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Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Alexander Lyon, MA, BM, BCh, MRCP, PhD
Walport Clinical Lecturer in Cardiology - Department of Cardiac Medicine National Heart and Lung Institute - Imperial College - Flowers Building 4th floor - London SW7 2AZ - UK (e-mail: a.lyon@imperial.ac.uk / www1.imperial.ac.uk/medicine/people/a.lyon) Dialogues Cardiovasc Med. 2011;16:129-139
Effects of enalapril on mortality in severe congestive The effect of spironolactone on morbidity heart failure. Results of the CONSENSUS… and mortality in patients with severe heart failure Consensus Trial Study Group. N Engl J Med. 1987
B. Pitt et al; RALES Investigators. N Engl J Med. 1999
Effect of enalapril on mortality and the develop- ment of heart failure in asymptomatic patients with on survival in severe chronic heart failure reduced left ventricular ejection fractions M. Packer et al; COPERNICUS Study Group.
SOLVD Investigators. N Engl J Med. 1992
Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after morbidity in patients with chronic heart failure… M. A. Pfeffer, et al; CHARM Investigators
and Committees. Lancet. 2003
M. A. Pfeffer et al. N Engl J Med. 1992
Amiodarone or an implantable cardioverter- defibrillator for congestive heart failure MERIT-HF Study Group. Lancet. 1999
G. H. Bardy et al; SCD-HeFT Investigators.
The Cardiac Insufficiency Bisoprolol Study II Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study CIBIS-II Investigators and Committees. Lancet. 1999
K. Swedberg et al; SHIFT Investigators. Lancet. 2010
Selection of seminal papers by Karl Swedberg, MD, PhD
Department of Emergency and Cardiovascular Medicine Sahlgrenska Academy - University of Gothenburg - SWEDEN Copyright 2011 LLS SAS. All rights reserved Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Effects of enalapril on mortality in severe congestive heart failure.
Results of the Cooperative North Scandinavian Enalapril Survival
Study (CONSENSUS)

N Engl J Med. 1987;316:1429-1435
hronic heart failure (CHF) has developed into at 12 months was due to an absolute difference of 20 pa- epidemic proportions during the second half tients between the study arms. But the denominator was of the 20th century. Life expectancy has in- small (126 and 127 patients) by the scale of later trials, Ccreasedby2to3decadesoverthecourseof andthesurvivalcurvesclearlyshowanearlydivergence, the last century, and with this has come the which continues through the follow-up period.
HF epidemic, not least due to the aging population, andalso improved survival from acute myocardial infarction.
In addition to reducing mortality, enalapril treatment also However, up to the second half of the 1980s, life expectancy significantly improved symptoms, with 42% patients receiv- from CHF was grim, with 50% mortality within 1 year of di- ing enalapril improving by at least one NYHA class score, agnosis following an admission with acute decompensation versus 22% in the placebo arm. These figures demonstrate of CHF. Against this malignant background, numerous ef- not only the benefit of ACE inhibitors upon symptoms forts had been made to improve prognosis with diuretics in this debilitating condition, but also the importance of and nitrate-based vasodilators without significant impact.
the placebo effect, particularly with close monitoring inresearch trial participants, reinforcing the critical impor- CONSENSUS (COoperative North Scandinavian ENalapril tance of blinding and randomization in clinical trials.
SUrvival Study) was the first study that changed the land-scape of pharmacological therapy for CHF, and ushered in An interesting observation was that the mortality benefit the paradigm of neurohormonal blockade as a therapeutic was almost entirely due to death from progressive pump strategy, which influenced the hard end points of mortality failure (50% relative risk reduction [RRR]), whereas no ben- and hospitalization. Conducted across 35 Scandinavian hos- efit upon sudden cardiac death (SCD) was observed. Initial- pitals, 253 patients with acute decompensated HF (NYHA ly it was concluded that ACE inhibitors do not reduce SCD.
Class IV symptoms) were randomized in a double-blinded However, this result probably reflects this patient popula- manner to receive enalapril, starting at 5 mg twice daily tion with New York Heart Association (NYHA) class IV (2.5 mg in high-risk patients), with uptitration to a target symptoms, where SCD does occur, but at a low rate (10%) of 20 mg bid, or placebo. Patients were required at base- relative to death from pump failure, and hence the trial line to have dilated hearts and be stabilized upon medical was underpowered to demonstrate benefit on SCD in the therapy with diuretics, digoxin, and other vasodilators, but were excluded if they had experienced a recent myocardialinfarction.
Subsequent 10-year follow-up was reported by the investi-gators, with the benefit of enalapril lasting for at least 4 Remarkably, the trial was halted when mean follow-up was years, and placebo arm survivors received the benefits of still less than 1 year (188 days) by the ethical review panel ACE inhibition as they were commenced upon enalapril due to the significant reduction in the enalapril arm. Enala- after unblinding. However, attrition in this patient popula- pril treatment reduced the primary end point of all-cause tion with advanced heart failure was relentless, with only mortality in absolute terms by 18% at 6 months and 16% at 5 patients alive at 10 years. More work was required! 12 months, translating as 40% and 31% relative risk reduc-tion at these time points, respectively. The magnitude ofthis therapeutic benefit had only been seen in the contem-porary thrombolysis trials of the 1980s, and this trial en-sured that angiotensin-converting enzyme (ACE) inhibitorshave been written into every guideline for advanced conges-tive cardiac failure. Interestingly, the difference in mortality Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Effect of enalapril on mortality and the development of
heart failure in asymptomatic patients with reduced
left ventricular ejection fractions

N Engl J Med. 1992;327(10):685-691
he SOLVD (Study of Left Ventricular Dysfunc- SOLVD-Prevention reported strong trends toward a reduc- tion) investigators studied the influence of an- tion in mortality (8%), and in particular cardiovascular giotensin-converting enzyme (ACE) inhibitors mortality secondary to progressive pump failure (12%), in Tinheartfailure(HF)patientswithmildersymp- theenalapriltreatedarm,butthesewerenotstatistically significant, and therefore one has to conclude that, at least (COoperative North Scandinavian ENalapril SUrvival Study).
in the duration of follow-up (mean 37.4 months), there was The SOLVD investigators screened 39 924 patients with HF no mortality benefit in this asymptomatic HF population and a reduced left ventricular ejection fraction (LVEF) be- with reduced LVEF. However, there was a significant reduc- fore enrolling 2569 patients in the treatment trial for pa- tion in HF hospitalization, and when presented a reduction tients with symptomatic HF and reduced ejection fraction in death or HF hospitalization the beneficial effect of enala- (≈87% in New York Heart Association [NHYA] II or III), and pril was statistically different, with a 3.9% absolute risk re- a further 4228 patients with asymptomatic left ventricular duction (20% relative risk reduction) at follow-up. It is in- dysfunction (LVEF <35%) into the SOLVD-Prevention study.
teresting to contrast these reductions with those achievedin CONSENSUS of advanced symptomatic HF, and SOLVD It is interesting to reflect upon the SOLVD-Prevention treatment with moderately symptomatic heart failure, and study from a 2011 viewpoint. In the 1980s and 1990s, hav- reflect the graded benefit of ACE inhibitors on the heart ing HF symptoms was a critical element for diagnosis.
failure populations with increasing symptom severity.
Hence the strategy to “prevent” HF was in essence preven-tion of the complications of chronic HF, expressed as death, This trial also evaluated progression to development of hospitalization, or symptom development. While still con- HF symptoms, reported as HF development in light of tentious, perhaps contemporary HF specialists may con- contemporary definitions as discussed above. Enalapril sider this strategy “stabilization” rather than “prevention,” significantly reduced the proportion of patients develop- unless the heart recovers normal function. The large num- ing HF symptoms (29.8% vs 38.6%), and the time to symp- bers in SOLVD-Prevention also reinforce the disconnect tom development (median time 8.3 months in the placebo between symptoms and LVEF in patients with chronic HF, arm was extended to 22.3 months for the same number of highlighting the limitations of using either, or any other clinical parameter, in isolation as a single stratifying valueto categorize HF patients.
Analogous to the CONSENSUS trial, the 12-year follow-upof the SOLVD trial demonstrated that the benefit of ACE SOLVD-Prevention randomized this patient group to enala- inhibition lasts for several years, but that by 12 years the pril 2.5 mg twice daily, uptitrated to 10 mg twice daily, or enalapril and placebo arms had met, with <5% survival. A placebo. An interesting observation in light of the evolu- final comment is that in an era which preceded the Inter- tion of trial design was that all patients in both study arms net and modern electronic record keeping, remarkably, received a test dose of the active study drug for 1 week.
only 7/4228 patients were lost to follow up, reflecting the Few if any trials would employ such a strategy in 2011, efficient organization of this large multicenter internation- particularly due to risk of unblinding, but tolerance to the al trial for which the investigators must be commended.
drug, particularly regarding concerns of ACE inhibitor–induced hypotension, dictated that this was deemed anappropriate strategy. Although presented as a trial in asymp-tomatic patients, a third were reported to be in NHYAclass II, with, by definition, limiting symptoms on moder-ate exertion.
Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Effect of captopril on mortality and morbidity in patients
with left ventricular dysfunction after myocardial infarction.
Results of the survival and ventricular enlargement trial

M. A. Pfeffer, E. Braunwald, L. A. Moyé, L. Basta, E. J. Brown Jr, T. E. Cuddy, B. R. Davis, E. M. Geltman, S. Goldman, G. C. Flaker, et al; SAVE Investigators N Engl J Med. 1992;327(10)669-677
AVE (Survival And Ventricular Enlargement) is a was attributable to reduction in cardiovascular death from wonderful example of translational biology from progressive HF, and in accordance with CONSENSUS the basic science laboratory to the clinic with a (COoperative North Scandinavian ENalapril SUrvival Study) Smajorimpactonthehardendpointsofmortality andSOLVD(StudiesOfLeftVentricularDysfunction),there and hospitalization in heart failure (HF). In the was no reduction in sudden cardiac death. Progression of 1980s, Marc and Janice Pfeffer, in the research laboratory the HF syndrome, with requirement for open-label ACE of Eugene Braunwald, first developed the rat model of inhibitors, identified a high-risk subgroup in this trial pop- surgical myocardial infarction (MI), and then characterized ulation. Early treatment with captopril significantly reduced postinfarction left ventricular (LV) remodeling and the the proportion of patients progressing into this high-risk adverse pathophysiological sequelae. These adverse remod- group (5% ARR, 37% RRR). This morbidity benefit also eling changes were mirrored in patient populations surviv- translated into a 3% ARR or 22% RRR for hospitalization ing after acute MI, which were becoming an ever-increasing with congestive HF. These benefits were consistent across patient population after the successful introduction of multiple subgroups (age, previous MI, degree of left ven- thrombolysis. Braunwald and the Pfeffers demonstrated that tricular dysfunction, MI territory, β-blocker, and aspirin treating infarcted rats with the angiotensin-converting en- use). As frequent in trials of HF and MI, the minority of zyme (ACE) inhibitor captopril attenuated the adverse post- women enrolled (18%) lead to nonsignificant differences MI LV remodeling, with improved survival, and Braunwald demonstrated similar observations upon LV dimensionsin patients.
The remodeling hypothesis was evaluated with follow-upradionuclide scans in 95% patients. A nonsignificant The SAVE trial also selected to treat patients early after (P=0.168) reduction in progressive LV remodeling, when acute MI, recognizing the importance of a “preventative” defined as >9% reduction in LVEF, was reported. However strategy. The SAVE trial recruited patients within 3 days this may underestimate the benefit as patients with the post infarction with reduced left ventricular ejection frac- most severely depressed LVEF at baseline (eg, <25%) are tion (LVEF <40%), and randomized eligible patients to cap- unlikely to survive a further reduction of 9% points.
topril therapy, starting at 12.5 mg tds, and uptitrating to atarget of 50 mg tds during follow-up. The investigators A further interesting observation, given that the patho- screened eligible patients with a 6.25-mg test dose, with physiological hypothesis was to target post-MI HF, was a only 19/2250 patients excluded for symptomatic hypotension significant reduction in new acute MI events (25% RRR) in or unstable angina. This was the basis of the “captopril tri- the captopril-treated group. The potential mechanisms are al” strategy for commencing angiotensin-converting enzyme multiple, but this observation initiated the evaluation of (ACE) inhibitors, which has since disappeared from rou- ACE inhibitors for treatment of patients with atherosclerosis tine clinical practice, predominantly due to greater clinical but without HF, resulting in the subsequent HOPE (Heart experience, and perhaps also the use of less potent ACE Outcomes Prevention Evaluation) and EUROPA (EUropean inhibitors initiated at relatively lower starting doses.
trial on Reduction Of cardiac events with Perindopril instable coronary Artery disease) trials.
Follow-up was exemplary in this pre-Internet era, with only6 out of 2231 enrolled patients, spread across 112 hospitals The SAVE trial established early ACE inhibition in the treat- in the USA and Canada, who were lost to follow-up. Cap- ment of post MI HF, and together with the CONSENSUS topril treatment resulted in a 5% absolute risk reduction and SOLVD trials established ACE inhibitors in the treat- (ARR) in mortality at mean of 42 months follow-up, trans- lating into a 19% relative risk reduction (RRR). The benefit Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Effect of metoprolol CR/XL in chronic heart failure:
Metoprolol CR/XL Randomised Intervention Trial
in Congestive Heart Failure (MERIT-HF)

Lancet. 1999;353(9169):2001-2007
etoprolol is a lipophilic β1-selective antag- Somewhat at odds with the CIBIS II data, there did not seem to be a dose-related effect of the benefits with metoprolol activity, though less selective than biso- succinate. However, those patients who could only toler- Mprolol.Thetartratepreparationwasde- atealowdosehadsimilarreductioninheartratetothe veloped first, but a single dose was insuf- high-dose group. This may reflect the heterogeneity of ficient to provide stable 24-hour β-blockade, and therefore β-adrenergic receptor sensitivity in HF patients. The ab- a twice-daily dosing regimen was recommended. Metoprolol solute degree of heart rate lowering from baseline was not succinate was developed as a slow release, longer-acting, correlated with mortality benefit, an interesting finding in once-daily preparation. The metoprolol succinate dose view of results from the recent SHIFT (Systolic Heart Failure required to produce equivalent blood metoprolol concen- Treatment with the If Inhibitor Ivabradine Trial). This may trations is 33% higher than that of metoprolol tartrate. This reflect the multiple mechanisms of benefit imparted by is important as different heart failure (HF) trials have used β-blockers in HF, with differing thresholds for beneficial different preparations, and comparisons of the data have effects on the ventricular cardiomyocytes versus the con- ducting system, and hence heart rate lowering is a useful,but not absolute, surrogate of β-blocker benefits to the The MERIT-HF study (MEtoprolol CR/XL Randomized Inter- vention Trial in congestive Heart Failure) compared meto-prolol succinate controlled release/extended release (CR/XL) A subgroup of 41 patients was followed with serial cardiac once daily and placebo in a double-blinded study of 3991 magnetic resonance imaging assessments during the study.
patients. The entry criteria included HF with New York The treatment group demonstrated significant improve- Heart Association (NYHA) class II-IV symptoms, and left ments with reduction in both left ventricular (LV) end-dias- ventricular ejection fraction (LVEF) <40%. Patients were tolic and end-systolic volumes, and a mean improvement randomly assigned metoprolol CR/XL 12.5 mg (NYHA III- in LVEF of 8% in the metoprolol CR/XL group (29% to 37%; IV) or 25.0 mg once daily (NYHA II) or placebo. The target P=0.005). There were no significant changes in the placebo dose was 200 mg once daily and doses were uptitrated group. This demonstrated that β-blockers can initiate re- verse remodeling in chronic HF patients.
The MERIT-HF trial was stopped early, with a mean follow- Another similarity with the CIBIS II results was the benefit up period of 1 year, due to a significant mortality reduction of metoprolol in patients with the most severe cardiac im- in the metoprolol succinate–treated group versus placebo pairment and symptoms. In a subgroup of NYHA class III/IV (7.2% vs 11.0% ARR; 3.8% RRR 34%). There was a significant patients (mean LVEF 19%), there was a mortality reduction reduction in sudden cardiac death (RRR, 0.59) and death of 39% (P=0.008) and hospitalizations with worsening car- due to worsening heart failure (0.51). MERIT-HF, together diac failure reduced by 45%. In addition, benefit was seen with CIBIS II (Cardiac Insufficiency BIsoprolol Study II), in the elderly (mortality reduction 37% in patients over 65 were the first trials to demonstrate reduction in sudden years), and patients with diabetes mellitus.
“arrhythmic” death in HF patients, as the ACE inhibitor andamiodarone trials had been neutral for this end point.
MERIT-HF, CIBIS II, and COPERNICUS (Carvedilol Prospec-tive Randomized Cumulative Survival) established β-block- Metoprolol reduced the number of hospitalizations due to ers as central therapeutic strategy for chronic HF (class I worsening heart failure (317 vs 451; P<0.001) and number indication in all HF guidelines), finally reversing the deeply of days in hospital due to worsening heart failure (3401 vs ingrained prejudice of avoiding β-blockers in the HF popu- Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II):
a randomised trial

CIBIS-II Investigators and Committees Lancet. 1999;353(9146):9-13
n 1975, Waagstein et al first proposed the use of There were significantly fewer hospitalization events in the β-blockers in heart failure (HF). However the cardi- bisoprolol-treated group (ARR 6%), including a reduction ological community reacted with skepticism, not in admissions for worsening heart failure, hypotension, I aidedbyaseriesofsubsequentstudiesthatpro- andventriculartachyarrhythmias.Interestingly,bisoprolol duced contradictory or inconclusive results. During reduced the mortality of patients in sinus rhythm (ARR the 1980s, the excessive sympathetic activation and reduc- 6%), but not those in atrial fibrillation. There was also a tion of β-adrenergic receptor (βAR) density in cardiac failure trend toward a greater benefit for women with cardiac fail- patients was identified, leading researchers to hypothesize ure receiving bisoprolol, although as they were the minority that antagonism of this system might be beneficial. The (20% cases), this did not reach statistical significance.
MERIT-HF (MEtoprolol CR/XL Randomized InterventionTrial in congestive Heart Failure) and CIBIS (Cardiac Insuf- Bisoprolol lowered both baseline heart rate and heart rate ficiency Bisoprolol Study) trials were the first large trials variability, and both were significantly related to survival to confirm irrefutably the beneficial effects of β-blockers and hospitalization for worsening heart failure, the lowest basal heart rate and the greatest heart rate control beingassociated with best survival and reduction of hospital Bisoprolol is the most selective clinically β1AR antagonist.
admissions. Bisoprolol provided benefit across all the high- The initial CIBIS trial (641 patients) demonstrated a non- risk groups such as elderly, diabetics, patients with chronic significant reduction in both mortality (20%) and hospital renal failure and NYHA class IV patients, reversing the admissions (30%) in patients receiving bisoprolol. The previous held belief that β-blockers were less beneficial or CIBIS II trial was designed to be powered to answer the even harmful in these high-risk subgroups. The cost-benefit question of benefit, and was a double-blind, randomized analysis showed that bisoprolol reduced the cost of care trial of 2647 patients with stable, but severe chronic car- for cardiac failure patients by 5% to 10% independent of diac failure. The patients all had left ventricular ejection the country and health service assessed.
fraction (LVEF) <35%, New York Heart Association [NYHA]class III-IV symptoms, and were treated with angiotensin- The final post-hoc analysis demonstrated a dose-related converting enzyme (ACE) inhibitors and diuretics. The effect of benefit. Those on the highest dose (10 mg od) mean LVEF was 27%, 50% of patients had documented had a 70% reduction in mortality, and those on moderate coronary artery disease, and 12% had dilated cardiomyo- dose (5 mg or 7.5 mg od) a 51% mortality reduction, rela- pathy. The active arm received bisoprolol once daily, with tive to those on the lowest doses (1.25 mg and 2.5 mg a starting dose of 1.25 mg, titrated by doubling every 1 to od), though all were superior to placebo. Patients who 4 weeks up to 10 mg daily or maximum tolerated dose.
withdrew from the bisoprolol group due to drug intoler- The average dose taken was 8.6 mg daily, with the target ance had a higher mortality. CIBIS II emphasized the im- dose of 10 mg daily reached in 43% cases.
portance of uptitration of β-blockers in HF patients inreal-world cardiology practice, and persisting with lower The CIBIS II trial was stopped at 2 years due to the signifi- doses in the patients intolerant of highest target doses.
cant reduction in mortality in the bisoprolol-treated groupfrom 17.3% to 11.8% (absolute risk reduction [ARR] 5.5%,relative risk reduction [RRR] 36%). There was a significantreduction in sudden cardiac deaths, but deaths due to“pump failure” and myocardial infarction where not reducedsignificantly. Intriguingly, one third of the difference indeaths between the groups was unexplained (26 of 72).
Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
The effect of spironolactone on morbidity and mortality in
patients with severe heart failure

B. Pitt, F. Zannad, W. J. Remme, R. Cody, A. Castaigne, A. Perez, J. Palensky, J. Wittes; Randomized Aldactone Evaluation Study Investigators N Engl J Med. 1999;341(10):709-717
ejection fraction of 25% to 26% and almost all (>99%) pa- Study) was a landmark study published in 1999, tients were in New York Heart Association (NYHA) class which established aldosterone antagonism as III or IV. A total of 95% enrolled patients were treated with Racentraltenetinthemanagementofchronic ACEinhibitorsatbaseline.
heart failure (HF). RALES was conducted in an era after publication of the angiotensin-converting enzyme Spironolactone (25 mg once daily) reduced all-cause mor- (ACE) inhibitor trials, and contemporary teaching was that tality by 11% at 24 months, which was a 30% relative risk ACE inhibitors also reduced aldosterone production as reduction on top of ACE inhibition, confirming the investi- part of their therapeutic effect. The RALES investigators gators’ hypothesis that breakthrough aldosterone produc- had previously recognized that in reality ACE inhibitors tion in the ACE-inhibitor–treated patient was a detrimental only transiently suppress aldosterone production, and the pathophysiological pathway. The mortality benefit was breakthrough of aldosterone production presented a new primarily due to cardiovascular death reduction, and in con- therapeutic target in the ACE-inhibitor–treated patient.
trast to the ACE inhibitor trials, both heart failure progres-sion and sudden cardiac death were reduced significantly.
Aldosterone promotes renal sodium and water retention, This reduction in sudden “arrhythmic” death is intriguing, with kaliuresis, but also has direct effects upon the myo- and raises the question of what are the antiarrhythmic cardium. Specifically, aldosterone increases extracellular mechanism(s) of aldosterone blockade. Aldosterone pro- fibrosis, a pathophysiological process enhanced in the fail- motes myocardial collagen deposition and fibrosis, which ing heart. In the 1990s, spironolactone was an established electrophysiologically can contribute to conduction slowing treatment of salt and water retention in liver failure, but or block and unmask the increased repolarization hetero- at high “diuretic” doses (200+ mg daily). Hyperkalemia geneity in the failing heart, both of which predispose to was a recognized complication of both spironolactone, at wavefront reentry. Aldosterone also directly increases cal- these high doses, and ACE inhibitors, and there was un- cium leak from the sarcoplasmic reticulum, which may be a derstandable concern of combining the two treatments. The subcellular origin of triggered arrhythmias. Finally, although RALES investigators performed phase 1 and 2 studies, re- not formally a diuretic dose, mean serum potassium lev- porting that low spironolactone doses (12.5-50 mg) were els were higher in the spironolactone-treated arm (0.30 tolerated in patients taking ACE inhibitors without hyper- mmol/L). Hypokalemia is proarrhythmic, stimulating IKr kalemia, and have a physiological effect, reducing circulat- channel internalization, action potential (and QT) prolon- ing natriuretic peptide levels. These low spironolactone gation, and is common in HF patients treated with loop doses also appear to lack a diuretic effect, with no change diuretics. Preventing hypokalemia in this patient population in body weight or urinary sodium. The RALES trial has may have a significant impact on sudden arrhythmic death.
helped establish the view, at least in the HF community,that spironolactone at 12.5-25 mg doses acts as a direct Spironolactone caused gynecomastia or breast discomfort in 10% of men, leading to the development of eplerenoneas a more selective aldosterone antagonist for HF patients.
The RALES investigators enrolled 1663 patients in 195 cen- However, spironolactone is a cheap drug, and the RALES ters across 15 countries, demonstrating the amazing logis- trial has had an enormous effect on the global HF popula- tical efforts to perform a phase 3 clinical trial. This is all tion as patients can receive this effective treatment with- the more remarkable without a large pharmaceutical com- out the prohibitive costs of a novel “in patent” drug.
pany supporting the trial financially, given the lack of intel-lectual property for spironolactone. The patients enrolledhad advanced symptomatic HF with mean left ventricular Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Effect of carvedilol on survival in severe chronic heart failure
M. Packer, A. J. Coats, M. B. Fowler, H. A. Katus, H. Krum, P. Mohacsi, J. L. Rouleau, M. Tendera, A Castaigne, E. B. Roecker, et al; Carvedilol Prospective Randomized Cumulative Survival N Engl J Med. 2001;344(22):1651-1658
arvedilol has a greater array of pharmacologi- (11.4%) (absolute risk reduction [ARR] 7.1% relative risk cal effects than metoprolol and bisoprolol. It reduction [RRR] 35% at 12 months). Mode of death was not is an antagonist of β1-, β2-, and α1-adrenergic reported in the COPERNICUS trial, but the subsequent Creceptors,andalsohasantioxidanteffects, COMET(CarvedilolOrMetoprololEuropeanTrial)would beneficial effects on insulin sensitivity, anti- support both antiarrhythmic effect and prevention of heart apoptotic activity, reduces hypokalemia, and alters the failure progression as benefits with carvedilol treatment.
HERG component of the IKr channel.
Total hospitalizations were reduced by 24%, with the impact Carvedilol was initially assessed with caution in heart fail- on admission with worsening HF significant, reducing from ure (HF) patients with minimal symptoms in the late 1980s 23.7% to 17.1% with carvedilol. This corresponded to 40% and early 1990s in the small US Carvedilol Heart Failure reduction in the number of days admitted to hospital, which Studies. On the basis of these studies carvedilol received had a significant impact on quality of life in this high-risk a Food and Drug Administration license for HF treatment patient group with a poor prognosis. These benefits were in the USA, but the European regulatory authorities re- independent of sex, age, LVEF and ischemic versus non- quired a larger randomized double-blinded placebo-con- ischemic etiology. It was subsequently reported that this trolled trial, and COPERNICUS (Carvedilol Prospective reduced rate of hospital admissions led to an estimated Randomized Cumulative Survival) was designed to meet overall reduction in the cost of patient care by 11.1% in the British National Health Service.
COPERNICUS assessed the effect of carvedilol in a more Carvedilol was well tolerated in this advanced HF popula- severe group of HF patients compared with the MERIT-HF tion, with 65% of patients reaching target dose. Due to drug (MEtoprolol CR/XL Randomized Intervention Trial in con- intolerance, 14.8% of patients withdrew from the carvedilol gestive Heart Failure) and CIBIS (Cardiac Insufficiency arm (18.5% in the placebo arm). A low systolic blood pres- BIsoprolol Study) trials, which also addressed an important sure at entry to the study was associated with a reduced concern regarding the use of β-blockers in the most symp- likelihood to tolerate maximal carvedilol doses, but this tomatic HF patients with severely impaired ventricles. A high-risk patient group also received the greatest benefit total of 2289 clinically stable patients with New York Heart from the carvedilol that they could tolerate.
Association (NYHA) class III or IV symptoms, left ventricularejection fraction (LVEF) <25%, and treatment with ACE A substudy demonstrated that carvedilol lowered N-termi- inhibitors (or angiotensin receptor blockers [ARBs]) and nal prohormone of brain natriuretic peptide (NT-proBNP) diuretics, were randomized to carvedilol or placebo. The levels, with an elevated NT-proBNP level being a sensitive starting dose was 3.125 mg bid, doubled fortnightly to a marker for adverse prognosis in HF patients.
target dose of 25 mg bid. Mean age was 63.4 years and80% of patients were male. A total of 67% patients had is- The absolute mortality benefits with carvedilol seen in chemic heart disease as their cause of cardiac failure, and COPERNICUS are greater than those reported in the average LVEF was 19%, confirming COPERNICUS as a trial β-blocker arms of CIBIS II and MERIT-HF. Whether this re- of more severe cardiac failure than CIBIS II or MERIT-HF.
flects the sicker population, or the superiority of carvedilolas the β-blocker of choice in HF, is a point for discussion.
The trial was stopped early after a prespecified boundary The subsequent COMET trial demonstrated superiority for end point had been reached. The mean follow-up was 10.4 carvedilol over metoprolol, but the argument of carvedilol months. There were 190 deaths in the placebo group (18.5% versus bisoprolol continues in 2011.
cumulative risk) versus 130 deaths in the carvedilol group Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Effects of candesartan on mortality and morbidity in patients
with chronic heart failure: the CHARM-Overall programme

M. A. Pfeffer, K. Swedberg, C. B. Granger, P. Held, J. J. McMurray, E. L. Michelson, B. Olofsson, J. Ostergren, S. Yusuf, S. Pocock; CHARM Investigators and Committees Lancet. 2003;362(9386):759-766
hospitalization (3.8% absolute risk reduction [ARR]; Assessment of Reduction in Mortality and mor- P=0.014) and mortality (4.6% ARR; P=0.02). This is an bidity) program is in some respects the “mega- interesting finding for several reasons. It is curious that Ttrialofmegatrials.”CHARMisthelargesttrial patientsenrolledonACEinhibitortreatmentinCHARM- program ever undertaken in heart failure (HF) Added had similar outcomes to those without ACE inhib- patients, with three trials rolled into one, allowing an over- itors enrolled in CHARM-Alternative (primary end point in all analysis in addition to the three parts. The CHARM placebo arms 40 and 42%), despite superior baseline thera- investigators compared the angiotensin receptor blocker py. This may possibly be explained by the sicker population (ARB) candesartan with placebo in three HF patient popu- enrolled in CHARM-Added—they were symptomatic de- lations with mild-to-moderate symptoms (>97% in New spite ACE inhibitors, with 73% of patients in NHYA class III York Heart Association [NYHA] classes II and III).
vs 48% in CHARM-Alternative, and in CHARM-Added meanLVEF, systolic blood pressure, and spironolactone prescrib- The combined analysis in the CHARM-Overall program ing were lower (LVEF: 28.0% vs 30%, systolic blood pressure: (7599 patients) showed that candesartan treatment reduced 125 vs 130 mm Hg, spironolactone: 17% vs 23%). Whether all-cause mortality by 1.6% (P=0.055) at median 37 months, these small differences are sufficient to account for the which became statistically significant after a prespecified paradoxically equal event rate in these two CHARM studies covariate analysis (P=0.03). Each substudy contained a different cohort of HF patients, and therefore I will evalu-ate each on its own merits.
CHARM-Added also refuted a clinical concern raised by theVal-HeFT trial regarding triple therapy with ACE inhibitors, CHARM-Alternative randomized 2028 HF patients with re- ARBs, and β-blockers. In Val-HeFT, patients receiving these duced left ventricular ejection fraction (LVEF) of <40%, in- three agents had higher mortality than those taking two tolerant of angiotensin-converting enzyme (ACE) inhibitors, alone, raising concerns that excessive neurohormonal to candesartan or placebo. At a median of 33.7 months, blockade may be deleterious. In the CHARM-Added trial, there was a 7% absolute risk reduction of cardiovascular the benefits were seen in patients taking ACE inhibitors, (CV) death or hospitalization (33% vs 40% P=0.0004).
β-blockers, and candesartan (triple therapy). Serendipitous- The reduction in CV hospitalization was significant (7.8% ly, only 55% of patients were taking β-blockers in CHARM- P<0.0001), whereas the mortality reduction was not (3.2% Added, providing sufficient statistical power to conclude P=0.07). These findings replicated those reported in Val- that triple therapy was beneficial, and not harmful.
HeFT (Valsartan Heart Failure Trial), whereas valsartan re-duced hospitalization, but not mortality, in ACE-inhibitor– CHARM-Preserved was the first trial to investigate the ben- intolerant patients. These two trials have placed ARBs as efit of ARBs in patients with heart failure and milder levels class 1 indication for treatment of HF with reduced LVEF of LV systolic dysfunction (LVEF >40%). Almost one third in ACE-inhibitor–intolerant patients.
of patients enrolled had LVEF >60%, a subgroup now de-fined as HF with preserved ejection fraction (HFpEF). Can- CHARM-Added randomized 2548 patients with HF and re- desartan reduced CV hospitalizations (2.4% ARR; P=0.04 duced LVEF who were treated with optimal ACE-inhibitor after covariate adjustment), whereas mortality was un- doses to treatment with candesartan or placebo. Analogous changed (11.2% vs 11.3 %). Subsequent trials have shown to CHARM-Alternative, candesartan reduced the combined that HFpEF is a difficult clinical problem, with few studies primary end point of death or hospitalization, although to demonstrating positive outcomes with pharmacological a lesser degree (38% vs 42% P=0.01). In contrast to CHARM- intervention. The reduction in hospitalization seen in Alternative, there was a significant reduction in both CV CHARM-Preserved is hence an important finding.
Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Amiodarone or an implantable cardioverter-defibrillator
for congestive heart failure

G. H. Bardy, K. L. Lee, D. B. Mark, J. E. Poole, D. L. Packer, R. Boineau, M. Domanski, C. Troutman, J. Anderson, G. Johnson, et al; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators N Engl J Med. 2005;352(3):225-237
CD-HeFT (Sudden Cardiac Death in Heart Failure mias in this patient population. However, it also confirmed Trial) was a pivotal heart failure (HF) trial published that the benefits of ICDs come at a price, given the psy- in 2005 that has molded the care of HF patients in chological and physical trauma of inappropriate shocks.
Stwocriticalways.Firstly,SCD-HeFTidentifiedthat in patients with significantly reduced left ventricu- This trial was published after the MADIT I and II trials lar systolic function and mild-to-moderate symptoms, (Multicenter Automatic Defibrillator Implantation Trials), primary prevention of cardiac death with an implantable confirming the benefit of ICDs in the postinfarction HF cardioverter-defibrillator (ICD) significantly reduced mor- population. SCD-HeFT helped to answer uncertainties re- tality. Secondly, SCD-HeFT confirmed that chronic prophy- garding ICD use in dilated cardiomyopathy patients raised lactic treatment with amiodarone had no benefit in this by the DEFINITE (DEFIbrillators in Non-Ischemic cardio- population. These represent two major landmarks for HF myopathy Treatment Evaluation) trial, which reported a nonsignificant trend toward benefit from ICD in the dilatedcardiomyopathy population (P=0.08). SCD-HeFT reported The trial investigators recruited 2251 patients with New benefit in both ischemic and nonischemic populations, York Heart Association (NYHA) class II or III symptoms and confirming the view that the DEFINITE trial was under- stable HF with reduced left ventricular ejection fraction powered, and also had a slightly lower risk population (LVEF) (inclusion criterion LVEF <35%, median 25%) due (1-year mortality in dilated cardiomyopathy patients 14% to ischemic or nonischemic cardiomyopathy from multiple centers across the USA and Canada. Patients were random-ized to amiodarone, ICD, or placebo in a permuted-block Perhaps the most provocative finding was the interaction randomization strategy to ensure equal distribution of is- with NYHA symptom class. In the milder symptom group chemic and nonischemic, and NHYA class II and III, patients (NYHA class II) there was an 11.9% absolute risk reduction in each study arm. Patients were followed up for a median in mortality (46% RRR), which was highly significant, where- of 45.5 months, with the vital status of all 2251 patients as in the NYHA class III patients there was no reduction in mortality with ICD therapy. This supports the observationsfrom MUSTT (Multicenter UnSustained Tachycardia Trial) Single-lead ICD therapy resulted in an absolute risk reduc- and epidemiological studies that SCD represents a greater tion (ARR) in mortality of 7% over 5 years compared with proportion of deaths in congestive HF patients with im- placebo (relative risk reduction [RRR], 23%; P=0.007). This paired systolic function, but low symptom burden, who benefit appeared from 18 months post enrollment, suggest- are potentially more active, compared with a higher rate ing that the benefit is dependent upon the long-term at- of “pump failure” death in patients with higher symptom trition of SCD in this patient population, and the develop- burden (NYHA class III and IV) for which ICD therapy may ment of electrical instability is a dynamic process, rather not be expected to reduce mortality.
SCD-HeFT has made primary prevention ICD therapy a A number of findings have made this trial even more in- class 1 indication in HF patients, but with cardiac resyn- teresting to practicing clinicians caring for HF patients. A chronization therapy developing in parallel, the use of sin- total of 31% of patients in the ICD group received shocks, gle-lead ICD devices in this patient population has become with 21% appropriate, and presumably life-saving in the exceedingly rare. Given that SCD-HeFT is the cornerstone context of the settings used, and 10% inappropriate. The trial for ICD therapy in HF, perhaps revisiting SCD-HeFT will annual rate of appropriate shocks was 5%, which may reflect also ensure more complex dual- and triple-lead devices the natural incidence of malignant ventricular tachyarrhyth- are implanted for the correct indications.
Dialogues in Cardiovascular Medicine - Vol 16 . No. 2 . 2011 Summaries of Ten Seminal Papers - Lyon
Ivabradine and outcomes in chronic heart failure (SHIFT):
a randomised placebo-controlled study

K. Swedberg, M. Komajda, M. Böhm, J. S. Borer, I. Ford, A. Dubost-Brama, G. Lerebours, L. Tavazzi; Lancet. 2010;376(9744):875-885
ystolic Heart Failure treatment with the If inhibitor β-blockers, for which they were repetitively asked to use Ivabradine Trial (SHIFT), published last year, was the highest dose tolerated. Indeed, only 23% of patients the first trial for 10 years that showed a benefit from recruited were at target dose for a licensed β-blocker for Saddinganewdrugtocontemporarypharmacolog- HF,and49%at>50%targetdose.This,therefore,reflects ical heart failure (HF) therapy. It also confirmed real-world β-blocker usage. In the subgroup of patients elevated heart rate (HR) in HF patients in sinus rhythm as receiving at least 50% of the target dose of β-blocker, effects on cardiovascular outcomes were not significant apart fromhospital admission for heart failure, which was significant- The SHIFT investigators recruited 6558 stable HF patients ly reduced by 19%. This finding might have been related across 37 countries with New York Heart Association (NYHA) to the lower event rate in this subgroup (13% per year for class II-IV symptoms, reduced left ventricular ejection frac- the primary end point) than in the overall population, re- tion (LVEF Յ35%), and a sinus HR Ն70 beats per minute ducing the power of this secondary analysis.
(bpm). HF patients were randomized to the selective Ifcurrent inhibitor ivabradine or placebo. The requirement The low prevalence of cardiac resynchronization therapy for a higher resting heart rate was critical, given the previ- (CRT) and implantable cardioverter-defibrillator (ICD) de- ous results from the BEAUTIFUL trial (morBidity-mortality vices (1% and 4%, respectively), was attributed to study EvAlUaTion of the If inhibitor ivabradine in patients with design (sinus rhythm had to be present Ն40% of the time coronary disease and left ventricULar dysfunction) where and the pacing threshold had to be <60 bpm), which led individuals with HR <70 bpm were enrolled, potentially to the exclusion of some patients with pacemakers. Given neutralizing benefit with respect to ivabradine treatment.
the significant reduction in morbidity and mortality withdevice therapy, further studies are required to determine Over a median follow up of 22.9 months, ivabradine treat- if HF patients with CRT and/or ICDs will obtain additional ment resulted in a significant 5% reduction in the primary end point of cardiovascular death or hospitalization forworsening HF (24% vs 29%; P<0.0001), with the end point No differences in sudden cardiac death were observed, driven by a significant reduction in HF hospitalization (rel- which could be attributable to the effect of the background ative risk reduction [RRR] 26%). There was no significant β-blocker treatment (used in 89% of patients), which has reduction in all-cause death or cardiovascular death, but intrinsic electrophysiological effects and is known to affect deaths from HF were significantly reduced (RRR, 26%). The benefits were consistent across all prespecified subgroupsand were greatest in patients with a resting HR >77 bpm, This trial reflects the evolution of HF trial design with the and ivabradine was well tolerated, with few adverse events.
primary end point encompassing CV mortality and hospi-talization, whereas in the angiotensin-converting enzyme Ivabradine treatment significantly lowered sinus HR in the inhibitor and β-blocker trials, all-cause mortality was the treatment arm, with a net reduction of 10.9 bpm detectable at 28 days, reducing to 8.1 bpm by the end of follow up.
In summary, the benefit of ivabradine in patients with HF This trial has raised debate regarding the role for ivabra- and high resting sinus heart rates (>70 bpm) was established dine therapy in modern cardiology practice, and in partic- in SHIFT (Systolic Heart Failure Treatment with the If Inhib- ular for HF patients receiving guideline-recommended itor Ivabradine Trial), and in my opinion ivabradine should therapies, including β-blockade. Investigators were asked be considered in HF patients in sinus rhythm with elevated to prescribe according to their routine practice except for heart rate who have an intolerance to high β-blocker doses.

Source: http://www.dialogues-cvm.com/document/DCVM60_05.pdf

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