New Heart Failure Guidelines Support the Use of BiDil(R)
Aug 18, 2005 - 11:34:38 AM

Updated heart failure guidelines released on Tuesday by the of Cardiology (ACC) and the American Heart Association (AHA) support the combined use of isosorbide dinitrate and hydralazine, now available as a proprietary fixed-dose formulation known as BiDil(R) (isosorbide dinitrate/hydralazine hydrochloride), as an adjunct to current standard heart failure therapy for black patients. BiDil was recently approved by the U.S. Food and Drug Administration (FDA) and launched by NitroMed, Inc. in July 2005.

"NitroMed is pleased that these most prestigious groups in the heart failure community -- the ACC and the AHA -- have recognized the important role that BiDil therapy can play in treating heart failure in self-identified black patients," said Manuel Worcel, M.D., Chief Medical Officer of NitroMed. "We hope that the use of BiDil according to the new heart failure guidelines will contribute to improved outcomes for black heart failure patients, who face a disproportionate burden from this serious disease."

According to the 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult, the addition of the combination to standard medical therapy for heart failure, including ACE inhibitors and beta- blockers, is "reasonable and can be effective in blacks with New York Heart Association (NYHA) functional class III or IV heart failure."

Although not mandatory, these heart failure practice guidelines are made available to help physicians and health care professionals make clinical decisions by providing a range of generally accepted approaches for the prevention, diagnosis and management of the disease. According to ACC and AHA, the guidelines focus on defining practices that meet the needs of most heart failure patients, in most cases.

In citing the results of the African American Heart Failure Trial (A- HeFT), the new guidelines further validate the landmark trial conducted by NitroMed in conjunction with the Association of Black Cardiologists, Inc. In A-HeFT, BiDil, a proprietary fixed-dose combination of isosorbide dinitrate and hydralazine, was shown to decrease the risk of mortality by 43 percent, reduce the risk of first hospitalization for heart failure by 39 percent and improve patient-reported functional status for self-identified black patients when taken as adjunctive therapy with current standard heart failure therapies. The trial was halted early by the study's safety review board due to the significant survival benefit seen with the drug.

Although the mechanism underlying the beneficial effects of BiDil in the treatment of heart failure is not known, the guidelines noted that the benefits seen with this treatment may be related to an improvement in nitric oxide bioavailability.

The issuance of these important guidelines for the management of heart failure comes within months of BiDil's approval by the FDA. NitroMed officially launched BiDil on July 1 and commercial product is now available in pharmacies.

About the ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult

The newly updated set of practice guidelines were developed by an expert panel of the ACC and AHA to reflect the most recent scientific findings on heart failure and guide physicians in its evaluation and management. The guidelines were developed in collaboration with the of Chest Physicians and the International Society for Heart and Lung Transplantation.

About BiDil

BiDil is indicated for the treatment of heart failure as an adjunct to current standard therapy in self-identified black patients, to improve survival, prolong time to hospitalization for heart failure and improve patient-reported functional status. There is little experience in patients with New York Heart Association (NYHA) class IV heart failure. Most patients in the clinical trial supporting effectiveness, referred to as A-HeFT, received, in addition to BiDil or placebo, a loop diuretic, an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, and a beta blocker, and many also received a cardiac glycoside or an aldosterone antagonist. BiDil is a fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride. While the exact mechanism of action underlying the beneficial effects of BiDil in the treatment of heart failure is unknown, it is known that isosorbide dinitrate is a vasodilator with effects on both arteries and veins. The dilator properties of nitrates result from the release of nitric oxide that leads to the relaxation of vascular smooth muscle. Hydralazine is an arterial vasodilator.

In A-HeFT, self-identified black patients taking BiDil in addition to current standard heart failure therapies experienced a significant 43 percent decrease in the risk of mortality (P=.012) (absolute mortality rate: BiDil, 6.2% vs. placebo, 10.2%), a 39 percent reduction in the risk of first hospitalization for heart failure (P less than .001) (absolute first hospitalization rate: BiDil, 16.4% vs. placebo, 24.4%) and a statistically significant improvement at most time points in response to the Minnesota Living with Heart Failure Questionnaire, which is a self-report of the patient's functional status, versus patients taking placebo in addition to current standard therapies.

BiDil treatment is orally-administered and is initiated at a dose of one tablet, three times per day, and may be increased to a maximum of two tablets, three times per day, based on patient tolerance. Adjustments to maximum dosage may occur in three to five days; however, adverse side effects, which may include headaches and dizziness, may require that some patients take more time to reach their highest tolerated dose.

Heart Failure Burden in Black Patients

Heart failure, or end-stage cardiovascular disease, affects approximately five million Americans, including an estimated 750,000 African Americans. Each year, over 550,000 people are diagnosed with heart failure for the first time, and there is no cure for this disease -- with more than 50 percent of patients dying within five years of diagnosis. With respect to heart failure, blacks are affected at a rate greater than that of the corresponding non-black population, presenting with the disease earlier and dying sooner. According to the Centers for Disease Control and Prevention (CDC), African Americans between the ages of 45 and 64 are 2.5 times more likely to die from heart failure than Caucasians in the same age range.

Important Safety Information

BiDil is contraindicated in patients who are allergic to organic nitrates. Augmentation of the vasodilatory effects of isosorbide dinitrate by phosphodiesterase inhibitors (e.g., Viagra(R)/RevatioTM, Levitra(R), Cialis(R)) could result in severe hypotension. Treatment with hydralazine may produce a clinical picture simulating systemic lupus erythematosus (SLE) including glomerulonephritis. If SLE-like symptoms occur, discontinuation of BiDil should be considered. Residua have been detected many years after discontinuation of hydralazine. Symptomatic hypotension may occur with even small doses of BiDil. BiDil should be used with caution in volume depleted or hypotensive patients. Hydralazine can cause tachycardia potentially leading to myocardial ischemia and anginal attacks. Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness and tingling, which may be related to an antipyridoxine effect. Caution should be exercised if BiDil is used with MAO inhibitors, alcohol, sildenafil, vardenafil or tadalafil.

Headache (50%) and dizziness (32%) were the two most frequent adverse events and were more than twice as frequent in the BiDil group.

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