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COMPARATIVE EFFECT OF A LOSARTAN-BASED REGIMEN AND AN ATENOLOL-BASED REGIMEN IN PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY: A LIFE SUBSTUDY IN THOSE WITH ISOLATED SYSTOLIC HYPERTENSION

  1. Top of page
  2. COMPARATIVE EFFECT OF A LOSARTAN-BASED REGIMEN AND AN ATENOLOL-BASED REGIMEN IN PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY: A LIFE SUBSTUDY IN THOSE WITH ISOLATED SYSTOLIC HYPERTENSION
  3. Comment
  4. LIFESTYLE MODIFICATION REDUCES LEFT VENTRICULAR HYPERTROPHY
  5. Comment
  6. EFFICACY OF EPLERENONE, A NEW ALDOSTERONE ANTAGONIST

Left ventricular hypertrophy (LVH) remains a major independent risk factor for stroke, myocardial infarction (MI), sudden cardiac death, and cardiovascular mortality. The Losartan Intervention For Endpoint Reduction (LIFE) Study (see Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359: 995–1003) found that a treatment regimen based on the use of an angiotensin-receptor blocker Losartan (L) reduced overall cardiovascular morbidity and mortality (mainly stroke) to a greater degree than the β blocker atenolol (A)-based program in 9193 patients with hypertension and evidence of LVH on electrocardiography (ECG; ECG-LVH). Whether a similar benefit would be seen in the 1326 men and women with isolated systolic hypertension (ISH), a prespecified endpoint of the original trial, was evaluated in this separate analysis of the LIFE cohort.

Patients 55–80 years of age (mean, 70 years) with ECG-LVH were eligible for this industry-sponsored sub-study if their systolic blood pressure (SBP) was 160 to 200 mmHg and their diastolic blood pressure was <90 mmHg. Thirty-two% of the enrollees had never been treated for ISH. Of the 13% of the overall trial enrolled in this sub-study, 60% were female, 92% white, and 6% black. Of note, 22% had underlying coronary artery disease, 11% cerebrovascular disease, 8% peripheral vascular disease, and 17% were diabetic, a group with higher risk compared to the original cohort.

Patients with similar baseline characteristics were randomly assigned once-daily L (n=660) or A (n=666), with hydrochlorothiazide added after 2 months as the second agent in both arms if the sitting systolic blood pressure was 140 mm Hg or higher. At 4 months, it was mandatory to up-titrate the original therapy to 100 mg of L or A once daily if the SBP was 160 mm Hg or higher. Additional agents (excluding angiotensin-converting enzyme (ACE) inhibitor, other angiotensin-receptor blocker or β blocker therapy) were added, if necessary. The primary end point was a composite end point including first evidence of cardiovascular death, stroke, or MI. Other prespecified end points included total mortality, hospitalization for angina pectoris or heart failure, the need for coronary or peripheral revascularization, and the development of new-onset diabetes mellitus.

Mean sitting blood pressure was 174/83 mm Hg on entry; the goal sitting SBP taken 24-hours after the dose of medication (range 22–26 hours) was <140 mm Hg. After a mean follow-up of 4.7 years, blood pressure was reduced 28/9 mm Hg in both the L and A arms. Heart rate was unchanged in the L group and reduced 6.6 beats/min in the A group.

The final once-daily dose of A was 76 mg and the final dose of L was 79 mg once daily. Of interest is that fewer than 10% of the patients were treated with monotherapy. The likelihood of receiving diuretic therapy was the same in both groups. The mean blood pressure at the last visit was 146/75 in the L group and 146/74 in the A group with no difference in the pulse pressure or mean arterial pressures. Of note, a blood pressure of <140/90 mm Hg was achieved in only 44% of the L group and 43% of the A group.

After adjustment for the degree of LVH and Framingham risk score at randomization, L reduced the main outcome of cardiovascular morbidity and mortality by 25% (cardiovascular death, stroke, and MI). There was also a 46% reduction in cardiovascular mortality, 40% reduction in fatal and nonfatal stroke, and a 28% reduction in total mortality compared to A. New onset diabetes was reduced by 38%. There was no difference between the two groups in the rate of hospitalization for angina pectoris or heart failure, or the need for coronary or peripheral revascularization. As in the overall study, a trend was noted in the risk of MI, with an 11% increase in the L group compared to the A group. L was better tolerated than A and more effective in reducing ECG-LVH.

The authors conclude that this is the first study in patients with ISH to show that one antihypertensive therapy reduces cardiovascular morbidity and mortality to a greater degree than another blood pressure-lowering agent while achieving similar reductions in blood pressure. They caution us that the vascular effects of L may be more pronounced in stroke protection but may be less protective than a β blocker regimen in protecting against MI. While it is currently unknown whether L is superior to diuretics or calcium channel blockers (CCBs) as a first-line treatment for ISH, the authors suggest that based on this study, L might be considered as a first line antihypertensive medication in patients with ISH.—Kjeldsen SE, Dahlof B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy. A Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA. 2002;288: 1491–1498.

Comment

  1. Top of page
  2. COMPARATIVE EFFECT OF A LOSARTAN-BASED REGIMEN AND AN ATENOLOL-BASED REGIMEN IN PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY: A LIFE SUBSTUDY IN THOSE WITH ISOLATED SYSTOLIC HYPERTENSION
  3. Comment
  4. LIFESTYLE MODIFICATION REDUCES LEFT VENTRICULAR HYPERTROPHY
  5. Comment
  6. EFFICACY OF EPLERENONE, A NEW ALDOSTERONE ANTAGONIST

The original LIFE study was a multinational, double-blind, randomized, active-controlled, parallel group study. It found that initial treatment with the angiotensin receptor blocker (ARB)-based regimen using L was more effective in reversing ECG-LVH and reducing the risk of the combined end point of cardiovascular death, MI, and stroke compared to the initial use of an A-based β blocker regimen. The overall 13% difference in the combined end point occurred mainly because of a 25% reduction in the risk of fatal and nonfatal stroke in those on L. There was no difference noted between groups in either cardiovascular or overall mortality.

The present substudy, prespecified when the trial was first organized, found that the initial use of L as a component of therapy is more beneficial than initial use of the βblocker A in older patients with ISH and ECG-LVH. In this group of patients at higher risk than the main trial participants, the primary composite end point was reduced 25%, with a 40% reduction in stroke. In contrast to the overall trial, where there was no benefit found in either cardiovascular or total mortality, there was a 46% reduction in cardiovascular death and 28% reduction in total mortality in the L group. The risk of MI once again showed a trend to be greater in the L group. It should be remembered that β blockers have been shown to be effective in decreasing the occurrence of myocardial infarction—these comparative results might have been expected. Similar findings were noted in the recently reported Study on Cognition and Prognosis in Elderly (SCOPE) trial with the ARB Candesartan (International Society of Hypertension, Prague, Czechoslavakia, June 2002).

Before we begin using L as preferred therapy in individuals with ISH, a closer look at the trial is in order. Less than 10% of all those with ISH were controlled with just the blinded agent. Thus, 90% of patients received multiple medications in an attempt to achieve goal blood pressure. As the distribution of additional drugs is said not to differ between the L and A groups, at least half the patients required additional therapy with a thiazide diuretic and a CCB. Even using multiple therapy, SBP was reduced to the goal of <140 mm Hg in only 44% of the L and 43% of the A patients. Thus, as in the isolated Systolic Hypertension in Europe in the Elderly (Syst-Eur) trial, multiple antihypertensive agents were necessary to effectively reduce SBP. In that trial, a CCB was used as initial therapy, although a diuretic and angiotensin-converting enzyme (ACE) inhibitor were necessary in more than 50% of the patients. As in the Syst-Eur trial, additional therapy in LIFE was also required, usually with diuretic and CCB therapy. Accordingly, although the Syst-Eur trial was placebo-controlled, and agents in these two ISH trials were used in differing order to antagonize the renin-angiotensin system (RAS), it appears that a cocktail of therapy with either an angiotensin-receptor blocker or an ACE inhibitor similarly improves outcome when given with a diuretic or CCB.

Why was the β blocker A not as effective as L in the LIFE trial? A was given once a day, a practice often duplicated in clinical practice. L was more effective in inhibiting the RAS than once-daily A; LVH regression occurred more frequently with L therapy even when adjusted for blood pressure reduction. In addition, both in the present trial when it was given as initial therapy or in the Systolic Hypertension in the Elderly (SHEP) trial where a β blocker was additive therapy, A was less effective. Although it reduces heart rate more than L, A needs to been given twice a day in these high-risk patients to more effectively block angiotensin II and reduce LVH. At present, β blocker therapy is not recommended as initial therapy in the elderly with or without ISH and is somewhat more effective in younger compared to older patients.

What about new-onset diabetes? Hypertension is an insulin-resistant state and most patients with hypertension have some degree of insulin resistance. In the 83% of patients without diabetes at randomization, diabetes developed in 6% of the L patients and in 9% of those on A. We are left wondering if the findings in this trial are due to the beneficial effect of L or the deleterious effect of A on insulin resistance. Regardless, this trial demonstrates the beneficial effect of an ARB in preventing diabetes, consistent with two previous studies with similar observations with ACE inhibitor therapy.

L was better tolerated than A as 21% fewer patients discontinued L than A by the end of the study. Physicians often consider ARB therapy before they use a β blocker because of this improved tolerability.

Although only 6% of the participants were black, raising questions as to whether or not the results of this trial can be generalized to all ethnic populations, the results appear applicable to clinical practice. While we continue to debate if the manner in which we reduce blood pressure is important for reducing cardiovascular disease, it appears that in patients with ISH and ECG-LVH it may matter. The LIFE trial suggests that LVH reversal in those with ISH leads to an improvement in outcome and L appears more effective than A as part of a multiple-agent treatment. ISH remains the most common form of hypertension in the elderly and the most difficult to treat. A diuretic, a CCB, and now an ARB are the only drug classes that have been tested as initial therapy in this group and the LIFE trial has thus far been the only trial to demonstrate benefit in patients with ECG-LVH. Many questions still remain. Do the implications of this trial apply for the entire ARB class? To answer this question, head-to-head ARB-based trials need to be conducted. Furthermore, ARB- vs. ACE inhibitor-based trials needs to be conducted. Until those trials are completed, an ARB-diuretic-CCB combination in hypertensive subjects with ECG-LVH and a CCB-ACE-diuretic combination appear to improve outcome in the older patient with ISH. Practitioners as well as patients need to be continually reminded about the importance of treating ISH.

LIFESTYLE MODIFICATION REDUCES LEFT VENTRICULAR HYPERTROPHY

  1. Top of page
  2. COMPARATIVE EFFECT OF A LOSARTAN-BASED REGIMEN AND AN ATENOLOL-BASED REGIMEN IN PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY: A LIFE SUBSTUDY IN THOSE WITH ISOLATED SYSTOLIC HYPERTENSION
  3. Comment
  4. LIFESTYLE MODIFICATION REDUCES LEFT VENTRICULAR HYPERTROPHY
  5. Comment
  6. EFFICACY OF EPLERENONE, A NEW ALDOSTERONE ANTAGONIST

The presence of left ventricular hypertrophy (LVH) increases the risk for cardiac morbidity and mortality. Regression of LVH is associated with a reduction in risk. It has been demonstrated that LVH can be reduced when blood pressure is lowered by antihypertensive therapy; similar evidence for lifestyle interventions has been lacking.

To determine if aerobic exercise or weight management counseling in addition to exercise have a beneficial effect on left ventricular mass, investigators randomized 82 overweight or obese, sedentary adults (37 men, 45 women) with high-normal or grade or stage 1 elevated blood pressure hypertension (mean 140/93 mm Hg) to one of three groups: 1) a supervised aerobic exercise program; 2) a behavioral weight-loss program that included exercise; or 3) a control group. The three groups were comparable in all baseline clinical and demographic characteristics except that there were more nonwhites in the control group than the active treatment groups. No participants took antihypertensive therapy. Blood pressure and echocardiographic measures of left ventricular structure were measured at baseline and at the end of the 6-month study.

Compared to baseline, systolic blood pressure and diastolic blood pressure fell by 3/4 mm Hg in the exercise only group and 7/6 mm Hg in the weight management-exercise group, respectively. These reductions in blood pressure were associated with favorable decreases in left ventricular relative wall thickness, as well as posterior and septal wall thickness. There was a trend toward a reduction in left ventricular mass, independent of sex or race.

Nonpharmacologic measures such as aerobic exercise and weight loss not only reduce blood pressure but also induce favorable changes in left ventricular structure in overweight, sedentary patients with high-normal or mildly elevated blood pressure. There were no significant changes in the control group.—Hinderliter A, Sherwood A, Gullette E, et al. Reduction of left ventricular hypertrophy after exercise and weight loss in overweight patients with mild hypertension. Arch Intern Med. 2002;162:1333–1339.

Comment

  1. Top of page
  2. COMPARATIVE EFFECT OF A LOSARTAN-BASED REGIMEN AND AN ATENOLOL-BASED REGIMEN IN PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY: A LIFE SUBSTUDY IN THOSE WITH ISOLATED SYSTOLIC HYPERTENSION
  3. Comment
  4. LIFESTYLE MODIFICATION REDUCES LEFT VENTRICULAR HYPERTROPHY
  5. Comment
  6. EFFICACY OF EPLERENONE, A NEW ALDOSTERONE ANTAGONIST

Lifestyle interventions, including weight loss and aerobic exercise continue to be recommended as initial therapy in patients with uncomplicated high-normal or stage 1 elevated blood pressure. While a number of studies have shown these interventions to lower blood pressure, evidence that they reduce end-organ damage or prevent cardiovascular events has been lacking. This is the first study, small as it is, in a group of overweight, sedentary men and women that demonstrates that these nonpharmacologic measures lead not only to reductions in blood pressure but also result in echocardiographically measured beneficial changes in left ventricular structure. Whether these changes can be sustained over a longer time period remains to be determined.