Spironolactone for heart failure - Diegori.it

Spironolactone for heart failure13/06/2011 17:04The effect of spironolactone on morbidity and mortality inpatients with severe heart failureAuthorsPitt B, Zannad F, Remme W, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, forthe Randomized Aldactone Evaluation Study (RALES) investigators.Source New England Journal of Medicine 341:709-17. September 2, 1999.InstitutionsSupportUniversity of Michigan (USA); Clinique de Nancy (France); Hopital Henri Mondor(France); STICARES Cardiovascular Research Foundation (Netherlands); SearlePharmaceuticals (USA); Statistics Collaborative (USA).Searle Pharmaceuticals.BackgroundAldosterone has multiple negative effects in patients with congestive heart failure, including theretention of sodium, depletion of potassium and magnesium, sympathetic activation, and causingmyocardial and vascular fibrosis and baroreceptor dysfunction.Aldosterone receptor antagonists have not been widely used in severe CHF, however, because ofthe belief that ACE inhibitors already inhibit the production of aldosterone and the fear thatcombining aldosterone blockers with ACE inhibitors would lead to hyperkalemia.There is evidence, however, that ACE inhibitors do not completely block the production ofaldosterone and that low doses of aldosterone blockers in conjunction with ACE inhibitors donot often lead lead to serious hyperkalemia.The Randomized Aldosterone Evaluation Study (RALES) was designed to investigate the effectof adding a relatively low dose of spironolactone to loop diuretics and ACE inhibitors, inpatients with severe congestive heart failure.MethodsPatientsEligibility criteriaNYHA class IV heart failure and EF

Spironolactone for heart failure13/06/2011 17:04transplantation.Potassium > 5.0 mmol/l or creatinine > 2.5 mg/dl.Primary hepatic failure; active cancer.Concommitent therapyTreatment with digitalis and vasodilators was allowed.Treatment with potassium sparing diuretics was not permitted.Potassium supplementation was not recommended unless serum potassium was less than3.5 mmol/l.InterventionPatients were randomized to either 25 mg of spironolactone daily or placebo. This dose couldbe increased to 50 mg daily after 8 weeks if there was evidence for progression of heart failure inthe absence of hyperkalemia.The dose could be decreased to every other day if hyperkalemia developed, but it wasrecommended that the dose of ACE inhibitors be decreased first. Study medication could bewithheld for medical reasons, including hyperkalemia or creatinine > 4.0 mg/dl.Follow-upClinical and laboratory evaluation were carried out every four weeks for the first twelve weeks,every 3 months for the rest of the first year and every 6 months thereafter. An additional serumpotassium measurement was performed at 9 weeks in those patients in whom the dose wasincreased at 8 weeks.AnalysisThe primary endpoint was all-cause mortality, analyzed by intention to treat.Secondary endpoints included cardiac mortality, hospitalization for cardiac causes, death orhospitalization for cardiac causes and change in NYHA class.Predefined subgroups for analysis of efficacy were ejection fraction, cause of heart failure,serum creatinine, age, use of ACE inhibitor and digoxin.ResultsPatientsA total of 1663 patients from 195 centers were randomized (822 to spironolactone, 841 toplacebo), between March 24, 1995 and December 31, 1996. Analysis was terminated on August24, 1998 (16 months early) after interim analysis demonstrated efficacy of the study drugexceeding preset limits.http://www.journalclub.org/vol2/a72.htmlPage 2 of 8

Spironolactone for heart failure13/06/2011 17:04The groups were well matched at baseline. Pertinent characteristics included (approximateaverage of both groups, unless otherwise indicated):Age 65; white 86%; male 73%BP 122/75; heart rate 81NYHAClass III: placebo - 69%; spironolactone - 72% (not significantly different)Class IV: placebo - 31%; spironolactone - 27% (nsd)LV ejection fraction: 25.5%; cause of CHF ischemic in 55%MedicationsAll were on loop diuretics95% were on an ACEI. Mean dose of captopril was 62 mg, of enalapril 15 mg, oflisinopril 14 mg.Digitalis 74%Aspirin 37%Beta blockers 10%Potassium supplements 28%Discontinuation of treatment occurred in 200 patients in the placebo group and in 214 in thespironolactone group (for lack of response, adverse effects or administrative reasons).Mean follow-up was 24 months.SurvivalCause of death Spironolactone Placebo RR and P-valueAll-cause 284 (35%) 386 (46%) 0.70; p 1.2 mg/dl), use of digitalis, use of ACEI, sex, median serum potassium (< or > 4.2 mmol/l),NYHA class (III or IV), beta-blocker use, and use of potassium supplements.HospitalizationA total of 336 patients in the placebo group (40%) were hospitalized for cardiac causes, vs. 260in the spironolactone group (32%), for a RR of 0.70 (p

Spironolactone for heart failure13/06/2011 17:04NYHA classChange in NYHA class Placebo SpironolactoneImproved 33% 41%Same 18% 21%Worsened or died 48% 38%Adverse effectsDuring the course of the study, the heart rate, blood pressure, weight and serum sodiumconcentrations did not differ between the two groups.In the spironolactone group, the median potassium concentration rose by 0.3 mmol/l and theserum creatinine rose by approximately 0.1 mg/dl. There was no change in the placebo group.Overall, adverse events were reported in 79% of patients taking placebo and in 82% of those onspironolactone. Discontinuation because of adverse events occurred in only 5% of placebopatients and 8% of spironolactone patients. Most of the adverse events occurred with equalfrequency in both groups, including serious hyperkalemia (10 patients in the placebo group, 14in the spironolactone group).The only adverse effect which happened significantly more often in patients in thespironolactone group was gynecomastia or breast pain, which occurred in 10% of men in thisgroup, vs 1% in the placebo group.Author's discussionThe authors note that the beneficial effects of spironolactone on morbidity and mortalitydemonstrated in this study were observed after 2 to 3 months of treatment and persistedthroughout the study.Recent research has shown that aldosterone can cause myocardial and vascular fibrosis, directvascular damage, baroreceptor dysfunction and can prevent the uptake of norepinephrine by themyocardium. The authors speculate that the beneficial effects of aldosterone receptor blockadeon progressive heart failure and sudden death are in part due to blocking these effects ofaldosterone. The beneficial effects were seen in patients who were almost all receiving ACEinhibitors; this implies that the reduction of aldosterone production by blockade of theangiotensin system alone is not sufficient to prevent the ill effects of aldosterone in heart failure.Although some of the effects of spironolactone could be due to natriuresis and retention ofpotassium, the authors point out that there was no evidence of a significant hemodynamic effectof spironolactone and they do not consider the rise in serum potassium in spironolactone treatedpatients to be clinically significant.Significant hyperkalemia was rare, which the authors attribute to the relatively low dose ofspironolactone used (mean dose 26 mg) and to the exclusion of patients with elevated serumhttp://www.journalclub.org/vol2/a72.htmlPage 4 of 8

Spironolactone for heart failure13/06/2011 17:04creatinine or potassium at baseline. Although gynecomastia and breast pain were significantproblems in men treated with spironolactone, they only led to discontinuation of the drug in 2%of men and may well be a much lesser problem with newer aldosterone receptor blockers thatare under investigation.CommentThis study of spironolactone in patients with severe congestive heart failure revealed a significantreduction (by about 30% relative risk) in death and hospitalizations among treated patients. Thesepatients were receiving reasonable therapy with diuretics, ACE inhibitors and digitalis, and, althoughonly 10% were on beta-blockers, the benefit was, if anything, greater in this subgroup. The results ofthe study should be applicable to a fairly large segment of patients with severe CHF, since theexclusion criteria should not rule out the majority of patients in clinical practice.The authors do not state whether or not baseline aldosterone levels were obtained in these patients. Ifthey were, it would be interesting to see whether the benefit of spironolactone was concentrated inpatients with higher aldosterone levels. If so, the drug could be targetted to those who would benefitthe most.I was initially surprised to see a major pharmaceutical company like Searle sponsoring a trial of suchan old drug, but Searle is also developing a newer aldosterone receptor blocker, eplerenone, whichmay cause less gynecomastia. Whether or not this newer drug will be as effective in CHF remains tobe seen.September 7, 1999ReferencesReferences related to this article from the NLM's PubMed database.Reader CommentsSeptember 12, 1999From: Hans Liedholm [Hans.Liedholm@smi.mas.lu.se]Dear Michael,We read with interest the publication of the results of the RALES study as this adds to the knowledgeon the pharmacological treatment of severe heartfailure (1). Earlier this year two trials on treatmentwith selective beta-blockers were published (2,3). Bisoprolol (CIBIS- II study) and metoprolol(MERIT-HF trial) respectively showed a significant effect on mortality compared to placebo whenadded to conventional treatment. The impact of the results of these trials is considerable and willhttp://www.journalclub.org/vol2/a72.htmlPage 5 of 8

Spironolactone for heart failure13/06/2011 17:04basically change our treatment of (systolic) heart failure.We want to make two points. Firstly, none of these trials has been properly reported according to theCONSORT guidelines for reports of randomised controlled trials (4). How many patients wereinitially involved and from where did they come? The omission of information on eligible patients ishard to understand, as the external validity depends on the representativity of included patients.Secondly, it would be clarifying if all major trials also reported the NNTs (with 95 % confidenceintervals).Yours Sincerely,Hans Liedholm, MD PhD, Agneta Björck Linné, B PharmThe Drugs and Therapeutics Committee, Malmö University Hospital, S-205 02 Malmö, Sweden.hans.liedholm@smi.mas.lu.se1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, for theRandomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity andmortality in patients with severe heart failure. N Engl J Med 1999;341: 709-17.2. CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomisedtrial. Lancet 1999;353:9-13.3. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XLrandomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001-7.4. Altman DG. Better reporting of randomised controlled trials: the CONSORT statement. BMJ1996;313:570-1.Date: September 22, 1999From: Sergio Emanuel Kaiser [kaiser@trip.com.br]In the latest issue of Circulation (Circ 1999;100:1311) the SOLVD investigators published arestrospective analysis addressing the relationship between use of diuretics and arrhythmic deaths.The relative risks of deaths according to the class of diuretic used is shown below. The influence ofnon-potassium sparing diuretics was independent of group assignment, i.e., enalapril or placebo.Relative risk of arrhythmic death according to diuretic use in the SOLVDpopulationNo diuretic 1.00Any diuretic 1.37 (1.08–1.73) p=0.009Non–potassium-sparing diuretic 1.33 (1.05–1.69) p=0.02Potassium-sparing diuretic 0.90 (0.61–1.31) 0.6Therefore, it is possible that part of the mortality reduction observed in the RALES study could beattributed to the potassium-sparing action of spironolactone.I also have some doubts whether we might extrapolate the RALES results to a larger population underbeta-blocker use, since only 10% were effectively taking such drugs. Nowadays, the use of betablockersin heart failure is consistently increasing and it remains to be proved whether spironolactoneadds incremental benefit beyond that of a combination of ACEI and beta-blocker to standard digitalishttp://www.journalclub.org/vol2/a72.htmlPage 6 of 8

Spironolactone for heart failure13/06/2011 17:04and diuretic therapy.Best regardsSergio Kaiser, MDThese are important points. The SOLVD study looked at the benefit of enalapril inpatients with CHF. The article referred to by Dr. Kaiser is a retrospective study ofpatients enrolled in SOLVD and found that use of non-potassium sparing diuretics, butnot potassium-sparing diuretics, was associated with an increased risk of arrhythmicdeath. Unfortunately, the exact type of potassium-sparing diuretics was not specified, soit is impossible to know whether the majority of patients taking potassium-sparingdiuretics were taking spironolactone or triamterene (not an aldosterone antagonist).If most of these patients were taking spironolactone, then much of the benefit seen in thissubgroup in SOLVD might actually be due to aldosterone antagonism (as hypothesizedhere, in RALES), rather than to the prevention of potassium depletion. If, on the otherhand, a significant benefit was also present in patients taking triamterene, then one wouldhave to postulate a beneficial effect simply due to the prevention of potassium loss.Prevention of potassium loss alone, however, probably does not account for all of thebenefit seen in RALES, since an effect was seen on death from progressive CHF also, notonly from arrhythmia.As for beta-blockers and aldosterone antagonism, a beneficial effect of spironolactonewas also seen in the subgroup of patients taking beta-blockers, but as you point out, thisrepresents only 10% of the study population. --mjDate: November 11, 1999From: Agostino Colli [agcolli@tin.it]In RALES the number of patients in atrial fibrillation is not stated. Evenif one could suppose it from the number of patients on digitalis ( 70%)which is just the same in both groups, balancing with respect to thisfeature is not shown.It is true that the number of patients in atrial fibrillation was not specified. Presumablydigitalis was given for heart failure, not for fibrillation, in the majority of patients studiedhere. However, I'm not sure that spironolactone would be likely to have more or less ofan effect in patients in fibrillation, so even if the groups were unbalanced in this regard, Idon't think it would have affected the outcome. -- mjJanuary 24, 2000From: Javier Ena (jena@san.gva.es)Received: November 30, 1999I read with great interest your article and I was surprised by the large proportion of patients thatdropped out from study (24% in the placebo group and 26% in the spironolactone group). Could youdetail in numbers the reasons for the drop-outs. In addition, there is some less degree of cardiacfailure in patients taking spironolactone (27% in class IV in the spironolactone group; 31% in class IVhttp://www.journalclub.org/vol2/a72.htmlPage 7 of 8

Spironolactone for heart failure13/06/2011 17:04in the placebo group). Were the differences in mortality and hospitalization maintained aftercontrolling for NYHA class?. Thanks for your answer.J. Ena MD (Alicante. Spain)As you note, about one quarter of patients dropped out during the course of the study.The authors do not detail the reasons for dropping out, other than to say it was "becauseof a lack of response, because of adverse events, or for administrative reasons". Thesepatients were included in the analysis of the results.Although there were slightly more patients in severe CHF in the placebo group, thereduction in mortality was almost identical when subgroups according to NYHA classwere looked at. -- mjJanuary 24, 2000Letters to the Editor about this article, from the January 13 New England Journal of Medicine.Topics covered include:Was conventional therapy maximized?Danger of hyperkalemia in diabeticsDanger of hyperkalemia in the geriatric populationRole of the beta-adrenergic systemSubmit a commentJournal Club homepagehttp://www.journalclub.org/vol2/a72.htmlPage 8 of 8