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Valsartan the First Blood Pressure Medication in a Large-Scale Clinical Trial to Lower C-Reactive Protein, an Important Marker of Inflammation

Recently Approved High Doses of Diovan HCT(R) (valsartan/hydrochlorothiazide) Helped Significant Number of Hard-to-Treat Patients Rapidly Reach Target Blood Pressure Goals

NEW YORK, N.Y. -- May 26, 2006 -- Diovan lowered the level of the inflammatory marker high sensitivity C-reactive protein (hsCRP), independently of its established efficacy in lowering blood pressure, according to findings presented at the American Society of Hypertension, Inc. (ASH) Annual Scientific Meeting and Exposition (ASH 2006) and published online in the journal Hypertension.

The study also showed that Diovan and Diovan HCT helped a significant number of hard-to-treat patients with a severe form of high blood pressure -- called "stage 2" -- quickly achieve blood pressure goals.

"Increased hsCRP levels are commonly found in those patients at increased risk for cardiovascular events," said Paul Ridker, MD, MPH, Eugene Braunwald Professor of Medicine, Brigham and Women's Hospital and Harvard Medical School, and lead investigator of the Val-MARC trial (Valsartan-Managing blood pressure Aggressively and evaluating Reductions in hsCRP). "Until now, statins were among only a few medicines known to lower hsCRP. This study showed that treating high blood pressure with valsartan can also reduce levels of this important inflammatory marker."

The new findings are from a large, randomized clinical trial called Val-MARC in 1,668 high blood pressure patients. Val-MARC is the largest study to investigate whether blood pressure medications, specifically Diovan or Diovan HCT, can lower hsCRP in addition to effectively treating stage 2 hypertension.

Val-MARC was conducted in 384 primary care clinics across the U.S. in a diverse range of hard-to-treat high blood pressure patients, including African Americans, Hispanics, those with diabetes and the elderly.

In Val-MARC, the reduction observed with Diovan on hsCRP levels was preserved in all subgroups in the trial, including those patients who were taking statins. There was no consistent effect observed with Diovan HCT on levels of hsCRP.

Val-MARC also demonstrated that Diovan HCT, including two new higher strengths recently approved by the FDA, produced double-digit blood pressure reductions up to 27 mm Hg in systolic and 14 mm Hg in diastolic blood pressure (P <.0001 from baseline). These reductions are consistent with other data at ASH 2006 that formed the basis of the recent FDA approval.

"There is a clear need to provide more powerful treatment options to help people with high blood pressure successfully manage their condition," said Marjorie Gatlin, MD, Vice President, US Clinical Development and Medical Affairs for the Cardiovascular and Metabolic Diseases Therapeutic Area, Novartis Pharmaceuticals Corporation. "Val-MARC, the latest achievement from our robust clinical trial program for Diovan, provides insight into the efficacy of this high blood pressure agent in helping patients achieve healthier blood pressure levels."

Val-MARC is one of the studies in the Diovan clinical trials program, which represents a large-scale research commitment across the cardiovascular continuum. The results of Val-MARC will be further explored in the MADE-ITT trial, which will examine the effects of Diovan, Diovan HCT and hydrochlorothiazide alone on insulin sensitivity and a range of inflammatory markers, including hsCRP. Other ongoing trials include NAVIGATOR, the first and largest study designed to understand the progression and prevention of diabetes and cardiovascular disease. Completed Diovan trials include VALUE in high blood pressure patients at high risk for cardiovascular events, VALIANT in post-heart attack patients and Val-HeFT in heart failure patients.

With the new strengths used in Val-MARC, Diovan HCT now provides physicians the widest range of dosing options in its class to help them address the continuing public health crisis of high blood pressure. One third of American adults -- more than 65 million -- have high blood pressure, and a significant number have the more severe stage 2 form of the disease. In fact, the risk of cardiovascular disease doubles with every increase of 20/10 mm Hg above a healthy blood pressure of 115/75 mm Hg.

Study Details
A prospective, randomized, blinded-endpoint, open-label, community-based study, Val-MARC compared the efficacy of Diovan alone (160 mg force-titrated to 320 mg at week two) versus Diovan HCT (160/12.5 mg force-titrated to 320/12.5 mg at week two) as initial therapy for 1,668 patients with stage 2 hypertension (defined as systolic blood pressure between 160-185 mm Hg and/or diastolic blood pressure of 100-109 mm Hg).

The trial was designed to examine the effect of Diovan on hsCRP levels and whether this effect was related to or independent of Diovan's established blood pressure-lowering efficacy. The primary blood pressure and inflammation endpoints were measured at the six week timepoint. After six weeks of therapy in either arm, physicians were allowed to prescribe an additional 12.5 mg hydrochlorothiazide if a patient's blood pressure was still uncontrolled.

The median change in hsCRP from baseline after six weeks in the Diovan group was -0.12 mg/L compared to +0.05 mg/L in the Diovan HCT group, representing a difference between the treatment groups of 13.3% (P <.001). No relationship was observed between the change in hsCRP levels and blood pressure reductions, suggesting the hsCRP-lowering effect of Diovan is independent of the agent's blood pressure efficacy.

Baseline blood pressure levels in Val-MARC were 164/101 mm Hg and 165/101 mm Hg in the Diovan and Diovan HCT arms respectively. At six weeks, the systolic and diastolic blood pressure of the participants in the Diovan group dropped a median of 18 mm Hg and 9 mm Hg (P <.0001 from baseline), respectively. Blood pressure was further reduced from baseline by a median of 22 mm Hg and 12 mm Hg (P <.0001) at 12 weeks after physicians were allowed to prescribe the equivalent of the new higher strength of Diovan HCT.

Blood pressure of patients in the Diovan HCT arm was reduced by 25 mm Hg and 14 mm Hg (systolic and diastolic, respectively, P <.0001) at six weeks, and at 12 weeks was further reduced from baseline by a median of 27 mm Hg and 14 mm Hg (P <.0001), respectively, when physicians could prescribe the equivalent of the newly approved highest dose of Diovan HCT. The blood pressure response was consistent across all patient populations studied.

Importantly, after the stage 2 patients in Val-MARC were treated with only two weeks of the initial starting dose of Diovan 160 mg or Diovan HCT 160/12.5 mg, 22% and 37%, respectively, reached a blood pressure goal of <140/90 mm Hg. At six weeks, goal rates increased to 32% and 48% and at 12 weeks further increased to 42% and 52% of these difficult-to-treat patients in the Diovan and Diovan HCT groups, respectively.

In Val-MARC, both Diovan and Diovan HCT were well tolerated with a low incidence of side effects. As can be anticipated with a more powerful blood pressure-reducing regimen, patients treated with Diovan HCT initially had higher rates of dizziness compared to those in the monotherapy group (8.5% compared to 4.7%, respectively, P=0.002). No other significant differences in adverse event rates were observed between the treatment groups.

About Diovan and Diovan HCT
Diovan and Diovan HCT should be discontinued as soon as pregnancy is detected because it may cause harm or even death to the unborn child. If you get pregnant or plan to get pregnant, call your doctor right away.

Do not take Diovan or Diovan HCT if you are allergic to any of the ingredients in these products.

Do not take Diovan HCT if you have a history of reduced urine output, or have allergic reactions to certain drugs known as sulfonamides. If you're taking Diovan HCT, tell your doctor about all your medical conditions and medicines you take, including: liver or kidney problems, lupus or if you take lithium.

In clinical studies with Diovan and Diovan HCT, side effects have generally been mild. The most serious side effects with both Diovan and Diovan HCT are low blood pressure (hypotension) and kidney problems, and additionally with Diovan HCT, skin rash.

High blood pressure medications like Diovan, that affect the renin-angiotensin system, have generally been found to be less effective in patients with low renin -- a condition more frequent among African Americans.

Diovan HCT is not for the initial treatment of high blood pressure. Diovan HCT may be the right medication for you if Diovan or certain other blood pressure medicines alone have not worked.

Diovan and Diovan HCT are approved to treat high blood pressure, and are not approved to prevent death, heart attack, stroke, kidney disease, or eye damage resulting from high blood pressure.


SOURCE: Novartis US Pharma

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