CHICAGO - (Business Wire) In a Phase III pilot dose-ranging study of patients hospitalized with acute heart failure syndrome and renal impairment treatment with rolofylline, an investigational adenosine A
1 receptor antagonist in development by Merck & Co., Inc., administered with intravenous (IV) loop diuretics was associated with improved dyspnea (shortness of breath) and preserved renal function compared to treatment with placebo and IV diuretics. In addition, in a post-hoc analysis, treatment with rolofylline was associated with a trend towards reduced 60-day mortality or hospital readmission for cardiovascular or renal causes. These results were presented today as a late-breaking abstract at the Annual Scientific Session of the American College of Cardiology.
Rolofylline increases renal blood flow and urine production by blocking adenosine-mediated vasoconstriction of the afferent arterioles of the kidneys and inhibiting salt and water reabsorption by the kidney.
"Preserving kidney function is an important goal for improving the prognosis of patients with acute heart failure," said lead investigator Barry M. Massie, M.D., chief of cardiology, VA Hospital, San Francisco. "Although current practice guidelines call for treatment with diuretics, it is well-established that diuretics can be associated with worsening renal function. We now need to assess in larger clinical trials whether rolofylline can positively affect acute symptoms of heart failure and help preserve renal function."
About the pilot study
The pilot study evaluated 301 patients with acute heart failure syndrome with elevated BNP (B-type natriuretic peptide) and renal impairment as defined by estimated creatinine clearance of 20-80 ml/min. Patients were randomized to placebo, 10 mg, 20 mg or 30 mg of rolofylline (four hour infusion, once daily for three days) administered with IV loop diuretics. Because of the potential for adenosine A1 receptor antagonism to reduce the seizure threshold in patients already at risk for seizures, high risk patients were excluded from the study and intermediate risk patients were treated prophylactically with oral lorazepam (1 mg).
The study was designed to identify the dose and, based on post hoc analyses of the treatment results and the patient population studied, refine the inclusion criteria and endpoints for the confirmatory Phase III studies. The results of the pilot study are limited by the study size and number of treatment groups and require confirmation in a larger prospective clinical study.
The study evaluated the proportion of patients in the categories of treatment failure, treatment success, or no change. Treatment failure was defined as death, hospital readmission or physician-determined worsening heart failure or persistent renal impairment (defined by serum creatinine increases ≥ 0.3 mg/dL at Day 7 confirmed at Day 14). Treatment success was defined as improvement in patient-reported dyspnea at 24 and 48 hours and not as a treatment failure. Re-hospitalization and death rates were recorded at 60 days.
Results with rolofylline
Patients treated with rolofylline 30 mg were more likely to achieve treatment success compared to patients treated with placebo, 53 percent (39/74) and 37 percent (29/78), respectively, and less likely to experience treatment failure compared to patients treated with placebo, 16 percent (12/74) and 28 percent (22/78), respectively. A similar number of patients in each treatment group were classified as unchanged; 31 percent (23/74) with rolofylline 30 mg versus 35 percent (27/78) on placebo.
Nearly 60 percent of patients treated with rolofylline 30 mg reported marked or moderately improved dyspnea at day 2 and day 3, compared to 41 percent of patients on placebo. Fewer patients on rolofylline 30 mg had persistent renal impairment compared to patients on placebo, 8 percent and 18 percent, respectively. Treatment with rolofylline 30 mg was associated with a trend towards reduced 60-day mortality or hospital readmission for cardiovascular or renal causes.
In this small pilot study, the rates of adverse events seen across treatment groups were similar.
The confirmatory Phase III studies with rolofylline 30 mg are underway. PROTECT 1 and PROTECT 2 studies (known as PROTECT) are currently enrolling patients in the US, Canada, Europe, Israel and Russia. Additional information is available on www.clinicaltrials.gov.
About acute heart failure
Acute heart failure (AHF) is the abrupt worsening of heart failure symptoms. It is the leading cause of hospitalization in patients over age 65, with over a million hospital discharges annually in the US. Despite current treatment options, AHF is associated with high mortality rates in Western countries (US and Europe) and frequent hospitalizations. AHF is associated with significant renal failure and renal deterioration which contribute to morbidity and mortality.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufacturers and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward-Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.
Merck & Co., Inc.
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