Hypertension management in the Multiple Risk Factor Intervention Trial (MRFIT). Six-year intervention results for men in special intervention and usual care groups.

The Multiple Risk Factor Intervention Trial was a large collaborative primary prevention trial designed to test the effects of lowering cardiovascular risk factors (ie, diastolic blood pressure [DBP], serum cholesterol, and cigarette smoking) on mortality rate from coronary heart disease in 12,866 high-risk men aged 35 to 57 years. Men were randomly assigned to either special intervention (SI) or usual care (UC) groups. Usual care men were referred to their regular source of medical care. Special intervention men were seen frequently and underwent intensive intervention initially followed by maintenance intervention in 22 different clinical centers. Hypertension intervention in SI men primarily consisted of a stepped-care pharmacologic approach designed to lower blood pressure (BP). After six years, 58.2% of SI men and 47.0% of UC men were given antihypertensive medication. In both study groups, mean systolic and diastolic BPs decreased from baseline; after six years, overall DBP was 3.2 mm Hg lower in SI men compared with UC men. In hypertensive men (DBP greater than or equal to 90 mm Hg or those taking antihypertensive medication at baseline), after six years, DBP was 4.4 mm Hg lower in the SI group compared with the UC group. Use of specific antihypertensive agents differed substantially between the two groups. Self-reported complaints while taking antihypertensive drugs were minimal in both groups. Weight loss was associated with BP lowering in both study groups, regardless of treatment status.

Relationships of quality-of-life measures to long-term lifestyle and drug treatment in the Treatment of Mild Hypertension Study.

OBJECTIVES: To compare 5 antihypertensive drugs and placebo for changes in quality of life (QL). To assess the relationship of lifestyle factors and change in lifestyle factors to QL in participants with stage I diastolic hypertension. METHODS: The Treatment of Mild Hypertension Study (TOMHS) was a randomized, double-blind, placebo-controlled clinical trial with minimum participant follow-up of 4 years. It was conducted at 4 hypertension screening and treatment academic centers in the United States. The cohort consisted of 902 men and women with hypertension, aged 45 to 69 years, with diastolic blood pressures less than 100 mm Hg. Informed consent was obtained from each participant after the nature of the procedures had been fully explained. Sustained nutritional-hygienic intervention was administered to all participants to reduce weight, to reduce dietary sodium and alcohol intake, and to increase physical activity. Participants were randomized to take (1) acebutolol (n = 132); (2) amlodipine maleate (n = 131); (3) chlorthalidone (n = 126); (4) doxazosin mesylate (n = 134); (5) enalapril maleate (n = 135); or placebo (n = 234). Changes in 7 QL indexes were assessed based on a 35-item questionnaire: (1) general health; (2) energy or fatigue; (3) mental health; (4) general functioning; (5) satisfaction with physical abilities; (6) social functioning; and (7) social contacts. RESULTS: At baseline, higher QL was associated with older age, more physical activity, lower obesity level, male gender, non-African American race, and higher educational level. Improvements in QL were observed in all randomized groups, including the placebo group during follow-up; greater improvements were observed in the acebutolol and chlorthalidone groups and were evident throughout follow-up. The amount of weight loss, increase in physical activity, and level of attained blood pressure control during follow-up were related to greater improvements in QL. CONCLUSIONS: In patients with stage I hypertension, antihypertensive treatment with any of 5 agents used in TOMHS does not impair QL. The diuretic chlorthali-done and the cardioselective beta-blocker acebutolol appear to improve QL the most. Success with lifestyle changes affecting weight loss and increase in physical activity relate to greater improvements in QL and show that these interventions, in addition to contributing to blood pressure control, have positive effects on the general well-being of the individual.

Cardiac status after four years in a trial on nutritional therapy for high blood pressure.

A randomized controlled trial demonstrated the ability of nutritional intervention in place of antihypertensive drugs to maintain blood pressure at normal levels for four years in 39% of less severely hypertensive patients whose blood pressure was previously well controlled by pharmacologic treatment. However, average blood pressures during the trial for patients in the intervention group were higher than those for a comparison group that continued to receive drug therapy throughout the study. Holter monitoring, echocardiography, roentgenography, and electrocardiography done at four years to determine whether blood pressure differences between groups were associated with differences in cardiac status did not indicate any differences in cardiac status favorable to one group compared with the other. Further investigation in larger samples is needed to assess any long-term differences in cardiac status based on such alternate therapies.

Transdermal clonidine reduced some withdrawal symptoms but did not increase smoking cessation.

BACKGROUND: Clonidine may be useful in controlling tobacco withdrawal and in facilitating smoking cessation. This study was developed to test the efficacy of transdermal clonidine in promoting smoking cessation. METHODS: We conducted a five-center, double-blind, placebo-controlled, randomized controlled trial of transdermal clonidine in conjunction with a minimal behavioral intervention for smoking cessation. The intervention was based on the American Lung Association's Freedom From Smoking program. Self report of not smoking was validated with exhaled air carbon monoxide of less than 8 ppm and salivary cotinine of less than 20 ng/mL. Transdermal clonidine therapy began 1 week before the target quit date: 0.1 mg/24 h for the first 4 days increasing to 0.2 mg/24 h for the next 3 days, if the lower dose was tolerated. The highest tolerated dose was then continued for 6 weeks after target quit day. Withdrawal symptoms were measured daily for the first 7 days after target quit day. RESULTS: A total of 213 patients were enrolled (106 active drug and 107 placebo). During the study, 15.5% of patients had drug therapy discontinued due to adverse effects, 24.5% (26/106) taking active drug vs 8.4% (9/107) receiving placebo. There was a significant reduction in anxiety score from 3.0 to 2.4 (placebo vs active) and irritability score from 2.2 to 1.7 (placebo vs active) during the first week after cessation. There was no reduction in other withdrawal symptoms. The overall 12-week abstinence rate was 33.0% (35/106) in the active drug group vs 34.5% (37/107) in the placebo group (not significant). CONCLUSION: This study demonstrated some reduction in early withdrawal symptoms with the use of a clonidine transdermal patch, but no increase in cessation rate, 6 weeks after medication had been discontinued.

Postural hypotension and postural dizziness in elderly women. The study of osteoporotic fractures. The Study of Osteoporotic Fractures Research Group.

BACKGROUND: Postural hypotension and dizziness are common findings in elderly individuals. Although postural hypotension and postural dizziness are often perceived to be strongly associated entities, evidence to support this view in sparse. In addition, there is a lack of knowledge regarding the relationship of postural hypotension and postural dizziness to potential clinical outcomes, such as falls, syncope, and restricted activity. METHODS: We utilized a cross-sectional examination to study the prevalence and correlates of postural hypotension (drop in systolic blood pressure of greater than or equal to 20 mm Hg after 1 minute of standing) and postural dizziness (self-reported dizziness on standing) in 9704 nonblack, ambulatory women aged 65 years and older enrolled in the multicenter Study of Osteoporotic Fractures. First, we examined postural hypotension and postural dizziness as outcomes of risk factors that included medical conditions, medications, and physical findings. Then, we examined falls, syncope, and impaired functional status as outcomes of postural hypotension and postural dizziness. RESULTS: Postural hypotension and postural dizziness were common findings, noted in 14% and 19% of subjects, respectively. However, they were not highly correlated with each other and did not share the same risk factors or associated outcomes. Postural dizziness was more strongly associated than was postural hypotension with history of falling (age-adjusted odds ratios, 1.32 vs 1.02), history of syncope (1.94 vs 1.35), and impaired functional status (1.95 vs 0.76). CONCLUSION: Assessment of dizziness on standing appears to be more important than measurement of postural blood pressure change in ascertaining functional status and risk of falls and syncope in elderly individuals. Future prospective studies of postural dizziness are needed to confirm its value as a predictor of clinical outcomes.

Population-derived comparisons of ambulatory and office blood pressures. Implications for the determination of usual blood pressure and the concept of white coat hypertension.

BACKGROUND: Ambulatory blood pressures (BPs) have generally been reported to be lower than office blood pressures, but population-based data are lacking. METHODS: To better characterize ambulatory and office BP relationships, we explored the interrelationships of BPs measured in the office by mercury sphygmomanometry, 24-hour ambulatory BP measured with a portable device, and echocardiographic left ventricular mass in a random sample of 50 men aged 51 to 72 years drawn from a much larger pool. Office BP was based on the mean of 10 measurements performed over five visits. RESULTS: Among all participants, mean 24-hour ambulatory and mean office BPs were highly correlated: r (systolic/diastolic) = .90/.79; and both mean 24-hour and mean awake ambulatory BPs were significantly higher than mean office BPs. For the subsample not receiving antihypertensive therapy, mean ambulatory and office BPs were similar in terms of their associations with Penn left ventricular mass index (LVMI). No association between BP and left ventricular mass was observed among the subjects receiving antihypertensive medication. CONCLUSIONS: We conclude that a single session of 24-hour ambulatory BP monitoring is unlikely to improve the determination of usual BP in older white men beyond that achievable with BP carefully measured over five separate office visits; and that white coat hypertension is rare in this population.

alpha 1-antagonists in the treatment of hypertension.

A number of agents are now available to treat hypertension. One relatively new class of agents is the selective alpha 1-inhibitors, which have distinct advantages over earlier nonselective alpha-adrenergic receptor-blocking agents. Three alpha 1-inhibitors are reviewed in this article: prazosin, terazosin, and doxazosin. These alpha 1-inhibitors are similar in chemical structure and pharmacological action. alpha 1-Inhibitors lower blood pressure by reducing vascular tone in resistance and capacitance vessels. alpha 1-Inhibitors are similar in effectiveness in blood pressure lowering to other commonly used antihypertensive agents like the thiazide diuretic drugs and beta-blockers, which are efficacious as monotherapy in lowering pressure, as initial agents, or in combination with other antihypertensive agents in multidrug therapeutic regimens. alpha 1-Inhibitors are associated with a reasonably low incidence of serious adverse effects and are essentially free of any adverse metabolic effects. alpha 1-Inhibitors have been shown to beneficially effect blood lipids in several studies. The favorable lipid effect makes alpha 1-inhibitors especially appropriate to use in diabetic hypertensive and other patients with elevated serum lipid levels. The beneficial lipid effects may enhance the ability of alpha 1-inhibitors to prevent coronary heart disease, an outcome that has been difficult to demonstrate in thiazide-based trials.

Dietary sodium reduction for hypertension prevention and treatment.

Nutritional-nonpharmacological approaches for the treatment and prevention of hypertension are of great interest. Sodium reduction is one of the primary methods recommended for these purposes. The general public is interested in the reduction of dietary sodium intake and has responded with a decrease in table salt use, the purchase of lowered sodium food products, and the use of food labels to help guide food purchases. Countervailing trends in the use of convenience foods and dining out increase the difficulty for individuals to lower sodium intake. Clinical trials that have used sodium reduction alone or in combination with other lifestyle therapies have demonstrated the feasibility of reducing dietary sodium intake from 30% to 50% for up to 4 years, in a variety of populations. Trials that used lifestyle and weight loss interventions have also achieved significant reductions in body weight and alcohol consumption and increases in physical activity. A variety of studies indicate that long-term sodium reduction is feasible and that it is acceptable to patients. No negative consequences of these interventions have been observed, and in some cases improvement in the intake of other nutrients has occurred. Nonpharmacological interventions have resulted in hypertension control in significant proportions of the trial populations. These studies demonstrate that the foregoing types of interventions can significantly contribute to hypertension treatment and prevention.

Serum calcium fractions in essential hypertensive and matched normotensive subjects.

Concentrations of serum total calcium and serum calcium fractions were compared between 28 hypertensive subjects and 28 race-sex-age-matched normotensive controls. Mean levels of serum total calcium were not different between the two groups. Hypertensive subjects had lower mean serum levels of ultrafilterable calcium (-0.32 mg/dl; p = 0.01), ionized calcium (-0.07 mg/dl; p = 0.09), and complexed calcium (-0.23 mg/dl; p = 0.04) and higher levels of protein-bound calcium (+0.36 mg/dl; p = 0.07). Estimated dietary calcium intake was similar in the two groups. These findings add to the evidence that essential hypertension is associated with perturbations in calcium metabolism.

Systolic Hypertension of the Elderly Program (SHEP). Part 10: Analysis.

The SHEP is a randomized, placebo-controlled trial that will follow standard clinical trial principles in analyzing data relating to its proposed hypotheses. The protocol has stated a priori the main objective as well as the secondary subgroup hypotheses. Sample size calculations for SHEP have accounted for dropins to and drop-outs from active therapy as well as for the risk of nonstroke death. The sample size achieved (4,736 participants) should be adequate to address the proposed questions. Monitoring procedures have been described and established. A data and safety monitoring board that uses these procedures is closely following the data from the trial. The board will periodically examine the data to determine whether termination of the study is warranted.

Racial and ethnic modifiers of the salt-blood pressure response.

The relation between sodium and blood pressure is a centuries-old question. A substantial body of epidemiological and experimental data has accumulated that strongly implicates NaCl as having a causal role in the genesis of arterial hypertension. Prospective studies that have been performed in diverse populations that have manipulated NaCl exposure by diet or infusion have repeatedly documented an NaCl pressor effect. Further, similar studies in biracial populations have also demonstrated a greater prevalence of "salt sensitivity" in blacks compared with whites. The reasons for this observation are not entirely clear; however, intrinsic or hypertension-induced renal abnormalities that limit natriuretic capacity, reduced Na+,K(+)-ATPase pump activity, other membrane ion transport disturbances, differential exposure to psychological stressors, greater insulin resistance, and dietary factors (reduced Ca+ and K+ intake) have all been suggested as possibly playing a role. Salt sensitivity appears to be a widespread phenomenon. However, it is critically important to determine what factors account for racial differences in salt sensitivity. Moreover, the prevalence of salt sensitivity in the general population is unknown. Current definitions of salt sensitivity are varied and unidirectional. In comparison with bidirectional criteria (blood pressure increase with salt loading and blood pressure decrease with salt restriction), they are probably inadequate to identify salt-sensitive individuals who manifest less extreme blood pressure change after dietary sodium or plasma volume manipulations. More sensitive criteria for diagnosing salt sensitivity will facilitate a better understanding of racial and ethnic differences in the prevalence of salt sensitivity.

Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS)

Problems with sexual function have been a long-standing concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. The Treatment of Mild Hypertension Study (TOMHS) provides an excellent opportunity for examination of sexual function and effects of treatment on sexual function in men and women with stage I diastolic hypertension because of the number of drug classes studied, the double-blind study design, and the long-term follow-up. TOMHS was a double-blind, randomized controlled trial of 902 hypertensive individuals (557 men, 345 women), aged 45 to 69 years, treated with placebo or one of five active drugs (acebutolol, amlodipine maleate, chlorthalidone, doxazosin maleate, or enalapril maleate). All participants received intensive lifestyle counseling regarding weight loss, dietary sodium reduction, alcohol reduction (for current drinkers), and increased physical activity. Sexual function was ascertained by physician interviews at baseline and annually during follow-up. At baseline, 14.4% of men and 4.9% of women reported a problems with sexual function. In men, 12.2% had problems obtaining and/or maintaining an erection; 2.0% of women reported a problem having an orgasm. Erection problems in men at baseline were positively related to age, systolic pressure, and previous antihypertensive drug use. The incidences of erection dysfunction during follow-up in men were 9.5% and 14.7% through 24 and 48 months, respectively, and were related to type of antihypertensive therapy. Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months than participants randomized to placebo (17.1% versus 8.1%, P = .025). Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between the chlorthalidone and placebo groups. Incidence was lowest in the doxazosin group but was not significantly different from the placebo group. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group. In many cases, erection dysfunction did not require withdrawal of medication. Disappearance of erection problems among men with problems at baseline was common in all groups but greatest in the doxazosin group. Incidence of reported sexual problems in women was low in all treatment groups. In conclusion, long-term incidence of erection problems in treated hypertensive men is relatively low but is higher with chlorthalidone treatment. Effects of erection dysfunction with chlorthalidone appear relatively early and are often tolerable, and new occurrences after 2 years are unlikely. The rate of reported sexual problems in hypertensive women is low and does not appear to differ by type of drug. Similar incidence rates of erection dysfunction in placebo and most active drug groups caution against routine attribution of erection problems to antihypertensive medication.

Thiazide diuretics and selective alpha blockers: comparison of use in antihypertensive therapy, including possible differences in coronary heart disease risk reduction.

The results of several important clinical trials have confirmed the benefits of pharmacologic treatment in patients with hypertension. However, some issues concerning this type of treatment have yet to be resolved. For example, it has not been determined whether there are differences among antihypertensive agents with respect to their effects on mortality and morbidity or whether such effects are independent of the alterations in blood pressure resulting from the use of such agents. Thiazide diuretics, the most commonly prescribed antihypertensive drugs, were the first agents proven to be effective and practical for the widespread treatment of hypertension. Alpha blockers, also commonly prescribed antihypertensive drugs, provide equally effective blood pressure control to that of the thiazides, but with a very different metabolic profile. In this article, these drugs are compared for efficacy, side-effect profiles, metabolic effects, and potential for reducing the risk of coronary heart disease.

Lipids and hypertension. Implications of new guidelines for cholesterol management in the treatment of hypertension.

The approach to management of cardiovascular risk factors has been greatly enhanced by the recent publication of results from several large intervention studies. This increased knowledge has led to rapid changes in perspective and to some controversies regarding cardiovascular risk management. The major cardiovascular disease risk factors are high blood pressure, elevated serum cholesterol, and cigarette smoking. In the past, physicians have paid little attention to the latter two factors, focusing primarily on severe hypertension. Initially, the pharmacologic treatment of hypertension consisted mostly of thiazide diuretics, since they were the only agents generally available that were well-tolerated by most patients. Over the past decade, however, new data from large-scale intervention studies and the development of many new classes of antihypertensive agents have considerably improved the approach to managing all three primary risk factors. Recently published results of major clinical trials are likely to further alter physicians' perspectives and influence their practice habits. This article proposes an approach to comprehensive risk management that simultaneously involves all the major risk factors, with emphasis on blood pressure and lipids. The rationale for this integrated approach is based on the following facts: Hypertension trials have not convincingly demonstrated that lowering blood pressure alone reduces the risk for coronary heart disease; Cholesterol lowering has been shown conclusively to reduce the risk of coronary heart disease; Several classes of antihypertensive agents have now been found to significantly affect blood lipids, either adversely or beneficially; and Past observational epidemiologic studies have shown a positive association between blood lipids (cholesterol and triglycerides) and blood pressure, implying that these two conditions commonly occur together. The background supporting these facts, as well as a practical approach to the treatment of hypertension that takes into consideration the management of blood lipids, is provided in this article.

Management of hypertension. Potential trade-offs on coronary risk.

The major risk factors for coronary heart disease remain high blood pressure, cigarette smoking, and abnormal serum lipid levels, including total cholesterol but more specifically elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol levels. Observations made from large-scale trials almost a decade ago suggested that commonly used antihypertensive agents, such as thiazide diuretics and beta-blockers, may adversely influence serum lipid levels. Over time, we realized that these lipid alterations persist long term and are of sufficient magnitude to potentially account for important differences in coronary heart disease risk reduction among various antihypertensive drug regimens. Considering recent National Cholesterol Education Program and Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure recommendations concerning lipid and blood pressure treatment, it is prudent and timely to rethink our approach to antihypertensive therapy in patients with abnormal serum lipid levels. Therefore, when lipids are a concern, appropriate dietary treatments should be advised and antihypertensive therapy that has a beneficial or neutral impact on serum lipid levels should be considered.

Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial.

The Multiple Risk Factor Intervention Trial was a randomized clinical trial that studied the efficacy of multiple risk factor reduction in lowering coronary heart disease mortality in high-risk men. Nutrition counseling based on a fat-modified eating pattern resulted in a significant reduction of total cholesterol and low-density lipoprotein cholesterol. However, based on further analysis not involving comparisons of randomized groups, the reduction in total cholesterol appeared to be blunted by the effects of the antihypertensive medication utilized in the stepped-care therapy in this study. The use of diuretics was associated with an increase in triglycerides and a lesser decrease in total plasma cholesterol when compared with non-diuretic users. The use of diuretic therapy was also associated with a slight decrease in high-density lipoprotein cholesterol, when compared with changes in those not receiving diuretic therapy. The combination of diuretics plus propranolol was related to a substantial decrease in high-density lipoprotein cholesterol in both the Special Intervention and Usual Care participants. The changes in lipoproteins for men receiving diuretic therapy are probably influenced substantially by nutritional factors, especially weight change. Concomitant nutritional changes must be considered when analyzing the short- and long-term effects of therapy with diuretics or other antihypertensive drugs on lipoprotein metabolism.

Background and design of the new U.S. trial on diet and drug treatment of "mild" hypertension (TOMHS).

A multicenter, randomized, controlled, double-blind U.S. trial is comparing the combined effects of diet treatment and 1 of 5 active drug regimens with diet treatment alone, for the long-term management of middle-aged adults with "mild" hypertension. Factors stimulating this trial are data documenting the high prevalence of mild hypertension in the adult population; mild hypertension's responsibility for a high proportion of morbidity and mortality attributable to hypertension overall; data from long-term hypertension intervention trials showing reduced morbidity and mortality of people with mild hypertension with use of either diuretics or beta blockers as step-1 therapy, and other trials that failed to demonstrate beneficial impact on morbidity and mortality, possibly due to residual questions concerning aspects of benefit to risk ratios with these medications; recent data from trials showing long-term control of mild hypertension and other risk factors by nutritional means; lack of data from long-term trials on benefit to risk ratios with newer drugs such as selective alpha 1 inhibitors, angiotensin converting enzyme inhibitors and calcium channel blockers; paucity of data from trials on long-term combined effects of diet and drug therapy, and of diet alone, for people with mild hypertension. During the next few years, phase 1 of the trial will study 6 groups of drugs. The step-1 drugs are angiotensin converting enzyme inhibitor (enalapril), alpha 1 inhibitor (doxazosin), beta blocker (acebutolol), calcium channel blocker (amlodipine), diuretic (chlorthalidone) and placebo. All participants are to receive vigorous sustained nutritional counseling to reduce obesity, moderate sodium intake and avoid heavy use of alcohol. Key endpoints for phase 1 of the study are the need for additional medication to control mild hypertension, side effects (i.e., clinical and biochemical) and consequent need to discontinue drug and quality of life. Phase-1 data are to be used to complete the phase-2 design, with the ultimate aim to assess effects on morbidity and mortality.

Characteristics of participants at baseline in the Treatment of Mild Hypertension Study (TOMHS).

The Treatment of Mild Hypertension Study (TOMHS) is a randomized, double-blind clinical trial currently being conducted to compare the effects of nonpharmacologic therapy alone with those of 1 of 5 active drug regimens combined with nonpharmacologic therapy, for long-term management of patients with mild hypertension. Six classes of drugs were studied: (1) acebutolol (beta blocker), (2) amlodipine (calcium antagonist), (3) chlorthalidone (diuretic), (4) doxazosin (alpha 1 antagonist), (5) enalapril (angiotensin-converting enzyme inhibitor) and (6) placebo. All participants received nutritional-hygienic advice to reduce weight and sodium and alcohol intakes and to increase physical activity. End points include blood pressure change, side effects and quality-of-life indices; incidence of electrocardiographic and echocardiographic abnormalities; and incidence of cardiovascular clinical events, including death, among participants receiving drugs as first-step treatment as well as nonpharmacologic treatment compared with incidence among those participants randomized to nonpharmacologic treatment only as the initial step.

The drug treatment of mild hypertension in the Multiple Risk Factor Intervention Trial. A review.

The Multiple Risk Factor Intervention Trial was a long term study on the benefit of lowering risk factors for coronary heart disease mortality in middle-aged men. Study participants were randomised to either 'special intervention' or 'usual care'. Intensive intervention for special intervention men involved cholesterol lowering dietary advice, behaviour modification for cigarette smoking and a stepped care pharmacological approach to lower blood pressure. Overall, at 6 years, there was a 7.1% lower coronary heart disease mortality in special intervention compared with usual care men, a statistically non-significant difference (Confidence Interval +25 to -15%). Subgroup analysis revealed that special intervention men who were hypertensive at baseline and who had resting ECG abnormalities experienced a higher coronary heart disease mortality than the comparable usual care group. Within group Cox regression analysis, with coronary heart disease mortality as the dependent variable, revealed an interaction between diuretic use and resting ECG abnormalities in special intervention men. Additional analyses of clinics revealed a higher special intervention/usual care mortality in those clinics that used mainly hydrochlorothiazide in special intervention hypertensives. Results of the Multiple Risk Factor Intervention Trial raise important questions concerning the treatment of mild hypertension, and the clinical significance of metabolic alterations of antihypertensive drugs.

A comparison of antihypertensive drug effects on the progression of extracranial carotid atherosclerosis. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS).

Hypertension is a major risk factor for coronary heart disease (CHD) and is the primary risk factor for stroke. Drug trials lowering blood pressure by pharmacological means have demonstrated impressive reduction in both fatal and nonfatal stroke (33 to 50%) that are virtually identical to the predicted stroke reduction, considering the observed diastolic blood pressure change (5 to 6mm Hg). On the other hand, reduction of CHD risk has been less impressive in these same trials. Although statistically significant, the reduction in CHD risk is roughly one-half (14%) of that predicted (25%) when results from these drug trials are analysed in aggregate. Most trials have used moderate to high dosages of thiazide diuretics or beta-blockers as therapies. Several factors may account for the disappointing results in CHD risk reduction. These drugs may induce metabolic disturbances in lipids, increased glucose tolerance, insulin resistance, or cause inadequate regression of left ventricular hypertrophy, thus attenuating the predicted reduction in CHD risk associated with pharmacological blood pressure lowering. Isradipine is a new dihydropyridine calcium antagonist that is highly effective in lowering blood pressure. Isradipine also has antiatherogenic properties in animal models of atherosclerosis. The effect of isradipine on atherosclerosis in humans is unknown. The Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS) is a 3-year double-blind, randomised trial in over 800 men and women with hypertension, aged 40 years or older. The primary aim of MIDAS is to compare the efficacy of isradipine 2.5 to 5.0mg twice daily vs hydrochlorothiazide 12.5 to 25mg twice daily in retarding the progression of extracranial carotid atherosclerosis.(ABSTRACT TRUNCATED AT 250 WORDS)