nuevas y tradicionales aproximaciones

8/14/2019 Nuevas y Tradicionales Aproximaciones

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Traditional and Novel Approaches to Managementof Heart Failure: Successes and Failures

Inder S. Anand, MD, FRCP, DPhil (Oxon), FA CC a ,b ,*,Viorel G. Florea, MD, PhD, ScD, FACC a ,b

a Division of Cardiology, University of Minnesota Medical School, 420 Delaware Street SE,MMC 508, Minneapolis, MN 55455, USA

b Heart Failure Clinic, Veterans Administration Medical Center, Cardiology 111-C, 1 Veterans Drive,

Minneapolis, MN 55417, USA

It is now generally recognized that heart failure(HF) progresses through a process of structuralremodeling of the heart, to which neur.ohormonal(NH) and cytokine activation make an importantcontribution [1]. Several lines of evidence supportthe role of neurohormones in the progression of HF. Norepinephrine [2], angiotensin II [3], and cy-tokines [4] are directly toxic to cardiac myocytes;the degree of neurohormonal activation in HF isproportional to disease severity, increases withthe progression of HF, and is related to prognosis[5]. Furthermore, changes in NH activation overtime, occurring either spontaneously or in responseto pharmacologic therapy, are also associated withproportional changes in subsequent mortalityand morbidity [6]. These ndings support thehypothesis that blocking the deleterious effects of vasoconstrictive hormones and stimulating pro-duction of vasodilator hormones would have ben-ecial effects. The spectacular success in reducing

HF morbidity and mortality by inhibiting thesympathetic and renin-angiotensin-aldosteronesystems with beta-blockers, angiotensin convertingenzyme-inhibitors (ACE-I), and aldosterone recep-tor antagonists further underscores the importanceof NH activation in the progression of HF [711],and raises the question as to whether an evenmore complete blockade of the NH system usingnew novel therapies would provide incremental

benet. Over the last decade the authors havebeen testing this hypothesis. However, recent clin-ical trial data evaluating strategies using novel NHblockers beyond ACE inhibition, beta-blockers,and aldosterone antagonists, have recently failedto improve the clinical outcomes of HF patients,and in some cases has even shown to be deleterious[1216].

How do we explain the remarkable success withblockers of the adrenergic and renin-angiotensin-aldosterone system, and why have the newer novelagents had neutral or even deleterious effects onHF outcomes? In this article, the authors provideevidence that agents that have benecial effects inHF also generally attenuate or reverse ventricularremodeling, whereas the newer novel agents thathave failed to improve clinical outcomes either hadno effect on remodeling or have been associatedwith adverse remodeling.

Blockade of the sympathetic nervous system

Beta-blockers reduce mortality in patients withNew York Heart Association (NYHA) class II toIV HF by 34% to 35% [9,10,17] . These effectswere associated with signicant reversal of ven-tricular remodeling [18,19].

Excessive blockade of the sympatheticnervous system

The association between the degree of sympa-

thetic activation and mortality [6,20] and dose-dependent favorable effects of beta-blockers on

* Corresponding author. Veterans AdministrationMedical Center, Cardiology 111-C, 1 Veterans Drive,Minneapolis, MN 55417.

E-mail address: [email protected] (I.S. Anand).

0733-8651/08/$ - see front matter. Published by Elsevier Inc.doi:10.1016/j.ccl.2008.01.001 cardiology.theclinics.com

Cardiol Clin 26 (2008) 5972
mailto:[email protected]://www.cardiology.theclinics.com/http://www.cardiology.theclinics.com/mailto:[email protected]


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left ventricular (LV) ejection fraction and mortal-ity [21] raised the possibility that a more com-plete adrenergic blockade might produce evengreater benet on outcomes. Moxonidine, a cen-trally acting a -agonist that greatly reduces circu-lating catecholamines [22], was used to test thishypothesis in the Moxonidine in Congestive HeartFailure trial [23]. The study had to be terminatedearly, with only 1,934 of the 4,533 subjects ran-domized because of a 38% higher mortality inthe moxonidine group. Hospitalizations for HFand myocardial infarctions were also increased.The increase in mortality and morbidity was ac-companied by signicant decrease in plasmanorepinephrine by moxonidine ( 18.8%) as com-pared with placebo ( 6.9%) [23]. It is likely that

the marked sympatholytic effects of moxonidinecould have produced severe myocardial depres-sion, bradycardia, or hypotension, though thiscould not be documented in the subjects whodied. Data on ventricular remodeling is not avail-able from that study.

Another example of the association betweenmarked sympatholytic effect and adverse out-comes was seen in a subgroup of patients in theBeta-blocker Evaluation of Survival trial (BEST)[24], which is the only beta-blocker HF trial thatfailed to demonstrate mortality benet. This couldbe related to the marked sympatholytic effects of bucindolol, not seen with carvedilol or metopro-lol. In BEST, subjects receiving bucindolol, whohad a decrease in norepinephrine of greater than224 pg/mL from baseline to 3 months, hada 169% increase in mortality when comparedwith subjects who had no signicant change innorepinephrine [25].

These two examples underscore the fact thatsevere decrease in adrenergic support may renderthe body devoid of any compensatory mecha-

nisms, resulting in adverse outcomes. Therefore,a more comprehensive blockade of the adrenergicnervous system is not a viable strategy.

Blockade of the renin-angiotensin-aldosteronesystem

The benecial effects of blocking the renin-angiotensin system with ACE-I in symptomaticand asymptomatic heart failure [7,8,26] and inpatients with post myocardial infarction and LVdysfunction [2729] is also associated with attenu-ation of ventricular remodeling [30,31]. Woulda more complete blockade of the renin-angiotensinsystem provide further benet?

Effect of high-dose versus low-dose ACE-I in heart failure

Two studies have compared the effects of low-versus high-dose ACE-I in patients with moderate

to severe HF. The ATLAS (Assessment of Treat-ment with Lisinopril And Survival) study ran-domly assigned 3,164 subjects with NYHA classII to IV HF and an ejection fraction less than orequal to 30% to either low doses (2.5 mg to 5.0 mgdaily) or high doses (32.5 mg to 35 mg daily) of the ACE-I lisinopril for a median of 45.7 months[32]. When compared with the low-dose group,subjects in the high-dose group had a nonsigni-cant 8% lower risk of death ( P .128) but a signif-icant 12% lower risk of death or hospitalizationfor any reason ( P .002), and 24% fewer hospi-talizations for HF ( P .002).

The second study was much smaller andcompared a very high dose of enalapril (average42 mg plus or minus 19.3 mg per day) with usualdose (average 17.9 mg plus or minus 4.3 mg perday) and could not nd any benet of high-doseACE-I [33]. This relative lack of benecial effectwith excessive blockade of ACE could be re-lated to the phenomenon of angiotensin II andaldosterone escape seen with the use of ACE-I,despite complete blockade of ACE. Tang and col-

leagues [34] have shown that whereas high-doseenalapril (40 mg per day) caused a much greatersuppression of serum ACE activity, levels of an-giotensin and aldosterone remained elevated tothe same extent in both the high- and low-doseACE-I groups. Thus, high doses of ACE-I pro-duce only minimal or no incremental benet butare associated with more adverse side effects.

Effect of dual ACE-I and angiotensin receptorblockers in heart failure

Because physiologically active levels of angio-tensin II persist despite chronic ACE inhibitortherapy [35,36], three separate studies, Val-HeFT(Valsartan Heart Failure Trial) [12], CHARM(Candesartan in Heart failure: Assessment of Re-duction in Mortality and Morbidity) [3740], andthe Valsartan In Acute Myocardial Infarction [41]trials were undertaken to determine whether an-giotensin receptor blockers (ARB) could furtherreduce morbidity and mortality in patients al-ready receiving an ACE-I. Val-HeFT showedthat the addition of valsartan to ACE-I did notreduce mortality, but caused a 28% reduction inhospitalizations for HF. However, in the 7% of subjects not receiving an ACE-I at baseline,

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a highly signicant 41% reduction in mortalitywas seen [42]. The CHARM study later conrmedthese ndings with the use of candesartan [3740].Were the benecial effects accompanied by im-provement in LV structure and function? Indeed,use of valsartan in Val-HeFT was associated withimprovement in LV remodeling in all subgroupsof subjects except those receiving both ACE-Iand beta-blockers at baseline, in whom additionof valsartan was not associated with any benet,and this was associated with a neutral effect onremodeling [43].

Role of aldosterone receptor antagonists

Aldosterone may contribute to structural re-modeling of the LV through its effects on theextracellular matrix, collagen deposition, myocar-dial brosis, and some other unique mechanisms[4446]. Aldosterone is also important in the path-ogenesis of salt and water retention in heart fail-ure [47]. The Randomized Aldactone EvaluationStudy showed a 30% reduction in mortality withspironolactone in subjects with advanced HF[11]. More recently, the Eplerenone Post-AcuteMyocardial Infarction Heart Failure Efficacyand Survival study has conrmed in a postmyocar-

dial infarction population the efficacy of analdosterone inhibitor, in this case eplerenone, inreducing mortality in patients receiving ACEinhibitors or beta-blockers [48]. Spironolactonehas also been shown to attenuate ventricular re-modeling after myocardial infarction [49]. Thus,the benecial effects of aldosterone receptorblockade on mortality are also associated withbenecial effects on LV remodeling.

Nitrates and hydralazine

Nitric oxide regulates cardiovascular pro-cesses, including myocardial hypertrophy andremodeling, as well as vascular function, inam-mation, and thrombosis [5054]. Substantial evi-dence exists that endothelial dysfunction andimpaired bioavailability of nitric oxide occur inboth ischemic and nonischemic models of HFand contribute to the pathophysiology of conges-tive HF [5558]. Basal release of nitric oxide is de-creased in HF [59] and the sensitivity to inhibitionof nitric oxide synthase is increased [60]. Evenbefore nitric oxide was discovered, the rst Vaso-dilator Heart Failure Trial (V-HeFT I) [61]demonstrated the benet of combining the nitric

oxide donor isosorbide dinitrate with the antioxi-dant hydralazine in patients with mild-to-severeHF. The African American Heart Failure Trial(A-HeFT) conrmed the ndings in V-HeFT I,even on top of ACE-I and beta blockers [62].Once again, the mortality benet with an isosor-bide hydralazine combination was accompaniedby regression of LV remodeling [61,63,64] .

Role of endothelin antagonists

Like norepinephrine and angiotensin II, endo-thelin (ET)-1 also plays a pivotal role in cardio-vascular regulation [65,66]. Plasma concentrationsof ET-1 and big ET-1 are elevated in HF [67,68]

and are independent predictors of mortality [69].In advanced HF, ET A receptors and endothelin-converting-enzyme-1 are up-regulated [70]. Ina rat model of HF, ET A -blockade improves sur-vival [71]. Both ET A selective (darusentan), andmixed ET A/B receptor antagonists (bosentan) ap-peared promising because single-dose administra-tion of these agents increased cardiac output andreduced systemic and pulmonary vascular resis-tance in patients with severe congestive HF[72,73]. In the Research on Endothelin Antago-nism in Chronic Heart Failure (REACH-1) trial[13], bosentan caused early worsening of HF buttended to improve symptoms at 6 months, sug-gesting a possible long-term benet. REACH-1was terminated prematurely because of a reversibleincrease in liver transaminases.

Because the nonselective ET A/B receptor antag-onist bosentan did not show any long-term bene-cial effects in HF, and because selective ET Breceptor blockade worsens hemodynamics inpatients with HF [74], a selective ET A receptor an-tagonist was postulated to be more effective than

the mixed ET A/B . The EndothelinA Receptor An-tagonist Trial in Heart Failure investigated thechronic effects of different doses of the orally ac-tive ET A -antagonist darusentan in 642 subjectswith NYHA class II to IV HF. Over 98% of thesesubjects were receiving ACE-I or ARB and 80%beta-blockers. The primary endpoint was a changein LV end-systolic volume at 24 weeks, comparedwith baseline, measured by magnetic resonanceimaging. Secondary endpoints included changesin LV mass, LV end-diastolic volume, ejectionfraction, neurohormones, 6-minute walk test,quality of life, and NYHA class. Darusentan didnot provide any clinical benet, and there wasno signicant change in the primary endpoint of

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LV end systolic volume or the other endpoints.Worsening HF was observed in 11.1% of the subjects, and 4.7% of the subjects died during the6 month study, with no difference between groups.Darusentan had no adverse effects on neurohor-mones, heart rate or blood pressure [16]. Thus,the use of selective or nonselective endothelinreceptor inhibitors also does not seem to addany incremental benet in patients adequatelytreated with beta-blockers and ACE-I, possiblybecause they could not attenuate or reverse LVremodeling.

Dual angiotensin converting enzyme and neutralendopeptidase inhibition

According to the NH model of the progressionof HF, blocking the deleterious effects of thevasoconstrictive hormones and stimulating thevasodilators are likely to have benecial effectson hemodynamics, LV remodeling, and survival.Because a majority of the circulating brain natri-uretic peptide (BNP) is cleared by neutral endo-peptidases (NEP), the dual ACE and NEPinhibitor omapatrilat was used to test the hypoth-esis of blocking the renin-angiotensin system andincreasing BNP. The OVERTURE (Omapatrilat

Versus Enalapril Randomized Trial of Utility inReducing Events) trial compared the effects of enalapril (20 mg per day) and omapatrilat (40 mgper day) in 5,770 subjects with NYHA class II toIV HF [14]. The primary endpoint of death andhospitalization for HF was not different in theenalapril and omapatrilat groups, but the studyfullled the prespecied criteria of noninferiorityfor omapatrilat. Omapatrilat however, did reducethe combined risk of cardiovascular deaths orhospitalization by 9% ( P .024). Although theevent rate in these high-risk subjects was high,lack of incremental benet may have been relatedto signicant episodes of hypotension during theperiod of drug up-titration. Thus, the OVER-TURE trial with dual ACE and NEP inhibitionis another example of how excessive use of NH in-hibition may result in signicant hypotension,again emphasizing that lack of attenuation of LV remodeling may be responsible for the lackof benecial effects on outcomes.

Role of cytokine inhibitionProinammatory cytokines, including tumor

necrosis factor (TNF)- a , interleukin (IL)-1, and

IL-6, are overexpressed in HF and are involvedin the progression of the disease [75]. Twoapproaches were used to antagonize the proin-ammatory cytokine TNF- a in patients withHF-soluble TNF receptors and monoclonalantibodies.

Soluble tumor necrosis factor receptors

The rst approach involved the use of etaner-cept (Enbrel), a genetically engineered recombi-nant human TNF receptor protein that binds tocirculating TNF- a , and prevents TNF- a frombinding to TNF receptors on target cell surface.Early preclinical studies showed that etanerceptreversed the deleterious negative inotropic effects

of TNF in vitro [76] and in patients with moderateto severe HF. These short-term studies in smallnumbers of subjects showed improvements inquality of life, 6-minute walk distance, and LVejection fraction after 3 months treatment withetanercept [77,78].

These encouraging ndings lead to the designof two multicenter clinical trials in subjects withNYHA class III to IV HF: the RENAISSANCE(Randomized Etanercept North American Strat-egy to Study Antagonism of Cytokines) study(n 900) in the United States, and the RECOVER(Research into Etanercept Cytokine Antagonismin Ventricular Dysfunction) study ( n 900), inEurope and Australia. Both trials had parallelstudy design but differed in the doses of etanerceptthat were used: RENAISSANCE used doses of 25 mg twice a week and 25 mg three timesa week, whereas RECOVER used doses of 25 mgonce a week and 25 mg twice a week. The primaryendpoint of these trials was a clinical composite.A third trial, termed Randomized EtanerceptWorldwide Evaluation (RENEWAL) ( n 1,500)

pooled the data from the RENAISSANCE (twiceand three times a week dosing) and RECOVER(twice a week dosing only), and had all-cause mor-tality and hospitalization for heart failure as theprimary endpoint. The Data Monitoring SafetyBoard stopped the studies early because it wasfelt that the studies were unlikely to show a benetin the primary endpoints if allowed to be com-pleted [79]. Preliminary analysis of the data showedno benet for etanercept on the clinical compositeendpoint in RENAISSANCE and RECOVER,nor a benet for etanercept on all-cause mortalityand HF hospitalizations in RENEWAL [80].

In a post hoc analysis, however, the hazardratios for death or hospitalization for worsening

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HF in subjects taking the twice a week dose of etanercept in RECOVER, was 0.87, as comparedto 1.21 and 1.23 for the subjects in RENAIS-SANCE receiving etanercept twice a week andthree times a week, respectively. These disparitiesin study ndings were considered to be relatedto the different length of follow-up in the twostudies. Subjects in RECOVER received etaner-cept for a median time of 5.7 months, whereassubjects in RENAISSANCE received etanerceptfor 12.7 months [4]. This suggests that the longerthe exposure to the drug, the worse the outcome.

Monoclonal antibodies

The second approach involved the use of

a genetically engineered monoclonal antibodyiniximab (Remicade) in the Anti-TNF a TherapyAgainst Chronic Heart Failure (ATTACH)phase II study in 150 subjects with moderate toadvanced HF. The primary endpoint of theATTACH trial was also the clinical compositescore. Subjects were randomized to receive threeseparate intravenous infusions of iniximab(5 mg/kg or 10 mg/kg) at baseline, 2, and 4 weeks.Assessment of the clinical composite was made at14 and 28 weeks. Analysis of the completed studydata showed that there was a 21% dose-relatedincrease in death and HF hospitalizations withiniximab when compared with placebo at14 weeks, and a 26% increase at 28 weeks [81].

Therefore, a careful examination of these twostudies shows that anticytokine strategies target-ing TNF- a were not neutral, but the results areindeed consistent with a trend of increasedmortality and morbidity. Two possible explana-tions have been offered to clarify these ndings[4]. The rst is that iniximab and etanercepthave intrinsic cytotoxicity. Iniximab exerts its

effects, at least in part, by xing complement incells that express TNF. Because myocytes expressTNF on sarcolemma, complement xation in theheart could lead to myocyte lysis and further de-terioration of cardiac function. Etanercept mayalso be toxic under certain settings. It has beenshown in human studies that etanercept bindsto TNF in the peripheral circulation, but thisbinding is not tight and may dissociate at anextremely fast rate. Rapid dissociation of TNFfrom etanercept can lead to a paradoxical in-crease in the duration of TNF bioactivity, oppo-site of what the therapy was intended to do. Thesecond explanation for worsening HF may be re-lated to the fact that physiologic levels of TNF

are cytoprotective and play an important rolein tissue remodeling and repair. Excessive antag-onism of TNF may, therefore, result in the lossof one or more of its benecial effects, with con-sequent loss of homeostasis and resulting inworsening HF. Moreover, the RENAISSANCEMRI remodeling substudy also showed a neutraleffect of etanercept on LV structure andfunction.

Immune modulation therapy

Recently, a novel approach to regulate in-ammatory cytokines in the blood has beendeveloped. In this approach, a patients blood isexposed to controlled oxidative stress in a special

device (Celacade) and subsequently administratedintramuscularly. Preliminary experimental studieshave demonstrated that this approach may down-regulate proinammatory cytokines and activateseveral anti-inammatory cytokines. The hypoth-esis was tested in the ACCLAIM (AdvancedChronic heart failure Clinical Assessment of Immune Modulation therapy) study [82], a multi-center, randomized, double-blind, placebo-controlled clinical trial in 2,408 NYHA class IIto IV HF subjects with LV ejection fraction of 30% or less. The primary endpoint of the studywas the combined endpoint of total mortality orcardiovascular hospitalization. Subjects in theACCLAIM trial were well treated with diuretics(94%), ACE-I (94%), beta blockers (87%), auto-matic implantable cardioverter debrillators(26%), and cardiac resynchronization therapy(10.5%). Although the primary endpoint wasnot different in the placebo and immune modula-tion therapy groups ( P .22), a prespeciedsubgroup analysis in 689 NYHA class II patientsshowed that Celacade immunotherapy reduced

the risk of mortality or cardiovascular hospitaliza-tions by 39% ( P .0003) [83], suggesting that thistherapy might be effective in patients who havenot reached more advanced stages of HF. Thequality of life in the entire study population wassignicantly improved in the Celacade group(P .04). The procedure was well tolerated,with no signicant between-group differences forany serious adverse events. A conrmatory studyin NYHA class II patients is being planned.

Vasopressin antagonismArginine vasopressin (AVP) activity is in-

creased or inappropriately elevated in patients



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with HF and contributes to uid retention andhyponatremia [84,85]. Whereas vasopressin V 1Areceptors primarily mediate vasoconstriction, di-rect positive inotropic and mitogenic effects, theV2 receptors inhibit free water clearance (aquare-sis). Agents that antagonize V 1A receptors wouldbe expected to reduce vascular tone and the directmitogenic myocardial effects of AVP. Because V 2antagonists increase aquaresis, the addition of anAVP V 2 antagonist to standard therapy in pa-tients with congestive HF could represent a novelmechanism to improve free water clearance, thusdecreasing the need for diuretic therapy, improv-ing diuretic resistance, reducing the frequency of hyponatremia, and attenuating disease progres-sion. Four agents, three oral selective V 2 antago-

nists (tolvaptan, lixivaptan, and satavaptan), andone intravenous dual AVP V 1A /V 2 antagonist(conivaptan) are under investigation in both HFand hyponatremia. The eld has advanced morein hyponatremia, where conivaptan has alreadyreceived United States Food and Drug Adminis-tration approval for intravenouos administrationin hospitalized patients with euvolemic or hyper-volemic hyponatremia [86].

Tolvaptan has the largest database in HF.Phase II trials have shown that use of tolvaptanis associated with an early and sustained reductionin body weight over 7 to 30 days, consistent withinhibition of an active V 2 receptor-mediated effecton uid retention. Patients lost weight during therst few days of therapy, but no further weightchange was seen thereafter, despite the drug beingcontinued. Tolvaptan administration also tendedto normalize serum sodium concentrations in pa-tients with baseline hyponatremia and was not as-sociated with hypokalemia [87,88].

Based on these results, the EVEREST (Efficacyof Vasopressin Antagonism in Heart Failure

Outcome Study With Tolvaptan) study was de-signed to examine whether short-term and long-term blockade of the V 2 receptor with tolvaptan isbenecial in patients with HF and signs and symp-toms of volume overload. The results conrmedthat tolvaptan, when added to standard therapyincluding diuretics, improves many d though notalld of the signs and symptoms of HF, as assessedby both subjects and physicians. The reductions inbody weight in response to tolvaptan on day 1were accompanied by signicant improvementsin subject and physician-assessed dyspnea, orthop-nea, fatigue, jugular venous distention, rales, andedema, showed improvements on day 1 and re-mained better than placebo during the rst

3 days or longer. However, despite the improve-ment in signs and symptoms of HF, no benet inglobal clinical status was seen at day 7 or dis-charge. These effects were achieved withoutadversely affecting heart rate, blood pressure, orserum electrolytes, and there was no excess of renalfailure. Over the long-term, however, tolvaptantreatment had no effect, either favorable or unfa-vorable, on all-cause mortality or the combinedendpoint of cardiovascular mortality or subse-quent hospitalization for worsening HF [15]. Thedrug also had no signicant effect on long-termLV remodeling in patients with mild to moderateHF with LV ejection fraction less than 30% [89].

Because selective blockade of the AVP V 2 re-ceptor may cause unopposed activation of the

V1A receptor, leading to the deleterious conse-quences of systemic and coronary vasoconstric-tion, a dual V 1A /V 2 antagonist might be moreeffective in HF. Although small phase II trialshave shown improvement in hemodynamics andurine output after a single intravenous dose of conivaptan [90], no long-term outcome data areavailable. Thus, although AVP antagonists mightbe useful in acute HF with or without diuretics, itis unlikely they will have an important role in themanagement of HF.

Calcium sensitizers

Calcium sensitizers are a new class of inotropicdrugs. They improve myocardial performance bydirectly acting on contractile proteins withoutincreasing intracellular calcium load. Thus, theyavoid the undesirable effects of arrhythmias andincrease in myocardial oxygen consumption asso-ciated with increased intracellular calcium thatoccurs with other inotropic agents, such ascatecholamines and phosphodiesterase-III (PDE)

inhibitors.Two calcium sensitizers have been investigatedin patients with HF. Pimobendan, a calciumsensitizer that also exerts a signicant inhibitionof PDE at clinically relevant doses, signicantlyincreased exercise duration, peak oxygen con-sumption per unit time (VO 2), and quality of lifein 149 patients with moderate to severe HF,over a 12-week period [91]. Its further develop-ment has, however, been stopped because of possible deleterious effects on mortality. Levosi-mendan is a calcium sensitizer with no majorinhibition of PDE at clinically relevant doses. Italso opens adenosine triphosphate-dependentpotassium channels and has vasodilating and

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cardioprotective effects. In HF patients, levosi-mendan causes a dose-dependent increase incardiac output and a decrease in pulmonarycapillary wedge pressure. Because levosimendanhas an active metabolite, OR-1896, with a half-life of about 80 hours, the duration of the hemo-dynamic effect signicantly exceeds the 1-hourhalf-life of the parent compound. Threemoderate-sized phase II clinical trials (LIDO,RUSSLAN, and CASINO) tested the effects of levosimendan in patients with acute decompen-sated HF.

Both the RUSSLAN [92] and LIDO [93] trialsshowed that levosimendan was safe and reducedmortality when compared with placebo anddobutamine, respectively. The results of the

CASINO trial [94] have been presented at theAmerican College of Cardiology meeting in 2004but not published. In this trial, levosimendanalso improved survival, compared with dobut-amine or placebo, in subjects with acute decom-pensated HF. These studies were performed insubjects with high lling pressures. In contrast,the two large mortality and morbidity studies(SURVIVE and REVIVE-II) in patients whowere hospitalized because of worsening HF didnot require lling pressures to be measured.

The SURVIVE (Survival of Patients WithAcute Heart Failure in Need of IntravenousInotropic Support) trial was a randomized, dou-ble-blind trial comparing the efficacy and safety of intravenous levosimendan ( n 664) or dobut-amine ( n 663) in subjects hospitalized with acutedecompensated HF who required inotropic sup-port [95]. The primary outcome of all-cause mor-tality at 180 days was no different, with 26%deaths in the levosimendan group and 28% deathsin the dobutamine group ( P .40). The other sec-ondary endpoints (all-cause mortality at 31 days,

number of days alive and out of the hospital, pa-tient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortalityat 180 days) were also not different. There wasa higher incidence of cardiac failure in the dobut-amine group, but a higher incidence of atrial -brillation, hypokalemia, and headache in thelevosimendan group. Because levosimendan wascompared with dobutamine, which is known to in-crease mortality, a neutral trial raises concernsabout the safety of levosimendan.

The REVIVE-II trial was presented at theAmerican Heart Association scientic sessions in2005 and reported a superior effect of levosimen-dan on the composite primary outcome,

compared with placebo [96]. However, the detailshave yet to be published. Thus, until the results of REVIVE-II can be fully scrutinized and placed inthe context of all available evidence, we will haveto conclude that levosimendan does not havea place in either acute or chronic HF.

Novel agents and approaches under investigation

A number of other and novel agents are beingactively investigated, but only a few have reachedthe stage of testing in phase III clinical trials.

Hydroxymethylglutaryl coenzyme-A reductaseinhibitors in heart failure

Hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors (statins) are widelyused to modify the lipid prole for primary andsecondary prevention of cardiovascular disease.Increasing attention has recently focused on otherpotentially favorable pleiotropic effects thatmay apply in the setting of HF [97]. Statins havebeen shown to induce angiogenesis by recruitingbone marrow stem cells [98], reducing levels of in-ammatory factors, and improving endothelialfunction [99,100]. On the other hand, epidemio-logic studies have observed a higher risk of adverse events with low levels of low-density lipo-protein cholesterol in patients with HF [101,102] .Statins may diminish the ability of lipoproteinsto bind endotoxins, leading to stimulation of proinammatory cytokines [103], and reducedlevels of coenzyme Q10 [104] and selenoproteins[105], which could adversely affect cardiac muscleand function. They also have deleterious interac-tions with medications commonly used for HF,such as digoxin [106].

Go and colleagues [107] evaluated the associa-

tion between initiation of statin therapy and risksfor death and hospitalization among 24,598 adultsdiagnosed with HF who had no prior statin use,and found that incident statin use was indepen-dently associated with lower risks of death andhospitalization among patients with or withoutcoronary heart disease [107]. Several post-hocsubgroup analyses of clinical trials have foundthat use of statin therapy was associated withimproved survival in patients with ischemic andnonischemic HF [108,109] . However, a recentlypublished CORONA trial (Controlled Rosuvasta-tin Multinational Study in Heart Failure) foundno effect of rosuvastatin on the primary compositeoutcome of death from cardiovascular causes,



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nonfatal myocardial infarction, or nonfatal strokein 5,011 older subjects with systolic heart failure[110]. The GISSI-HF trial (Gruppo Italiano perlo Studio della Sopravvivenza nellInfarto Micar-dico Heart Failure) is currently investigatingthe effects of rosuvastatin and n-3 polyunsatu-rated fatty acids on mortality and morbidity in7,000 subjects with NYHA class II to IV HF of any etiology [111]. The results are expected in2008 or 2009.

Anemia and heart failure

Anemia is common in patients with HF and isan independent risk factor for worse outcomes[101,112114] . Although the pathogenesis of ane-

mia in patients with HF is unclear, several mech-anisms have been implicated. Impaired renalperfusion with decreased erythropoiesis is proba-bly an important factor. However, there is evi-dence that erythropoietin levels are increased inHF [115,116] , suggesting a relative erythropoietinresistance in this condition. Inammation has alsobeen implicated: TNF- a and several other proin-ammatory cytokines [117], and circulating neu-trophils and C-reactive protein, are elevated inHF patients [118]. TNF- a may cause anemia bya number of mechanisms, including inhibition of erythropoietin production in the kidney, prevent-ing erythropoietin from stimulating bone marrowproduction of erythrocytes and preventing therelease of iron from body stores [119]. ACE-inhib-itors [120] and angiotensin receptor blockers [114]used in the treatment of HF cause a modest reduc-tion in hemoglobin, probably by inhibiting eryth-ropoietin synthesis, and may contribute to thedevelopment of anemia [121]. Although hematinicabnormalities are generally not seen in HF [122],iron deciency may be common [123] because of

impaired metabolism in HF-associated cachexia[124] and aspirin-induced gastrointestinal bleed-ing. Finally, hemodilution, because of the increasein plasma volume, has been found to be the causeof anemia in nearly half the patients with severeend-stage HF [125]. Thus, multiple mechanismscould cause anemia in patients with HF.

Should we treat anemia in patients with HF?Several small uncontrolled studies have shownthat treatment of anemia with erythropoietin wasassociated with improvements in LV ejectionfraction, peak oxygen consumption, NYHA func-tional class, and a decrease in diuretic requirement[126128] . However, blood transfusions to in-crease hemoglobin are associated with an increase

in systemic vascular resistance and blood pressure,and a decrease in cardiac output [129,130] . In pa-tients with chronic kidney disease (CKD) under-going hemodialysis, raising hematocrit witherythropoietin was associated with an increase inadverse cardiovascular events [131]. More re-cently, the CHOIR (Corrections of Hemoglobinand Outcomes in Renal Insufficiency) trial showedthat treating CKD patients not on hemodialysis,with epoetin alfa targeted to achieve a hemoglobinlevel of 13.5 g/dL versus 11.3 g/dL, was associatedwith increased risk of the composite of death,myocardial infarction, hospitalization for conges-tive HF, and stroke (hazard ratio, 1.34; 95% con-dence interval, 1.03 to 1.74; P .03) [132]. Thesendings therefore raise important concerns about

the optimal level of hemoglobin and whetherhemoglobin should be raised in patients with HF.Recently, the results of STAMINA-HeFT

(Study of Anemia in Heart FailureHeart FailureTrial), the largest multicenter, randomized, dou-ble-blind, placebo-controlled trial to date evalu-ating the effect of treating anemia in HF wasreported [133]. In this study, 319 subjects withsymptomatic HF, LV ejection fraction less thanor equal to 40%, and hemoglobin greater thanor equal to 9.0 g/dL and less than or equal to12.5 g/dL, were randomized to placebo or darbe-poetin alfa subcutaneously every 2 weeks for1 year, to achieve a target hemoglobin of 14.0 g/dL plus or minus 1.0 g/dL. The primary endpointwas change from baseline to week 27 in treadmillexercise duration. Secondary endpoints werechange from baseline in NYHA class and qualityof life at week 27. All cause mortality or rst HFhospitalization and all-cause mortality at 1 yearwas a prespecied efficacy and safety endpoint.At baseline, the median and interquartile range(IQR) hemoglobin was 11.4 (10.9, 12.0) g/dL. At

week 27, darbepoetin alfa treatment increased me-dian (IQR) hemoglobin by 1.80 (1.1, 2.5) g/dL(placebo: 0.3 ( 0.2, 1.0) g/dL; P ! .001). Darbe-poetin alfa treatment did not signicantly improveexercise duration, NYHA class, or quality of lifescore compared with placebo. A nonsignicanttrend was observed toward a lower risk of all-cause mortality or rst HF hospitalization at1 year in darbepoetin alfa-treated subjects, com-pared with placebo (hazard ratio 0.68; 95% con-dence interval 0.43, 1.08; P .10). Adverse eventswere similar in both treatment groups. The trendof a lower risk of morbidity and mortality, andthe safety results of this study have encouragedthe conduct of an adequately powered outcome

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trial RED-HF (Reduction of Events with Darbe-poetin in Heart Failure Trial) for the treatmentof anemia in HF. The results of the trial maynot be known until 2010.

Summary

Inhibiting the deleterious consequences of activated renin-angiotensin-aldosterone and sym-pathetic systems with ACE-inhibitors, beta-blockers, and aldosterone receptor antagonistshave had an enormous impact on reducing HFmortality and morbidity. These agents currentlycomprise the standard of care of HF treatment.However, extending this paradigm to other acti-vated NH and cytokine systems by stackingmultiple NH blockers together has not shownany incremental benet, and may have deleteriousconsequences. It must be recognized that all newtherapies for HF have to be tested on incrementalbenet above the effects achieved by the stan-dard of care therapies. There is, therefore, noway to assess whether newer therapies are aseffective, or indeed even more effective than eitherACE-inhibitors, beta-blockers, or aldosteroneblockers. Hence, the disappointing results of recent HF trials is no reection on the soundness

of the neurohormonal hypothesis nor on theeffectiveness of the drug being tested, but ratheron the strategy of stacking newer drugs on top of the standard of care.

Another fact that needs to be emphasized isthat treatment with the standard of care medica-tions and use of devices have resulted in very lowmortality rates in clinical trials, which may bedifficult to improve upon. Testing the neweragents in higher risk patients may have yieldeddifferent results. This notwithstanding, there arenumerous examples where clear-cut deleteriousconsequences of excessive NH and cytokine in-hibition are seen. These ndings underscore thefact that not all of the bodys responses in HF areharmful and need to be blocked. Hence, it doesappear that we may have reached a therapeuticceiling for the neurohormonal approach. Thus,further improvement in the management of HFpatients may require new paradigms.

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