence of baseline lipids on effectiveness of pravastatin in the CARE trial

OBJECTIVESnWe sought to assess the influence of baseline lipid levels on coronary event rates and the effectiveness of pravastatin therapy in the Cholesterol And Recurrent Events (CARE) study.nnnBACKGROUNDnThe CARE study cohort provided a relatively unique opportunity to examine the relation between lipid levels and clinical events in a post-myocardial infarction (MI) population with relatively low cholesterol and low density lipoprotein (LDL) cholesterol values.nnnMETHODSnThere were 4,159 patients with a previous infarct and a total cholesterol level <240 mg/dl, LDL cholesterol level 115 to 174 mg/dl and triglyceride level <350 mg/dl randomly allocated to placebo (n=2,078) or pravastatin 40 mg/day (n=2,081). Time to either coronary death or nonfatal MI (primary end point) or to the secondary end point, which included undergoing a coronary revascularization procedure, was determined as a function of baseline lipids (total, LDL, high density lipoprotein [HDL] cholesterol and triglyceride levels).nnnRESULTSnQuartile analysis indicated important effects for LDL cholesterol, in which a higher LDL was associated with greater cardiac event rates (in the placebo group, every 25-mg/dl increment in LDL was associated with a 28% increased risk [5% to 56%, p=0.015]) in the primary event. The differential event rates with respect to baseline LDL cholesterol for placebo and pravastatin groups reduced the difference in clinical outcomes at lower LDL cholesterol levels. In both the placebo and pravastatin groups, an inverse relation between baseline HDL cholesterol and cardiac events was observed (10 mg/dl lower baseline HDL cholesterol level was associated with a 10% [0% to 19%, p=0.046] increase in coronary death or nonfatal MI).nnnCONCLUSIONSnWithin the LDL cholesterol levels in CARE (115 to 174 mg/dl), baseline values influenced both the risk of events in the placebo group as well as the clinical effectiveness of pravastatin therapy.

Baseline characteristics in the Cholesterol and Recurrent Events (CARE) trial of secondary prevention in patients with average serum cholesterol levels.

Abstract CARE will determine whether 5 years of cholesterol-lowering therapy reduces recurrent coronary disease events in 4,159 patients who have had an AMI. The mean total cholesterol and LDL-C levels in CARE (209 and 139 mg/dl) are similar to the average levels for the US population. The results of CARE will have relevance to the treatment of the majority of patients with coronary disease who have average rather than elevated cholesterol levels.

A double-blind parallel trial to assess the efficacy of doxazosin, atenolol and placebo in patients with mild to moderate systemic hypertension

The antihypertensive and lipid effects of doxazosin and atenolol were compared in a 10-week, double-blind, parallel, placebo-controlled study. The 129 adults enrolled had mild to moderate hypertension (average supine diastolic blood pressures for doxazosin, atenolol and placebo were 100.6, 101.0 and 99.7 mm Hg, respectively). Patients were randomly assigned to treatment with doxazosin, 1 to 16 mg daily, atenolol, 50 to 100 mg daily or placebo. Among 114 patients included in the efficacy analysis, standing blood pressure (systolic/diastolic) changed by -13/-11 mm Hg with doxazosin (n = 37), -12/-12 mm Hg with atenolol (n = 39) and +1/-1 mm Hg with placebo (n = 38). Mean reductions in blood pressure for doxazosin and atenolol were significantly greater than those for placebo (p less than 0.01), although no statistically significant differences between the active agents were noted. Serum lipid measurements were evaluable for 116 patients, and the 38 doxazosin-treated patients in this group experienced reductions in total cholesterol, total triglyceride and very low density lipoprotein cholesterol levels. Both doxazosin and atenolol demonstrated comparable acceptance profiles. Doxazosin is an effective hypotensive agent with beneficial effects on serum lipid levels.

Translating current knowledge into dementia prevention.

Considerable knowledge has been gained from epidemiologic studies and randomized clinical trials regarding risk factors for dementia, including Alzheimer disease (AD) and vascular dementia (VaD). Most identified risk factors for dementia are similar to vascular disease risk factors for heart disease and stroke. In 2010, the National Institutes of Health Conference concluded that there are no validated modifiable factors to reduce the incidence of AD or to change its course. This research perspective specifically concerning AD disregards the fact that in community-dwelling elderly, the most common forms of dementia involve the cerebral macrovasculature and microvasculature, manifesting as VaD and mixed dementia (the combination of VaD and AD) in autopsy-confirmed cases. Thus, prevention of dementia in clinical practice should be considered from this broader and more relevant view and not just a research perspective on “pure” AD. Practicing clinicians can reasonably state to patients that, although more definitive research is clearly needed, the management and treatment of vascular disease risk factors are likely beneficial not only to prevent heart disease and stroke, but also common forms of dementia in the community.

Achieving BP goals with valsartan and HCTZ alone and in combination: pooled analysis of two randomized, double-blind, placebo-controlled studies

ABSTRACT Background: Most patients with hypertension will require combination therapy to achieve blood pressure (BP) goals, especially the elderly, obese, or those with stageu20092 hypertension. Objective: To assess BP response and time to achieve BP goals in a diverse population of hypertensive patients treated with hydrochlorothiazide, valsartan, or a combination. Methods: For this secondary post-hoc analysis, data were pooled from two similar randomized, double-blind, 8-week trials that evaluated hydrochlorothiazide (12.5–25u2009mg) and valsartan (160u2009mg) monotherapies, their combination (160/12.5u2009mg), and placebo. Subgroups were defined by age, hypertension severity, and obesity. Adults with diastolic BP ≥u200995 and ≤u2009115u2009mmHg were included. Goal rates were estimated from a logistic model with treatment, study, age group, race, and baseline body mass index as factors and baseline diastolic BP as a covariate. Kaplan–Meier estimates were used to calculate the time to achieve BP goals. Main outcome measures: Efficacy variables were reductions from baseline to study end in systolic BP and diastolic BP, rates of achieving BP goals (<u2009140/90u2009mmHg), and time to achieve BP goals. Adverse events were also reported for the pooled trials. Results: BP reductions at study end and goal achievement rates were greater with combination therapy (–20/15u2009mmHg and 72%, respectively) than with either monotherapy (valsartan 160u2009mg: –14/11u2009mmHg, 61%; hydrochlorothiazide 25u2009mg: –14/10u2009mmHg, 50%) for the overall population (Nu2009=u20091313) and in patient subgroups. Patients treated with initial combination therapy reached goal in 27–56% of the time needed for those treated with monotherapy. Combination therapy was well tolerated and was associated with a decreased incidence of hypokalemia compared with hydrochlorothiazide monotherapy. Conclusions: Compared with monotherapy, combination therapy resulted in greater reductions in BP and achievement of goal BP in a shorter period of time. Although interpretation of this study is subject to the limitations associated with any post-hoc analysis, the results suggest that initiating treatment with combination therapy may be considered for expedient and effective BP control.

Gluten Sensitivity: New Epidemic or New Myth? Every Major Change in Our Diet Carries With It the Possibility of Unforeseen Risks

Fueled in part by recent best-selling books that warn of the evils of gluten in our diets, a significant proportion of our population is now either avoiding foods that contain gluten or eliminating gluten entirely from their diets, and these numbers continue to grow. The gluten-free trend-and the accompanying multibillion dollar industry it has created-stems from the spreading belief that eating foods containing wheat or other gluten-laden grains may not only result in weight gain and obesity but can also lead to a laundry list of ailments ranging from depression and anxiety to arthritis and autism. One popular book contends that current recommendations for a high-grain, low-fat diet underlie much of todays chronic health problems and that a low-carbohydrate, high-fat/cholesterol diet is ideal. Every major change in our diet carries with it the possibility of unforeseen risks. Concern about the impact of such popularized dietary recommendations on overall well-being-and on cardiovascular health in particular-warrants discussion in the medical community.

Gluten Sensitivity - New Epidemic or New Myth

Fueled in part by recent bestselling books that warn of the evils of gluten in our diets, a significant proportion of our population is now either avoiding foods that contain gluten or eliminating gluten entirely from their diets, and these numbers continue to grow. The gluten-free trend—and the accompanying multibillion-dollar industry it has created—stems from the spreading belief that eating foods containing wheat or other gluten-laden grains may not only result in weight gain and obesity, but can also lead to a laundry list of ailments ranging from depression and anxiety to arthritis and autism. One popular book contends that current recommendations for a high-grain/low-fat diet underlie much of todays chronic health problems and that a low-carbohydrate, high-fat/cholesterol diet is ideal. Every major change in our diet carries with it the possibility of unforeseen risks. Concern about the impact of such popularized dietary recommendations on overall well-being—and on cardiovascular health in particular—warrants discussion in the medical community.

Commentary on “A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.” Primary prevention of dementia in Alzheimer's disease: A perspective from prevention research in cardiovascular disease and stroke

Symposium 2008.’’ Primary prevention of dementia in Alzheimer’s disease: A perspective from prevention research in cardiovascular disease and stroke Howard Fillit*, David T. Nash, Diana Shineman Institute for the Study of Aging and Alzheimer’s Drug Discovery Foundation, New York, NY, USA Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, NY, USA Syracuse Preventive Cardiology and College of Medicine, Upstate Medical University, Syracuse, NY, USA Alzheimer’s & Dementia 5 (2009) 149–153

Need for a moratorium on percutaneous transluminal coronary angioplasty in stable coronary artery disease

Available evidence suggests that medical treatment of low-risk patients with stable coronary artery disease (CAD) may be at least equivalent in efficacy to percutaneous transluminal coronary angioplasty (PTCA) in reducing the occurrence of myocardial ischemic events. Despite extensive use of this procedure, the superiority of PTCA over medical therapy for prolongation of life has not been demonstrated. In fact, use of PTCA in patients with stable CAD without first attempting to modify risk factors is currently considered by some experts to be suboptimal therapy. Therefore, it is reasonable to suggest that a moratorium be declared on the use of PTCA in the treatment of chronic stable angina in low-risk patients until such patients undergo an aggressive program to control modifiable risk factors, particularly low-density lipoprotein (LDL) cholesterol levels, for a minimum of 6 weeks. This period of time will not unduly delay the effective use of invasive treatment, and, if patients are seen weekly, blood pressure and lipid levels can usually be controlled within this time frame. A moratorium on a procedure that occurs 1,300 times every day in the United States alone may appear to be a draconian measure, but a review of the who, what, where, when, why, and how of this moratorium suggests it is appropriate, if not overdue.