From
Journal of Clinical Hypertension

Analysis of Recent Papers in Hypertension

Jan Basile, MD, Medical University of South Carolina, Ralph H. Johnson VA Medical Center, Charleston, SC

Contents:

Controlling Systolic Blood Pressure Prevents All Types Of Strokes

Additive Lifestyle Modification Is More Effective Than One Intervention in Reducing Blood Pressure in Both Men and Women With Elevated Blood Pressure

ACE Inhibitors Slow the Progression in Both Diabetic and Nondiabetic Chronic Renal Disease

Pulse Pressure Predicts Cardiovascular Risk in Older Hypertensive Patients

Hypertension Itself and Not the Antihypertensive Agent Affects Sexual Function in Women

Moderately Intense Exercise Lowers Stroke Risk in Women

Controlling Systolic Blood Pressure Prevents All Types Of Strokes

The Systolic Hypertension in the Elderly Program (SHEP) demonstrated that effectively treating isolated systolic hypertension (ISH) decreases both fatal and nonfatal stroke. In an effort to evaluate whether all types of strokes were reduced and to determine the distribution of those strokes (ischemic or hemorrhagic) in relation to the attained systolic blood pressure (SBP), a recent reanalysis was performed of the original SHEP cohort.

A total of 4736 men and women 60 years of age or older with ISH were followed for an average of 4.5 years. If not randomized to the placebo group, they were treated with chlorthalidone and either atenolol or reserpine, with the goal systolic pressure of <160 mm Hg and at least a 20-mm Hg reduction from baseline. At the end of the study, there was a 37% reduction in the odds of having an ischemic stroke, and a 54% reduction in the odds of having a hemorrhagic stroke. A favorable effect was seen within the first year for hemorrhagic stroke, but not until the second year for ischemic stroke. Within the four subtypes of ischemic stroke, there was a 47% reduction in lacunar stroke, as well as a 44% reduction in embolic stroke. Of particular importance, the stroke incidence decreased in the participants who attained study-specific systolic blood pressure goals. Participants whose prestroke SBP was lower than 160 mm Hg experienced a significant 33% reduction in total stroke incidence as compared with those with a higher in-trial prestroke SBP. Whereas achieving a SBP lower than 150 mm Hg was associated with a 38% reduction in total stroke incidence, there was only a 22% reduction in stroke incidence when comparing 140 mm Hg as the in-trial goal.

By achieving specific SBP goals, antihypertensive drug treatment favorably reduced the incidence of both hemorrhagic and ischemic (including lacunar) strokes. -- Perry HM, Davis BR, Price TR, et al. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke. The Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens. 2000;13:724-733.

Comment

A recent clinical advisory statement issued from the Coordinating Committee of the National High Blood Pressure Education Program of the National Heart, Lung, and Blood Institute (NHLBI) emphasized the importance of controlling systolic blood pressure (SBP) in older Americans (See JCH, Sep/Oct 2000). With the evidence showing substantial reductions in stroke, myocardial infarction, heart failure, kidney failure, and overall cardiovascular disease morbidity and mortality, they recommended a SBP target of <140 mm Hg, although no trial has specifically measured the added degree of benefit by achieving this goal.

This reanalysis of the SHEP trial shows that achieving a SBP of at least <160 mm Hg and/or 20 mm Hg below the baseline SBP decreased the risk of ischemic stroke, including both lacunar and embolic types, as well as hemorrhagic stroke. In keeping with our pathophysiologic understanding, hemorrhagic events took but 1 year to prevent, while the prevention of ischemic events began after 2 years of active therapy.

It is important to note that although there was a benefit in reducing SBP to 140 mm Hg, the greater benefit occurred with reduction to a pressure of 150 mm Hg, which is the lowest endpoint goal tested in any outcome-based trial.

This study re-emphasizes the importance of controlling ISH and explains its beneficial impact on preventing both fatal and nonfatal stroke. Although a goal not often achieved, clinicians should continually reduce SBP to as close to 140 mm Hg as possible in order to prevent both ischemic and hemorrhagic stroke.

Additive Lifestyle Modification Is More Effective Than One Intervention in Reducing Blood Pressure in Both Men and Women With Elevated Blood Pressure

The Joint National Committee continues to recommend lifestyle modification as the initial treatment strategy for lowering elevated blood pressure. Outside of the studies involving sodium restriction, there have been few studies comparing the effect of modifying one lifestyle element against a strategy of combining multiple lifestyle changes. Furthermore, few of these studies have involved women.

In a study from Duke University Medical Center, 133 unmedicated, sedentary, overweight men and women (average weight, 202 pounds) whose initial blood pressure was 130-180 mm Hg/85-110 mm Hg (average, 141/93) were randomly assigned to one of three treatment groups for 6 months. The first was an exercise-only group that aerobically exercised for 45 minutes three or four times a week at 75%-85% of heart rate reserve, the second combined a weekly behavioral weight management program with the aerobic exercise program, and the third was a control group. Compliance was achieved in over 81% of the participants. Blood pressure was measured in the clinic at both the beginning and the end of the study, as well as by 24-hour ambulatory monitoring (ABPM). In addition, it was measured during mental stress and exercise testing. Hemodynamic measures and metabolic function was also assessed.

The participants in the combined treatment group lost 17 pounds, compared to 4 pounds in the exercise-only group and 1.5 pounds in the control group. This was associated with a reduction in clinic pressure of 7/5 mm Hg (systolic/diastolic) in the combination group, 4/4 mm Hg in the exercise-only group, and 1/1 mm Hg in the control group. Similar effects were seen in ABPM, mental stress, and exercise measurements. Insulin sensitivity was improved only in the combined group. Participants in both treatment groups had a reduction in peripheral vascular resistance with an increased cardiac output, although the combined treatment group showed the greatest reduction in peripheral vascular resistance.

Although exercise alone was effective in reducing blood pressure, the addition of a weight loss program enhanced this effect. Aerobic exercise in addition to a weight loss program is recommended for the management of hypertension in sedentary, overweight individuals. -- Blumenthal JA, Sherwood A, Gullette, E, et al. Exercise and weight loss reduce blood pressure in men and women with mild hypertension: Effects on cardiovascular, metabolic, and hemodynamic functioning. Arch Intern Med. 2000; 160:1947-1958.

Comment

Although recommended as first-line therapy in the treatment of hypertension, physicians have remained pessimistic over the ability of lifestyle modification to effectively control hypertension.

In this well-designed trial of lifestyle modification in which 56% of the participants were women, a combined approach of weight loss and exercise achieved 13 additional pounds of weight loss and an additional 3 mm Hg of systolic blood pressure reduction over the group that exercised only. Although this may not seem to be a large additional blood pressure reduction, observational studies would predict a major reduction in both stroke and heart attack with this additional systolic pressure reduction. In the combined treatment group, two thirds of those with stage 1 hypertension on entry and more than one half of those with stage 2 hypertension became normotensive, suggesting that these changes may enable those with borderline hypertension to avoid the use of antihypertensive medication altogether.

Pathophysiologically, the exercise and weight loss interventions resulted in a reduction of peripheral resistance, the hallmark of established hypertension. Furthermore, the weight management participants demonstrated lower fasting and postprandial glucose and insulin levels, suggesting an improvement in insulin resistance.

Although exercise training alone is effective in reducing blood pressure, the addition of a weight loss program enhances this effect. Combining a program of exercise and weight loss is recommended in managing overweight individuals with elevated blood pressure. Although beginning treatment with drug therapy may enable our overweight patients to more quickly "get to goal," with adjunctive weight loss and exercise, the need for pharmacologic treatment may become less necessary. The time has come for additive lifestyle modifications, including both weight loss and exercise, as a means of reducing elevated blood pressure.

ACE Inhibitors Slow the Progression in Both Diabetic and Nondiabetic Chronic Renal Disease

Although clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors slow the progression of diabetic renal disease, there has been less evidence from clinical trials in nondiabetic renal disease. This recently updated meta-analysis evaluated the results of ACE inhibitors in slowing the progression of both diabetic and nondiabetic renal disease, over a wide range of baseline renal impairment.

The primary goals were to determine whether ACE inhibitors could prevent microalbuminuria (30-300 mg protein over 24 hours) from progressing to macroalbuminuria (>300 mg protein over 24 hours), and whether ACE inhibitors could prevent the development of end-stage renal disease (ESRD) or a doubling of serum creatinine in patients with overt proteinuria (>330 mg protein over 24 hours) at baseline. The authors included both published and unpublished (personal communication), placebo-controlled, parallel trials in adults with at least 1 year of follow-up comparing ACE inhibitor therapy with placebo.

Including studies from January, 1970 to June, 1999, in nine trials involving 642 individuals with diabetic nephropathy and microalbuminuria (average follow-up of 3 years), the relative risk (RR) for developing macroalbuminuria was 0.35 for those on ACE inhibitor therapy vs. placebo. In seven trials involving 1389 individuals with overt proteinuria and renal insufficiency (baseline creatinine >=1.2 mg/dL for women and 1.4 mg/dL for men) from both diabetic (30%) and nondiabetic (70%) causes (average follow-up, 2.1 years), the RR of doubling of serum creatinine or developing ESRD was 0.6 for those treated with an ACE inhibitor compared with placebo.

The authors conclude that ACE inhibitors preserve renal function in individuals with both diabetic and nondiabetic renal disease. -- Kshirsagar AV, Joy MS, Hogan SL, et al. Effect of ACE inhibitors in diabetic and nondiabetic chronic renal disease: A systematic overview of randomized placebo-controlled trials. Am J Kidney Dis. 2000;35:695-707.

Comment

Angiotensin II is felt to play a key role in the pathophysiology of progressive renal disease. Although clinical trials have supported the use of ACE inhibitors in proteinuria and progression of renal disease in diabetic nephropathy, the evidence in nondiabetic renal disease has been less robust.

This meta-analysis suggests that regardless of the etiology of renal disease, be it nondiabetic glomerulonephritis, polycystic kidney disease, interstitial disease, or diabetes, when the serum creatinine ranges from 1.3-5.2 mg/dL, ACE inhibitors should be used to delay the progression of renal functional decline.

As in past meta-analyses, the mean arterial pressure difference was greater in ACE inhibitor-treated patients than in those assigned to placebo, making it difficult to distinguish the unique effect of ACE inhibitor treatment from the blood pressure reduction it causes. Although several ACE inhibitors, including captopril, enalapril, lisinopril, benazepril, and ramipril, were tested, there was no difference in outcome when they were tested for heterogeneity, verifying a protective effect of the entire class of agents.

As the incidence of chronic renal failure and ESRD continues to increase, and as both blacks and Native Americans continue to make up a disproportionately greater proportion of these patients, the reduction in the outcomes studied in this meta-analysis is particularly appealing. We anxiously await the results of the Antihypertensive Lipid-Lowering Trial to Prevent Heart Attack, which compares an ACE inhibitor, a calcium channel blocker, and a diuretic on renal outcomes in 15,000 diabetics with normal baseline renal function, as well as the African-American Study of Kidney Disease, contrasting an ACE inhibitor, a calcium channel blocker, and a ß blocker in those with baseline renal insufficiency. Until those results are available, we will continue to recommend ACE inhibitor therapy as part of the treatment strategy to slow the progression of renal disease in both the diabetic and nondiabetic patient.

Pulse Pressure Predicts Cardiovascular Risk in Older Hypertensive Patients

From both a historical perspective and the fact that early trials evaluated younger patients with hypertension, diastolic pressure has often been used as a means of predicting cardiovascular risk. More recently, especially in the older patient, Framingham data have identified systolic pressure, and especially pulse pressure, as the better predictor of cardiovascular outcomes.

To determine whether the pulsatile nature of the arterial waveform, as represented by the pulse pressure, better predicted cardiovascular mortality than either systolic pressure or mean arterial pressure in elderly patients with hypertension, investigators from France, Belgium, and China performed a meta-analysis of three major trials in elderly hypertensive patients. They pooled the results from the nearly 8000 patients in the European Working Party on High Blood Pressure in the Elderly trial, the Systolic Hypertension in Europe trial, and the Systolic Hypertension in China trial. Across all three studies, they found that pulse pressure at entry, not mean pressure, independently predicted cardiovascular complications and all-cause mortality.

For each 10 mm Hg increase in pulse pressure, a 10%-20% increase in the risk of any endpoint, including stroke and cardiovascular and coronary events, as well as cardiovascular and total mortality, occurred. A 10 mm Hg increase in the mean pressure, however, did not produce any significant increase in risk. These results were consistent in both Asian as well as Caucasian patients and persisted after adjustment for potential confounders as well as antihypertensive drug treatment. – Blacher J, Staessen J, Girerd X, et al. Pulse pressure not mean pressure determines cardiovascular risk in older hypertensive patients. Arch Intern Med. 2000; 160:1085-1089.

Comment

Although blood pressure is measured by two specific points usually considered in isolation of one another – the systolic and diastolic blood pressure – blood pressure actually travels through the arterial tree as a repetitive, continuous wave. This wave has both a pulsatile component, the pulse pressure, and a static component, the mean pressure. Pulse pressure is determined by ventricular ejection, arterial stiffness, and the timing of wave reflections, and, as such, primarily indicates the degree of vascular arteriosclerosis. Cardiac output as well as peripheral vascular resistance, and the other hand, determine mean pressure.

As pointed out by the authors of this study, in the evaluation of elderly patients with both combined systolic and diastolic as well as isolated systolic hypertension, pulse pressure and not mean arterial pressure independently predicts the incidence of vascular complications as well as all-cause mortality. Whether this applies to younger patients, and whether this implies a causal or reversible relationship, needs to be evaluated in prospective, randomized clinical trials.

Until we perform trials that evaluate the effects of different antihypertensive agents on the pulse pressure, we will continue to target systolic blood pressure reduction as the primary therapeutic goal.

Hypertension Itself and Not the Antihypertensive Agent Affects Sexual Function in Women

With more effective pharmacologic therapy recently available for the treatment of sexual dysfunction, there has been renewed interest in the effect of hypertension itself, as well as its treatment, on sexual function. Although rarely researched in women, investigators from upstate New York conducted an ambulatory, medical record-based, case-controlled study to evaluate sexual function in treated and untreated hypertensive women compared to healthy controls.

Completing both a self-administered questionnaire and a telephone interview, 211 white, premenopausal women were analyzed (107 healthy controls and 104 mild hypertensives, of whom 37 were unmedicated and 67 were medicated).

In this age-adjusted analysis, women did not differ on their sexuality scores regardless of the requirement for antihypertensive medication. Women who were hypertensive, however, reported decreased orgasm and lubrication, as well as increased pain, during intercourse when compared to their normotensive counterparts. In addition, diminshed orgasm was reported in smokers regardless of their age or the presence of hypertension.

In contrast to these physical impairments, there was no difference in the emotional aspects of sexual function in these women. The desire, satisfaction, and quality of the relationships were similar regardless of their blood pressure. -- Duncan LE, Lewis C, Jenkins P, et al. Does hypertension and its pharmacotherapy affect the quality of sexual function in women? Am J Hypertens. 2000;13: 640-647.

Comment

Recent survey data suggest that the prevalence of sexual dysfunction among women in the United States is approximately 40%. With almost one half of all treated hypertensives being women, the effect of antihypertensive treatment, as well as the condition of hypertension itself, is of extreme importance to the practitioner. Although considerable research has been done on sexual function in the male hypertensive, there has been a lack of research on sexual function in women with hypertension.

This ambulatory, outpatient, case-controlled study, adjusted for age, suggests that women with hypertension, regardless of their being treated with medication, have less enjoyable sexual activity than their normotensive counterparts, while the emotional aspects of their relationships seem to be unaffected. In addition, regardless of their age or hypertensive status, women who are current smokers experience diminished orgasm compared to nonsmokers.

What are the implications for the physician? In these premenopausal women, whose estrogen status would appear to be ideal, we should ask about vaginal dryness and achievement of orgasm and offer lubricating agents for use prior to intercourse. It appears that it is the hypertensive state itself and not the medications we use that are responsible for these effects. In addition, emotional aspects of sexual functioning do not appear to be impaired. Furthermore, all women who smoke should be counseled about its effect on sexual performance. Finally, while we await further research to explain these findings, all hypertensive women should be routinely assessed with a careful sexual history and problems should be managed appropriately.

Moderately Intense Exercise Lowers Stroke Risk in Women

Although increased physical activity is associated with a decreased risk of developing coronary heart disease, its exact role in the prevention of stroke has been less well studied and, when evaluated, the results have been inconsistent. Most previous studies have focused on men, as in the Framingham Heart Study, where the results have been favorable, but when women were also evaluated, high levels of physical activity did not protect against stroke. A recent analysis of the Nurses Health Study now shows the same favorable relationship between increased physical activity and the reduction of stroke in women.

Investigators from Harvard Medical School performed an analysis of the Nurses Health Study, a prospective cohort study of 72,488 women 40-65 years of age, to assess the relationship between physical activity and the risk of stroke and stroke subtypes. They surveyed participants three times over an 8-year period for the amount of time spent in physical activity and the pace maintained during that activity. After adjusting for risk factors, they found an inverse relationship between the amount of physical activity and the risk of both total stroke and ischemic stroke, with no effect, however, on either subarachnoid or intracerebral hemorrhage. Walking lowered the risk of stroke to the same degree as more vigorous activity when equivalent amounts of energy were expended. In addition, the pace of walking was inversely associated with the risk of total and ischemic stroke.

Exercise, in the form of leisure-time physical activity, has a protective, dose-dependent effect on the risk of total and ischemic stroke in women. -- Hu FB, Stampfer MJ, Colditz GA, et al. Physical activity and risk of stroke in women. JAMA. 2000;283:2961-2967.

Comment

The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure states that blood pressure can be lowered with moderately intense physical activity, such as 30-45 minutes of brisk walking most days of the week. Furthermore, when compared with their sedentary peers, those who remain more active and fit have a 20%-50% reduced risk of developing hypertension. Accordingly, we recommend 30 minutes of moderately intense exercise on most, if not all, days of the week. The implications of walking in the elderly, however, continue to go unrecognized.

Now come these findings from the Nurses Health Study, which continue to solidify the relationship between various risk factors and vascular health. With their large sample size and both detailed and repeated measures of physical activity, the authors provide strong evidence for a graded inverse relationship between physical activity levels and risk of stroke.

You may ask yourself, Why place this review in a hypertension journal? Although the authors adjusted for various risk factors, including the use of antihypertensive medications, blood pressure itself was not mentioned as a specifically measured variable. Nevertheless, we remain committed to improving the overall vascular health of our patients. In this regard, physical activity not only lowers blood pressure and increases the high-density cholesterol concentration, it also contributes to weight loss and can increase insulin sensitivity, as well as decrease the risk for developing type 2 diabetes. Furthermore, it has been associated with reductions in plasma fibrinogen and platelet aggregation, as well as elevations in plasma tissue plasminogen activator activity. As stroke remains the number one cause of disability in the elderly and the number three cause of death, the implications of lowering stroke rates in our hypertensive population are staggering!

As we treat hypertension and continue to "get to goal," remember the implications of this study. Women who were previously sedentary and become physically active through leisure time walking have a lower risk of stroke than those who remain sedentary. This prompt response to physical activity should be recommended to all of our patients.