Losartan impresses in LIFE

March 20, 2002

Atlanta, GA - In the 4-year LIFE study in hypertensive patients, treatment with the angiotensin II antagonist losartan (Cozaar® - Merck) has reduced the incidence of stroke by 25% compared to -blocker therapy with atenolol[2]. The findings were announced by Dr Björn Dahlöf (Göteborg University, Sweden) in a late-breaking session at the American College of Cardiology 51st Annual Scientific Session today and will be published in the March 23, 2002 issue of the Lancet.

"This is the first time this kind of difference has been shown between two active agents in the field of hypertension," Dahlöf stated. "This study shows that it matters how we lower blood pressure, not just that we lower it. The results of this trial thus have immediate implications for clinical practice."

At a Merck-sponsored press conference after the late-breaking sessions, he told journalists he "would probably change a patient [who fitted the profile] to losartan therapy," on the basis of the LIFE results. Co-investigator Dr Richard Devereux (Weill Medical College of Cornell University) said: "I agree completely, although one would have to take into account the economic implications." He added that it was not just a matter of switching patients to losartan; for example, it could be added to -blocker therapy.

The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study was a double-masked, randomized, parallel-group trial in more than 9000 patients with essential hypertension and electrocardiographic evidence of left ventricular hypertrophy, who were assigned to once-daily losartan-based (n=4605) or atenolol-based (n=4588) therapy (both at maximum doses of 100 mg), to which diuretics and other antihypertensive drugs - with the exception of ACE inhibitors, or other angiotensin II antagonists or -blockers - could be added as needed to normalize blood pressure (BP). The trial was designed to last for at least 4 years, and until 1040 patients had a primary cardiovascular event (death, MI, or stroke).

Primary endpoint reduction driven solely by stroke

There was a significant difference in the primary composite endpoint in favor of losartan but this was driven solely by the stroke reduction; the rates of MI and cardiovascular mortality were not significantly different between the groups (see table). Both losartan and atenolol provided similar BP-lowering effects.

Dahlof told the press conference that, when the study was first designed and begun, "We expected to see more effects of losartan on MIs than on stroke, to be honest." However, during the course of the trial, new evidence about the renin-angiotensin system emerged, so that "by the time we got the stroke result we were not so surprised." Devereux told journalists it was important to remember that the effect of losartan on MIs "came out the same as that of atenolol, which we already know reduces the risk of MI by 30% in this patient population."

In their paper, Dahlof and colleagues say: "A 25% further reduction in stroke with losartan is important since stroke is a major cause of death and disability and was more frequent than myocardial infarction in our study and others during the past decade. That losartan could have a significant effect on stroke over and above blood pressure extends the results of the placebo-controlled HOPE trial, which suggested that ACE inhibitors protect against stroke beyond reducing blood pressure."

In addition to the reduction in stroke, there were 25% fewer cases of new diabetes in the losartan group compared with the atenolol group, and in a subgroup of diabetes patients, total mortality was reduced by 39% in the losartan group (see below). Dahlöf said that in the US, use of losartan among patients with hypertension and evidence of LVH would avoid 70 000 cardiovascular morbidity/mortality endpoints, including 66 000 fewer strokes. There would also be 54 000 fewer new cases of diabetes, he noted.

In an editorial accompanying the Lancet paper[2], Dr Hans R Brunner (Boston University Medical Center) says: "The highly significant difference in the frequency of stroke deserves comment. Diuretics are more effective in preventing stroke than -blockers. . . . Although at baseline there were more patients (25) with atrial fibrillation in the atenolol group, the large difference in absolute numbers that had a stroke (77 more with atenolol) suggests that additional factors were involved." A treatment strategy based on the combination of an angiotensin II blocker with low-dose hydrochlorothiazide "provides at least equal cardioprotection to -blockers and more protection from strokes with the further benefit of fewer side effects," he says.

Prespecified endpoints

Endpoint

Losartan

n (%)

Rate

Atenolol

n (%)

Rate

Adjusted hazard ratio (95% CI)

p value

Primary composite endpoint 508 (11) 23.8 588 (13) 27.9 0.87 (0.77-0.98) 0.021
Cardiovascular mortality 204 (4) 9.2 234 (5) 10.6 0.89 (0.73-1.07) 0.206
Stroke 232 (5) 10.8 309 (7) 14.5 0.75 (0.63-0.89) 0.001
MI 198 (4) 9.2 188 (4) 8.7 1.07 (0.88-1.31) 0.491
Total mortality 383 (8) 17.3 431 (9) 19.6 0.90 (0.78-1.03) 0.128
Angina pectoris hospitalization 160 (3) 7.4 141 (3) 6.6 1.16 (0.92-1.45) 0.212
Heart failure hospitalization 153 (3) 7.1 161 (4) 7.5 0.97 (0.78-1.21) 0.765
Revascularization 261 (6) 12.2 284 (6) 13.3 0.94 (0.79-1.11) 0.441

Losartan also provided better regulation of left ventricular hypertrophy (LVH) than atenolol, but even after adjusting for LVH effects, "only a third of the difference in benefit could be explained by this," Dahlöf said. One possible mechanism to explain this extra benefit is the effect of losartan on uric acid, he said - serum uric acid concentrations were significantly lower in those treated with losartan than in those on atenolol at the end of the trial.

What is the benefit of angiotensin II blockers over ACE inhibitors?

When asked by heartwire whether some might not just assume the same effect with ACE inhibitors as seen with losartan in this trial, Devereux said, "That's an attractive speculation but it's hard to know, because the studies comparing ACE inhibitors to traditional therapy have been disappointing." He said that all previous outcome trials with ACE inhibitors versus other antihypertensives have failed to show any benefit of the former.

One ongoing megatrial, the Antihypertensive Lipid Lowering Heart Attack Trial (ALLHAT), may yet turn out to be unique in this regard, but the final results of this have not yet been reported. "The ALLHAT trial may show more benefit for ACE inhibitors, in this case compared to diuretics," Devereux told heartwire , adding that, "They decided to forge ahead despite the lack of separate documentation of benefit in pre-existing heart attack and stroke." One advantage of ALLHAT, however, is that it is very large, he said, "but it has some limitations in terms of the study design. My understanding is that there has been a substantially higher drop-out rate in terms of treatments which may confound results."

On the issue of whether the LIFE results could be extrapolated to other angiotensin II blockers, Dahlöf said, "Each and every drug has to show it's own merits." He cited the example of the withdrawal of cerivastatin (Baycol®/Lipobay® - Bayer) last year as one of the dangers of assuming that all drugs within a certain class are the same. However, in his editorial, Brunner says that it is probably reasonable to extrapolate these findings obtained with losartan to any other angiotensin II blocker.

Although losartan has "one unique feature" different from other angiotensin II blockers - it is uricosuric, which is a desirable feature, especially for patients who require combination with a thiazide diuretic - it "nevertheless . . . seems unlikely and difficult to understand how this small difference in uric acid [see in LIFE] could be responsible for the protection from stroke," Brunner notes. "Therefore, it seems appropriate to postulate that the observed effect could probably be obtained by any angiotensin II blocker."

Brunner notes that in 2004 the results of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial will become available, comparing the use of the angiotensin II blocker valsartan (Diovan® - Novartis) with the calcium channel antagonist amlodipine (Norvasc® - Pfizer) in high-risk hypertensive patients: "To date all evidence suggests that the beneficial effects of ACE inhibitors can be duplicated with angiotensin II blockers without the nuisance of side effects [such as cough]."

Regarding the issue of whether the LIFE results could be extrapolated to lower-risk patients with hypertension, Dahlöf and Devereux were both in agreement that they probably could. In a subgroup analysis of low-risk patients in LIFE - in this case those without vascular disease or diabetes - there was still an 18% reduction in the primary endpoint in favor of the losartan group.

Diabetics benefit even more from losartan

The results in the diabetes subgroup, which comprised 1195 patients (586 treated with losartan), were "very impressive," Dahlöf told the ACC delegates. There was a 24% reduction in risk of the primary endpoint in the losartan group (p=0.031), and a notable 39% reduction in all-cause mortality (see table). Admission for heart failure was also reduced by 40% in the losartan group, but strokes and MIs occurred in small numbers that did not reach significance.

Prespecified endpoints in diabetics

Endpoint

Losartan-treated diabetics

Atenolol-treated diabetics

Adjusted relative risk

p value

Primary composite endpoint 103 139 0.76 0.031
Cardiovascular mortality 38 61 0.63 0.028
Total mortality 63 104 0.61 0.002

"Our results accord with those of CAPPP and to some extent HOPE, but differ from those of UKPDS, STOP Hypertension-2, NORDIL and INSIGHT," say the authors of the Lancet paper on the diabetes subgroup[3], led by Dr Lars H Lindholm (Umea Hospital, Sweden). They conclude, "The general message to the practicing physician is that hypertensive diabetic patients with LVH benefit more from losartan than atenolol."

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