Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.

OBJECTIVES: To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older. SUBJECTS AND METHODS: A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit. RESULTS: The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy. CONCLUSIONS: Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.

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.

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.

Temporal patterns of antihypertensive medication use among elderly patients. The Cardiovascular Health Study.

OBJECTIVES: To estimate the incidence of newly treated hypertension and to describe the patterns of antihypertensive medication use among those aged 65 years and older. DESIGN: Medicare eligibility lists from four US communities (Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh, Pa) were used to obtain a representative sample of 5201 community-dwelling elderly for the Cardiovascular Health Study, a prospective cohort study of risk factors for coronary heart disease and stroke. Participants were examined at baseline and again 1 year later. The two examinations included standardized questionnaires, blood pressure measurements, and the assessment of medication use by medication inventory. In this cohort analysis, we excluded 231 subjects (4.4%) who did not return for follow-up, 69 (1.3%) who had missing data for medications, and another 495 (9.5%) who were taking "antihypertensive" medications for an indication other than high blood pressure. INTERVENTIONS: None. RESULTS: Among the 4406 participants, 1613 used antihypertensive medications at both visits. Between the two visits, 144 started and 115 stopped antihypertensive therapy. Among nonusers at baseline, the annual incidence of newly treated hypertension was 5.2% in women and 5.6% in men. Due to the number of participants who stopped therapy, the overall prevalence of antihypertensive treatment increased only slightly, from 40.7% to 41.1% in women and from 37.1% to 38.2% in men, during 1 year of follow-up. After adjustment for age, systolic blood pressure, number of antihypertensive drugs, diabetes, and cardiovascular disease, the newly treated hypertensives were about half as likely as the previously treated hypertensives to receive diuretics (odds ratio [OR], 0.59; P = .008) or beta-blockers (OR, 0.52; P = .01); and they were about twice as likely to receive calcium channel blockers (OR, 1.88; P < .004) or angiotensin converting enzyme inhibitors (OR, 2.40; P < .001). A similar pattern of within-person changes over time was apparent among the continuous users. CONCLUSIONS: Between June 1990 and June 1991, physicians were increasingly prescribing angiotensin converting enzyme inhibitors and calcium channel blockers in place of diuretics and beta-blockers for the treatment of hypertension in elderly patients, especially for those just starting therapy.

Perindopril as monotherapy in hypertension: a multicenter comparison of two dosing regimens. The Perindopril Study Group.

Perindopril erbumine, a new long-acting, non-sulfhydryl-containing angiotensin converting enzyme inhibitor, was evaluated in 289 patients with hypertension in a 16-week, double-blind, placebo-controlled dose-ranging study. After 4 weeks of single-blind placebo treatment, patients with supine diastolic arterial pressures from 95 to 114 mm Hg were randomized to receive placebo, 4 mg perindopril once daily, or 2 mg perindopril twice daily. The daily dose of perindopril was increased by 4 mg every 4 weeks to a maximum of 16 mg per day. Mean decreases in systolic and diastolic arterial pressure were greater with perindopril than with placebo (p < 0.05). The dose-response curve flattened after 8 mg per day, and there was no difference in arterial pressure reduction or in the percentage of responders between once- and twice-daily administration of perindopril. Adverse reactions with perindopril were generally mild and, with the exception of cough, were similar with placebo. The findings of this study indicate that perindopril is effective, well tolerated, and suitable for once-daily administration for the treatment of hypertension.

Comparison of ambulatory and clinic blood pressure and heart rate in older persons with isolated systolic hypertension.

We compared the blood pressure (BP) measurements obtained with a random-zero sphygmomanometer and an ambulatory BP monitor in older persons with isolated systolic hypertension at one site of the multicenter, randomized, double-blind clinical trial, the Systolic Hypertension in the Elderly Program (SHEP) randomized clinical trial. The subjects were community-dwelling elderly participants with isolated systolic hypertension enrolled in the SHEP study and already receiving stable doses of double-blind medication (n = 35 for active treatment group; n = 32 for placebo group). We measured seated (clinic) BP obtained with a random-zero sphygmomamanometer, pulse rate, and BP and heart rate measurements obtained with an ambulatory BP monitor (average 24 h, daytime, and nighttime BP and heart rate). Across treatment groups clinic and ambulatory systolic BPs were not significantly different, but the placebo group had higher ambulatory, but not clinic, diastolic BPs. Within each treatment group (active treatment and placebo) there were no significant differences between clinic and average 24 h, daytime, or nighttime ambulatory systolic BPs. There were also no significant differences between clinic diastolic BP and average 24 h, daytime, or nighttime ambulatory diastolic BPs in the active treatment group, but in the placebo group average 24 h diastolic BP obtained by the ambulatory monitor was 4.6 mm Hg higher than clinic diastolic BP (P = .001). The average 24 h heart rate was 6 to 7 beats/min higher as measured by the ambulatory monitor compared to clinic pulse (P < .01). In the placebo group of this study, average 24 h ambulatory diastolic BPs were consistently higher than clinic diastolic BPs.(ABSTRACT TRUNCATED AT 250 WORDS)

Are race differences in the prevalence of hypertension explained by body mass and fat distribution? A survey in a biracial population.

Body mass and body fat distribution are important considerations in the study of hypertension. However, few studies have investigated the relationships with regards to race differences in elevated arterial pressure. A population-based sample of black and white adults was assessed by interview and physical measurement. The prevalence of hypertension (defined as 140/90 mmHg and/or medically treated) was disproportionately higher among blacks than whites. In addition, blacks had a higher prevalence of the more severe hypertension (160/95 mmHg) and hypertension with higher prevalence at earlier ages than whites. Black females had a significantly higher distribution of body mass index (BMI) than white females, while no difference was found in the distributions of males. White males had a higher distribution of waist to hip ratio (WHR) than black males, while black females had the higher values compared to white females. The prevalence of hypertension increased with BMI and WHR. Blacks maintained higher rates of hypertension after controlling for BMI and WHR, however, the margin of difference diminished when BMI and WHR was considered together. The black-white difference in hypertension was not completely explained by BMI and WHR. In addition, the strength of the association of hypertension and body size was different for blacks and whites which suggests possible differences in the mechanisms regulating blood pressure.

Hypertension, creatinine, and plasma renin activity in heart transplant recipients.

Development of de novo hypertension in a large proportion of orthotopic heart transplant recipients receiving cyclosporine has previously been reported. This hypertension is characterized by a persistence of increased peripheral resistance, sodium retention, and loss of nocturnal decline in BP. Vascular nephropathy with plasma renin activity (PRA) elevation from cyclosporine (CsA) may also be major factor in the progress of hypertension. To investigate this hypothesis, observations of BP, creatinine (Cr), and PRA were made in 144 heart transplant recipients followed for up to four and a half years. Median Cr was 133 mumol/l. Average diastolic BP and mean PRA values were significantly higher in patients with Cr greater than or equal to the median. Cr and PRA were significantly correlated (r = 0.4; P less than 0.001) in recipients with Cr greater than or equal to 133 mumols/l but not in those with Cr less than 133 mumols/l. In a selected subsample of heart transplant recipients with repeated Cr and PRA values, Cr and PRA appeared to increase longitudinally after transplant. These data are derived from a case series of patients managed on a variety of antihypertensive agents (excluding ACE inhibitors) needed to control the persistent hypertension.

Premenopausal and postmenopausal women differ in their cardiovascular and neuroendocrine responses to behavioral stressors.

Middle-aged (45-51 years) women performed four tasks while their heart rate, blood pressure, and plasma catecholamines were measured. The tasks were serial subtraction, mirror image tracing, speech, and postural tilt. The speech task was considered to be particularly relevant to women because of its emphasis on social skills. Fifteen premenopausal women reported menstruating regularly and were tested in the early follicular phase. Sixteen postmenopausal women reported not menstruating for at least 12 months and their hormonal status was verified by serum levels of follicle-stimulating hormone. Results showed that postmenopausal women exhibited greater increases from baseline in heart rate during all tasks, relative to premenopausal women, with a particularly pronounced increase during the speech task. Postmenopausal women exhibited greater increases from baseline in systolic blood pressure and epinephrine, relative to premenopausal women, during the speech task only. Explanations for the stressor-specific effect of menopausal status were discussed. The results suggest that reproductive hormones may interact with stressor characteristics to determine middle-aged women's physiological responses to stress.

A historical perspective of elevated systolic vs diastolic blood pressure from an epidemiological and clinical trial viewpoint.

The decision to use diastolic blood pressure as the basis for therapeutic intervention for hypertension was based primarily on clinical trials experience. The majority of observational studies shows as great or greater risk for elevated systolic blood pressure readings. Even many of the clinical trials in which a posteriori analyses have been performed confirm a greater effect of systolic rather than diastolic blood pressure as a predictor of coronary heart disease mortality. The current practice of using diastolic blood pressure readings as the sole treatment criterion should be reexamined in light of the observational studies and clinical trials reviewed here.

Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) pilot study.

The pilot study of the Systolic Hypertension in the Elderly Program was a randomized, double-blind, placebo-controlled trial of drug therapy for isolated systolic hypertension. It followed 551 elderly participants with untreated blood pressures of greater than 160/less than 90 mm Hg for an average of 34 months. Mean age of the participants was 72 years; 63% were women, and 82% were white. Pretreatment blood pressures averaged 172/75 mm Hg. Participants were randomly assigned to treatment with chlorthalidone or placebo as Step I medication. Blood pressures at annual visits averaged 141/68 and 157/73 mm Hg for the drug-treated and placebo-treated groups, respectively, with 60% and 33% of the survivors on blinded medication having systolic blood pressures of less than 160 mm Hg at their last annual visit. All-cause mortality rates for the drug-treated and placebo-treated groups were 25.4 and 22.7 deaths per 1,000 participant-years of risk, and rates for definite "first stroke" were 8.3 and 12.8 per 1,000 years of risk. Differences between groups were significant for systolic and diastolic blood pressure but not for death or stroke rates. A full-scale study has begun to determine the effects of drug therapy for isolated systolic hypertension on stroke and mortality rates.

The evolution of current hypertension therapy.

There has been a continuous evolution in hypertensive therapy during the last 30 years. Now, physicians have access to more than 40 agents for treating this widespread condition. Large-scale clinical trials have established that lowering blood pressure in patients with mild to moderate diastolic hypertension results in a decreased incidence of stroke and, to a lesser extent, a reduction in incidence of coronary heart disease [MacMahon SW, Cutler JA, Furberg CD, et al: Prog Cardiovasc Dis 1986; 29 (suppl 1): 99-118]. Even so, the decrease in overall mortality rate is not consistent. Although hypertension occurs with increasing frequency in those over 60 years of age, patients in this age group represent less than 12 percent of the subjects in large trials. Currently, stepped-care is the recommended approach for managing hypertension in patients of all ages. However, the availability of a variety of agents for initial therapy, all with approximately equal efficacy but differing side-effect profiles, calls such an approach into question.

Comparison of the antihypertensive effects of betaxolol to atenolol.

A randomized double-blind multicenter study compared a new oral beta 1-adrenergic antagonist, betaxolol 10 to 40 mg (n = 71), with atenolol 25 to 100 mg (n = 75). Each drug was administered once daily for 24 weeks in patients with mild to moderate hypertension. Blood pressure (BP) measurements were taken 24 hours after dosing. Each drug produced significant (p less than 0.01) reductions in mean supine diastolic BP. The mean decrease in supine diastolic BP with betaxolol was significantly greater at weeks 4, 6, 10 and 12 (p less than 0.05). Throughout the remainder of the trial (weeks 14 to 24), no significant differences in BP reduction were noted between treatment groups. Normotension (supine diastolic BP less than or equal to 90 mm Hg) was achieved in 72% of those given betaxolol compared with 52% of those given atenolol (p less than 0.05). The most common side effects noted were bradycardia, fatigue and headache. The incidence of these and of central nervous system side effects was similar between the betaxolol and atenolol groups. Both agents were well tolerated. At recommended doses, betaxolol once daily may be more effective than atenolol once daily in patients with mild to moderate hypertension.

Mortality associated with diastolic hypertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial.

The large cohort of white men (317,871) 35 to 57 years old at initial screening for possible enrollment into the Multiple Risk Factor Intervention Trial (MRFIT) was examined with regard to initial blood pressure levels and subsequent coronary heart disease (CHD), stroke, and all-cause mortality. The overall prevalence of isolated systolic hypertension (ISH), defined as systolic blood pressure (SBP) greater than or equal to 160 mm Hg and diastolic blood pressure (DBP) less than 90 mm Hg, was 0.67% among white men screened for MRFIT and increased with age (0.31% among 35- to 39-year-olds to 1.7% among 55- to 57-year-olds). The 6 year CHD and all-cause mortality rates in men over 50 were highest in those with ISH compared with both subjects with diastolic hypertension and those with normal pressure. The relative risk of death from stroke in those with ISH, compared with that in those with SBP less than 160 mm Hg and those with DBP less than 90 mm Hg, was 3.0 (95% confidence interval 1.3 to 6.8). In addition, at any level of DBP, the level of SBP appeared to be the major determinant of all-cause and CHD mortality. The determinants of ISH in individuals under 60 years of age as well as the possible efficacy of its treatment should be evaluated further.

Patient characteristics and their influence on therapy and its outcome in hypertension of the elderly.

A retrospective study was undertaken to analyze the effects of various patient factors on therapy and its outcome in elderly hypertensive subjects. Two hundred and three male hypertensives with a mean age of 63.1 years at entry, were followed in a special hypertension clinic by nurse practitioners under physician supervision, for 2 years or more (mean 3.7 years). Good patient compliance (84%) and blood pressure (BP) reduction were achieved and these were enhanced by advancing age. Neither excessive weight, nor widespread atherosclerosis seemed to interfere with BP control. However, while diastolic BP was well controlled with antihypertensive therapy, systolic BP tended to remain higher than 160 mm Hg in many of the older and more atherosclerotic subjects. Pharmacological treatment did not prevent a gradual although modest deterioration of renal function, which was related to both age and hypertension, and represents a greater problem in black patients. Because of the limitations of such a retrospective study, its conclusions may not be extrapolated for treatment of hypertension in all the elderly.

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.

Relaxation therapy for hypertension. Comparison of effects with concomitant placebo, diuretic, and beta-blocker.

We compared the effects of relaxation therapy in hypertensive patients taking placebo, a beta-blocker (atenolol, 100 mg/d), or a diuretic (chlorthalidone, 50 mg/d), and we also compared the effects of relaxation therapy with the effects of the latter two drugs alone. Blood pressures were measured not only in the relaxation therapists' office and at a hypertension clinic, but also in the patient's environment by means of 24-hour ambulatory blood pressure recordings. The effect of relaxation therapy, while statistically significant, was modest. There was no generalization of effect to ambulatory blood pressure. Atenolol was significantly more effective than relaxation in reducing both systolic and diastolic pressure. Chlorthalidone was significantly more effective than relaxation in reducing systolic but not diastolic pressure in the hypertension clinic only. The long-term effects of relaxation were independent of concomitant drug use, but within the actual relaxation sessions blood pressure dropped further during chlorthalidone than during placebo or atenolol treatment.