No benefit of fenoldopam in reducing contrast-induced nephropathy: The CONTRAST trial

Shelley Wood

April 08, 2003

Tue, 08 Apr 2003 16:30:00

Chicago, IL - A drug approved for the treatment of severe hypertension and frequently used off label to reduce contrast-induced nephropathy (CIN) in patients with chronic renal insufficiency undergoing cardiovascular procedures has failed show any benefit over placebo for this latter application. Dr Gregg W Stone (Lenox Hill Heart and Vascular Institute, New York, NY) presented the negative results of the CONTRAST trial of fenoldopam mesylate (Corlopam®, Neurex) at the American College of Cardiology 2003 Scientific Sessions.

Taking into account prior negative studies of other vasodilators, the results from CONTRAST suggest that reversing the medullary renal blood-flow reduction that results from contrast agents may not be the right pathway to target in preventing CIN, Stone said.

"The outcomes and implications of this study also reaffirm the importance of completing adequately powered, randomized controlled trials before active therapies are adopted into widespread use," Stone told delegates.

CIN occurs in up to 15% of all patients undergoing invasive cardiovascular procedures and in as many as half of all patients with preexisting renal insufficiency and diabetes undergoing the same procedures. CIN is also an independent predictor of early and late mortality after CAD and of need for dialysis. Other than hydration and low-osmolality contrast media, studies of other methods of preventing CIN have either been negative or deleterious or have reported mixed results, as in the case of acetylcysteine (Mucomyst®, AstraZeneca), Stone noted.

No benefits with fenoldopam

The 28-center CONTRAST trial, led by Stone and Dr William O'Neil, enrolled 315 patients with a baseline creatinine clearance (CrCl) of <60 cm3/min, who were not on dialysis and who were undergoing cardiac catheterization with or without angioplasty. All patients were well hydrated and randomized in a 1:1 fashion to either IV fenoldopam (0.05 g/kg per min titrated up to 0.10 g/kg per min) or matching placebo, starting one hour before angiography and continuing for 12 hours thereafter.

Investigators measured serum creatinine levels at baseline and at 1, 24, 48, and between 72 and 96 hours following completion of study drug. The primary end point of the study was incidence of CIN, defined as an increase in serum creatinine of >25% from baseline during this 96-hour period. Secondary end points included hospital length of stay, adverse cardiac events, rehospitalization, and need for dialysis within 30 days.

Stone reported that the study drug was discontinued due to real or perceived side effectsusually hypotension or tachycardiain 13.4% of fenoldopam-treated patients, compared with 7.0% in placebo-treated patients. Ability to tolerate entire maximal dose of the study drug was 73.9% in fenoldopam patients and in 88% of the placebo group. Total study drug duration was 13 hours for the fenoldopam patients and 13.8 hours for the placebo group.

The number of patients who reached the primary end point of the study of a >25% increase in serum creatinine did not differ between the fenoldopam- and placebo-treated patients (36.6% vs 30.1%, p=0.54). Mean maximum increase in serum creatinine from baseline was 0.32 mg/dL in the fenoldopam group, compared with 0.26 mg/dL in the placebo group. Stone added that he and his colleagues "looked at every possible important subgroup we could think of" and found "absolutely no difference" between the two treatment groups.

There were also no differences in mortality, need for dialysis, incidence of MI, repeat angiography/PCI, bypass surgery, or rehospitalizations within 30 days between the two groups. Stone et al did, however, see an anticipated difference in the rates of 30-day adverse eventsdeath, MI, need for dialysisbetween patients who did and did not develop CIN. At 30 days, 12.2% of patients who had CIN experienced an adverse event, compared with 4.1% of patients free of CIN.

"From this prospective, randomized, double-blind trial, which is the largest study to date of any preventive measure for CIN, we conclude that the specific dopamine 1 receptor agonist fenoldopam mesylate is ineffective in preventing further renal function deterioration in patients with chronic renal insufficiency receiving contrast and should not be used for this application," Stone stated. "The negative findings from this investigation in concert with prior disappointing studies of other vasodilators suggest that disturbances in interrenal hemodynamics may not be or are probably not the critical pathophysiologic insult that produces contrast nephropathy."

Related links

1. [HeartWire > News; Feb 5, 2003]

2. [HeartWire > News; Mar 17, 2002]

3. [Satellite education > CyberSessions (non-CME); Sep 26, 2001]


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