NEW YORK — Monotherapy with valsartan has been shown for the first time to lower serum levels of C-reactive protein, raising the possibility that valsartan—and possibly other antihypertensive agents—might have a beneficial effect on cardiovascular events that goes beyond blood pressure reduction.

Results from Val-MARC (Valsartan-Managing Blood Pressure Aggressively and Evaluating Reductions in hsCRP) also showed that valsartan's effect on C-reactive protein (CRP) was independent of blood pressure reduction, suggesting that a pleiotropic, anti-inflammatory effect by this angiotensin II receptor blocker (ARB) might have produced the result. And in the study, with more than 1,600 patients, concurrent treatment with the popular diuretic hydrochlorothiazide (HCTZ) plus valsartan appeared to blunt the CRP reduction, raising questions about possible adverse, pleiotropic effects of HCTZ.

“The current data raise the hypothesis that some antihypertensive regimens may have additional anti-inflammatory properties,” Dr. Paul M. Ridker reported at the annual meeting of the American Society of Hypertension. “Whether this translates to a net clinical advantage will require well-designed, prospective trials of hypertension treatment that specifically target” patients with elevated CRP levels, said Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital in Boston.

Results from the landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) “suggested that HCTZ is an excellent antihypertensive drug in a study that enrolled all comers,” said Dr. Ridker, who is also the Eugene Braunwald Professor of Medicine at Harvard Medical School in Boston. We now need to do large trials to see if the potential exists for real differences in the effects of HCTZ, ARBs, and ACE inhibitors in patients with an enhanced, innate immune response that might have been masked in ALLHAT by enrolling all comers, he said.

The study enrolled patients with stage 2 hypertension at 384 U.S. centers from January 2004 to June 2005. Patients were randomized in an open-label fashion, with 836 assigned to 320 mg valsartan daily, and 832 assigned to receive daily treatment with 320 mg valsartan and 12.5 mg HCTZ. The study's primary end point was blood pressure reduction and changes in serum levels of CRP after 6 weeks. It was sponsored by Novartis Pharmaceuticals, which markets valsartan (Diovan). Dr. Ridker has received research support from Novartis and is co-owner of a patent for a CRP test.

After 6 weeks, valsartan monotherapy cut systolic pressure by an average of 18 mm Hg, compared with an average drop of 25 mm Hg in patients on the combined regimen. The percentage of patients who reached the goal pressure target of 140/90 mm Hg or less was 32% in the monotherapy group and 48% in the valsartan plus HCTZ group. Simultaneously with Dr. Ridker's report at the meeting, these results were published online (Hypertension 2006 [doi:10.1161/01.HYP.0000226046.58883.32]).

CRP measurements showed that patients treated with only valsartan had a median reduction in their serum level of 0.12 mg/L, a reduction of 8.9% from baseline. In contrast, among patients treated with valsartan plus HCTZ, the median change in CRP was an increase of 0.05 mg/L, a median rise of 4.4%. The difference in the change in CRP levels between the two groups was statistically significant.

“We saw no relationship whatsoever between the extent of blood pressure reduction and the extent of CRP reduction,” Dr. Ridker said. “The data lead to the hypothesis that valsartan reduces inflammation in a way that's independent of blood pressure reduction.” In addition, the almost 9% median drop in CRP seen in the valsartan-only group was comparable to the reduction in CRP that's been linked to statin treatment.

The effect of valsartan alone and of valsartan plus HCTZ on CRP levels was “remarkably consistent” across every patient subgroup examined, including patients who were also treated with statins and those who were not, he said. This last observation suggests that the ability of valsartan alone to lower CRP levels is independent of the action of statins, and so the two effects might be additive.

Although Dr. Ridker acknowledged that CRP-lowering may be a class effect for all ARBs, he stressed that so far the effect has been proved only for valsartan: “We've been [wrong] about class effects for statins; it may not be as simple as we once thought.” ARBs were hypothesized to have an effect on CRP because of angiotensin II's proinflammatory effects. (ARBs block the angiotensin II receptor.)

It's unclear whether other antihypertensive drugs—including the ACE inhibitors, calcium channel blockers, and β-blockers—also exert anti-inflammatory effects, Dr. Ridker said. It's also unclear what effect HCTZ might have on inflammatory processes. The drug is known to boost insulin resistance, the incidence of diabetes, and serum levels of plasminogen activator inhibitor-1. All of these activities track with elevated CRP levels, but it's too soon to say whether this explains the study's results, Dr. Ridker said. Even if HCTZ is eventually shown to block a beneficial reduction in CRP levels, and despite the drug's other adverse effects, physicians will probably find it hard to avoid using the drug in patients with refractory hypertension.

“In many patients with hypertension, it's extremely hard to get them to their goal pressure without a diuretic,” commented Dr. Joel M. Neutel, medical director of clinical pharmacology at the Orange County Research Center in Tustin, Calif.

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Valsartan Lowers Serum C-Reactive Protein Levels : Results suggest that an anti-inflammatory effect by the angiotensin II receptor blocker may be responsible.