Gregory A. Grandits

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.

Components of hostility as predictors of sudden death and myocardial infarction in the multiple risk factor intervention trial

&NA; We tested the hypothesis that hostility is associated with increased relative risk (RR) for coronary death and nonfatal myocardial infarction among participants in the prospective Multiple Risk Factor Intervention Trial (MRFIT). Cases (N = 192) were compared with matched controls (N = 384) on a variety of behavioral characteristics associated with the Type A behavior pattern (TABP), including three different but interrelated components of hostility. Logistic regression analyses revealed that only two of the eight TABP attributes analyzed on the overall sample were significant. Only total Potential for Hostility, when dichotomized into “low” and “high” categories, and the antagonistic interpersonal component of hostility (Stylistic Hostility) had positive unadjusted associations with coronary heart disease (CHD) incidence (RR = 1.7, p = 0.003; and RR = 1.5, p = 0.016, respectively). The global TABP and related paralinguistic attributes were not significantly related to CHD incidence. After adjustment for the traditional risk factors of age, serum cholesterol, blood pressure, and cigarette smoking, only dichotomous Potential for Hostility showed a significant relative risk (RR = 1.5, p = 0.032). Ordinal logistic regression revealed a nonsignificant effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Relation of Apolipoprotein E Phenotype to Myocardial Infarction and Mortality from Coronary Artery Disease

The apolipoprotein E polymorphism is a genetic determinant of low-density lipoprotein (LDL) cholesterol. Its status as a risk factor for coronary artery disease (CAD), either through a causal relation with LDL cholesterol level or independently, is less clearly established. Data from the Multiple Risk Factor Intervention Trial were used to examine the influence of apolipoprotein E phenotype on risk of coronary events. Of the 12,866 randomized participants, 619 were studied in a nested case-control design. CAD deaths (93) and nonfatal myocardial infarctions (113) were matched to 412 controls. The allele frequencies of apolipoprotein E in the white subset (epsilon 2 = 0.06, epsilon 3 = 0.79, and epsilon 4 = 0.15) were very similar to other nonselected white American populations, and the relation of apolipoprotein E on total and LDL cholesterol was generally similar to that seen in other studies, with the epsilon 2 allele being associated with lower and the epsilon 4 allele with higher total and LDL cholesterol. Allele frequencies were not the same for patients and control subjects. The presence of epsilon 4 was associated with an increased risk of CAD that was most evident for fatal cases. There was no relation between changes in LDL cholesterol over time during the trial and apolipoprotein E phenotypes.

Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial

Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator’s choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average±SD age 65.6±7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.

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.

Relation of body mass and alcohol, nutrient, fiber, and caffeine intakes to blood pressure in the special intervention and usual care groups in the Multiple Risk Factor Intervention Trial.

This chapter presents analyses of relations of dietary variables to blood pressure, systolic (SBP) and diastolic (DBP), for men in the special intervention (SI) and usual care (UC) groups in the Multiple Risk Factor Intervention Trial. For each dietary factor, analyses were done at baseline, for trial years 1-6, and for change from baseline to years 1-6. Analyses were done for all participants and for men receiving or not receiving antihypertensive drug treatment and were controlled for age, race, education, serum cholesterol, smoking, special diet status, and (for specific nutrients) body mass index and alcohol intake. Nutrient data for trial years 1-6, which are based on four or five dietary recalls per man, are more reliable than the baseline or change data, which are based on only one recall. Therefore, this summary focuses on data for trial years 1-6, for SI and UC men pooled. Regression analyses confirmed direct independent relations of body mass index, alcohol intake, sodium, and ratio of sodium to potassium to SBP and DBP, and an inverse relation of potassium to SBP and DBP. Dietary starch was directly related to SBP and DBP; dietary saturated fatty acid and cholesterol and Keys score were directly related to DBP; dietary magnesium, fiber, and caffeine were inversely related to SBP and DBP; and dietary protein, polyunsaturated fatty acids, the ratio of polyunsaturated to saturated fatty acid, and other simple carbohydrates were inversely related to DBP. Method problems, all tending to produce underestimations, are also reviewed.

Baseline factors associated with smoking cessation and relapse. MRFIT Research Group

Background. Data on smoking cessation and relapse for 6 years of the Multiple Risk Factor Intervention Trial were evaluated in univariate and multivariate analyses to determine the relationship between variables measured at the beginning of the trial and smoking cessation and relapse for special intervention and usual care participants. Results. The variables positively associated with smoking cessation in both the SI and the UC groups included age, education, and past success in quitting; there was a negative association with the number of cigarettes smoked per day. The expectation of quitting was positively associated with cessation in the special intervention group only, while life events, alcohol, and the presence of a wife who smokes were significant predictors of reduced cessation for the usual care group. The special intervention program may have overcome obstacles which interfered with cessation among the usual care participants. Associations with relapse were generally stronger in the usual care group than in the special intervention group. For usual care participants, multivariate analyses showed that education, past success in quitting smoking, alcohol, and life events were associated with relapse rates. For special intervention participants, only alcohol emerged as a significant predictor. Conclusion. The data are relevant in terms of factors that govern smoking cessation and relapse for adult smokers who take part in formal intervention programs and for those who are left to modify their behavior on their own.BACKGROUND Data on smoking cessation and relapse for 6 yers of the Multiple Risk Factor Intervention Trial were evaluated in univariate and multivariate analyses to determine the relationship between variables measured at the beginning of the trial and smoking cessation and relapse for special intervention and usual care participants. RESULTS The variables positively associated with smoking cessation in both the SI and the UC groups included age, education, and past success in quitting; there was a negative association with the number of cigarettes smoked per day. The expectation of quitting was positively associated with cessation in the special intervention group only, while life events, alcohol, and the presence of a wife who smokes were significant predictors of reduced cessation for the usual care group. The special intervention program may have overcome obstacles which interfered with cessation among the usual care participants. Associations with relapse were generally stronger in the usual care group than in the special intervention group. For usual care participants, multivariate analyses showed that education, past success in quitting smoking, alcohol, and life events were associated with relapse rates. For special intervention participants, only alcohol emerged as a significant predictor. Conclusion. The data are relevant in terms of factors that govern smoking cessation and relapse for adult smokers who take part in formal intervention programs and for those who are left to modify their behavior on their own.

Insulin as a predictor of coronary heart disease: Interaction with apolipoprotein E phenotype A report from the multiple risk factor intervention trial

The objective of this study was to examine whether fasting serum insulin is a predictor of coronary heart disease in high-risk US men, and whether any such predictive role explains the enhanced cardiovascular risk seen in subjects with the apolipoprotein (Apo) E 3/2 phenotype. This was a nested case-control study of participants in the Multiple Risk Factor Intervention Trial. Ninety-four subjects who died from coronary heart disease (post-trial follow-up) and 114 case patients with myocardial infarction (during trial) were compared to control subjects (n = 414) matched (1:2) by age, center, randomization date, and intervention group. Overall, fasting serum insulin at baseline was not associated with case-control status. (Means for cases versus controls: 16.8 and 16.6 microU/mL), although serum insulin showed significant correlations with low-density-lipoprotein cholesterol, triglycerides, and uric acid. When stratified by the three Apo E phenotypes, 3/2, 3/3, 3/4, a significant association of fasting insulin with case-control status was seen for Apo E 3/2 individuals (19.9 versus 14.5 microU/mL; P = 0.02) but not for those with the other two phenotypes. Though fasting insulin is not a risk factor overall in this high-risk male population, it appears to contribute to cardiovascular risk in those with the Apo E 3/2 phenotype but does not explain the increased risk seen in these subjects. This new finding, if confirmed, may throw further light on the role of insulin in atherosclerosis.

Long-term effects on plasma lipids of diet and drugs to treat hypertension. Treatment of Mild Hypertension Study (TOMHS) Research Group

OBJECTIVE - To compare long-term plasma lipid changes among 6 antihypertensive treatment interventions for stage I (mild) hypertension. DESIGN - Multicenter, randomized, double-blind, parallel-group clinical trial. SETTING - Four academic clinical research units in the United States. PARTICIPANTS - A total of 902 men and women, aged 45 to 69 years, with stage I diastolic hypertension (diastolic blood pressure <100 mm Hg), recruited from 11914 persons screened in their communities. INTERVENTIONS - Participants were randomized to 1 of 6 treatment groups: (1) placebo, (2) beta-blocker (acebutolol), (3) calcium antagonist (amlodipine), (4) diuretic (chlorthalidone), (5) alpha1-antagonist (doxazosin), and (6) angiotensin-converting enzyme inhibitor (enalapril). All groups received intensive lifestyle counseling to achieve weight loss, dietary sodium and alcohol reduction, and increased physical activity. MAIN OUTCOME MEASURES - Changes in plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides from baseline to annual visits through 4 years. RESULTS - Mean changes in all plasma lipids were favorable in all groups. The degree of weight loss with fat-modified diet and exercise was significantly related to favorable lipid changes. Significant differences (P<.01) among groups for average changes during follow-up in each lipid were observed. Decreases in plasma total cholesterol and LDL cholesterol were greater with doxazosin and acebutolol (for plasma total cholesterol, 0.36 and 0.30 mmol/L [13.8 and 11.7 mg/dL], respectively), less with chlorthalidone and placebo (0.12 and 0.13 mmol/L [4.5 and 5.1 mg/dL], respectively). Decreases in triglycerides were greater with doxazosin and enalapril, least with acebutolol. Increases in HDL cholesterol were greater with enalapril and doxazosin, least with acebutolol. Significant relative increases in plasma total cholesterol with chlorthalidone compared with placebo at 12 months were no longer present at 24 months and beyond, when mean plasma total cholesterol for the chlorthalidone group fell below baseline. Analyses of participants continuing to receive chlorthalidone throughout the 4 years of follow-up indicated this was not due solely to an increasing percentage of participants changing or discontinuing use of medication during follow-up. CONCLUSIONS - Weight loss with a fat-modified diet plus increased exercise produces favorable long-term effects on blood pressure and all plasma lipid fractions of adults with stage I hypertension; blood pressure reduction is enhanced to a similar degree by addition of a drug from any one of 5 classes of antihypertensive medication. These drugs differ quantitatively in influencing the degree of long-term favorable effects on blood lipids obtained with nutritional-hygienic treatment.

Rationale and Design for the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial

The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial is a randomized, prospective, double-blind, parallel-group, two-arm, actively controlled, multicenter, international 5-year clinical trial involving 15,000 patients. CONVINCE will compare the incidence of fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or cardiovascular-disease-related death in two antihypertensive treatment regimens. One treatment arm begins with controlled onset-extended release (COER)-verapamil, which has its major antihypertensive effect 6-12 hours after administration. The other arm (standard of care (SOC)) begins with either hydrochlorothiazide (HCTZ) or atenolol, one of which is preselected by the investigator for an individual patient prior to randomization. Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint (separately), death or hospitalization related to cardiovascular disease, efficacy in lowering blood pressure to goal, primary events occurring between 6 am and noon, all-cause mortality, withdrawals from blinded therapy, cancer, and hospitalizations due to bleeding. Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease. Initial medications include COER-verapamil (180 mg/d), HCTZ (12.5 mg/d), or atenolol (50 mg/d). Initial doses are doubled if blood pressure (BP) does not reach goal (systolic BP < 140 mm and diastolic BP < 90 mm Hg). If BP is not controlled by the higher dose of the initial medication, HCTZ is added to COER-verapamil, or the SOC choice not initially selected is added in the SOC arm. An ACE-inhibitor is recommended (although nearly any open-label medication is allowed) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications. Patients take two sets of tablets daily, one in the morning and one in the evening. Although most patients switch from an established antihypertensive medication to randomized treatment, untreated patients with stages I-III hypertension (SBP between 140 and 190 or DBP between 90 and 110 mm Hg) are eligible. Outcomes are monitored by an independent Data and Safety Monitoring Board. Enrollment began during the third quarter of 1996, and follow-up is to be completed in the third quarter of 2002.