Two Renin Inhibitors Found to Equal Lower Blood Pressures

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<0.0001; valsartan alone, 9.7 mm Hg decrease, P<0.0001), or placebo, 4.1 mm Hg decrease, P<0.0001).
The proportion of patients achieving a successful response to treatment at week eight was 66% in the combined category, versus 53% for aliskiren alone (P=0.0003) and 55% for valsartan alone (P=0.0010), the researchers reported.
The rates of adverse events (headache, nasopharyngitis, and dizziness) and laboratory abnormalities were similar in all groups, they said.
The proportion of patients with serum potassium concentrations over 5.5 mmol/L at any time after the start was higher in the combination group (4%) than for either of the monotherapy patients (2%) or those in the placebo group (3%).
Serum potassium values returned to normal by the end of the study for most patients with raised concentrations in the combination group (13 of 18 patients), without the need for treatment or discontinuation, the researchers said.
In discussing whether these findings apply to clinical practice, the researchers said that the large proportion of obese patients in the study, not unusual for hypertension trials, might reflect the number of overweight and obese patients with hypertension physicians are likely to see.
The additional reduction in blood pressure in the second four weeks of the study was probably attributable to the dose increase. This dose increase most likely reflects the situation in clinical practice they said.
In an accompanying comment, Willem H. Birkenhäger, M.D., of Erasmus University in Rotterdam in Holland, and Jan A. Staessen, M.D., Ph.D., 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. Birkenhäger 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."
This study was funded by Novartis Pharmaceuticals, maker of the two drugs in this study.
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. Birkenhäger 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.Primary source: The LancetSource reference: Oparil S, et al "Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomized double-blind trial" The Lancet; 2007; 370:221-229. Additional source: The LancetSource reference: Birkenhäger WH, Staessen JA "Dual inhibition of the renin system by aliskiren and valsartan" The Lancet 2007; 370: 195-196.