Página 1 de 5 Return to Medscape coverage of: American Society of Hypertension 21st Annual Scientific Meeting and Exposition Val-MARC: Valsartan-Managing Blood Pressure Aggressively and Evaluating Reductions in hs-crp Disclosures Linda Brookes, MSc Presenter: Paul M. Ridker, MD, MPH (Center for Cardiovascular Disease Prevention, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts) In the Valsartan-Managing Blood Pressure Aggressively and Evaluating Reductions in hs-crp (Val-MARC) trial, combination therapy with valsartan plus hydrochlorothiazide (HCTZ) was superior to valsartan monotherapy in reducing blood pressure, but only valsartan monotherapy significantly reduced levels of the inflammatory biomarker high-sensitivity C-reactive protein (hs-crp). [1] These results suggest that valsartan monotherapy may lower inflammation in a manner independent of the degree of blood pressure reduction. In the study overall and within each treatment arm, there was minimal evidence of correlation between change in blood pressure and change in hs-crp. This is "almost prima facie evidence that these 2 phenomena are quite independent of each other," Dr. Ridker stated. Simultaneously with their presentation at the American Society of Hypertension (ASH) annual meeting, [1] the Val-MARC results were also published online in Hypertension. [2] They will appear in the print issue in July. Rationale Increased levels of the inflammatory marker hs-crp are known to be associated with incident hypertension, and the vasoconstrictor angiotensin is a potent proinflammatory mediator. Clinical studies are ongoing to evaluate the role of inflammatory biomarkers, including hs-crp, in the development and clinical consequences of hypertension. However, whether therapy with an angiotensin receptor blocker (ARB) lowers hs-crp and whether this effect is independent of blood pressure reduction has been uncertain. Val-MARC was set up to test the hypothesis that blood pressure therapy with an ARB, alone or in combination with a diuretic, lowers plasma levels of hs- CRP, and if so, to determine whether any effects of ARB or ARB/HCTZ are dependent or independent of the expected blood pressure reduction. Patients and Treatment
Página 2 de 5 Patients aged 18-75 years with stage 2 hypertension (systolic blood pressure [SBP] 160 mm Hg or diastolic blood pressure [DBP] 100 mm Hg) were eligible for Val-MARC. Between January 2004 and June 2005, 1668 patients with mean blood pressure 164/101 mm Hg were enrolled into the study at 384 sites across the United States. Their mean age was 50 years, 45% were female, 68% white, 23% black, and 6% Hispanic. The population was generally obese, with a mean body mass index (BMI) of 31.6 kg/m 2, and 28% were smokers. At enrollment, 12% were on statins and 16% were taking aspirin. Patients were randomized to monotherapy with valsartan 160 mg (n = 836) or to combination therapy with valsartan 160 mg plus HCTZ 12.5 mg (n = 832). After 2 weeks, the dose of valsartan was force uptitrated to 320 mg in all patients who were still symptomatic. Patients remained on this dose of valsartan with or without HCTZ for 6 weeks, after which, if blood pressure remained uncontrolled, patients previously on monotherapy were allowed HCTZ 12.5 mg at the physician's discretion, and the dose of HCTZ in the combination therapy arm could be raised to 25 mg until Week 12. Primary Blood Pressure Endpoint There was a significantly greater reduction in SBP between randomization and Week 6 in the combination therapy group compared with the monotherapy group (Table 1), "not surprisingly," showing that the combination therapy was "clearly superior," Dr. Ridker reported. Table 1. Six-Week Change in Blood Pressure (mm Hg) Valsartan Valsartan + HCTZ* Total -18-25 Men -16-22 Women -19-28 White -20-26 Black -13-24 *P <.001 for all comparisons A significantly greater proportion of patients on combination therapy reached a blood pressure level of 140/90 mm Hg after 6 weeks of therapy compared with those on monotherapy (48% vs 32%, P <.0001). This difference was similar in men and women and in white patients and black patients. The benefit of combination therapy on SBP and DBP was seen as early as 2 weeks (Table 2). This
Página 3 de 5 difference was maintained even after add-on therapy, showing that patients always do better starting with 2 drugs, Dr. Ridker commented. Table 2. Blood Pressure Responses to Therapy Duration of Therapy Valsartan Valsartan + HCTZ Valsartan Valsartan + HCTZ 2 wks -14-21 -8-12 6 wks -18-25 -9-14 12 wks -21-27 -12-15 P <.0001 for all comparisons of valsartan vs valsartan + HCTZ Primary Inflammation Endpoint At baseline, mean hs-crp was similar in the 2 treatment groups, with values in both groups representative of the average in the general community (Table 3). At 6 weeks, the change in hs- CRP, the primary inflammation endpoint of the study, was significantly greater in the monotherapy group vs the combination therapy group (-0.12 mg/dl vs +0.05 mg/dl, respectively; P <.001), a net difference of 13.3%. Table 3. Median Change in hs-crp at 6 Weeks (mg/l) Valsartan Valsartan + HCTZ hs-crp geometric mean: Baseline 2.11 2.07 6 wks 1.90 2.09 hs-crp median: Baseline 2.17 2.09 6 wks 1.98 2.15 Median change (mg/l) -0.12* +0.05 Median change (%) -8.9* +4.4 Net difference 13.3% reduction* *P <.001
Página 4 de 5 These results was consistent across all major subgroups analyzed by age, gender, ethnicity, smoking status, BMI, diabetic status, and use/nonuse of concomitant medications, including aspirin, statin, and hormone replacement therapy (HRT). The statin result was surprising, since a number of clinical trials have shown that statins reduce hs-crp levels, Dr. Ridker commented. hs-crp was reduced in the subgroups of patients on monotherapy who had a blood pressure reduction of > 20 mm Hg or < 20 mm Hg, but not in these subgroups of patients on combination therapy. Further analysis showed that < 1% of the change in hs-crp could be explained by the change in blood pressure, regardless of the group evaluated. Follow-up Analysis The reduction in hs-crp levels at 6 weeks with valsartan monotherapy was maintained over the extended period of follow-up. By contrast, for patients initially on monotherapy, add-on HCTZ appeared to neutralize the effect of monotherapy seen on hs-crp at 6 weeks. Safety Therapy in both arms was well tolerated. Higher rates of dizziness were reported in the combination therapy arm compared with the monotherapy arm (8.5% vs 4.7%, respectively; P =.002), consistent with the greater reduction in blood pressure in this arm. All other side effects were similar between the groups. Implications Although these data raise the hypothesis that monotherapy with angiotensin receptor blockade may lower inflammation in a manner independent of blood pressure reduction, whether this translates to a net clinical advantage will require the performance of well-designed prospective trials of hypertension treatment and prevention that specifically target those with an enhanced innate immune response, Dr. Ridker said. He proposed a trial in patients with elevated CRP randomized to a thiazide-type diuretic vs an ARB vs an angiotensin converting enzyme inhibitor. As an endpoint trial, this would be very informative and would provide information about the core biology, he said. Dr. Ridker was cautious about concluding whether the effect on hs-crp seen with valsartan in Val- MARC is a class effect of ARB therapy. He also admitted that the effect of HCTZ on hs-crp in Val- MARC is not yet understood, although HCTZ is known to increase insulin resistance and has the potential to increase levels of plasminogen activator inhibitor type 1 (PAI-1) and change the HOMA index, all factors correlated with increases in CRP. Data on the effects on CRP of other antihypertensive drug classes are also insufficient, he added. Dr. Ridker stressed that, to date, there is no evidence to prove that lowering hs-crp levels per se also lowers cardiovascular risk, although many ongoing clinical trials are addressing that question. The Pravastatin or Atorvastatin Evaluation and Infection Therapy -- Thrombolysis in Myocardial
Página 5 de 5 Infarction 22 (PROVE IT-TIMI 22) study showed that acute coronary syndrome patients with low hs- CRP levels after statin therapy had better clinical outcomes than those with higher CRP levels, regardless of low-density lipoprotein cholesterol, [3] and lifestyle changes that lower cardiovascular event rates such as diet, exercise, smoking cessation, and lipid lowering all lower hs-crp. This does not prove causality, Dr. Ridker explained, but he hopes that it "will drive the clinical trials showing that this matters." Val-MARC was investigator led and funded by Novartis. References 1. Ridker PM, Danielson E, Rifal N, Glynn RI; the Val-MARC Investigators. Effects of blood pressure reduction on high sensitivity C-reactive protein (hscrp): the Val-MARC (Valsartan - Managing BP Aggressively and Evaluating Reductions in hscrp) trial. Program and abstracts from the American Society of Hypertension, Inc. 21st Annual Scientific Meeting and Exposition; May 16-20, 2006; New York, NY. Recent and Late Breaking Clinical Trials. 2. Ridker PM, Danielson E, Rifai N, Glynn RI; the Val-MARC Investigators. Valsartan, blood pressure reduction, and C-reactive protein: Primary report of the Val-MARC trial. Hypertension. 2006;48:1-7. Published online before print May 19, 2006. 3. Ridker PM, Cannon CP, Morrow D, et al; the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20-28. Abstract Copyright 2006 Medscape.