ANGIOTENSIN RECEPTOR BLOCKER COMPARED TO A β BLOCKER‐BASED TREATMENT REGIMEN IN HYPERTENSIVE PATIENTS WITH LEFT VENTRICULAR HYPERTROPHY: THE LIFE TRIAL
In patients with hypertension, left ventricular hypertrophy (LVH) is a major independent risk factor for stroke, myocardial infarction (MI), sudden cardiac death, and cardiovascular mortality. It is still uncertain if one specific class of blood pressure lowering agent is more effective than another in causing LVH regression. Controlled data indicate that angiotensin‐converting enzyme (ACE) inhibitors and diuretics appear to be somewhat more effective than calcium channel blockers and β blockers. It is clear that patients who experience regression of LVH on treatment experience less cardiovascular disease and death than patients whose LVH does not regress. Both β blocker and angiotensin II type 1 receptor blocker (ARB) therapy antagonize the effects of angiotensin II and cause LVH regression. Accordingly, a study was performed in patients with essential hypertension and LVH to specifically compare the effects of these two classes of antihypertensive agents on cardiovascular death, MI, and stroke as well as their ability to regress LVH independent of blood pressure reduction.
The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study was an international multicountry study that evaluated 9193 patients 55–80 years of age (mean age, 67) with previously treated (72%) or untreated (28%) hypertension and ECG evidence of LVH (ECG‐LVH). Patients were eligible for the trial if their trough sitting systolic blood pressure was 160–200 mm Hg and/or their diastolic blood pressure was 95–115 mm Hg after a 14‐day placebo washout period. Baseline characteristics, similar in the overall treatment group, found 54% were female, 92% white, 6% black, and 13% diabetic, with 16% having a history of coronary artery disease and 8% a history of cerebrovascular disease. Those with a history of an MI or stroke within the previous 6 months, angina requiring treatment, or heart failure were excluded.
Patients were double‐blindly randomized in parallel groups to either atenolol (A) (n=4558), or losartan (L) (n=4605). The starting dose of both drugs was 50 mg once daily. After 2 months, if the target blood pressure of <140/<90 mm Hg was not met, open‐label hydrochlorthiazide, 12.5 mg, was added. If necessary, 100 mg once daily of L or A were then used to reach the target blood pressure level, with additional therapies added (excluding ACE inhibitors, other ARBs, or β blockers), if necessary. The primary end point was a composite end point including first evidence of cardiovascular death, MI, or stroke. Other pre‐specified 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 blood pressure was reduced from 175/98 mm Hg to 145.4/80.9 mm Hg in the A group and 175/98 mm Hg to 144.1/81.3 mm Hg in the L group. Heart rate was reduced 2 beats/min in the L group and 8 beats/minute in the A group.
The mean dose of A was 79 mg once daily, with 43% of the A patients requiring 100 mg, with or without additional therapy including hydrochlorthiazide and the mean dose of L was 82 mg once daily with 50% of the L patients taking 100 mg, with or without additional therapy. Only 9% of the L group and 10% of the A group were controlled with the initial dose of blinded therapy and only 11% of all the participants were controlled just with the blinded agent. Thus, almost 90% of patients received multiple medications in an attempt to achieve goal blood pressure. Even using multiple agent therapy, blood pressure was reduced to the goal of <140/<90 mm Hg in only 48% of the L and 45% of the A patients.
The study was stopped after 1040 patients had experienced a primary composite end point, occurring after a mean follow‐up of 4.8 years. By an intention‐to‐treat analysis, after adjusting for differences in achieved blood pressure levels, L reduced the primary composite end point of first stroke, MI, or cardiovascular death by 13%. Most of the benefit was driven by a 25% reduction in the risk of fatal and nonfatal stroke, with no benefit seen for fatal and nonfatal MI or cardiovascular death. Of the secondary end points, new onset diabetes was reduced 25% with L. In addition, L was more effective in regressing ECG‐LVH than A. According to the authors, only part of the benefit on study outcome was explained after adjusting for differences in both the achieved blood pressure and degree of ECG‐LVH regression.
Tolerability was slightly better with L than with A. At the end of the trial, 23% of the participants were off L and 27% were off A. More A subjects discontinued therapy because of adverse, or drug‐related events including bradycardia, cold extremities, and sexual dysfunction. There was no difference between the two groups in either the risk of cough or angioedema.
The authors conclude that in patients with essential hypertension and ECG‐LVH, treatment based on L, as compared to a treatment regimen based on A, was associated with less overall cardiovascular morbidity and mortality, stroke, and new onset of diabetes although no difference was noted between groups in the occurrence of MI or cardiovascular death. In addition, L was better tolerated and caused greater regression of ECG‐LVH for a similar amount of blood pressure reduction. L appears to confer benefits beyond blood pressure reduction in older patients with hypertension and ECG‐LVH.—Dahlof B, Kjeldsen SE, Devereux RB, 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.
Comment
Up to now, there have been only a few comparative trials that have examined the effects of specific blood pressure lowering agents on reducing cardiovascular morbidity and mortality. The LIFE study found that initial treatment with the ARB 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 a β blocker‐based regimen using A. This 13% difference occurred, however, mainly because of a 25% reduction in the risk of fatal and nonfatal stroke in those on L with no difference noted between groups in either cardiovascular or overall mortality. The risk of MI, although not significantly different, was 7% more likely to have occurred in the L group (198 events with L compared to 188 with A), a trend that remains unexplained. Even though the systolic blood pressure was reduced 1 mm Hg more in the L group, the authors state that there was no appreciable change in the outcome after adjusting for this difference.
What are the clinical implications of this trial?
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Although an echocardiogram is more sensitive in detecting the presence of LVH, the studies' clinical utility is strengthened by the use of a screening ECG. This is a recommended screening test for all hypertensives as stated in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI).
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Only 11% of patients at the end of the study remained on single‐agent therapy with only 2% on 100 mg of L or A as monotherapy. As the distribution of additional drugs is said not to differ between the L and A groups, almost all patients required additional therapy with a thiazide diuretic. As “other drugs,” a calcium antagonist (not specifically mentioned in the paper), was probably also required in about one half of the patients. In a treatment program that includes an ARB, L appears more effective than a regimen based on A, to reduce the risk of stroke and regress LVH. The practice of using an ARB with a thiazide diuretic appears to improve outcome.
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A was given once a day, a practice often duplicated outside of clinical trials. Although it reduced heart rate more than L, it needed to be given twice a day in these high‐risk patients to more effectively block angiotensin II and reduce LVH. Furthermore, LVH regression may occur less frequently with β blocker therapy than with ARB therapy, even when adjusted for blood pressure reduction.
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In the 87% of patients without diabetes at randomization, diabetes developed in 6% of the L patients and 8% of those on A. Although this would appear to be a high rate overall for the development of diabetes, hypertension is an insulin‐resistant state and most patients with hypertension have some degree of insulin resistance. As some but not all studies have noted β blocker therapy to be more often associated with the development of new‐onset diabetes, 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. That being said, this trial demonstrates the benefit of an ARB on the prevention of diabetes; this is consistent with two previous studies noting similar observations with ACE inhibitor therapy. It is of interest to note that the United Kingdom study in more than 1100 type 2 diabetic patients over an 8+ year period failed to demonstrate a difference in cardiovascular outcome where an ACE inhibitor group of subjects was compared to a group of patients on a β blocker (A) based regimen.
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L was better tolerated than A. Clinicians, based on similar observations in their own practice, often consider ARB therapy before they use a β blocker.
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The significant 25% reduction in stroke is impressive and needs comment. Stroke was the most likely primary end point to occur among the three composite end points and continues to be the most devastating consequence of hypertension. LVH remains a blood‐pressure‐independent predictor for stroke. That L was more effective in regressing LVH and reducing stroke than A complements the Heart Outcomes Prevention Evaluation (HOPE) study, which also found a protective effect on stroke when a group of patients on antihypertensive drugs that included the ACE inhibitor ramipril was compared to subjects not receiving an ACE inhibitor. Although blood pressure reduction is essential for reducing the rate of stroke, blockade of the renin‐angiotensin system seems to have importance as well.
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As only 6% of the participants were black, it is unclear if the results can be generalized to all ethnic populations.
With these comments noted, the results of this trial remain directly applicable to clinical practice. Although we continue to debate if the manner in which we reduce blood pressure is important for reducing cardiovascular disease in those with hypertension, it appears that in hypertensive patients with ECG‐LVH it does. The selection of the ARB L may be a better choice than the β blocker A as part of a treatment regimen. Multiple agents are, however, needed to control blood pressure. We remain unclear regarding the implications of this trial for the entire ARB class. Accordingly, head‐to‐head ARB and ARB vs. ACE‐inhibitor‐based trials, need to be conducted. Until those trials are completed, an ARB‐diuretic combination should be considered to achieve blood pressure control when there is evidence of ECG‐LVH.
EFFECTS OF AN ARB‐BASED REGIMEN COMPARED TO A β BLOCKER‐BASED PROGRAM IN DIABETICS WITH LVH
The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (see above) found that losartan (L) reduced cardiovascular morbidity and mortality (mainly stroke) better than atenolol (A) in hypertensive patients with evidence of left ventricular hypertrophy (LVH) on ECG (ECG‐LVH). Whether this same benefit was seen in the 13% of the participants who were diabetics on entry into the trial was evaluated in this separate analysis of the overall LIFE cohort.
Utilizing World Health Organization criteria for the diagnosis of diabetes, patients randomized to either A (n=609) or L (n=586) were evaluated in a similar fashion as performed in the overall trial. There was a significantly greater number of patients with atrial fibrillation in the A group compared to the L cohort. This substudy found that those with diabetes randomized to L experienced a 24% reduction in the primary composite end point (more favorable than the 13% reduction seen in the overall trial). Although there was no benefit on the specific end point of cardiovascular mortality in the entire study, L reduced the risk of cardiovascular death by 37% and the secondary end point of total mortality by 39% as well as hospitalization for heart failure by 41%. As in the overall trial, there was no difference in the risk of myocardial infarction between the two groups.
Interestingly, at the conclusion of the trial, although systolic blood pressure was reduced 2 mm Hg more in the L (146/79 mm Hg) than in the A group (148/79 mm Hg), there was no difference in the risk of stroke, which accounted for the majority of benefit in the overall analysis.
L was more effective than A in reversing LVH. Interestingly, serum glucose did not differ between the two groups throughout the study. Although the percent of patients with clinical nephropathy (at least 300 mg of protein/g creatinine/day) was similar in the two groups at study entry, fewer patients in the L group still had evidence of nephropathy at the study's conclusion.
L was more effective than A in reducing cardiovascular and all‐cause mortality in patients with hypertension, diabetes, and LVH. The observation in this substudy that there was no difference in the risk of stroke as noted in the overall trial remains unexplained. —Lindholm L, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:1004–1010.
Comment
This substudy seems to raise some interesting observations.
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Few patients remained only on the blinded medicine (9%) as almost all participants ended up on two or more medicines and still fell short of the blood pressure goal recommended for those with diabetes (<130/80 mm Hg).
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Although the authors adjusted for the 2 mm Hg greater reduction in systolic blood pressure seen in those on L, this should have accounted for a further reduction in stroke as seen in the overall trial but not in the diabetic cohort.
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As the diabetic cohort usually accounts for the greatest clinical benefit seen within a trial, the discordant findings between the overall cohort and the diabetic cohort on the primary end points remains unexplained. Cardiovascular mortality was reduced in the diabetics on L when compared to A. However, it is of interest to speculate on possible differences in the groups at baseline in the presence of atrial fibrillation. Did the A subjects have more cardiovascular disease before the study started?
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In the L group, proteinuria was present in 11% of patients at study entry and was reduced to 8%, whereas A was associated with a 12%–11% reduction at the study's conclusion suggesting that an angiotensin receptor blocker may be more effective in reducing clinical nephropathy than a β blocker.
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While L decreased the risk of new‐onset diabetes by 25% in the overall trial, once diabetes occurred, there was no difference between the groups in serum glucose levels over a mean 4.7 years.
The LIFE trial suggests that LVH reversal leads to an improvement in outcome in the diabetic. Many questions still remain. Until more information is forthcoming, multiple agents continue to be necessary to achieve the goal blood pressure of <130/80 mm Hg recommended for the diabetic patient. The initial use of the angiotensin receptor blocker as a component of therapy appears more beneficial than the initial use of the β blocker in those with hypertension, diabetes, and ECG‐LVH.
STROKE INCIDENCE REDUCED IN HIGH‐RISK PATIENTS WITH THE ACE INHIBITOR RAMIPRIL
Stroke remains the third leading cause of death in the United States. The Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends diuretics and β blockers to prevent the occurrence of initial stroke in those with uncomplicated hypertension. Although antiplatelet agents can prevent stroke in those at high risk, antihypertensive therapy has not previously been evaluated to prevent an initial stroke in high‐risk individuals with diabetes, underlying cardiovascular or peripheral vascular disease, or in those without hypertension. Prevention of a recurrent stroke in those with a history of previous stroke has recently been reported with the use of angiotensin‐converting enzyme (ACE) inhibitor/diuretic combination therapy.
As previously shown in the Heart Outcomes Prevention Evaluation (HOPE) study, participants 55 years of age and over had a reduction in the risk of myocardial infarction, stroke, cardiovascular death, as well as total mortality, when the ACE inhibitor ramipril was added to the patients' established therapy compared to a group of subjects on other agents that did not include an ACE inhibitor. Now, in a subanalysis of the 9297 patients who participated in the original HOPE trial, the secondary prevention of stroke, transient ischemic attack (TIA), and cognitive function was evaluated. Stroke was confirmed by computed tomography, magnetic resonance imaging, or autopsy in 84% of the cases. Blood pressure was recorded at study entry, after 2 years, and at the study's four and one‐half year conclusion with the lower of the two values at each visit recorded.
In those who received an ACE inhibitor plus other drugs, compared to a regimen that did not include an ACE inhibitor, the risk of overall stroke was decreased by 32% while the risk of fatal stroke was reduced by 61%. Mean baseline blood pressure in those who experienced a stroke was 143/79 mm Hg compared to 139/79 mm Hg in those who did not develop a stroke. After adjusting for differences in baseline blood pressure as well as changes in blood pressure in those who received ramipril, there was still a 28% reduction in the risk of stroke in this group. These benefits were seen across all subgroups including patients with (11%) and without previous stroke, underlying coronary artery disease (80%), peripheral arterial disease (43%), or diabetes (38%). In addition, the benefit was seen at all levels of blood pressure including those hypertensive and those with an initial blood pressure < 120/70 mm Hg. Cognitive decline or functional impairment also occurred less often on ramipril.
The authors of this subanalysis conclude that patients at high risk for stroke should continue to receive aspirin and, in addition to other blood pressure lowering agents required to achieve blood pressure control, an ACE inhibitor. They believe the widespread use of an ACE inhibitor, such as ramipril, in those at high risk for stroke, may have a major impact on public health.—Bosch J, Yusuf S, Pogue J, et al., on behalf of the HOPE investigators. Use of ramipril in preventing stroke: double blind randomized trial. BMJ. 2002;324:699–702.
Comment
The HOPE study, in which 11% of the patients enrolled had a history of a stroke or TIA, found that treatment with an ACE inhibitor (plus other medications) reduced the risk of fatal and nonfatal stroke and TIA at all levels of entry blood pressure. The benefit was seen in all subtypes of stroke and, according to the authors, was independent of the modest reduction in blood pressure that occurred with ramipril (3/2 mm Hg), compared to other agents. In the HOPE study, blood pressure was only measured several times throughout the study.
These results are consistent with another ACE inhibitor trial, the Perindopril Protection Against Stroke Study (PROGRESS) (Lancet 2001;358: 1033–1041), in which 100% of the 6105 patients had a previous stroke or TIA. Patients were randomized to placebo or 4 mg of perindopril, with the addition of 2.5 mg of indapamide left to the discretion of the clinician. Overall, the risk of recurrent stroke was reduced by 28% with an average blood pressure reduction of 9/4 mm Hg. In the 58% of patients on combination therapy who experienced a blood pressure reduction of 12/5 mm Hg, the reduction in stroke risk was 43% whereas in the 42% of patients treated only with perindopril, in whom blood pressure was reduced by only 5/3 mm Hg, there was no reduction in stroke. In this trial, as opposed to the HOPE study, blood pressure was measured five times during the first year and twice a year during the second and subsequent 4 years of the trial. The benefit of combination therapy over single‐drug therapy occurred in those both with and without hypertension, as most patients were on antiplatelet therapy and almost one half of the patients were on concomitant antihypertensive therapy.
The PROGRESS trial emphasizes that the degree of blood pressure reduction achieved with an ACE inhibitor/diuretic based combination appears more important than less effective blood pressure reduction with ACE inhibitor monotherapy. It should be noted that most of the patients included in the HOPE study were on diuretic therapy at entry. Therefore, blood pressure reduction with treatment with an ACE inhibitor/diuretic combination appears beneficial in reducing the risk of first and recurrent stroke in high‐risk patients with and without hypertension. These two agents can be recommended for patients with a history of stroke or TIA, regardless of their initial blood pressure. Benefit is greater in patients with hypertension—it should be noted that stroke reduction in both the young and elderly has also been noted with other antihypertensive agents when given with a diuretic.
A 90% LIFETIME RISK OF DEVELOPING HYPERTENSION FOR MIDDLE‐AGED MEN AND WOMEN
The lifetime risk statistic, the probability that an individual will develop a disease over their lifetime, offers the public an easy‐to‐use estimate rather than the difficult to explain age‐specific prevalence, which conveys nothing about an individual's risk for a specific disease. For example, according to the American Cancer Society, the lifetime risk for a woman developing breast cancer remains at 1 in 9. Although lifetime risk estimates are available for a number of chronic diseases, the lifetime risk for developing hypertension has not been previously reported.
In order to estimate the residual lifetime risk for hypertension in older US adults from 1976–1998, researchers from the Framingham Heart Study evaluated 1298 study participants (589 men and 709 women) who were 55–65 years of age and free of hypertension in 1975. To evaluate temporal trends in that same lifetime risk for hypertension, they were compared to Framingham participants evaluated 25 years earlier, from 1952–1975.
In both 55 and 65‐year‐old participants, the cumulative lifetime risk for the development of hypertension (at or above 140/90 mm Hg regardless of treatment) was 90%. Compared with a study group evaluated 25 years earlier (1952–1975), men had a 60% increased risk for developing hypertension in the more recent 1976–1998 period whereas the risk in women during the same time periods remained unchanged. This temporal trend was felt secondary to the age‐adjusted increase in body mass index in men, which, in contrast, was slightly decreased in women.
As more patients with stage 2 or higher hypertension (at least 160/100 mm Hg) have been more aggressively treated, the residual lifetime risk from 1976–1998 for this degree of hypertension was 35%–44%. This was a considerable decline from the 35%–57% seen in the study group evaluated from 1952–1975, 25 years earlier.
The authors note that despite the decline in lifetime risk for stage 2 or higher hypertension, the observation that 90% of middle‐aged and older individuals have a residual lifetime risk for the development of hypertension represents a major public health challenge. These results are based on a single blood pressure measurement with all of its inherent variability performed only once every two years in an almost entirely white population. Despite this limitation, the importance of advising patients and their children to adopt healthier lifestyles as well as to prevent weight gain remains of concern.—Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle‐aged women and men. The Framingham Heart Study. JAMA. 2002;287:1003–1010.
Comment
The longitudinal surveillance of the same community‐based cohort over a 50‐year period, now estimates that 9 out of 10 middle‐aged and older adults are likely to develop hypertension over their lifetime. In addition, more than one half of that lifetime risk occurs during the 10‐year period between the ages of 55–65 years of age. With 60% of individuals having a lifetime probability of needing antihypertensive medication, the public health implications of an aging population who may require drug therapy for more than 20 years are staggering.
The Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) calls for early lifestyle modification in those with high‐normal blood pressure as well as in subjects with established hypertension. Weight reduction, physical activity, moderation of alcohol intake, reduction in sodium intake, and a diet high in potassium, calcium, and magnesium are all recommended. In addition, eating a diet high in fruits, vegetables, and grains, as well as one low in salt and saturated fats as applied in the Dietary Approaches to Stop Hypertension (DASH) trial is an evidence‐based strategy that results in a significant reduction in blood pressure. It is of concern in the more recent time period that men had a 60% increase in the risk of developing hypertension that was related to their being heavier than the previous 25‐year time period. Dramatic increases in the prevalence of obesity will continue to contribute to the epidemic of hypertension unless societal changes occur.
Although only individuals who were free of hypertension between the ages of 55–65 were studied, a considerable proportion of individuals experience the onset of hypertension before this age. Accordingly, the lifetime risk for younger individuals may be different than those studied here. Prevention of hypertension remains the best strategy. Sodium intakes continue to increase while leisure‐time activity remains at an all‐time low and continues to decrease. Until local, state, and national governmental agencies require the food industry to provide more healthy choices for our schoolchildren, and exercise becomes a way of life, significant changes in lifestyle will not occur. Hypertension remains an important public health problem that needs a better solution than just an increase in the use of drug therapy. It is time to increase efforts to convince people to live a healthier lifestyle and, if unsuccessful, to understand the consequences that may occur.