Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

16th European Meeting on Hypertension

Madrid, Spain / June 12-15, 2006

As reported by Dr. Sverre E. Kjeldsen, Adjunct Professor of Medicine, Division of Hypertension, University of Michigan, Ann Arbor, and Chief Physician, Department of Cardiology, Ullevaal University Hospital, Oslo, Norway, results of a meta-analysis demonstrated that the antihypertensive efficacy of the angiotensin II antagonists (AIIAs) losartan, valsartan, irbesartan and candesartan are comparable (Conlin et al. Am J Hypertens 2000;13(4 Pt 1): 418-26). Dose titration and the addition of low-dose hydrochlorothiazide (HCTZ) markedly improved the efficacy of treatment.

Dr. Kjeldsen also discussed how AIIAs compare with calcium channel blockers (CCBs), the most widely used class of antihypertensive agents. He reported the results of a study in which elderly patients with isolated systolic hypertension were treated with losartan or the CCB amlodipine. Titration of both compounds, from 50 to 100 mg for losartan and 5 to 10 mg for amlodipine, was allowed as was addition of HCTZ. After 18 weeks of treatment, there were no significant differences in the mean changes from baseline in sitting systolic blood pressure (BP) for the two treatment groups (-27.4 mm Hg for the AIIA group vs. -28.1 mm Hg for the CCB group). The incidence of adverse effects was, however, significantly greater in the CCB cohort (79.8% vs. 42.8%, P£0.001) and more patients on the CCB withdrew due to adverse events.

The LIFE Study

The antihypertensive efficacy and clinical outcomes of losartan treatment were compared with those of atenolol in the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study (Dahlöf et al. Lancet 2002; 359(9311):995-1003). This important trial randomized 9193 patients with hypertension and ECG signs of left ventricular hypertrophy (LVH) to either losartan or atenolol, both at doses of 50 mg initially with titration up to 100 mg and the addition of low-dose HCTZ and other antihypertensive treatments if necessary to attain BP goals. The primary end point was any cardiovascular (CV) event.

Mean follow-up lasted 4.8 years. The BP goal of 140/90 mm Hg was achieved in 2051 patients (45%). Mean decreases in systolic, diastolic and mean arterial BP were similar in both treatment groups at all times. For the primary composite end point, the risk reduction after baseline risk adjustment was 13.0% greater in the losartan group (P=0.021). When the composite end point was broken down into individual end points, the adjusted relative risk reduction in favour of the AIIA was 13.3% (P=0.136) for CV mortality. For stroke, the protection afforded was much greater and statistically significant at 25.8% (P=0006). No significant treatment differences were reported for myocardial infarction. In the opinion of Dr. Kjeldsen, “An important consideration is the favourable safety profile of losartan, as reflected by the significantly lower proportion of patients who dropped out due to an adverse event in the losartan group. A breakdown of adverse events showed bradycardia was reported in 1% of patients on losartan compared to 9% on atenolol.”

Cardioprotection

According to Dr. Richard B. Devereux, Director, Adult Echocardiography Laboratory, Weill Cornell Center, New York Presbyterian Hospital, “The importance of reducing BP to manage the risk of CV events is evident. The LIFE study and other studies have suggested that AIIAs may provide additional protection beyond that afforded by the antihypertensive effects.” He explained how the development of echocardiography has been important in that heart conditions such as LVH can now be detected, which before could only have been confirmed at autopsy. LVH correlates with future clinical CV events so it is important to know whether treatment can reduce the risk of such events and also whether it is possible to reverse LVH.

Dr. Devereux presented data from a prospective cohort substudy of the LIFE study. Study patients underwent echocardiography to determine LV mass at baseline (Devereux et al. JAMA 2004;292(19):2350-6). The analysis showed that change in LV mass was a significant predictor of CV events. The overall survival, which “is of overriding importance to physicians,” was markedly lower for patients with echocardiographic LVH (hazard ratio [HR], 0.36).

Another subanalysis of the LIFE study assessed patients with a history of atrial fibrillation (AF). Hypertensive patients are at a greater risk of developing AF, which is, in turn, associated with a greater risk of CV events, such as stroke. In this setting, losartan reduced the primary end point (HR 0.58, P=0.009), CV death (HR 0.58, P=0.048) and stroke (HR 0.55, P<0.039).

Inhibiting Thrombus Formation

An important finding of the LIFE study was the greater protection against stroke associated with losartan than could be expected from reduced BP alone. The majority of strokes associated with hypertension are ischemic in nature. In his presentation, Dr. Carlos M. Ferrario, Director, Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, discussed how AIIAs might be able to reduce the incidence of ischemic stroke in hypertensive patients.

Angiotensin II has been shown to increase production of the vascular superoxide anion in animal models and this species has been linked to endothelial dysfunction and ultimately hypertension. Increased superoxide levels associated with angiotensin II were corroborated with human internal mammary arteries and saphenous veins collected from cardiac surgery (Berry et al. Circulation 2000;101(18):2206-12). Dr. Ferrario suggested that angiotensin II might be implicated in molecular mechanisms that encourage the adhesion of oxidatively modified LDL to endothelial cells through expression of LOX-1. Through this mechanism, angiotensin II could be involved in atherogenic processes.

According to Dr. Ferrario, “Many clinical events have a thrombotic component, and losartan can inhibit thrombus formation, as it is a selective inhibitor of the thromboxane A2 receptor.” A study confirmed the antiplatelet effect of the agent in hypertensive patients (Levy et al. Am J Cardiol 2000;86(11):1188-92). Furthermore, its P450 metabolism in the liver gives rise to two cardioactive metabolites, EXP3174 and EXP3179. In the opinion of Dr. Ferrario, these metabolites also contribute to the compound’s cardioprotective properties. In particular, EXP3179 appears to have anti-inflammatory properties (inhibiting COX-2 mRNA upregulation and PGF2a generation). The metabolite may also stimulate endothelial nitric oxide synthase phosphorylation and suppress apoptosis by activating the VEGFR2/PI3K/Akt pathway.

Dr. Ferrario also cited a review in which the authors recognized the clinical benefit of lowering BP but affirmed that treatments that block the renin-angiotensin system offer additional advances (Sleight P, Yusuf S. J Hypertens 2003;21(9):1599-608). While the choice of treatment will depend on the patient, Dr. Ferrario concluded that “even within the same therapeutic class, there can be important chemical differences, and losartan has some unique properties.”

Summary

The studies discussed here during the scientific sessions all confirm that AIIAs can reduce BP in patients with hypertension. Many of the studies have also shown that addition of low-dose HCTZ can be a particularly efficacious combination. In the LIFE study, losartan demonstrated greater protection against stroke than atenolol. This protection could not be explained by the decreases in BP alone and may point to an AIIA class effect. This class effect may be explained by mechanisms such as reduced oxidative stress and decreased angiotensin II-mediated atherosclerosis. Within the AIIA class, losartan may provide addition protection against stroke through selective inhibition of receptors implicated in thrombus formation and through the P450 metabolism of the compound in the liver to yield cardioactive metabolites.