World Congress of Cardiology trials focus on RAS agents

October 23, 2006

The 2006 World Congress of Cardiology (WCC) was host to more than 25,000 cardiologists this year. Noteworthy among the thousands of presentations were several large-scale drug trials, most of which evaluated agents affecting the renin-angiotensin system (RAS).

First, a clinical trial conducted in Japan suggests that, at least for its population, the choice of blood pressure (BP) medications matters beyond their absolute BP-lowering effects. In the Jikei Heart Study, two groups treated to the same BP levels but with different classes of agents experienced significant differences in several cardiovascular endpoints.

The study population, 3,081 Japanese patients with hypertension, coronary heart disease (CHD), and/ or heart failure (HF) conventionally treated, was differentiated only in that half received the angiotensin receptor blocker (ARB) valsartan while the other half received non-ARB-based therapy. Those in the valsartan arm were started on 80 mg and titrated up or down to 40-160 mg over 16 weeks. Patients' BP levels were under control at study entry, with mean BP of ~139/81 mmHg in both groups.

Investigator professor Böjrn Dahlöf, M.D., Sahlgrenska University Hospital, Gothenburg, Sweden, observed, "There was a quite substantial benefit for a short-term trial by just adding a specific blocker of the renin-angiotensin system on top of other therapy."

A large meta-analysis showed efficacy and placebo-like tolerability and safety for an investigational first-in-class antihypertensive agent. Aliskiren (Rasilez, Novartis), an oral direct renin inhibitor, has a long plasma half-life of 40 hours allowing once-daily dosing, according to professor Matthew Weir, M.D., head of the division of nephrology, University of Maryland School of Medicine.

"By directly inhibiting renin, aliskiren suppresses the renin system at its point of activation," Weir said. He presented results from an analysis pooling data from seven randomized, double-blind, multicenter trials among more than 7,000 hypertensive patients. The trials assessed aliskiren in doses from 75 to 600 mg as monotherapy or in combination with valsartan (Diovan, Novartis), hydrochlorothiazide, ramipril, or amlodipine.

The pooled trials, all with six to eight weeks of active treatment following washout and placebo run-in, had change from baseline in mean sitting diastolic BP (msDBP) as the primary endpoint. Baseline msDBP was 99.3 mmHg and systolic (msSBP) was 153.6 mmHg. While BP lowering proved to be dose-dependent, analysis showed that the highest dose, 600 mg, did not provide substantially greater effects than 300 mg.

In the five placebo-controlled trials (two monotherapy, three combinations), msDBP was reduced (mmHg) by 3.3-8.6 in the placebo groups and by 10.3-12.3 for aliskiren 300 mg. Systolic BP reductions were similarly significant. Responder rates were significantly higher across all aliskiren doses compared with placebo.

In patients with recent stroke or transient ischemic attack (TIA) and free of known CHD, reducing cholesterol levels with atorvastatin (Lipitor, Pfizer) reduces stroke risk, according to SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial results.

SPARCL enrolled 4,731 patients with LDL-cholesterol (C) levels ≥100 mg/dl and "190 mg/dl, randomizing them double-blind to placebo or atorvastatin 80 mg/day. All subjects had previously documented stroke or TIA within six months. The primary endpoint was time to first occurrence of a fatal or nonfatal stroke.