Archief Roodbont

he study should be interpreted in the context of the Losartan Intervention for Endpoint (LIFE) reduction in hypertension study in high-risk patients with hypertension and left ventricular hypertrophy.[7,8] This randomised, double-masked, parallel-group comparison of losartan and the ß-adrenoceptor antagonist atenolol showed that losartan-based therapy was more effective than atenolol-based treatment in reducing the primary combined endpoint of cardiovascular death, stroke and myocardial infarction in patients with hypertension.[7] Importantly, the most pronounced effect was the reduction in fatal and non-fatal stroke, which was 25% lower in the losartan group, an effect that was beyond that expected from blood pressure control alone. Contrary to common belief, stroke occurs more frequently than myocardial infarction, as a meta-analysis of 11 major studies[3] and the LIFE study[7,8] have shown. On the basis of these findings, the LIFE investigators concluded that losartan should be used more widely in hypertensive patients in clinical practice.[7] As well as blocking the angio-tensin II type 1 receptor, losartan also acts as an antagonist at the thromboxane A2 receptor and has uricosuric effects, which may provide additional mechanisms by which losartan provides protective benefits against stroke beyond its antihypertensive action.[8,9]

Our study was not designed to evaluate 'hard' endpoints. However, it shows that in general practice the majority of hypertensive patients have more than one risk factor, including left ventricular hypertrophy, diabetes and/or nephropathy, and therefore carry a substantial risk of future stroke: more than a quarter of unselected patients in primary care will have a stroke within the next 10 years. Losartan treatment is capable of reducing this risk substantially. It should be noted that this calculated effect takes into account only the blood pressure-lowering effect of the drug, and according to the results of the LIFE study, a further beneficial effect beyond blood pressure control versus atenolol can be expected.

It is well known that blood pressure control is more difficult in patients who have concomitant diabetes and/or nephropathy. Furthermore, the target levels in these high-risk patients are lower than those in other hypertensive patients in order to address the extravascular risk carried by these patients.[10-12] In the present study, the antihypertensive effect of losartan in both the diabetes and nephropathy subgroups was of the same magnitude as that seen in the total cohort, and the calculated stroke risk reduction was only slightly less pronounced. While two-thirds of patients in the two subgroups achieved the 'normal' blood pressure target of =140/90mm?Hg – a much higher proportion than that reported in the LIFE study (45%)[7] – only 22% of the diabetes group and 25% of the nephropathy group met the =130/80mm?Hg threshold for these groups. Physicians and patients should be aware that despite the substantial blood pressure-lowering effect of losartan, patients in the two subgroups at study end still faced a substantial 10-year stroke risk of 30% (diabetes) or 36% (nephropathy), respectively. Consequently, further efforts have to be made either through lifestyle intervention (diet and exercise) or, with a higher prospect of success, addition of further antihypertensive drugs to the current regimen.

In the LIFE study,[7] patients taking losartan experienced significantly fewer AEs and had significantly lower discontinuation rates than those taking atenolol. As antihypertensive therapy is usually life-long, good drug tolerability has direct practical implications on patient compliance and persistence.[13] In our study, the absolute number of AEs was very low irrespective of the losartan dosage, and irrespective of diuretic combination treatment. As Law et al. have pointed out in a large meta-analysis, ARBs do not have a dose-response curve in terms of AEs, as opposed to the other major drug classes.[14] We also showed that addition of hydrochlorothiazide at a low dose of 12.5mg did not compromise tolerability and safety. Most hypertensive patients need combination therapy to achieve treatment targets, and diuretics are a central component of such combinations.[15]

When interpreting the results of the present trial, several limitations must be taken into account. As a result of the real-life, observational study design, the study was not blinded, which might have led to an overestimation of treatment effects.[16] In addition, patient selection cannot be excluded. We aimed to estimate the risk reduction in a typical unselected population, which was not limited to patients without previous cerebrovascular events (7% of patients had a previous cerebrovascular event). While the Framingham Stroke Risk Score has not been investigated in a secondary prevention cohort, the major risk factors in primary and secondary prevention are the same. Furthermore, the study was of short duration, and no statement about the persistence of treatment effects can be derived from these data. However, the long-term LIFE data, in which the SBP- and DBP-lowering effects of losartan were -30mm Hg and -17mm?Hg, respectively, unequivocally showed a sustained effect for the drug.[7] Finally, the documented number of AEs was substantially lower than in controlled studies, which is a typical finding of observational studies: physicians tend to under-report AEs that they expect to occur with the assigned drug therapy