BIRMINGHAM, Ala.-- Combining two classes of renin inhibition led to significantly lowered blood pressures than did treatment with either alone.
BIRMINGHAM, Ala. July 20 -- Combining two classes of renin inhibition led to significantly lowered blood pressures than did treatment with either alone, researchers reported.
Dual inhibition of the renin system with the maximum recommended doses of aliskiren (Tekturna), an orally active direct renin inhibitor, and valsartan, an angiotensin receptor blocker (ARB), reduced mean sitting systolic and diastolic pressures significantly more than did either drug alone, found Suzanne Oparil, M.D., of the University of Alabama at Birmingham, and international colleagues.
Tolerability and rates of adverse events were similar to those of monotherapy, they reported in the July 21 issue of The Lancet.
However, the authors of an accompanying commentary warned of potentially life-threatening high levels of blood potassium, which would require monitoring and limit use of the treatment.
The double-blind study included 1,797 men and women, 18 and older, with hypertension (mean sitting diastolic blood pressure 95 to 109 mm Hg). Almost 60% of the patients had stage 2 hypertension, and almost half were obese.
The study was done at 312 centers in the U.S., Germany, and Spain, and patients were recruited from June 27, 2005 to Sept. 5 2006.
Of the patients, 437 were randomized to once-daily aliskiren at 150 mg, 455 to valsartan at 160 mg, 446 to a combination of aliskiren and valsartan, once daily at the same doses, and 459 to placebo for four weeks. This was followed for another four weeks by double the dose titrated up to the maximum recommended dose.
A total of 196 patients (11%) discontinued study treatment before the end of the trial (63 in the placebo group, 53 in the aliskiren group, 43 in the valsartan group, and 37 in the aliskiren-valsartan group), mainly due to lack of therapeutic effect.
At eight weeks, the combination of aliskiren (300 mg) and valsartan (320 mg) lowered mean sitting diastolic blood pressure (the primary endpoint) from baseline by 12.2 mm Hg.
This was significantly more than the decrease for aliskiren alone, 9.0 mm Hg decrease, P
In an accompanying comment, Willem H. Birkenhger, M.D., of Erasmus University in Rotterdam in Holland, and Jan A. Staessen of the University of Leuven in Belgium, cautioned that the proportion of patients with a transient increase of serum potassium above 5.5 mmol/L suggests a risk of hyperkalemia.
High potassium levels can result in severe complications, such as paralysis, arrhythmias, and cardiac arrest, and often remains unrecognized, with few symptoms prior to cardiac arrest, they wrote.
As a result, "one wonders therefore why Oparil opted to combine aliskiren with valsartan, rather than with a diuretic or a calcium-channel blocker, as recommended by current guidelines. Such agents decrease serum potassium, and counteract the increase in serum potassium on renin-system inhibitors.
In the end, dual renin inhibition might find a niche in selected hypertensive patients at high risk with associated conditions or in treatment-resistant hypertension, the editorialists added.
However, Drs. Birkenhger and Staessen wrote, that "because of the potential life-threatening side-effects, which require biochemical monitoring, this concept of treatment is unlikely to make it to general practice or even to primary prevention in specialist care."
Dr. Oparil reported that she is the recipient of grants-in-aid from Abbott Laboratories, Astra Zeneca, Aventis, Biovail, Boehringer Ingelheim, Bristol Myers-Squibb, Forest Laboratories, GlaxoSmithKline, Novartis, Merck, Pfizer, Sankyo Pharma, Sanofi Synthelabo, and Schering-Plough. She is a consultant for Bristol Myers-Squibb, Daiichi Sankyo, Merck, Novartis, Pfizer, Sanofi Aventis, and the Salt Institute, and is a member of the board of directors for Encysive Pharmaceuticals. One co-author has served as a speaker for Novartis; others are employees of Novartis Pharmaceuticals and are therefore eligible for Novartis stock and stock options.
Dr. Birkenhger reported no conflict of interest. Dr. Staessen has consulted for AstraZeneca, Daiichi-Sankyo, Pfizer, Sigma-Tau, and Tanabe, and has received funding for studies, seminars, or travel from these companies.