Spironolactone for HF boomed after RALES, but are the right patients getting it?

July 01, 2005

Dallas, TX - Spironolactone (Aldactone, Pfizer) prescriptions for heart failure, which expanded dramatically after publication of the Randomized Aldactone Evaluation Study (RALES)[1] established that indication for the drug, often go inappropriately to high-risk patients, while many who might benefit the most are passed over, suggests a Medicare-data analysis [2].

"Prescription of spironolactone increased more than sevenfold after publication of RALES," write Dr Frederick A Masoudi (University of Colorado Health Sciences Center, Denver) and associates, who compared pre- and post-RALES Medicare data on discharge prescriptions for the drug in systolic HF. "Of the discharge prescriptions written after RALES, almost one third were provided to patients not fitting the study enrollment criteria, many of whom were at high risk for hyperkalemia."

Importantly, RALES excluded patients with risk factors for hyperkalemia or renal dysfunction, and patients "were also followed very carefully," observed Masoudi for heart wire . But after the trial was released, "what we found was that the use appeared to be fairly indiscriminate in terms of the factors that might subject patients to potentially adverse outcomes."

Many patients with hyperkalemia or evidence of substantial renal dysfunction at discharge were getting prescriptions for the potassium-sparing diuretic, his group found. Prior studies in limited populations have shown that such inappropriate prescriptions can cause the patients to be rehospitalized for dialysis, Masoudi said.

What we found was that the use appeared to be fairly indiscriminant in terms of the factors that might subject patients to potentially adverse outcomes.

RALES had randomized 822 patients with HF and LV systolic dysfunction who were on ACE inhibitors, a loop diuretic, and usually digoxin to receive spironolactone or placebo. Those getting the active drug showed significant 30% and 35% drops in the relative risks of death and HF hospitalization, respectively, compared with controls.

Masoudi said his group's study especially complements one published almost a year ago in the New England Journal of Medicine, and covered by heart wire , which found a striking increase in spironolactone use in Ontario, Canada hospitals after the RALES publication[3]. The increase was accompanied by significant growth in the rates of hospitalization for hyperkalemia and related hospital mortality. The causes, the authors speculated, may have been frequent use of spironolactone in patients with risk factors for hyperkalemia along with inadequate follow-up, especially with respect to potassium levels and changes in renal function. The current study, Masoudi said, supports those speculations in a different population and "on a national scale."

He and his colleagues compared rates of discharge spironolactone prescriptions for systolic HF and their recipients over two 12-month periods, one ending a few months before the September 1999 RALES publication and the other beginning July 2000.

They found that the prescription rates:

  • Increased from 3% among the 9758 pre-RALES patients to 21.3% for the 9468 in the later cohort (p<0.001).

  • Increased more sharply among younger patients and those with a lower admission blood pressure or angina (p<0.001 for all three differences) compared to the overall cohorts.

Also among patients treated after RALES:

  • Only 24.1% of those consistent with its entry criteria received prescriptions for the drug.

  • 17.4% of such patients who did not meet the study's entry criteria did receive spironolactone.

  • 30.9% of spironolactone prescriptions in the later period were to non-RALES-like patients.

And among patients receiving a discharge prescription, those who didn't meet RALES entry criteria were:

  • More likely to be age 75 to 84 (OR 1.40, 95% CI 1.14-1.72; p<0.01) compared with being age 65 to 74,

  • Showed a trend toward being >85 years (1.28, 95% CI 0.96-1.70; p=0.09).

  • Less likely to be female (0.80, 0.66-0.97, p=0.02).

  • More likely to have been discharged to a skilled nursing facility (2.31, 95% CI 1.71-3.11; p<0.001).

RALES entry criteria used in the analysis consisted of prescriptions for diuretics and an ACE inhibitor or angiotensin-receptor blocker, serum creatinine <2.5 mg/dL, and serum potassium <5.0 mmol/L at discharge, consistent with the current accepted guidelines for spironolactone use in HF.

According to Masoudi, the findings may suggest there has been "inadequate attention" paid to RALES patient-eligibility criteria. "Physicians might perceive that spironolactone is a relatively easy drug to use," at least compared with beta blockers, "that can be started at a fixed dose and continued thereafter, without considering the possibility that, particularly in patients with high baseline potassium, particular caution is required."

Masoudi and one other coauthor are reported to have received honoraria from Pfizer. The Medicare analysis was conducted under a contract with the US Centers for Medicare and Medicaid Services .


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