Frontiers of Therapy for Patients With Heart FailureStanley S. Liu, MD, Jennifer Monti, MD, Hamid M. Kargbo, MD, MPhil, Muhammad W. Athar, MD,Kapil Parakh, MD, MPH, PhD
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.
Heart failure affects 5.7 million people in the United States,accounting for approximately 1 million admissions and 1 in9 deaths annually.1 The rapid evolution of evidence in thefield poses a major challenge to providers, and this reviewaims to provide a general framework within which to con-sider the literature and understand the frontiers of therapy.
CLASSIFICATION OF HEART FAILUREHeart failure, defined as the inability of the heart to pumpenough blood to meet the body’s demands, is a heteroge-neous condition that cannot be approached with homoge-nous therapies. Classification systems help characterize thisheterogeneity and include the New York Heart Association(NYHA) classification (based on symptoms and used inclinical trial enrollment criteria) and American College ofCardiology staging (stage A: risk factors for heart failure;stage B: asymptomatic structural heart disease; stage C: symp-
Funding: None.Conflict of Interest: None.Authorship: All authors had access to the data and played a role in
writing this manuscript.Requests for reprints should be addressed to Kapil Parakh, MD, MPH,
PhD, Director of Heart Failure, Johns Hopkins Bayview Medical Center,
tomatic heart failure; and stage D: refractory to medical ther-apy requiring consideration for transplant, mechanical support,or hospice). Classification defined by left ventricular ejectionfraction is based on the prevalence of heart failure with pre-served ejection fraction or diastolic heart failure2 and its lack ofresponse to systolic heart failure therapies.3
Acute heart failure is increasingly recognized as a dis-tinct syndrome for which management emphasizes hemo-dynamics (Figure 1), unlike chronic heart failure for whichneurohormonal modulation is key.4 The Evaluation Study ofCongestive Heart Failure and Pulmonary Artery Catheter-ization Effectiveness (ESCAPE) trial demonstrated that theroutine use of pulmonary artery catheters was not associatedwith improved outcomes,5 and clinical evaluation was ef-ective in ascertaining hemodynamic profiles.
Risk stratification of acute heart failure is evolving butags behind analogous work in acute coronary syndromes.isk scores have been developed from large registries (eg,lood urea nitrogen � 43 mg/dL, systolic blood pres-ure � 115 mm Hg, creatinine � 2.5 mg/dL, age, and heartate predicted mortality).6 Biomarkers, such as mid-regionro-atrial natriuretic hormone and MR-adrenomedullin,7
may improve these algorithms. Much interest lies in brain
natriuretic peptides and N-terminal pro-brain natriuretic
peptides, which are sensitive (but not specific) for a diag-nosis of heart failure8 and may have a role in risk stratifi-ation and management.
TREATMENT OF HEARTFAILURE
Pharmacologic TherapyMedical management of heart fail-ure involves treatment of volumeoverload for symptom relief anddisease modification to reducemortality.
Diuretic TherapyLoop diuretics are used as a first-line treatment for symptomatic re-lief of volume overload in heartfailure with the addition of thiazidediuretics in resistant patients.9 Therere no placebo-controlled trials, andew studies have examined the ef-ectiveness of diuretic therapy, withhe exception of the landmark Di-retic Optimization Strategies Eval-ation (DOSE) trial.10 This trialhowed comparable safety and effi-acy for furosemide given as a con-inuous infusion or bolus dose inatients with acute heart failure. In this trial, high-dose furo-emide caused greater diuresis, somewhat faster relief of symp-oms, and transient worsening of renal function. Overall out-omes were comparable between high- and low-dose groups.ore studies are needed to explore the effectiveness of diuret-
cs individually and in combination.
UltrafiltrationVenovenous ultrafiltration is an alternative therapy for thetreatment of volume overload that has historically beendone through hemodialysis. Recent advances have permit-ted ultrafiltration through a peripheral intravenous line thatis safe and may be effective at reducing rehospitalization,resulting in approval of the device for diuretic-resistantpatients.11 Ongoing studies are further defining the role ofultrafiltration.
Renin-Angiotensin-Aldosterone SystemInhibitionRenin-angiotensin-aldosterone system inhibition by angio-tensin-converting enzyme inhibitors, angiotensin receptorblockers, and aldosterone antagonists forms a cornerstoneof chronic systolic heart failure therapy. The landmark CO-operative North Scandinavian Enalapril Survival Study(CONSENSUS) demonstrated that angiotensin-convertingenzyme inhibition in NYHA class IV patients3 provided a
CLINICAL SIGNIF
● Heart failure is ation for which evaries based on sdynamic classific
● Neurohormonalcornerstone of trdiastolic, heart f
● Frontiers of heartfrom advances inmedical engineer
● Integrating bothevidence into theure patients willpatients receivecare
40% relative risk reduction in mortality compared with
placebo (number needed to treat [NNT] � 6) at 6 months).The Studies Of Left Ventricular Dysfunction (SOLVD) trialconfirmed the benefit of angiotensin-converting enzyme in-hibitors in class NYHA II and III patients with a relativerisk reduction of 16% (NNT � 22) over 41 months.3 The
Candesartan in Heart Failure(CHARM) trials demonstratedthat angiotensin receptor blockersprovide comparable benefits in pa-tients intolerant to angiotensin-converting enzyme inhibitors,3
but no supplemental benefitfrom combination angiotensin-converting enzyme and angiotensinreceptor blocker therapy.12
The Randomized ALdactoneEvaluation Study (RALES) trialdemonstrated the benefit of addingan aldosterone antagonist to ang-iotensin-converting enzyme inhi-bition in patients with systolicheart failure, with a 30% relativereduction in mortality (NNT � 9)over 24 months.3 The EplerenonePost–acute myocardial infarctionHeart failure Efficacy and SUrvivalStudy (EPHESUS) extended thisfinding to patients with mild leftventricular systolic dysfunction
after myocardial infarction with a 15% relative risk reduc-tion (NNT � 44) over 16 months.3 More recently, the Epler-enone in Patients with Systolic Heart Failure and MildSymptoms (EMPHASIS) trial found a 24% relative riskreduction in mortality (NNT � 33) at 21 months.13 How-ever, the benefits of aldosterone antagonism must be coun-terbalanced by the risk of fatal hyperkalemia.14
The role of the novel renin-angiotensin-aldosterone sys-tem inhibitors aliskiren15 and neprilysin16 in treating heartfailure is under investigation. In addition, the role of renin-angiotensin-aldosterone system inhibition in heart failurewith preserved ejection fraction is unclear, with large stud-ies on angiotensin-converting enzyme inhibitors17 and an-iotensin receptor blockers18 showing no mortality benefit.
Ongoing studies will determine the utility of aldosteroneantagonism in heart failure with preserved ejection fraction.
Sympathetic System ModulationInitially contraindicated in heart failure, beta-blockers are nowa cornerstone of therapy, based on mortality benefits in chronicsystolic heart failure: Carvedilol was associated with a 65%relative risk reduction (NNT�22),19 bisoprolol was associ-ted with a 56% relative risk reduction (NNT�18),3 andetoprolol succinate (not tartrate) was associated with a 66%
elative risk reduction (NNT�26),3 all with an average fol-low-up of approximately 1 year. These dramatic results haveprompted the study of other approaches to sympathetic mod-
CE
rogeneous condi-ce-based therapyomatic and hemo-.
lation forms theg systolic, but not.
re treatment rangermacology to bio-
blished and newment of heart fail-that heart failure
st evidence-based
ICAN
hetevidenymptation
modueatinailure
failupha
ing.
estatreat
ensurethe be
ulation, such as renal artery denervation.
abifv
ncfi
cstag
tAppc
s
baw
pt
8 The American Journal of Medicine, Vol 126, No 1, January 2013
VasodilatorsThe Vasodilator-Heart Failure Trial (V-HeFT) was one ofthe first randomized controlled trials in cardiology andshowed a reduction in mortality in patients randomized tohydralazine/isosorbide dinitrate versus prazosin or placebo,but this did not reach statistical significance.3 The Vasodi-lator-Heart Failure Trial II (V-HeFT II) trial followed andfound that the hydralazine/isosorbide dinitrate group had alower mortality than historical controls, but enalapril had aneven lower mortality.20 Subgroup analyses suggested a mor-tality benefit in self-identified black patients, which wasconfirmed prospectively in the African American HeartFailure Trial (A-HEFT), in which hydralazine/isosorbidedinitrate was associated with a relative risk reduction of43% (NNT � 25) in patients with systolic dysfunction al-ready receiving standard therapy.3 These data led to thepproval of a fixed-dose combination hydralazine/isosor-ide dinitrate pill for black patients. Studies are now ongo-ng to assess whether other groups (eg, those with heartailure with preserved ejection fraction) benefit from oralasodilator therapy.
Intravenous vasodilators, arterial (nitroprusside) and ve-ous (nitroglycerin), are used to treat acute heart failure butan cause hypotension, particularly in conditions with a
Figure 1 Hemodynamic profiles of heart failure. †Hot/Warm/Cold: This refers to vascular tone or systemic vascularresistance measured by a pulmonary artery catheter. Hot de-scribes excessive vasodilation (very low systemic vascular re-sistance) as occurs in sepsis, which can result in warm periph-ery and hypotension. Cold describes excess vasoconstriction asoccurs in cardiogenic shock, which can be accompanied byseemingly normal blood pressure, but manifest with signs ofpoor perfusion such as cool periphery, elevated lactate, orcreatinine. Vasopressors with inotropy (norepinephrine) orwithout (vasopressin or phenylephrine) are used to treat “hot”patients. “Cold” patients are treated with vasodilators withinotropy (milrinone or dobutamine) or without (nitroprusside,captopril, hydralazine). ‡Too Dry/Dry/Wet: This refers to thevolume status or pulmonary capillary wedge pressure measuredby a pulmonary artery catheter. “Wet” describes volume over-load, which is usually accompanied by elevated jugular venouspressure, edema, and rales. “Too dry” describes volume deple-tion, which is accompanied by low central venous pressure andpoor skin turgor. “Wet” patients are treated by removing excessvolume by diuretics or ultrafiltration, whereas “too dry” pa-tients are treated with fluids.
xed cardiac output, such as aortic stenosis, hypertrophic
ardiomyopathy, or right ventricular failure.21 Althoughtudies have demonstrated the hemodynamic benefits ofhese agents in systolic but not diastolic heart failure,3 therere little data on outcomes, and it is not clear which sub-roups benefit from this therapy.
Nesiritide, an intravenous natriuretic peptide and vasodila-or, has fallen in and out of favor over the last decade. Thecute Study of Clinical Effectiveness of Nesiritide in Decom-ensated Heart Failure (ASCEND-HF) study randomized 7141atients and found no mortality benefit of nesiritide over pla-ebo at 30 days.22 On this basis, nesiritide cannot be recom-
mended for routine use in the broad population with heartfailure, and studies are ongoing to identify groups that maybenefit.
InotropesInotropes increase myocardial contractility, and digoxin isarguably the oldest agent in this class. Digoxin reducedhospitalizations but not mortality in the Digitalis Investiga-tion Group (DIG) trial of 6800 patients.3 Secondary analy-es found an increased risk of mortality in women23 and a
possible mortality benefit (23% relative risk reduction,NNT � 25) in patients with systolic heart failure with aserum digoxin concentration of 0.5 to 0.9 ng/mL.24 On theasis of these findings, digoxin is used as a second-linegent, with careful monitoring of levels and with caution inomen, the elderly, and those with renal failure.Studies of other inotropes have been generally disap-
ointing. A meta-analysis showed increased mortality withhe �-1 agonist dobutamine (odds ratio, 1.47; P � .06).25
Milrinone (phosphodiesterase-3 inhibitor) was associatedwith increased mortality (28%) with a number needed toharm of 17.26 Therefore, the use of these inotropes is re-stricted to advanced heart failure as palliation or a bridge todefinitive therapy.
Newer agents seem to be more promising. The calciumsensitizer levosimendan, approved in Europe but not in theUnited States, showed a mortality benefit in a recent meta-analysis of 5480 patients (20% relative risk reduction,NNT � 17).27 The cardiac myosin activator omecamtivmecarbil, currently under development, has shown a dose-dependent increase in left ventricular ejection fraction,28
and studies on mortality and safety are underway.
Vasopressin AntagonistsVasopressin mediates vasoconstriction (V1 receptors) andsodium reabsorption (V2), and its antagonists representnovel avenues for heart failure treatment. Tolvaptan (selec-tive V2 antagonist) was not associated with any mortalitybenefit in the Efficacy of VasoprEssin antagonism in heaRtfailure outcome Study with Tolvaptan (EVEREST).29 Othervasopressin antagonists (lixivaptan, conivaptan, and sata-vaptan) have favorable effects on serum sodium concentra-tion in hyponatremic patients, but not on mortality. Cur-rently limited to the treatment of refractory hyponatremia,the appropriate role of these novel therapies remains a major
frontier.
C
aSdpd
Cs(tI((t
anor
pspfM(wa
aRtaprpei
tsdp
t
9Liu et al Frontiers in Heart Failure Therapy
AnticoagulantsPatients with heart failure have a 2- to 3-fold increased riskof ischemic stroke, presumably due to left ventricular hy-pokinesis.30 The Warfarin/Aspirin Study in Heart failure(WASH)31 and Warfarin and Antiplatelet Therapy in
hronic Heart Failure (WATCH)32 trials did not show ben-efit from anticoagulation but had methodological and powerissues. The role of anticoagulation in patients with reducedejection fraction is one focus of current studies.
Miscellaneous AgentsIvabradine lowers heart rate without affecting contractilityby inhibiting the If current of the sinoatrial node and ispproved in Europe, but not in the United States. Theystolic Heart Failure treatment with the If inhibitor Ivabra-ine Trial (SHIFT) found no mortality benefit in 6558atients, although there was a reduction in cardiovasculareath and hospitalization.33 Sildenafil, a phosphodiesterase
inhibitor, has shown potential in the treatment of heartfailure with preserved ejection fraction and is currentlybeing investigated in the PhosphodiesteRasE-5 Inhibition toImprove Quality of Life And EXercise Capacity in DiastolicHeart Failure (RELAX) study.34
NONPHARMACOLOGIC THERAPIES
Biventricular PacingBiventricular pacing (or cardiac resynchronization therapy)reduces dysynchrony associated with left bundle branchblock, and early studies demonstrated benefit in patientswith systolic heart failure with severe symptoms or low leftventricular ejection fraction, whereas more recent trials ex-tend this finding to less severe disease.35 For example, the
Ardiac REsynchronization–Heart Failure (CARE-HF)tudy found a 36% relative risk reduction in mortalityNNT � 10) over 2.4 years in 813 NYHA class III/IV pa-ients.36 In contrast, the Multicenter Automatic Defibrillatormplantation Trial with Cardiac Resynchronization TherapyMADIT-CRT) found a 24% reduction in mortalityNNT � 125) over 2.4 years in 1089 NYHA class I/II pa-ients.37 As with other heart failure therapies, lower acuity is
associated with a larger NNT.A major challenge continues to be identifying patients
who benefit the most from cardiac resynchronization ther-apy. Although current guidelines recommend cardiac resyn-chronization therapy for symptomatic patients with a leftventricular ejection fraction � 35% and a left bundle branchblock pattern with QRS � 120 ms, approximately 20% to30% of recipients do not respond to cardiac resynchroniza-tion therapy, and current tools are inadequate for identifyingthese patients.38 QRS duration (particularly � 150 ms) isssociated with better response, but imaging studies areotoriously unreliable at predicting responders. The studyf emerging approaches to improve response to cardiac
esynchronization therapy is underway. l
Implantable Cardiac DefibrillatorsImplantable cardiac defibrillators represent a major advancein preventing sudden cardiac death in systolic heart failure.The Antiarrhythmics Versus Implantable Defibrillators(AVID) trial found a 31% reduction in mortality at 3 years(NNT � 9) in patients with malignant arrhythmias39 andrompted approval of implantable cardiac defibrillators forecondary prevention. The benefit was shown to extend toatients with both ischemic and nonischemic systolic dys-unction but no prior arrhythmia (primary prevention). The
ulticenter Automatic Defibrillator Implantation Trial IIMADIT-II) of 1232 patients after myocardial infarctionith a left ventricular ejection fraction � 30% demonstrated31% relative risk reduction (NNT � 17) at 20 months.40
The Sudden Cardiac Death in Heart Failure Trial(SCD-HeFT) of 2521 patients with nonischemic cardiomy-opathy with an ejection fraction � 35% found a 23% rela-tive risk reduction (NNT � 14) at 45 months.3 Enthusiasmround implantable cardiac defibrillators led to the Immediateisk-Stratification Improves Survival (IRIS) study of 898 pa-
ients with an ejection fraction�40% enrolled 4 to 31 daysfter myocardial infarction, which showed no benefit of im-lantable cardiac defibrillator therapy over 37 months.41 As aesult, implantable cardiac defibrillators are recommended inatients with symptomatic heart failure with a left ventricularjection fraction�35%, but only after several months of med-cal therapy.3 Frontiers of therapy include refinement of the
exact timing of device placement, reduction in inappropriatedefibrillator shocks, and better identification of high-riskpatients.
Patient MonitoringNewer implantable cardiac defibrillators that indirectlymonitor pulmonary fluid status using changes in thoracicimpedance have shown promise in observational studies.42
However, the combination of this technology with an audi-ble alert did not improve outcomes but rather increasedheart failure admissions.43 Standalone implantable deviceso monitor intravascular pressure have shown promise inome studies,44 but not others.45 Studies are needed toetermine which are the best variables to measure, whichatients would benefit, and the impact on outcomes.
Left Ventricular Assist DevicesLeft ventricular assist devices are increasingly used to treatend-stage heart failure. The Randomized Evaluation of Me-chanical Assistance for the Treatment of Congestive HeartFailure (REMATCH) trial showed that a pulsatile left ven-tricular assist device was superior to medical therapy with a36% mortality reduction (NNT � 4) at 1 year.46 Anotherrandomized control trial showed that second-generation,continuous-flow left ventricular assist devices were superiorto pulsatile devices, with a 39% mortality reduction(NNT � 6) at 2 years.47 To illustrate the impact of left ven-ricular assist devices, patients treated with continuous-flow
eft ventricular assist devices in this trial had a 1-year mortality
emt
umrit
epm
i
10 The American Journal of Medicine, Vol 126, No 1, January 2013
of 32% compared with a 75% mortality in the medical therapyarm of the Randomized Evaluation of Mechanical Assistancefor the Treatment of Congestive Heart Failure trial. Thesedramatic results prompted the approval and propagation ofthese devices in patients awaiting cardiac transplantation(“bridge to transplant”) and in those who are not transplantcandidates (“destination therapy”).48 As the technologyvolves, it is likely to play a greater role in heart failureanagement, and studies are needed to better understand long-
erm complications and define ideal recipients for the therapy.
Cell-based TherapyEvidence on stem cell therapy for heart failure suggests thatcontemporary techniques are generally safe, with somestudies showing improved left ventricular ejection frac-tion,49 but not others.50 Another novel cell-based approachses synthetic anti-sense microRNAs to block translation ofessenger RNA, but many challenges remain, including
efining delivery mechanisms and ensuring safety.51 Ongo-ng research in these areas may help realize the potential ofhese technologies.
ExerciseExercise training generally has been found to be safe inheart failure. The Heart Failure—A Controlled Trial Inves-tigating Outcomes of exercise traiNing (HF-ACTION) ran-domized 2331 symptomatic patients with left ventricularejection fraction � 35% to exercise training versus usualcare and found a 7% reduction in mortality (NNT � 33), butthis did not reach statistical significance (P � .13), possiblybecause of declining compliance over time.52 Because ex-rcise is associated with decreased hospitalizations, im-roved quality of life, and physiologic benefits, it is recom-ended by the guidelines.3 The benefits of exercise seem to
extend to heart failure with preserved ejection fraction,53
and studies are ongoing to define the most effective exerciseinterventions and improve compliance.
Treatment of ComorbiditiesTreatment of comorbidities is increasingly emphasized inheart failure management. For example, percutaneous treat-ment of aortic stenosis, an important cause of heart failure,reduced mortality in patients ineligible for surgery.54 Like-wise, catheter ablation of atrial fibrillation in patients withheart failure improved cardiac function and quality of life.55
Conversely, coronary bypass with or without ventricularreconstruction56 surgery did not reduce mortality in a largetrial. The treatment of depression (Sertraline Against De-pression and Heart Disease in Chronic Heart Failure trial[SADHART-CHF])57 and sleep apnea (CANadian continu-ous Positive Airway Pressure [CANPAP])58 in patients withheart failure was not associated with improved outcomeseven though both conditions are associated with increasedmortality in heart failure. Studies are ongoing to assess theefficacy of adaptive servo-ventilation59 and phrenic nerve
stimulation60 in the treatment of sleep apnea in heart failure.
Although a comprehensive review of all comorbidities isbeyond the scope of this article, it should be noted thatadvances in these areas will undoubtedly have an impact onheart failure management.
CONCLUSIONSHeart failure is an exciting field with a rich evidence basethat underpins current treatment guidelines. The field israpidly evolving as evidenced by the more than 700 studiesactively enrolling patients in the ClinicalTrials.gov registry.Although this review cannot cover every aspect, it providesa framework within which to consider the evidence andunderstand the frontiers of therapy. The ultimate frontierwill be to integrate these data effectively to ensure thatpatients with heart failure consistently receive the best ev-idenced-based care possible.
The online version of this article contains additionalnformation and references.
References1. Roger VL, Go AS, Lloyd-Jones DM, et al; American Heart Associa-
tion Statistics Committee and Stroke Statistics Subcommittee. Heartdisease and stroke statistics—2011 update: a report from the AmericanHeart Association. Circulation. 2011;123:e18-e209.
2. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence andoutcome of heart failure with preserved ejection fraction. N EnglJ Med. 2006;355:251-259.
3. Lindenfeld J, Albert NM, Boehmer JP, et al. Executive summary:HFSA 2010 Comprehensive Heart Failure Practice Guideline. J CardFail. 2010;16:475-539.
4. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syn-dromes: current state and framework for future research. Circulation.2005;112:3958-3968.
5. The Escape Investigators and Study Coordinators. Evaluation study ofcongestive heart failure and pulmonary artery catheterization effec-tiveness: the ESCAPE trial. JAMA. 2005;294:1625-1633.
6. Abraham WT, Fonarow GC, Albert NM, et al. Predictors of in-hospitalmortality in patients hospitalized for acute heart failure. J Am CollCardiol. 2008;52:347-356.
7. Maisel A, Mueller C, Nowak R, et al. Mid-region prohormone markersfor diagnosis and prognosis in acute dyspnea: results from the BACH(Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol. 2010;55:2062-2076.
8. Mueller C, Scholer A, Laule-Kilia K, et al. Use of B-type natriureticpeptide in the evaluation and management of acute dyspnea. N EnglJ Med. 2004;350:647-654.
9. Jentzer JC, DeWald TA, Hernandez AF. Combination of loop diureticswith thiazide-type diuretics in heart failure. J Am Coll Cardiol. 2010;56:1527-1534.
10. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients withacute decompensated heart failure. N Engl J Med. 2011;364:797-805.
11. Costanzo MR, Saltzberg MT, Jessup M, et al. Ultrafiltration is asso-ciated with fewer rehospitalizations than continuous diuretic infusionin patients with decompensated heart failure: results from UNLOAD.J Card Fail. 2010;16:277-284.
12. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartanin patients with chronic heart failure and reduced left-ventricularsystolic function taking angiotensin-converting-enzyme inhibitors: theCHARM-Added trial. Lancet. 2003;362:767-771.
13. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients withsystolic heart failure and mild symptoms. N Engl J Med. 2011;364:
14. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemiaafter publication of the Randomized Aldactone Evaluation Study.N Engl J Med. 2004;351:543-551.
15. Krum H, Massie B, Abraham WT, et al. Direct renin inhibition inaddition to or as an alternative to angiotensin converting enzymeinhibition in patients with chronic systolic heart failure: rationale anddesign of the Aliskiren Trial to Minimize OutcomeS in Patients withHEart failuRE (ATMOSPHERE) study. Eur J Heart Fail. 2011;13:107-114.
16. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacody-namics of LCZ696, a novel dual-acting angiotensin receptor-neprilysininhibitor (ARNi). J Clin Pharm. 2010;50:401-414.
17. Cleland JG, Tendera M, Adamus J, et al. The perindopril in elderlypeople with chronic heart failure (PEP-CHF) study. Eur Heart J.2006;27:2338-2345.
18. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients withheart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-2467.
19. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol onmorbidity and mortality in patients with chronic heart failure. U.S.Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-1355.
20. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril withhydralazine-isosorbide dinitrate in the treatment of chronic congestiveheart failure. N Engl J Med. 1991;325:303-310.
21. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines forthe diagnosis and treatment of acute and chronic heart failure 2008: theTask Force for the Diagnosis and Treatment of Acute and ChronicHeart Failure 2008 of the European Society of Cardiology. Developedin collaboration with the Heart Failure Association of the ESC (HFA)and endorsed by the European Society of Intensive Care Medicine(ESICM). Eur Heart J. 2008;29:2388-2442.
22. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritidein patients with acute decompensated heart failure. N Engl J Med.2011;365:32-43.
23. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in theeffect of digoxin for the treatment of heart failure. N Engl J Med.2002;347:1403-1411.
24. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction inmortality and hospitalization in heart failure: a comprehensive post hocanalysis of the DIG trial. Eur Heart J. 2006;27:178-186.
25. Tacon CL, McCaffrey J, Delaney A. Dobutamine for patients withsevere heart failure: a systematic review and meta-analysis of ran-domised controlled trials. Intensive Care Med. 2012;38:359-367.
26. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone onmortality in severe chronic heart failure. N Engl J Med. 1991;325:1468-1475.
27. Landoni G, Biondi-Zoccai G, Greco M, et al. Effects of levosimendanon mortality and hospitalization. A meta-analysis of randomized con-trolled studies. Crit Care Med. 2012;40:634-646.
28. Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiacmyosin activator, omecamtiv mecarbil, on cardiac function in systolicheart failure: a double-blind, placebo-controlled, crossover, dose-rang-ing phase 2 trial. Lancet. 2011;378:676-683.
29. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oraltolvaptan in patients hospitalized for worsening heart failure: theEVEREST outcome trial. JAMA. 2007;297:1319-1331.
30. Haeusler KG, Laufs U, Endres M. Chronic heart failure and ischemicstroke. Stroke. 2001;42:2977-2982.
31. Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heartfailure (WASH): a randomized trial comparing antithrombotic strategiesfor patients with heart failure. Am Heart J. 2004;148:157-164.
32. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of war-farin, aspirin, and clopidogrel in patients with chronic heart failure: theWarfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH)
trial. Circulation. 2009;119:1616-1624.
33. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes inchronic heart failure (SHIFT): a randomized placebo-controlled study.Lancet. 2010;376:875-885.
34. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction:pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670-679.
36. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiacresynchronization on morbidity and mortality in heart failure. N EnglJ Med. 2005;352:1539-1549.
37. Moss AJ, Hall WJ, Cannom DS, et al. Cardiac-resynchronizationtherapy for the prevention of heart-failure events. N Engl J Med.2009;361:1329-1338.
38. Smith SA, Abraham WT. Device therapy in advanced heart failure:what to put in and what to turn off. Congest Heart Fail. 2011;17:220-226.
39. The Antiarrhythmics versus Implantable Defibrillators (AVID) Inves-tigators. A comparison of antiarrhythmic-drug therapy with implant-able defibrillators in patients resuscitated from near-fatal ventriculararrhythmias. N Engl J Med. 1997;337:1576-1583.
40. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of adefibrillator in patients with myocardial infarction and reduced ejec-tion fraction. N Engl J Med. 2002;346:877-883.
41. Steinbeck G, Andresen D, Seidl K, et al. Defibrillator implantationearly after myocardial infarction. N Engl J Med. 2009;361:1427-1436.
42. Whellan DJ, Ousdigian KT, Al-Khatib SM, et al. Combined heartfailure device diagnostics identify patients at higher risk of subsequentheart failure hospitalizations: results from PARTNERS HF (Programto Access and Review Trending Information and Evaluate Correlationto Symptoms in Patients With Heart Failure) study. J Am Coll Cardiol.2010;55:1803-1810.
43. van Veldhuisen DJ, Braunschweig F, Conraads V, et al. Intrathoracicimpedance monitoring, audible patient alerts, and outcome in patientswith heart failure. Circulation. 2011;124:1719-1726.
44. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonaryartery haemodynamic monitoring in chronic heart failure: a ran-domised controlled trial. Lancet. 2011;377:658-666.
45. Bourge RD, Abraham WT, Adamson PB, et al. Randomized controlledtrial of implantable continuous hemodynamic monitoring in patientswith advanced heart failure: the COMPASS study. J Am Coll Cardiol.2008;51:1073-1079.
46. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a leftventricular assist device for end-stage heart failure. N Engl J Med.2001;345:1435-1443.
47. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failuretreated with continuous-flow left ventricular assist device. N EnglJ Med. 2009;361:2241-2251.
48. Kirklin JK, Naftel DC, Kormos RL, et al. Third INTERMACS AnnualReport: the evolution of destination therapy in the United States.J Heart Lung Transplant. 2011;30:115-123.
49. Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med.2006;355:1210-1221.
50. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow celltransfer after myocardial infarction: eighteen months’ follow up datafrom the randomized control trial BOOST (Bone Marrow Transfer toenhance ST-elevation infarct regeneration) trial. Circulation. 2006;113:1287-1294.
51. van Rooij E, Marshall WS, Olson EN. Toward MicroRNA-basedtherapeutics for heart disease: the sense in anti-sense. Circ Res. 2008;103:919-928.
52. O’Connor CM, Whellan DJ, Lee KL, et al. Efficacy and safety ofexercise training in patients with chronic heart failure: HF-ACTIONrandomized controlled trial. JAMA. 2009;301:1439-1450.
53. Edelmann F, Gelbrich G, Düngen HD, et al. Exercise training im-proves exercise capacity and diastolic function in patients with heart
failure with preserved ejection fraction: results of the Ex-DHF (Exer-
12 The American Journal of Medicine, Vol 126, No 1, January 2013
cise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol.2011;58:1780-1791.
54. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic-valve im-plantation for aortic stenosis in patients who cannot undergo surgery.N Engl J Med. 2010;363:1597-1607.
55. Hsu LF, Jaïs P, Sanders P, et al. Catheter ablation for atrialfibrillation in congestive heart failure. N Engl J Med. 2004;351:2373-2383.
56. Jones RH, Velazquez EJ, Michler RE, et al. Coronary bypass surgerywith or without surgical ventricular reconstruction. N Engl J Med.2009;360:1705-1717.
57. O’Connor CM, Jiang W, Kuchibhatla M, et al. Safety and efficacy
of sertraline for depression in patients with heart failure: results of
the SADHART-CHF (Sertraline Against Depression and HeartDisease in Chronic Heart Failure) trial. J Am Coll Cardiol. 2010;56:692-699.
58. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airwaypressure for central sleep apnea and heart failure. N Engl J Med.2005;353:2025-2033.
59. Teschler H, Cowie MR, d’Ortho MP, et al. Rationale and design of theSERVE-HF Study: treatment of sleep-disordered breathing with pre-dominant central sleep apnea by adaptive servo ventilation in patientswith heart failure. Am J Respir Crit Care Med. 2010;181:A5580.
60. Ponikowski P, Javaheri S, Michalkiewicz, et al. Transvenous phrenicstimulation for the treatment of central sleep apnea in heart failure. Eur
Heart J. 2012;33:889-894.
P
v
J
B
M
J
M
B
C
T
T
G
P
P
G
12.e1Liu et al Frontiers in Heart Failure Therapy
Related ReferencesWeintraub NL, Collins SP, Pang PS, et al. Acute heart failure syndromes:
emergency department presentation, treatment, and disposition: currentapproaches and future aims: a scientific statement from the AmericanHeart Association. Circulation. 2010;122(19):1975-1996
Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identifies hemo-dynamic profiles that predict outcomes in patients admitted with heartfailure. J Am Coll Cardiol. 2003;40:1797-1804
Fonarow GC, Adams KF, Abraham WT, et al. Risk stratification forin-hospital mortality in acute decompensated heart failure: classifica-tion and regression tree analysis. JAMA. 2005;293(5):572-580
eacock WF, DeMarco T, Fonarow GC, et al. Cardiac troponin andoutcome in acute heart failure. New Engl J Med. 2008;358:2117-2126
an Kimmenade RR, Januzzi JL Jr, Ellinor PT, et al. Utility of amino-terminal pro-brain natriuretic peptide, galectin-3, and apelin for theevaluation of patients with acute heart failure. J Am Coll Cardiol.2006;48(6):1217-1224
anuzzi JF, Peacocok F, Maisel AS, et al. Measurement of the interleukinfamily member ST2 in patients with acute dyspnea: results from thePRIDE study. J Am Coll Cardiol. 2007;50:607-613
ueller C, Laule-Kilia K, Schindler C et al. Cost effectiveness of B-typenatriuretic peptide in patients with acute dyspnea. Ann Int Med. 2006;166:1081-1087
anuzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing fordiagnosis and short-term prognosis in acute destabilized heart failure:an international pooled analysis of 1256 patients. Eur Heart J. 2006;27(3):330-337
ichtalik HJ, Yeh HC, Campbell CY, et al. Acute changes in N-terminalpro-B-type natriuretic peptide during hospitalization and risk of read-mission and mortality in patients with heart failure. Am J Cardiol.2011;107(8):1191-1195
art BA, Boyle A, Bank AJ, et al. Ultrafiltration versus usual care forhospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure(RAPID-CHF) trial. J Am Coll Cardiol. 2005;46(11):2043-2046
ostanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versusintravenous diuretics for patients hospitalized for acute decompensatedheart failure. J Am Coll Cardiol. 2007;49(6):675-683
he CONSENSUS Trial Study Group. Effects of enalapril on mortality insevere congestive heart failure: Results of the Cooperative North Scan-dinavian Enalapril Survival Study (CONSENSUS). N Engl J Med.1987;316:1429-1435
he SOLVD Investigators. Effect of enalapril on survival in patients withreduced left ventricular ejection fractions and congestive heart failure.N Engl J Med. 1991;325:293-302
ranger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan inpatients with chronic heart failure and reduced left-ventricular systolicfunction intolerant to angiotensin-converting-enzyme inhibitors: theCHARM-Alternative trial. Lancet. 2003;362(9386):772-776
itt B, Zannad F, Remme W, et al. The effect of spironolactone onmorbidity and mortality in patients with severe heart failure. N EnglJ Med. 1999; 341:709-717
itt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosteroneblocker, in patients with left ventricular dysfunction after myocardialinfarction. N Engl J Med. 2003;348:1309-1321
heorghiade M, Albaghdadi M, Zannad F, et al. Rationale and design ofthe multicentre, randomized, double-blind, placebo-controlled Al-iskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT). EurJ Heart Fail. 2011;13(1):100-106
Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patientswith chronic heart failure and preserved left-ventricular ejection frac-tion: the CHARM-Preserved Trial. Lancet. 2003;362(9386):777-781
Desai AS, Lewis EF, Li R, et al. Rationale and design of the treatment of
preserved cardiac function heart failure with an aldosterone antagonist
trial: a randomized, controlled study of spironolactone in patients withsymptomatic heart failure and preserved ejection fraction. Am Heart J.2011;162(6):966-972
Edelmann F, Schmidt AG, Gelbrich G, et al. Rationale and design of the‘aldosterone receptor blockade in diastolic heart failure’ trial: a double-blind, randomized, placebo-controlled, parallel group study to deter-mine the effects of spironolactone on exercise capacity and diastolicfunction in patients with symptomatic diastolic heart failure. EurJ Heart Fail. 2010;12(8):874-882
CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II(CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9-13
The MERIT-HF Investigators. Effect of metoprolol CR/XL in chronicheart failure: Metoprolol CR/XL Randomised Intervention Trial inCongestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001-2007
Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation inpatients with treatment-resistant hypertension (The Symplicity HTN-2Trial): a randomised controlled trial. Lancet. 2010;376(9756):1903-1909
Birks EJ, George RS, Hedger M, et al. Reversal of severe heart failure witha continuous-flow left ventricular assist device and pharmacologicaltherapy: a prospective study. Circulation. 2011;123(4):381-390
Cohn, JN, Johnson G, Ziesche S, et al. Effect of Vasodilator Therapy onMortality in Chronic Congestive Heart Failure: Results of a VeteransAdministration Cooperative Study. N Engl J Med. 1986;314:1547-1592
Taylor Al, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrateand hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057
Schwartzenberg S, Redfield MM, From AM, et al. Effects of vasodilationin heart failure with preserved or reduced ejection fraction implicationsof distinct pathophysiologies on response to therapy. J Am Coll Car-diol. 2012;59(5):442-451
The Digitalis Investigation Group. The effect of digoxin on mortality andmorbidity in patients with heart failure. N Engl J Med. 1997;336(8):525-533
Pullicino P, Thompson JL, Barton B, et al. Warfarin versus aspirin inpatients with reduced cardiac ejection fraction: rationale, objective, anddesign. J Card Fail. 2006;12:39-46
Guazzi M, Vicenzi M, Arena R, et al. Pulmonary hypertension in heartfailure with preserved ejection fraction: a target of phosphodiesterase-5inhibition in a 1-year study. Circulation. 2011;124(2):164-174
Hare JM, Mangal B, Brown J, et al. Impact of oxypurinol in patients withsymptomatic heart failure: results of the OPT-CHF study. J Am CollCardiol. 2008;51(24):2301-2309
McMurray JJ, Teerlink JR, Cotter G, et al. Effects of tezosentan on symptomsand clinical outcomes in patients with acute heart failure: the VERITASrandomized controlled trials. JAMA. 2007;298(17):2009-2019
Gheorghiade M, Erdmann E, Ferrari R, et al. Treatment of acute decom-pensated heart failure with the soluble guanylate cyclase activatorcinaciguat: The COMPOSE program – three randomized, controlled,phase IIb studies. J Card Fail. 2011;17(11): 971-971
Spragg, DD. Optimal left ventricular endocardial pacing sites for cardiacresynchronization therapy in patients with ischemic cardiomyopathy.J Am Coll Card. 2010; 56:774-781
Burger H, Schwarz T, Ehrlich W, et al. New generation of transvenous leftventricular leads:first experience with implantation of multipolar leftventricular leads. Exp Clin Cardiol. 2011;16(1):23-26
Khan FZ, Virdee MS, Hutchinson J, et al. Cardiac resynchronizationtherapy optimization using noninvasive cardiac output measurement.Pacing Clin Electrophysiol. 2011;34(11):1527-1536
Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantablecardioverter-defibrillator for congestive heart failure. N Engl J Med.2005;352(3):225-237
Brachmann J, Bohm M, Rybak K, et al. Fluid status monitoring with awireless network to reduce cardiovascular- related hospitalizations andmortality in heart failure: rationale and design of the OptiLink HFStudy (Optimization of Heart Failure Management using OptiVol Fluid
Status Monitoring and CareLink). Eur J Heart Fail. 2011;13:796-804
12.e2 The American Journal of Medicine, Vol 126, No 1, January 2013
Adamson PB, Magsieski A, Braunschweig F, et al. Ongoing right ventric-ular hemodynamics in heart failure: clinical value of measurementsderived from an implantable monitoring system. J Am Coll Cardiol.2003;41:565-571
Ritzema J, Troughton R, Melton I, et al. Physician-directed patient self-management of left atrial pressure in advanced chronic heart failure.Circulation. 2010;121:1086-1095
Chaudhry S, Mattera JA, Curtis JP, et al. Telemonitoring in patients withheart failure. N Engl J Med. 2010;363(24):2301-2309
Koehler F, Winkler S, Scheiber M, et al. Telemedical interventional mon-itoring in heart failure (TIM-HF), a randomized, controlled interventiontrial investigating the impact of telemedicine on mortality in ambula-tory patients with heart failure: study design. Eur J Heart Fail. 2010;12:1354-1362
Mansour S, Roy DC, Bouchard V, et al. COMPARE-AMI trial: com-
parison of intracoronary injection of CD133� bone marrow stem
cells to placebo in patients after acute myocardial infarction and leftventricular dysfunction: rational and design. J Cardiovasc TranslRes. 2010;3(2):153-159
Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantationof progenitor cells after acute myocardial infarction. New Engl J Med.2006;355:1222-1232
Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow stemcell transfer in patients with ST-elevation myocardial infarction:a double blind, randomized controlled trial. Lancet. 2006;367:113-121
Lunde K, Solheim S, Aakhus S, et al. Intraocoronary injection of mono-nuclear bone marrow cells in acute myocardial infarction. New EnglJ Med. 2006;355:1199-1209
Velazquez EJ, Lee KL, Deja MA, et al. Coronary-artery bypass surgery inpatients with left ventricular dysfunction. N Engl J Med. 2011;364(17):
1607-1616
12.e3Liu et al Frontiers in Heart Failure Therapy
Supplemental Figure Example of evidence-based CHF order set used at Johns Hopkins Bayview Medical Center.
12.e4 The American Journal of Medicine, Vol 126, No 1, January 2013
Supplemental Figure (cont’d)
12.e5Liu et al Frontiers in Heart Failure Therapy
Supplemental Figure (cont’d)
12.e6 The American Journal of Medicine, Vol 126, No 1, January 2013
