Heart Failure Treatment: What Role for ARBs?

September 1, 2002
David T. Nash, MD
David T. Nash, MD

Heart failure(HF), the mostcommon Medicarediagnosisrelatedgroup,has a significant and growingimpact on health careresources. The incidenceof HF has tripled during thelast decade. Almost 5 millionAmericans have HF, and anestimated 500,000 new casesare diagnosed yearly. Thelifetime risk of HF is about20%.1 Drug therapy has improvedconsiderably in recentyears, but the magnitudeand severity of theproblem has created a needfor newer therapies--particularlysince HF is associatedwith an increased risk ofsudden death and a diminishedquality of life.2

Heart failure(HF), the mostcommon Medicarediagnosis relatedgroup,has a significant and growingimpact on health careresources. The incidenceof HF has tripled during thelast decade. Almost 5 millionAmericans have HF, and anestimated 500,000 new casesare diagnosed yearly. Thelifetime risk of HF is about20%.1 Drug therapy has improvedconsiderably in recentyears, but the magnitudeand severity of theproblem has created a needfor newer therapies-particularlysince HF is associatedwith an increased risk ofsudden death and a diminishedquality of life.2

THE ROLE OF ANGIOTENSIN IIIn chronic HF, activationof neurohormonalmechanisms promotes maladaptivegrowth, remodeling,and progressive myocardialdysfunction. Angiotensin II isa potent vasoconstrictor andgrowth-stimulating hormonethat may contribute to impairmentof left ventricular(LV) function and progressionof HF through suchmechanisms as:

  • Increased impedance ofLV emptying.
  • Adverse long-term structuraleffects on the heartand vasculature.
  • Potentially harmful activationof other neurohormonalagonists, such as epinephrine,aldosterone, andendothelin.

RECENT TRIAL RESULTS
Physiologically activelevels of angiotensin II persistdespite long-term therapywith angiotensin-convertingenzyme (ACE) inhibitors. Researchers thereforesought to determinewhether the angiotensin IIreceptor blocker (ARB) valsartancould further reducemortality and morbidityamong patients already receivingpharmacologictherapy considered optimalby their physicians.

Details of the study.The Valsartan Heart FailureTrial (Val-HeFT) was a randomized,double-blind,placebo-controlled, parallelgroupstudy that recruited5010 patients in 302 centersin 16 countries.3 Participantswere clinically stableadults with New York HeartAssociation (NYHA) classII, III, or IV HF who wereassigned to take valsartan,160 mg, or placebo twicedaily. At the time of randomization,93% of the patientswere taking ACE inhibitors;35%, β-blockers; and 5%,spironolactone. Patientswere followed for 2 years.

Total mortality wassimilar in the 2 treatmentgroups. The combined endpoint of mortality and morbiditywas 13% lower in thevalsartan group than in theplacebo group (P = .009).The incidence of hospitalizationfor HF decreased by27% (P < .001). The meanimprovement in ejectionfraction was 4% for those inthe valsartan group and3.2% in the placebo group(P = .001). More patients inthe valsartan group had improvementsin NYHA class,and fewer had worsening.There was a greater reductionin dyspnea, fatigue,edema, and rales in the valsartan-treated group, andless worsening in the measuredquality-of-life analysisthan in the placebo group.

Valsartan was associatedwith improved outcomein all age groups and bothsexes and in those with andwithout diabetes or coronaryheart disease. Valsartanwas generally well tolerated:the drug was discontinuedby 9.9%, comparedwith 7.2% who discontinuedthe placebo.3


A word of caution.

Subgroup analysis seemedto indicate that backgroundtherapy with neurohormonalinhibitors influenced the responseto valsartan. In the226 patients who were nottaking either a β-blocker oran ACE inhibitor, mortalitywas reduced by 33% with valsartan(P = .012). In the 366patients who were not takingACE inhibitors (some ofwhom were receiving β-blockers), there was a 44%reduction in the combinedend point of mortality andmorbidity and a 33% reductionin mortality.3 In contrast,there was a trend toward increasedmortality and morbidityin the subgroup of patientswho were taking anACE inhibitor and a β-blockerin addition to valsartan(P = .10).

3

Future trials willdetermine whether multipleneurohormonal blockade isharmful in patients with HF.

OPTIMAL TREATMENT
Despite the known efficacyof combined ACEinhibitor and -blocker therapyin HF, only one third ofthe patients enrolled in theVal-HeFT study were takingdrugs from both classes atbaseline. Current guidelinesrecommend that an ACEinhibitor and a β-blocker beconsidered for every patientwith chronic HF, regardlessof disease severity (Table).1Improved compliance withthe guidelines may reducethe number of inadequatelytreated patients.

 Table - Drugs and dosages used to treat chronic heart failure in clinical trials
Drug Starting dosage (mg/d)Target dosage (mg)Reduce symptomsReduce HF eventsImprove survival

ACE inhibitors +++++++++
Captopril 6.25 - 12.550 tid

Enalapril 2.5 - 510 bid

Lisinopril 2.5 - 510 - 20 qd

Ramipril 1.25 - 2.510 qd

ARBs +++++/-
Candesartan 416 qd

Losartan 2550 qd

Valsartan 80160 qd

ß-Blockers  +/++++++++

Bisoprolol 1.2510 qd

Carvedilol 3.125 - 6.2525 - 50 bid

Metoprolol succinate 12.5150 - 200 qd

Aldosterone antagonist   ++++++++
Spironolactone 12.5 - 2525 qd

Other   ++++0

Amlodipine 2.5 - 55 qd

Digoxin 0.1250.125 qd

HF, heart failure; ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers.

The improvement inthe quality-of-life measurementand in the combinedend point seen with valsartansuggests that the drugmay have a role in the managementof HF. Valsartanhad a favorable side-effectprofile, a feature that wasalso noted in a trial of anotherARB, losartan.4 In thesecond Evaluation of Losartanin the Elderly (ELITEII) trial, fewer patients withdrewfrom losartan therapythan from captopril therapybecause of adverse effects.

Ongoing studies ofother ARBs should furtherclarify their role in themanagement of cardiovasculardisease (Box). In themeantime, ARBs are a reasonablechoice in the treatmentof patients with HFwho cannot tolerate ACEinhibitors because of sideeffects such as cough orrash.1,5-7

References:

REFERENCES:1. Hunt SA, Baker DW, Chin MH, etal. ACC/AHA guidelines for the evaluationand management of chronic heartfailure in the adult: executive summary.J Am Coll Cardiol. 2001;38:2101-2113.
2. Packer M, Cohn JN, Abraham WT, etal. Consensus recommendations for themanagement of chronic heart failure.Am J Cardiol. 1999;83(suppl):1A-38A.
3. Cohn JN, Tognoni G, for the ValsartanHeart Failure Trial Investigators.A randomized trial of the angiotensin-receptor blocker valsartan inchronic heart failure. N Engl J Med.2001;345:1667-1675.
4. Pitt B, Poole-Wilson PA, Segal R,et al, for the Losartan Heart FailureSurvival Study ELITE II. Effect oflosartan compared with captopril onmortality in patients with symptomaticheart failure: randomised trial.Lancet. 2000;355:1582-1587.
5. Konstam MA, Cohn JN, TognoniG. Val-HeFT and angiotensin-receptorblockers in perspective: a tale of theblind man and the elephant. J CardFail. 2002;8:56-58.
6. Jamali AH, Tang WHW, Khot UN,Fowler MB. The role of angiotensinreceptor blockers in the managementof chronic heart failure. Arch InternMed. 2001;161:667-672.
7. Tang WHW, Francis GS. Chronicheart failure: 10 questions physiciansoften ask. Consultant. 2002;42:678-686.