Importance of potassium in cardiovascular disease.

The pivotal role of potassium (K+) in cardiovascular disease and the importance of preserving potassium balance have become clinical hot points, particularly as relates to new and emerging cardioprotective and renoprotective therapies that promote potassium retention. Although clinicians may be aware of the critical nature of this relationship, quite frequently there is some uncertainty as to the best way to monitor potassium levels in the face of a host of pathologic states and/or accompanying drug therapies that affect serum levels and/or total body potassium balance. Moreover, guidelines for monitoring of serum potassium levels are at best tentative and oftentimes are translated according to the level of concern of the respective physician. To address these uncertainties, an expert group was convened that included representatives from multiple disciplines. They attempted to reach consensus on the importance of K+ in hypertension, stroke, and arrhythmias as well as practical issues on maintaining K+ balance and avoiding K+ depletion. Because of the complexity of this topic, issues of hyperkalemia will be addressed in a forthcoming manuscript.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): clinical center recruitment experience.

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) is a randomized clinical outcome trial of antihypertensive and lipid-lowering therapy in a diverse population (including substantial numbers of women and minorities) of 42,419 high-risk hypertensives aged > or = 55 years with a planned mean follow-up of 6 years. In this paper, we describe our experience in the identification, recruitment, and selection of clinical centers for this large simple trial capable of meeting the recruitment goals outlined for ALLHAT, and we highlight factors associated with clinical center performance. Over 135,000 recruitment brochures were mailed to physicians. Requests for information and application packets were received from 9351 (6.8%) interested investigators. A total of 1053 completed applications were received and 909 sites (86%) were eventually approved to join the trial. Of the approved sites, 278 either later declined participation or were never activated, and 8 were closed within a year for lack of enrollment. The final 623 randomizing centers exceeded the trial's recruitment goal to enroll at least 40,000 participants into the trial, although the recruitment period was extended 1.5 years longer than planned. Fewer than a quarter of the sites (22.6%) were recruited from academic medical centers or Department of Veterans Affairs Medical Centers. More than half of the sites (54.7%) were private solo or group practices, which contributed 53% of randomized participants. Community health centers comprised about 8% of the ALLHAT sites and 2.9% were part of health maintenance organizations. More than 22% of the principal investigators reported that they had no previous clinical research experience. In summary, ALLHAT was successful in recruiting a diverse group of clinical centers to achieve its patient recruitment goals.

Pulse pressure changes with six classes of antihypertensive agents in a randomized, controlled trial.

Pulse pressure has been more strongly associated with cardiovascular outcomes, especially myocardial infarction and heart failure, than has systolic, diastolic, or mean arterial pressure in a variety of populations. Little is known, however, of the comparative effects of various classes of antihypertensive agents on pulse pressure. In retrospective analyses of the Veterans Affairs Single-Drug Therapy for Hypertension Study, we compared changes in pulse pressure with 6 classes of antihypertensive agents: 1292 men with diastolic blood pressure of 95 to 109 mm Hg on placebo were randomized to receive hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, prazosin, or placebo. Drug doses were titrated to achieve a goal diastolic blood pressure of <90 mm Hg during a 4- to 8-week medication titration phase. Pulse pressure change (placebo subtracted) was assessed from baseline to the end of the 3-month titration and 1-year maintenance. Mean baseline systolic, diastolic, and pulse pressures were 152, 99, and 53 mm Hg, respectively. Reductions in pulse pressure during titration were greater (P<0.001) with clonidine (6.7 mm Hg) and hydrochlorothiazide (6.2 mm Hg) than with captopril (2.5 mm Hg), diltiazem (1.6 mm Hg), and atenolol (1.4 mm Hg); reduction with prazosin (3.9 mm Hg) was similar to all but clonidine. After 1 year, pulse pressure was reduced significantly more (P<0.001) with hydrochlorothiazide (8.6 mm Hg) than with captopril and atenolol (4.1 mm Hg with both); clonidine (6.3 mm Hg), diltiazem (5.5 mm Hg), and prazosin (5.0 mm Hg) were intermediate. These data show that classes of antihypertensive agents differ in their ability to reduce pulse pressure. Whether these differences affect rates of cardiovascular events remains to be determined.

Clinical overview of hypertension and emerging treatment considerations.

Managing hypertension is a complex undertaking, where even the definition of the disorder is subject to discussion. Recently, there has been controversy concerning the most appropriate measure to determine health risks associated with hypertension. In the past, diastolic blood pressure (DBP) was the prime measure for defining hypertension, but currently systolic blood pressure (SBP) and pulse pressure have gained favor. Evidence now suggests that all three measures should be considered as part of the hypertensive profile, with the patient's age determining the relative importance of each. Aggressive treatment of hypertension may reduce morbidity and mortality. Data from trials clearly indicate that, for all stages of hypertension, the goal should be a maximum SBP of <150 mm Hg and a DBP of <90 mm Hg, with DBP values as low as 70 mm Hg being safe. For individuals with diabetes mellitus, these target values should be even lower--SBP <140 mm Hg and DBP <80 mm Hg. As a significant number of deaths attributable to hypertension occur in patients who are not diagnosed as hypertensive but whose blood pressure (BP) is above the optimal level of 120/80 mm Hg, lowering BP levels in this group is recommended as well, with lifestyle modification being first-line therapy. Because controlling BP to <140/90 mm Hg often requires the use of two or three agents, the tolerability of the entire regimen must be considered. However, with the multitude of antihypertensive drugs currently available, no patient's BP should remain above the 150/90 mm Hg level.

Alcohol consumption and hypertension.

Many observational studies have shown a relationship between three or more alcoholic drinks daily and hypertension. Reduction in alcohol intake is associated with lowering of blood pressure in randomized clinical trials: each drink per day reduction in intake lowers systolic and diastolic blood pressure by approximately 1 mm Hg. Although regular alcohol consumption seems to reduce the incidence of atherothrombotic cardiovascular events, excessive alcohol intake increases the risk of many medical and psychosocial problems. For persons with hypertension who drink excessively, average maximum alcohol intake of one drink per day in women and two drinks per day in men is a reasonable goal, if drinking is not otherwise contraindicated.

Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program.

The treatment of hypertension with high-dose thiazide diuretics results in potassium depletion and a limited benefit for preventing coronary events. The clinical relevance of hypokalemia associated with low-dose diuretics has not been assessed. To determine whether hypokalemia that occurs with low-dose diuretics is associated with a reduced benefit on cardiovascular events, we analyzed data of 4126 participants in the Systolic Hypertension in the Elderly Program (SHEP), a 5-year randomized, placebo-controlled clinical trial of chlorthalidone-based treatment of isolated systolic hypertension in older persons. After 1 year of treatment, 7.2% of the participants randomized to active treatment had a serum potassium <3.5 mmol/L compared with 1% of the participants randomized to placebo (P<0.001). During the 4 years after the first annual visit, 451 participants experienced a cardiovascular event, 215 experienced a coronary event, 177 experienced stroke, and 323 died. After adjustment for known risk factors and study drug dose, the participants who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo. Within the active treatment group, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia (P<0.05). The participants who had hypokalemia after 1 year of treatment with a low-dose diuretic did not experience the reduction in cardiovascular events achieved among those who did not have hypokalemia.

Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: Stroke incidence and mortality rates are higher in the southeastern region of the United States, which is called the "Stroke Belt." We compared the response to antihypertensive medication use in patients from different US regions. METHODS: The short-term and 1-year efficacy of the antihypertensive medications hydrochlorothiazide, atenolol, diltiazem hydrochloride (sustained release), captopril, prazosin hydrochloride, and clonidine was compared by US region in a randomized controlled trial of 1,105 men with hypertension from 15 US Veterans Affairs medical centers. RESULTS: Compared with patients outside the Stroke Belt, patients inside the Stroke Belt achieved significantly lower treatment success rates of diastolic blood pressure control at 1 year with hydrochlorothiazide (63% vs 41%), atenolol (62% vs 46%), captopril (60% vs 30%), and clonidine (69% vs 43%); there were no differences in treatment success rates with diltiazem (70% vs 71%) or prazosin (54% vs 53%). When controlling for race, patients inside the Stroke Belt had significantly lower treatment success rates with hydrochlorothiazide (P = .003) and clonidine (P = .003), and the lower success rate with atenolol approached significance (P = .15). Regardless of region, blacks were less likely than whites to achieve treatment success with atenolol (P = .02) or prazosin (P = .03) and more likely with diltiazem (P = .05). There was a trend for blacks residing inside the Stroke Belt to have a lower treatment success rate than other race-region groups when treated with captopril (P = .07). Many regional and racial differences in diet, lifestyle, and other characteristics were observed. After adjustment for these characteristics by regression analysis, the effect of residing inside the Stroke Belt remained for captopril (P = .01) and clonidine (P = .01) and approached significance for hydrochlorothiazide (P = .10). CONCLUSIONS: Hypertension in patients residing inside the Stroke Belt responded less to the use of several antihypertensive medications and important differences were shown in a number of characteristics that may affect the control of blood pressure, compared with patients residing outside the Stroke Belt.

Accessing data from external centralized sources to enhance analysis of a completed clinical trial.

After the data collection phase of a clinical trial has been completed, new hypotheses may surface which require additional data before they can be tested. In the Veterans Affairs Cooperative Study on Single Drug Therapy of Hypertension, we investigated the relationship between location of the participating center, race and ability to control blood pressure. The analysis indicated poorer blood pressure control among sites located in the "stroke belt" (southeastern United States), especially among African-Americans. We sought to determine whether the effect was attributable to socioeconomic patterns; however, income data were not collected as part of the original study. Therefore, we accessed centralized data bases to obtain zipcode-level income information for the randomized study patients. This approach yielded estimates of income data for 94.3% of the patients and compared favorably to data acquisition rates for variables which were collected prospectively in the study.

The role of diastolic blood pressure when treating isolated systolic hypertension.

OBJECTIVE: To assess the role of treated diastolic blood pressure (DBP) level in stroke, coronary heart disease (CHD), and cardiovascular disease (CVD) in patients with isolated systolic hypertension (ISH). DESIGN: An analysis of the 4736 participants in the Systolic Hypertension in the Elderly Program (SHEP) was undertaken. The SHEP was a randomized multicenter double-blind outpatient clinical trial of the impact of treating ISH in men and women aged 60 years and older. MAIN OUTCOME MEASURES: Cox proportional hazards regression analysis, with DBP and systolic blood pressure (SBP) as time-dependent covariables. RESULTS: After adjustment for the baseline risk factors of race (black vs other), sex, use of antihypertensive medication before the study, a composite variable (diabetes, previous heart attack, or stroke), age, and smoking history (ever vs never) and adjustment for the SBP as a time-dependent variable, we found, for the active treatment group only, that a decrease of 5 mm Hg in DBP increased the risk for stroke (relative risk, [RR], 1.14; 95% confidence interval [CI], 1.05-1.22), for CHD (RR, 1.08; 95% CI, 1.00-1.16), and for CVD (RR, 1.11; 95% CI, 1.05-1.16). CONCLUSIONS: Some patients with ISH may be treated to a level that uncovers subclinical disease, and some may be overtreated. Further studies need to determine whether excessively low DBP can be prevented by more careful titration of antihypertensive therapy while maintaining SBP control. It is reassuring that patients receiving treatment for ISH never perform worse than patients receiving placebo in terms of CVD events.

Diuretics and beta-blockers do not have adverse effects at 1 year on plasma lipid and lipoprotein profiles in men with hypertension. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

BACKGROUND: Concern based on the reported short-term adverse effects of antihypertensive agents on plasma lipid and lipoprotein profiles (PLPPs) has complicated the therapy for hypertension. OBJECTIVE: To compare the long-term (1-year) effects of 6 different antihypertensive drugs and placebo on PLPPs in a multicenter, randomized, double-blind, parallel-group clinical trial in 15 US Veterans Affairs medical centers. PATIENTS AND METHODS: A total of 1292 ambulatory men, 21 years or older, with diastolic blood pressures (DBPs) ranging from 95 to 109 mm Hg taking placebo were randomized to receive placebo or 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, or prazosin. After drug titration, patients with a DBP of less than 90 mm Hg were followed up for 1 year. Plasma lipids and lipoprotein profiles were determined at baseline, after initial titration, and at 1 year. RESULTS: After 8 weeks on a regimen of hydrochlorothiazide, increases of 3.3 mg/dL (0.09 mmol/L) in total cholesterol and 2.7 mg/dL in apolipoprotein B were significantly different (P< or =.05) from decreases of 9.3 mg/dL in total cholesterol and 5.4 mg/dL in ApoB levels while receiving prazosin but not from placebo. Patients achieving positive DBP control using hydrochlorothiazide (responders) showed no adverse changes in PLPPs, whereas nonresponders exhibited increases in triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. Plasma lipids and lipoprotein profiles did not change significantly among treatment groups after 1 year except for minor decreases in high-density lipoprotein 2 levels using hydrochlorothiazide, clonidine, and atenolol. CONCLUSIONS: None of these 6 antihypertensive drugs has any long-term adverse effects on PLPPs and, therefore, may be safely prescribed. Previously reported short-term adverse effects from using hydrochlorothiazide are limited to nonresponders.

Hypertension in the elderly.

The decade of the 1990s has clarified the perspective on treating hypertension in the elderly and provided a wealth of evidence to assist in the treatment of elevated blood pressure in older persons. Despite this wealth of information, important questions remain about treatment of hypertension in the elderly.

The clinical significance of systolic hypertension.

Large-scale epidemiologic studies and clinical trials have contributed to an increased recognition of the importance of systolic hypertension. Data from landmark epidemiologic studies such as the Multiple Risk Factor Intervention Trial screenee follow-up and the Framingham Heart Study have demonstrated that elevated systolic blood pressure dramatically increases the risk of cardiovascular events. Of particular concern is the extremely high risk associated with isolated systolic hypertension (ISH), which is much more common in the elderly than in young adults. Clinical trials have identified significant risk reductions after treatment with diuretics or the dihydropyridine calcium antagonist nitrendipine in older individuals with ISH. Beta blockers have not been associated with such benefits. The recently released sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends drug therapy for all patients with stage 1 (140 to 159 mm Hg) or stage 2-3 (> or = 160 mm Hg) systolic hypertension, whether it occurs in isolation or in conjunction with diastolic hypertension. The sixth JNC report identified diuretics as the initial therapy of choice, with a long-acting dihydropyridine calcium channel blocker as an alternative if diuretics are ineffective or not well tolerated. More research is needed to evaluate other classes of drugs in this setting. Regardless of the choice of therapy, patients should be encouraged to adopt lifestyle modifications such as weight loss, exercise, sodium restriction, and reduced alcohol consumption.

Age-race subgroup compared with renin profile as predictors of blood pressure response to antihypertensive therapy. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents.

CONTEXT: Renin profiling and age-race subgroup may help select single-drug therapy for stage 1 and stage 2 hypertension. OBJECTIVE: To compare the plasma renin profiling and age-race subgroup methods as predictors of response to single-drug therapy in men with stage 1 and 2 hypertension as defined by the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. DESIGN: The Veterans Affairs Cooperative Study on Single-Drug Therapy of Hypertension, a randomized controlled trial. SETTING: Fifteen Veterans Affairs hypertension centers. PATIENTS: A total of 1105 ambulatory men with entry diastolic blood pressure (DBP) of 95 to 109 mm Hg, of whom 1031 had valid plasma and urine samples for renin profiling. INTERVENTIONS: Randomization to 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem (sustained release), or prazosin. MAIN OUTCOME MEASURE: Treatment response as assessed by percentage achieving goal DBP (<90 mm Hg) in response to a single drug that corresponded to patients' renin profile vs a single drug that corresponded to patients' age-race subgroup. RESULTS: Clonidine and diltiazem had consistent response rates regardless of renin profile (76%, 67%, and 80% for low, medium, and high renin, respectively, for clonidine and 83%, 82%, and 83%, respectively, for diltiazem for patients with baseline DBP of 95-99 mm Hg). Hydrochlorothiazide and prazosin were best in low- and medium-renin profiles; captopril was best in medium- and high-renin profiles (low-, medium-, and high-renin response rates were 82%, 78%, and 14%, respectively, for hydrochlorothiazide; 88%, 67%, and 40%, respectively, for prazosin; and 51%, 83%, and 100%, respectively, for captopril for patients with baseline DBP of 95-99 mm Hg). Response rates for patients with baseline DBP of 95 to 99 mm Hg by age-race subgroup ranged from 70% for clonidine to 90% for prazosin for younger black men, from 50% for captopril to 97% for diltiazem for older black men, from 70% for hydrochlorothiazide to 92% for atenolol for younger white men, and from 84% for hydrochlorothiazide to 95% for diltiazem for older white men. Patients with a correct treatment for their renin profile but incorrect for age-race subgroup had a response rate of 58.7%; patients with an incorrect treatment for their renin profile but correct for age-race subgroup had a response rate of 63.1% (P = .30). After controlling for DBP and interactions with treatment group, age-race subgroup (P<.001) significantly predicted response to single-drug therapy, whereas renin profile was of borderline significance (P= .05). CONCLUSIONS: In these men with stage 1 and stage 2 hypertension, therapeutic responses were consistent with baseline renin profile, but age-race subgroup was a better predictor of response.