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.

22nd Scientific Meeting of the American Society of Hypertension

Chicago, Illinois / May 19-22, 2007

Studies in both obese hypertensive patients as well as those with the metabolic syndrome in whom the metabolic effects of an antihypertensive regimen are particularly important indicate that the majority of both groups can successfully achieve blood pressure (BP) goals of <140/90 mm Hg. The strategy includes the use of the AT1 receptor antagonist losartan, either on its own or in combination with one of two doses of hydrochlorothiazide (HCTZ).

These findings suggest that the management of obese patients and those with the metabolic syndrome is not necessarily more challenging than for other patient populations. They also validate the efficacy and safety of the combination strategy for individuals at higher-than-normal risk for cardiovascular disease (CVD) events.

Current president of the American Society of Hypertension Dr. Suzanne Oparil, Director, Vascular Biology and Hypertension Program, Division of Cardiovascular Disease, and Professor of Medicine, Physiology and Biophysics, University of Alabama at Birmingham, presented results of a double-blind, placebo-controlled, randomized study. Dr. Oparil and colleagues randomized a total of 260 patients, mean body mass index 37 to 38 kg/m2 and a mean waist circumference of 114.3 cm, to low-dose losartan 50 mg or placebo for four weeks. After four weeks, the agent was titrated to 100 mg/day and at eight weeks, the fixed-dose combination of losartan 100 mg/HCTZ 12.5 mg was introduced. At week 12, the fixed-dose combination of losartan 100 mg/HCTZ 25 mg was initiated and patients were treated for a total of 16 weeks of active therapy or placebo.

The primary end point was change from baseline in mean trough sitting systolic BP at 12 weeks, particularly when the active therapy group was receiving losartan 100 mg/HCTZ 12.5 mg. Results out to week 16 were also reported. Mean sitting systolic BPs at baseline were similar between the active and control groups at approximately 152/99 mm Hg.

As Dr. Oparil reported, there was a “fairly significant” placebo response at week 16, with BP dropping by 7/6 mm Hg in the placebo group. In comparison, systolic BP dropped by 16.9 mm Hg at week 12 with the combination, while diastolic BP dropped by 13.1 mm Hg at the same time point. Reductions in systolic BP were even greater at week 16 with the higher dose of HCTZ at 19.1 mm Hg systolic BP and 14.1 mm Hg diastolic BP. All changes between active therapy and placebo controls were significant at P<0.001.

Regarding rates of BP control at weeks 12 and 16, investigators found that approximately two-thirds of patients had achieved a systolic BP of <140 mm Hg on the fixed-dose combination, as did three-quarters of patients by week 16. Very similar percentages of patients achieved a diastolic BP of <90 mm Hg at weeks 12 and 16 as well. Among placebo controls, approximately 38% achieved similar systolic and diastolic BPs at weeks 12 and 16.

“Clinical adverse events were rare and did not differ between treatment groups,” Dr. Oparil observed, “and there were no cases of hypotension, syncope or worsening renal function.” Two patients in the active treatment group and three in the placebo cohort developed hypokalemia but there were no cases of hyperkalemia in either arm, data which “support the excellent tolerability of losartan either alone or in combination with HCTZ,” she added.

In a recent study, the direct renin inhibitor aliskiren was combined with HCTZ 25 mg and compared with irbesartan 150 mg/HCTZ 25 mg and amlodipine 5 mg/ HCTZ 25 mg (Jordan et al. Hypertension 2007;49(5):1047-55). The study group was composed of obese patients with arterial hypertension who had not responded to four week of HCTZ therapy. Findings showed that approximately 57% of patients in the aliskiren arm achieved BP goals of <140/90 mm Hg. BP control rates were comparable in the combination irbesartan arm and slightly lower in the amlodipine combination arm. “In these obese patients, you need multiple medications to get them to goal and a fixed-dose combination of an angiotensin receptor blocker and a diuretic will work very well,” Dr. Oparil commented.

Hypertension in the Metabolic Syndrome

Also discussed here at ASH 2007 were results from a phase IV study carried out by 209 general practitioners across Canada. Findings indicated that a significant proportion of patients with the metabolic syndrome can also achieve a BP target of <140/90 mm Hg with losartan 50 and 100 mg alone, and that almost all patients get to goal when the compound is combined with HCTZ 12.5 mg and 25 mg. Importantly, mean fasting blood glucose levels remained stable throughout the 32-week treatment interval and the combination was again very well tolerated.

As discussed here during the scientific sessions by Dr. Natacha Bastien, Montreal, Quebec, a total of 616 patients with baseline fasting blood glucose levels of at least 5.6 mmol/L but <7.0 mmol/L initially received losartan 50 mg. Thirty-eight per cent of patients on the initial dose reached target BP goals, as did another 22.4% when the dose was doubled to 100 mg. Following the addition of HCTZ 12.5 mg, another 16.1% of patients reached BP targets, as did another 19.2% when the dose of HCTZ was doubled. Only 4.3% of patients required a third agent to achieve BP goals of <140/90 mm Hg. Stratified by their cardiovascular disease risk status at baseline, similar proportions of patients reached BP goals at week 32, at 79.8%, 76.4% and 84.9% for low-, moderate- and high-risk patients, respectively. “Based on these interim results, patients with the metabolic syndrome are not more difficult to treat than hypertensive patients without the metabolic syndrome because at 32 weeks, over 80% of them were at goal,” Dr. Bastien reported, adding that because this phase IV study was carried out exclusively by general practitioners, “it is quite reflective of clinical practice today.”

Diabetic Hypertensive Groups

That losartan has a dose-dependent effect on macroalbuminuria in hypertensive, diabetic patients with overt nephropathy was demonstrated in a study presented by investigators under lead author Dr. Gen Yasuda, Division of Nephrology, Yokohama City University School of Medicine, Japan. As researchers pointed out, a previously published study showed that good BP control is not enough to reduce macroalbuminuria and it is necessary to use a renin-angiotensin system inhibitor such as losartan to stimulate an antiproteinuric effect.

In the current study, investigators assessed whether up-titrating the dose of either losartan or amlodipine would lead to greater reductions in macroalbuminuria independent of BP control. The effect of step-up doses of losartan 0, 50 and 100 mg/day were compared to the effects of amlodipine at 0, 2.5, 5, 7.5 and 10 mg/day for 24 weeks. Both BP and overnight urinary albumin:creatinine ratios were measured before and after treatment. BP control was similar for patients receiving losartan 100 mg/day and those receiving amlodipine in doses >7.5 mg/day.

In contrast, overnight urinary albumin:creatinine ratios were reduced by 18% from baseline with losartan 50 mg/day (P=0.01) and by 32% from baseline on 100 mg/day (P<0.01). In comparison, the same excretion ratio was reduced by 7% from baseline with amlodipine 2.5 mg, by 8% with 5 mg/day and by 14% at 7.5 mg/day and more, suggesting, as the authors concluded, that losartan demonstrated dose-dependent antiproteinuric effects regardless of BP control in a patient population at extreme risk for cardiovascular events.