Kenneth H. Svendsen

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.

Long-term Cardiovascular Mortality Among Middle-aged Men With Gout

BACKGROUND There are limited data available on the association of gouty arthritis (gout) in middle age with long-term cardiovascular disease (CVD) mortality. METHODS We performed a 17-year follow-up study of 9105 men, aged 41 to 63 years and at above-average risk for coronary heart disease, who were randomized to the Multiple Risk Factor Intervention Trial and who did not die or have clinical or electrocardiographic evidence of coronary artery disease during the 6-year trial. Risk of CVD death and other causes subsequent to the sixth annual examination associated with gout was assessed by means of Cox proportional hazards regressions. RESULTS The unadjusted mortality rates from CVD among those with and without gout were 10.3 per 1000 person-years and 8.0 per 1000 person-years, respectively, representing an approximately 30% greater risk. After adjustment for traditional risk factors, use of diuretics and aspirin, and serum creatinine level, the hazard ratio (gout vs no gout) for coronary heart disease mortality was 1.35 (95% confidence interval [CI], 1.06-1.72). The hazard ratio for death from myocardial infarction was 1.35 (95% CI, 0.94-1.93); for death from CVD overall, 1.21 (95% CI, 0.99-1.49); and for death from any cause, 1.09 (95% CI, 1.00-1.19) (P = .04). The association between hyperuricemia and CVD was weak and did not persist when analysis was limited to men with hyperuricemia without a diagnosis of gout. CONCLUSION Among middle-aged men, a diagnosis of gout accompanied by an elevated uric acid level imparts significant independent CVD mortality risk. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000487.

Association of Single Measurements of Dipstick Proteinuria, Estimated Glomerular Filtration Rate, and Hematocrit with 25-Year Incidence of End-Stage Renal Disease in the Multiple Risk Factor Intervention Trial

The incidence of ESRD is increasing rapidly. Limited information exists regarding early markers for the development of ESRD. This study aimed to determine over 25 yr the risk for ESRD associated with proteinuria, estimated GFR (eGFR), and hematocrit in men who did not have identified kidney disease and were randomly assigned into the Multiple Risk Factor Intervention Study (MRFIT). A total of 12,866 men who were at high risk for heart disease were enrolled (1973 to 1975) and followed through 1999. Renal replacement therapy was ascertained by matching identifiers with the United States Renal Data Systems data; vital status was from the National Death Index. Men who initiated renal replacement therapy or died as a result of kidney disease were deemed to have developed ESRD. Dipstick urine for proteinuria, eGFR, and hematocrit were related to development of ESRD. During 25 yr, 213 (1.7%) men developed ESRD. Predictors of ESRD were dipstick proteinuria of 1+ or > or =2+ (hazard ratio [HR] 3.1 [95% confidence interval (CI) 1.8 to 5.4] and 15.7 [95% CI 10.3 to 23.9] respectively) and an eGFR of <60 ml/min per 1.73 m(2) (HR 2.4; 95% CI 1.5 to 3.8). Correlation between eGFR and serum creatinine was 0.9; the risk for ESRD with a 1-SD difference of each was identical (HR 1.21). Bivariate analysis demonstrated a 41-fold increase in ESRD risk in those with an eGFR <60 ml/min per 1.73 m(2) and > or =2+ proteinuria (95% CI 15.2 to 71.1). There was no association between hematocrit and ESRD. Other baseline measures that independently predicted ESRD included age, cigarette smoking, BP, low HDL cholesterol, and fasting glucose. Among middle-aged men who were at high risk for cardiovascular disease but had no clinical evidence of cardiovascular disease or significant kidney disease, dipstick proteinuria and an eGFR value <60 ml/min per 1.73 m(2) were strong predictors of long-term development of ESRD. It remains unknown whether intervention for proteinuria or early identification of those with chronic kidney disease reduces the risk for ESRD.

The relationship of smoking cessation to coronary heart disease and lung cancer in the Multiple Risk Factor Intervention Trial (MRFIT)

The impact of smoking cessation on coronary heart disease (CHD) and lung cancer was assessed after 10.5 years of follow-up in the 12,866 men in the Multiple Risk Factor Intervention Trial (MRFIT). Those men who died of lung cancer (n = 119) were either cigarette smokers at entry or ex-smokers; no lung cancer deaths occurred among the 1,859 men who reported never smoking cigarettes. The risk of lung cancer for smokers, adjusted for selected baseline variables using a Cox proportional hazards model, increased as the number of cigarettes smoked increased (B = 0.0203, SE = 0.0076). There was not the same graded response for CHD among smokers at entry. The risk of CHD death was greater among smokers than nonsmokers (RR = 1.57) (B = -0.0034, S.E. = 0.0048). After one year of cessation, the relative risk of dying of CHD for the quitters as compared to non-quitters (RR = 0.63) was significantly lower even after adjusting for baseline differences and changes in other risk factors. The relative risk for smokers who quit for at least the first three years of the trial was even lower compared to non-quitters (RR = 0.38). However, the relative risk for lung cancer for quitters versus non-quitters was close to 1 both for quitters at 12 months and at three years. These data support the benefits of cessation in relation to CHD and are consistent with other epidemiologic studies which suggest that the lag time for a beneficial effect of smoking cessation on lung cancer may be as long as 20 years.

Incidence of type 2 diabetes in the randomized multiple risk factor intervention trial

Context Weight loss and exercise decrease the development of diabetes in people with impaired glucose tolerance, but the effectiveness of these interventions in people with normal glucose tolerance is unknown. Contribution Using data from a large randomized, controlled trial of cardiovascular disease prevention in men, the investigators show that participants with normal glucose tolerance at baseline developed diabetes at similar rates whether they received the diet and exercise intervention or usual care. However, the intervention was associated with lower risk of diabetes among nonsmokers. Implications While diet and exercise may reduce the development of diabetes in nonsmokers with normal glucose metabolism at baseline, this benefit was not apparent among smokers. The Editors Epidemiologic studies have identified several potentially modifiable risk factors for type 2 diabetes mellitus, including obesity, a diet in which a high proportion of calories comes from fat, and low levels of physical activity (1-7). Authorities have advocated that trials should test promising hypotheses about the primary prevention of type 2 diabetes (1). Randomized intervention studies have demonstrated that, among those who already have impaired glucose tolerance, interventions that promote weight loss and increased exercise can reduce the risk for incident diabetes (8-10). However, interventions should occur before at-risk individuals develop impaired glucose tolerance. A 2-year randomized trial of diet, exercise, or both in individuals with a parental history of diabetes showed a statistically imprecise lower risk for developing diabetes in the intervention group (11). To test such a hypothesis in groups who do not necessarily have a parental history of diabetes would be expensive. Strategies proposed for the primary prevention of type 2 diabetes include weight reduction, reduced dietary fat intake, and increased exercise (2, 4, 7). These interventions are similar to those developed for preventing coronary heart disease; therefore, examination of type 2 diabetes incidence rates in coronary heart disease prevention trials can provide preliminary evidence on the potential of such interventions to reduce type 2 diabetes risk. The Multiple Risk Factor Intervention Trial (MRFIT) enrolled 12866 middle-aged men at high risk for coronary heart disease and delivered either special intervention or usual care over 6 to 7 years. The researchers obtained fasting glucose values yearly, and participants self-reported their use of insulin or oral hypoglycemic agents. The glucose values and reports of diabetes medication use enable estimation of diabetes incidence during the trial. Previous reports from MRFIT have described risk factors for the development of diabetes in the usual care group (12) and the risk for death associated with incident diabetes in the combined special intervention and usual care groups (13). In this paper, we compare the incidence of diabetes in the intervention and control groups of the MRFIT, report on an unexpected subgroup finding related to baseline cigarette smoking status, and explore reasons for the different results among smokers and nonsmokers. Methods Procedures Detailed descriptions of the MRFIT have been published (14-17). Briefly, between 1973 and 1976, the MRFIT investigators screened 361662 men for eligibility at 22 U.S. clinical centers. Of this group, 12866 men age 35 to 57 years were randomly assigned: 6428 men to the special intervention group and 6438 men to the usual care group. Screening occurred at 3 visits. At the first screening visit, investigators assessed the risk for coronary heart disease by using measurements of serum cholesterol level, diastolic blood pressure, and self-reported cigarette smoking (14). Men who were in the upper 15% (changed to 10% after one third of the screening was completed) of risk were invited to attend a second screening visit. Because of the eligibility criteria used in the MRFIT, the usual relationships among these risk factors were modified. For example, nonsmokers had to have higher blood pressure and lipid levels on average than smokers to be eligible for the trial. At the second screening visit, a blood sample was taken after an overnight fast. A central laboratory at the Institute of Medical Sciences in San Francisco, California, analyzed the blood samples by using a protocol previously described (18) and measured serum glucose in the fasting sample and in a sample taken 1 hour after a 75-g oral glucose load. The MRFIT also measured height and weight (after the patient had disrobed). Individuals with body weight 150% or more of desirable weight were excluded from the trial (defined as 0.9 of the average for men of the same height in the 19601962 National Health Examination Survey [19]). We used body mass index (BMI) as the measure of relative weight in our report. Men without evidence of cardiovascular or other life-threatening diseases were invited to attend a third screening visit. At this visit, eligible men who consented to the trial were randomly assigned. All participants had annual examinations for at least 6 years. A fasting blood sample was taken at each annual examination, from which serum glucose concentration and plasma lipid levels were measured. In addition, at the sixth annual visit, a blood sample taken 1 hour after a 75-g oral glucose load was obtained. At each annual examination, participants were asked whether a physician had told them that they had diabetes at any time in the previous 12 months. Each participant was also asked whether he was using insulin or oral hypoglycemic agents. In the MRFIT, 24-hour dietary recalls were obtained at baseline and during follow-up (20, 21). We cited data from baseline and year 6 in our report. Intervention Details of the intervention program of the MRFIT have been reported (16, 22). Briefly, the special intervention group received nutritional counseling that was aimed at reducing saturated fat and dietary cholesterol consumption and increasing polyunsaturated fat intake. Smokers participated in a behavioral intervention program aimed at cessation. In men at or more than 115% of desirable weight, reductions in caloric intake and increases in moderate physical activity were recommended. Elevated blood pressure was treated pharmacologically according to a stepped-care protocol that started with 50 mg of chlorthalidone or hydrochlorothiazide if weight reduction and moderate salt restriction did not achieve the desired blood pressure goals. Definition of Diabetes The definition of incident diabetes followed the American Diabetes Association (ADA) guidelines (23). With this definition, a participant was considered to have developed diabetes if at any annual visit the fasting glucose level was 7 mmol/L or greater (126 mg/dL) or the participant reported taking insulin or oral hypoglycemic agents. Use of a single fasting glucose determination to designate diabetic participants is consistent with the ADA criteria for epidemiologic studies. Exclusions The MRFIT attempted at baseline to exclude men with identified diabetes from the trial. The trial excluded individuals who were using hypoglycemic drugs, as well as those who were not being treated but who exhibited clinical symptoms of hyperglycemia (15). Despite these exclusion criteria, the trial included 42 men who reported (without confirmation) taking insulin, 414 men with a baseline fasting glucose level of 7 mmol/L or greater (126 mg/dL), and 52 men with a glucose level of 16.65 mmol/L or greater (300 mg/dL) 1 hour after a 75-g oral glucose load. We excluded these 508 men and an additional 531 men (291 in the usual care group and 240 in the special intervention group) with fewer than 2 fasting glucose values throughout the trial from our analyses, leaving 11827 men (5893 in the usual care group and 5934 in the special intervention group) who, by our criteria, were at risk for developing diabetes over the next 6 years (Figure). Figure. Description of study exclusions. Statistical Analysis We used time-to-event methods appropriate for interval-censored data to compare incidence of diabetes in the special intervention and usual care groups (24). We estimated the cumulative percentage of patients developing diabetes, assuming that participants at risk who did not attend an annual visit did not meet our criteria for diabetes. We used proportional hazards regression models to study the influence of baseline predictors on hazard ratio estimates and to investigate treatment by subgroup interactions. We also used these models to study the influence of risk factor changes on the incidence of diabetes and on special interventionusual care hazard ratios. We checked the proportional hazards assumption by including a covariate corresponding to the interaction of failure time and special intervention or usual care. In these models, we updated risk factor levels (for example, BMI, use of antihypertensive drugs, and smoking status) annually and considered them to be time-dependent covariates. With this approach, we considered the latest values of risk factors (those immediately preceding diabetes) and baseline levels as predictors. We also used longitudinal regression models for binary data (25). With these models, participants could be classified as diabetic on several annual visits or at 1 annual visit and not the next. We used analysis of variance with covariates corresponding to baseline level of the factor being considered to compare risk factor levels at 6 years for special intervention and usual care men, both overall and according to baseline cigarette smoking status. With these models, we also investigated the interaction between treatment and smoking status. Both time-to-event analyses and analyses of variance are stratified by clinical center. We performed all analyses by using SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sourc

Spinal Manipulation, Medication, or Home Exercise With Advice for Acute and Subacute Neck Pain: A Randomized Trial

BACKGROUND Mechanical neck pain is a common condition that affects an estimated 70% of persons at some point in their lives. Little research exists to guide the choice of therapy for acute and subacute neck pain. OBJECTIVE To determine the relative efficacy of spinal manipulation therapy (SMT), medication, and home exercise with advice (HEA) for acute and subacute neck pain in both the short and long term. DESIGN Randomized, controlled trial. (ClinicalTrials.gov registration number: NCT00029770) SETTING 1 university research center and 1 pain management clinic in Minnesota. PARTICIPANTS 272 persons aged 18 to 65 years who had nonspecific neck pain for 2 to 12 weeks. INTERVENTION 12 weeks of SMT, medication, or HEA. MEASUREMENTS The primary outcome was participant-rated pain, measured at 2, 4, 8, 12, 26, and 52 weeks after randomization. Secondary measures were self-reported disability, global improvement, medication use, satisfaction, general health status (Short Form-36 Health Survey physical and mental health scales), and adverse events. Blinded evaluation of neck motion was performed at 4 and 12 weeks. RESULTS For pain, SMT had a statistically significant advantage over medication after 8, 12, 26, and 52 weeks (P ≤ 0.010), and HEA was superior to medication at 26 weeks (P = 0.02). No important differences in pain were found between SMT and HEA at any time point. Results for most of the secondary outcomes were similar to those of the primary outcome. LIMITATIONS Participants and providers could not be blinded. No specific criteria for defining clinically important group differences were prespecified or available from the literature. CONCLUSION For participants with acute and subacute neck pain, SMT was more effective than medication in both the short and long term. However, a few instructional sessions of HEA resulted in similar outcomes at most time points. PRIMARY FUNDING SOURCE National Center for Complementary and Alternative Medicine, National Institutes of Health.

Cigarette smoking and mortality.

Abstract Methods. The relationship of cigarette smoking and smoking cessation to mortality was investigated among men screened for the MRFIT, cigarette smoking was an important risk factor for all-cause, coronary heart disease (CHD), stroke, and cancer mortality. These risks, on the log relative scale, were strongest for cancers of the lung, mouth, and larynx. The excess risk associated with cigarette smoking was greatest for death from CHD. Overall, approximately one-half of all deaths were associated with cigarette smoking. Among the 12,866 randomized participants, weak positive associations with duration of cigarette smoking habit and tar and nicotine levels were found with all-cause mortality. For both SI and UC men, substantial differences in subsequent CHD (34–49%) and all-cause (35–47%) mortality were evident for men who reported cigarette smoking cessation by the end of the trial compared with those continuing to smoke. There was no evidence that lung cancer death rates were lower among cigarette smokers who quit compared with those who continued to smoke in this 10-year follow-up period. Conclusion. The data are consistent with results of previous epidemiologic studies indicating that the benefits of smoking cessation on CHD are rapid, while for lung cancer, the benefit is not evident in a 10-year follow-up period.

The Influence of Oral Potassium Chloride on Blood Pressure in Hypertensive Men on a Low-Sodium Diet

Clinical and epidemiologic studies suggest that the intake of potassium chloride lowers blood pressure. To investigate whether supplemental potassium chloride (96 mmol of microcrystalline potassium chloride a day) reduced the need for antihypertensive medication in hypertensive men on a restricted-sodium diet, we conducted a randomized, placebo-controlled, double-blind clinical trial. A total of 287 men 45 to 68 years of age, 142 given potassium chloride and 145 given placebo, were followed for an average of 2.2 years after the withdrawal of their antihypertensive medication. Men in both groups received instructions on following a low-sodium diet. Overnight urinary sodium excretion fell from 63 mmol per eight hours at base line to an average of 45 mmol per eight hours during follow-up. Participants given supplemental potassium chloride had significantly higher (P less than 0.001) serum potassium levels and urinary potassium excretion (averaging 4.5 mmol per liter and 42.5 mmol per eight hours, respectively) during follow-up than participants given placebo (4.2 mmol per liter and 20.0 mmol per eight hours). Seventy-nine participants in each group required reinstitution of antihypertensive medication according to strict indications defined by the protocol. No significant differences in systolic or diastolic blood pressure were observed between the two groups. During follow-up, systolic and diastolic blood pressure averaged 130.6 and 82.5 mm Hg, respectively, for participants given supplemental potassium, and 132.5 and 83.1 mm Hg for participants given placebo. We conclude that supplemental potassium chloride does not reduce the need for antihypertensive medication in hypertensive men on a restricted-sodium diet.

Supervised exercise, spinal manipulation, and home exercise for chronic low back pain: a randomized clinical trial

BACKGROUND CONTEXT Several conservative therapies have been shown to be beneficial in the treatment of chronic low back pain (CLBP), including different forms of exercise and spinal manipulative therapy (SMT). The efficacy of less time-consuming and less costly self-care interventions, for example, home exercise, remains inconclusive in CLBP populations. PURPOSE The purpose of this study was to assess the relative efficacy of supervised exercise, spinal manipulation, and home exercise for the treatment of CLBP. STUDY DESIGN/SETTING An observer-blinded and mixed-method randomized clinical trial conducted in a university research clinic in Bloomington, MN, USA. PATIENT SAMPLE Individuals, 18 to 65 years of age, who had a primary complaint of mechanical LBP of at least 6-week duration with or without radiating pain to the lower extremity were included in this trial. OUTCOME MEASURES Patient-rated outcomes were pain, disability, general health status, medication use, global improvement, and satisfaction. Trunk muscle endurance and strength were assessed by blinded examiners, and qualitative interviews were performed at the end of the 12-week treatment phase. METHODS This prospective randomized clinical trial examined the short- (12 weeks) and long-term (52 weeks) relative efficacy of high-dose, supervised low-tech trunk exercise, chiropractic SMT, and a short course of home exercise and self-care advice for the treatment of LBP of at least 6-week duration. The study was approved by local institutional review boards. RESULTS A total of 301 individuals were included in this trial. For all three treatment groups, outcomes improved during the 12 weeks of treatment. Those who received supervised trunk exercise were most satisfied with care and experienced the greatest gains in trunk muscle endurance and strength, but they did not significantly differ from those receiving chiropractic spinal manipulation or home exercise in terms of pain and other patient-rated individual outcomes, in both the short- and long-term. CONCLUSIONS For CLBP, supervised exercise was significantly better than chiropractic spinal manipulation and home exercise in terms of satisfaction with treatment and trunk muscle endurance and strength. Although the short- and long-term differences between groups in patient-rated pain, disability, improvement, general health status, and medication use consistently favored the supervised exercise group, the differences were relatively small and not statistically significant for these individual outcomes.

Smoking cessation and change in diastolic blood pressure, body weight, and plasma lipids. MRFIT Research Group

Cigarette smoking cessation was examined for its impact on diastolic blood pressure, weight, and plasma lipids in 3,470 special intervention males in the Multiple Risk Factor Intervention Trial. Change in smoking status (quitters vs nonquitters) was not independently associated with change in diastolic blood pressure or the subsequent use of antihypertensive medication for smokers who were normotensive at entry. More quitters (35%) became hypertensive than nonquitters (27%, P less than 0.01), although the groups had similar baseline diastolic blood pressure levels. Weight gain subsequent to cessation probably contributed to this excess incidence of hypertension in quitters. Stepped-care antihypertensive therapy lowered diastolic blood pressure similarly for hypertensive quitters and nonquitters. Weight increases of 6 lb or more by the 72-month visit occurred in 47% of quitters vs 25% of nonquitters (P less than 0.01); quitters did not differ from nonquitters in their change in total kilocalories from baseline to the 72-month visit. Quitters who gained 6 lb or more tended to be less obese at baseline, be less physically active, and smoke more cigarettes per day than those who did not gain this amount. Finally, quitters relative to nonquitters experienced an adjusted increase of 2.4 mg/dl high-density lipoprotein cholesterol, but no difference in total or low-density lipoprotein cholesterol. The implications for intervention are discussed as they relate to the common, but not inevitable, increase in weight subsequent to cessation.