Cardiovascular mortality of patients with left ventricular hypertrophy, a target organ damage due to hypertension, exceeds that of patients with hypertension without secondary myocardial hypertrophy to a considerable degree.(1) Since March 2002 a long-term study with the angiotensin II antagonist losartan (LORZAAR; a-t 1995; No. 11: 107-108) selectively tailored to this high risk group has been published (LIFE*) (2,3): A losartan-based regimen was compared with an atenolol-based (e.g. TENORMIN) regimen for a mean follow-up of 4.8 years. In addition to essential hypertension with blood pressure readings of 160/95 mm Hg or more, participants had to have electrocardiographic signs of left ventricular hypertrophy.
MSD, the manufacturer of losartan, had financed the study and controled the study data base.(2,3) MSD employees are listed among the steering committee members and the study authors.(2-4)
9,222 patients aged 55 - 80 years were enrolled. Treatment began with a daily dosage of 50 mg of losartan or 50 mg of atenolol. If blood pressure did not drop below 140/90 mm Hg, 12.5 mg of hydrochlorothiazide (HCTZ, e.g. ESIDRIX) were added after two months. This was followed by doubling the dosage of the angiotensin II antagonist or beta-blocker, respectively, after the next two months. Furthermore, other anti-hypertensive drugs were added or the dosage of HCTZ was doubled. A combination with angiotensin-converting-enzyme (ACE) inhibitors, beta-blockers or angiotensin II antagonists was not permitted. While beta-blockers and ACE inhibitors have a proven life extending efficacy in patients with myocardial infarction or heart failure, patients with a history of either of these diseases were not strictly excluded. 16% of participants had coronary heart disease (2) and 1.6% had a history of heart failure.(5)
The data do not clearly show whether both groups achieved comparable blood pressure readings. In the losartan group, the dose was doubled in 50% of participants as compared to 43% in the atenolol group.(2) Measurements were taken at trough, just before the application of the next dosage.(2,4) Graphical presentation appeared to indicate consistently lower systolic blood pressure readings under losartan. Systolic blood pressure decreased significantly more under losartan than under atenolol from the beginning of the study until the final examination.(2) No readings during the effective time of action of either drug were recorded. Adverse events point to lower blood pressure values under losartan: hypotensive reactions occurred more often under the angiotensin II antagonist.(2,3) In the subgroup of patients with diabetes mellitus, 12% of participants in the losartan group complained of vertigo versus 7% in the atenolol group (p=0.01).(3) This adverse event points to an increased incidence of orthostatic hypotension, a classic result of tight blood pressure control, especially in patients with diabetes.
In the losartan group, 11% of participants developed myocardial infarction or stroke or died subsequent to cardiovascular events (primary endpoint) versus 13% of patients under atenolol. This difference is significant (Number Needed to Treat [NNT]year = 244). The favourable outcome in the losartan group was mainly caused by a significantly reduced incidence of stroke (5% vs. 7%; NNTyear = 270). The incidence of myocardial infarction (4% each), the rate of cardiovascular mortality (4% vs. 5%) and the secondary endpoint of total mortality (8% vs. 9%) did not significantly differ. New-onset diabetes was less often diagnosed in the losartan group than under atenolol (6% vs. 8%; NNTyear = 227).(2)
In the predefined subgroup of patients with diabetes mellitus (n = 1,195), the primary endpoint decreased from 23% under atenolol to 18% under losartan (NNTyear = 69). In addition, cardiovascular mortality (6% vs. 10%; NNTyear = 122), overall mortality (11% vs. 17%; NNTyear = 68) and hospitalizations for heart failure (5% vs. 9%; NNTyear = 112) differed significantly.(3)
It appears that losartan was better tolerated. Discontinuation due to adverse events occurred significantly less often in losartan than in atenolol patients.(1) However, one has to consider that double-blind studies testing beta-blockers are likely to be biased by unblinding because of the effect of these drugs on heart rate. The LIFE study confirms doubts in the supposed nephroprotective effects of losartan (see a-t 2001; 32: 97-98): Serum creatinine increases throughout the course of the study did not differ significantly both in the total group and in the subgroup with diabetes.(2,3)
|Six years following the marketing of losartan (LORZAAR), a long-term study has been presented with clinical endpoints for approved treatment of hypertension - however, only for a high risk group with additional echocardiographic signs of left ventricular hypertrophy. MSD, the manufacturer of losartan, exercises substantial influence upon the execution and publication of the study.|
|Over a period of 4.8 years, the stroke rate under a losartan-based regimen is 5% as compared to 7% under an atenolol-based (e.g. TENORMIN) regimen (NNTyear = 270). Incidence of myocardial infarction and mortality do not differ siginificantly.|
|In the predefined subgroup of patients with diabetes hospitalizations due to heart failure (NNTyear = 112), cardiovascular mortality (NNTyear = 122) and total mortality (NNTyear = 68) were significantly lower in the losartan group as compared to the atenolol group.|
|The crucial question, whether losartan has a specific, blood pressure independent advantage over atenolol, cannot be answered with the data presented. Differences in dose adjustments and hypotensive adverse events lead to the conclusion that blood pressure control may have been more effective in the losartan group.|