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Beyond Angiotensin-Converting Enzyme

Inhibitors and Beta-Blockers

Nicholas B. Norgard, Pharm.D.;Jennifer E. Stark, Pharm.D.

Posted: 09/08/2008; Pharmacotherapy. 2008;28(7):920-931. © 2008 PharmacotherapyPublications

Abstract and Introduction

Abstract

Angiotensin-converting enzyme (ACE) inhibitors and β-blockers make up the cornerstoneof therapy for patients with heart failure involving left ventricular dysfunction. These drugclasses have been proven to decrease morbidity and mortality in patients with heart failure.Unfortunately, many patients remain symptomatic and experience disease progressiondespite taking both an ACE inhibitor and a β-blocker. Others may be unable to tolerate oneor both of these agents. In recent years, several other drug classes have been shown to provide additional morbidity and mortality benefits in patients with heart failure. Theseinclude angiotensin II receptor blockers (ARBs), aldosterone antagonists, and thecombination of isosorbide dinitrate plus hydralazine. To select the most appropriate drugtherapy for patients with heart failure, clinicians should consider results from clinical trialsin specific patient populations, adverse-event profiles, tolerability, cost, and dosingregimens.

Introduction

Heart failure with left ventricular dysfunction (left ventricular ejection fraction [LVEF]<40%) is a major source of morbidity and mortality in the United States. As the populationages, the prevalence of heart failure will continue to grow, placing a huge economic burdenon the health care system. The multitude of drug options and abundance of evidencerelating to heart failure therapy may be disconcerting to clinicians attempting to maximize pharmacotherapy. The core of therapy for heart failure with left ventricular dysfunctionconsists of angiotensinconverting enzyme (ACE) inhibitors and β-blockers. Numerouslarge-scale clinical trials involving patients with a wide range of causes and severity of heart failure provide compelling evidence for the first-line use of these agents. In patientswith heart failure involving left ventricular dysfunction, β-blockers and ACE inhibitorsalleviate symptoms, improve clinical status, enhance quality of life, and more importantly,reduce the risk of death and heart failure – related hospitalization.

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Despite the widespread use of β-blockers and ACE inhibitors, a substantial number of people remain at risk of poor outcomes from heart failure and, therefore, need additionaldrug therapy. Additive therapies that can provide further benefits in morbidity and in somecases mortality include the angiotensin II receptor blockers (ARBs), aldosteroneantagonists, and the combination of isosorbide dinitrate plus hydralazine. The optimum

therapeutic choice among these options has not been established. Agents such as diureticsand digoxin provide relief that is primarily symptomatic; however, this review is limited toARBs, aldosterone antagonists, and isosorbide dinitrate plus hydralazine. An understandingof the rationale for and evidence behind these additive therapies, as well as their potentialadverse effects, can help clinicians provide individualized pharmacotherapy options for patients with heart failure involving left ventricular dysfunction.

Renin-Angiotensin-

Under normal conditions, the renin-angiotensinaldosterone system (RAAS) works tomaintain blood volume, arterial pressure, and cardiac and vascular function. In

pathophysiologic conditions such as heart failure, activation of the RAAS plays amaladaptive role that contributes to the pathogenesis of cardiovascular disease.[1] The major effectors of the RAAS are angiotensin II and aldosterone (Figure 1).



Figure 1. Angiotensinogen is cleaved by renin, an enzyme released primary by the kidneys,to form angiotensin I. Angiotensin-converting enzyme (ACE) cleaves angiotensin I to formangiotensin II, although many other pathways in the body can also promote formation of angiotensin II. The ACE is also responsible for breakdown of the vasodilator bradykinininto inactive particles. Angiotensin II acts on two receptors: AT1 and AT2. Stimulation of

AT1 triggers the adrenal cortex to release aldosterone, which in turn acts on the kidneys toincrease sodium and fluid retention. Therapeutic manipulation of the reninangiotensin-aldosterone system (RAAS) is very important in treating heart failure. Angiotensin IIreceptor blockers (ARBs), ACE inhibitors, and aldosterone antagonists block the RAAS atvarious points in the cascade.

Angiotensin II, which is among the most potent natural vasoconstrictors, increases peripheral resistance and thereby augments cardiac preload and afterload. It also stimulatessodium reabsorption by the proximal tubules of the kidney, stimulates release of norepinephrine, and promotes synthesis and secretion of aldosterone.[2] Angiotensin IIelicits its effects on the cardiovascular system by means of two receptor subtypes – AT1 andAT

2. These receptors have similar affinities for angiotensin II but are linked to different

internal signaling pathways, thus producing distinctly different effects.[3] Most pathologiccardiovascular effects of angiotensin II, including vasoconstriction, sodium and water retention, sympathetic activation, aldosterone release, myocyte hypertrophy, and cardiacfibrosis, are mediated through the AT1 receptor.[3] Activation of the AT2 receptor appears tocounterbalance the detrimental effects of AT1 by triggering decreases in blood pressure,myocyte hypertrophy, and cardiac fibrosis.[3,4]

Aldosterone is a potent mineralocorticoid secreted by the adrenal gland. This hormoneenhances fluid retention by increasing sodium reuptake by the distal tubules of the kidney,thereby contributing to a rise in blood pressure that further increases cardiac afterload.Aldosterone also potentiates vasoconstriction by other neurohormones. However, it has been implicated in cardiac hypertrophy independently of its effects on sodium retention andincreased arterial blood pressure. Both animal and select human models have shownaldosterone to have a detrimental effect on both fibroblast proliferation and collagendeposition in the myocardium.[5-8]

Several cardiovascular drugs have RAAS inhibition as their target. It was once thought thatACE inhibitors would sufficiently reduce the production of angiotensin II and aldosterone.Indeed, an initial response to ACE inhibitors is the potent reduction of both aldosterone andangiotensin II. However, a significant number of patients experience an "escape" phenomenon, in which plasma aldosterone and angiotensin II levels rapidly return to pre – ACE inhibitor levels.[9-11] This suggests that other pathways and mediators also contributeto the production of these hormones. Accordingly, the combination of ACE inhibitors withagents such as angiotensin II receptor blockers (ARBs) and aldosterone antagonists wouldseemingly provide more complete RAAS inhibition than occurs with ACE inhibitors alone.

Angiotensin II Receptor Blockers



Controlled trials have established that inhibition of angiotensin II helps prevent thedevelopment and progression of heart failure.[12] Angiotensin II inhibition reduces systemicarterial pressure, and it can also reduce and even reverse cardiovascular remodeling.[13] Angiotensin II is largely generated through the cleavage of angiotensin I by ACE. Blockageof ACE by ACE inhibitors prevents conversion of angiotensin I to angiotensin II. However,

ACE inhibitors cause only temporary reductions in angiotensin II, possibly because severalalternative pathways also contribute to angiotensin II production.[14,15] The most establishedof these is the cardiac chymase pathway. This pathway is ACE inhibitor – resistant and may be responsible for up to 75% of cardiac angiotensin II – induced heart failure.[16] Patientswith elevated angiotensin II levels despite ACE inhibitor therapy have a worse functionalstatus and a poorer prognosis than other patients with heart failure.[17]

Blockade of angiotensin II at the receptor would theoretically negate the adverse effects of angiotensin II escape. The ARBs selectively prevent angiotensin II from binding the AT1 receptor, but they also upregulate and allow angiotensin II activation of the AT2 receptor.[18] Accordingly, these agents block the RAAS and exert favorable vascular effects.Comparative trials have shown that ARBs can be used in patients who are intolerant toACE inhibitors; however, trials have not demonstrated superiority of ARBs over ACEinhibitors.[19-21] The long-term benefits of ACE inhibitors despite rebound of angiotensin IIsuggests that the chronic benefit from ACE inhibitors may be due to something other thanangiotensin II inhibition. Specifically, ACE inhibitors block the metabolism of bradykinin,thereby raising serum levels of this potent vasodilator. Bradykinin-mediated vasodilationcontributes to the hemodynamic effects of chronic ACE inhibitor therapy but is not relatedto the benefits of ARBs.[22] Thus, the combination of an ACE inhibitor and an ARB mayhave additive benefits in patients with heart failure.

Studies with surrogate end points suggest that addition of an ARB to conventional drugs for heart failure (ACE inhibitors and β-blockers) further inhibits neurohormonal activation andleft ventricular remodeling, while simultaneously improving functional and exercisecapacity. However, trials that use morbidity and mortality as end points offer moreclinically meaningful results. Two large-scale trials with these end points have addressedthe therapeutic benefit of adding ARBs to conventional heart failure treatment regimens:the Valsartan Heart Failure Trial (Val-HeFT) and the Added component of the Candesartanin Heart Failure – Assessment of Reduction in Mortality and Morbidity (CHARMAdded)trial.

The Val-HeFT assessed the benefit of adding valsartan 160 mg twice/day to conventionaltherapy for heart failure.[23] The study involved 5010 clinically stable patients with heartfailure of New York Heart Association (NYHA) class II, III, or IV. If participants werereceiving other drug therapy, their condition needed to be stable on a fixed regimen, whichcould include ACE inhibitors, diuretics, digoxin, and β-blockers. Primary end points wereall-cause mortality and the combined mortality and morbidity rate. Morbidity was definedas nonfatal cardiac arrest, heart failure – related hospitalization, or need for intravenousinotropic or vasodilator drugs.

The study showed no significant difference between valsartan versus placebo in the all-cause mortality end point (19.7% vs 19.4%, p = 0.80). However, valsartan reduced the



composite mortality and morbidity end point by 13.2% (28.8% for the treatment group vs32.1% for the placebo group, p = 0.009). This was driven by a 24.2% relative risk reductionin heart failure – related hospitalizations. Valsartan provided significant symptomaticimprovement, although this did not improve overall quality of life measures. The benefit of valsartan was maintained in all demographic and clinical subgroups with respect to the

composite end point. However, the greatest risk reduction was seen in patients with NYHAclass III or IV heart failure and in those with LVEFs below 27%. These findings suggestthat valsartan is most likely to benefit patients with increased disease severity.

Subgroup analysis shed light on the influence of background therapy. Patients were dividedinto four groups based on whether or not they were receiving ACE inhibitors and/or β- blockers. Nearly all (93%) patients were taking ACE inhibitors, whereas 35% of patientswere receiving β-blockers. Valsartan had a favorable effect on the group taking ACEinhibitors alone. However, its most substantial benefit was seen in the 7% of patients nottaking an ACE inhibitor, whether they were also receiving a β-blocker or not. When these7% were eliminated from the analysis, valsartan failed to maintain its benefit. Anunexpected finding was that valsartan had a significant harmful effect on mortality in the30% of patients receiving concomitant ACE inhibitors and β-blockers. This led to thequestion of whether overblockade of the neurohormonal systems with triple therapy isdetrimental to clinical outcomes.

The CHARM-Added study examined the value of adding candesartan to conventionaltherapy for heart failure.[24] The 2548 participants were required to have an LVEF below40% and heart failure categorized as NYHA class II – IV (patients in class II were includedonly if they had a recent heart failure – related hospitalization). All patients were taking anACE inhibitor at a stable dosage before randomization.

Patients were randomly assigned to receive candesartan titrated to a target dose of 32mg/day or placebo. The primary end point was a composite of cardiovascular death andunplanned heart failure – related hospitalization. Candesartan was associated with asignificant 15% relative risk reduction versus placebo (38% vs 42%, p = 0.011),corresponding to a number needed to treat (NNT) of 25. In addition, both individualcomponents of the primary end point were significantly reduced. Candesartan reduced therelative risk of cardiovascular death by 16% (23.7% for the candesartan group vs 27.3% for placebo, p = 0.029). However, as in Val-HeFT, there was not a significant difference between groups with regard to death from any cause (30% for candesartan vs 32% for placebo, p = 0.086). Unlike Val-HeFT, the benefit of candesartan was maintained in all prespecified subgroups, including patients receiving ACE inhibitors and β-blockers.

The CHARM-Added investigators stated that 96% of patients in each group receivedoptimized ACE inhibitor therapy, but they did not define what optimized therapy entailed.The mean daily dose of enalapril was 17 mg; this was identical to the mean daily dose usedin large-scale studies of ACE inhibitors in patients with heart failure, such as the Study of Left Ventricular Dysfunction (SOLVD).[25] However, the CHARM-Added study facedcriticism for not ensuring that participants received maximized ACE inhibitor doses. A posthoc analysis compared outcomes of patients at the ACE inhibitor dosage prespecified bythe CHARM-Added researchers with outcomes of patients receiving the maximum dosage



recommended by the United States Food and Drug Administration (FDA).[26] This analysisshowed that the benefit of candesartan on the primary end point was maintained regardlessof whether the ACE inhibitor dosage was low, moderate, or high. The average ACEinhibitor dosage in Val-HeFT was similar to that of CHARM-Added.[23] However, Val-HeFT showed greater benefits of valsartan in those receiving low-dose versus high-dose

ACE inhibitors, with the greatest benefit seen in patients not receiving an ACE inhibitor.

[23]

Adding to the questions raised by these discrepant findings are data from the Valsartan inAcute Myocardial Infarction Trial (VALIANT).[21] This trial found no benefit from additionof valsartan to ACE inhibitors in patients with a recent myocardial infarction and leftventricular dysfunction. The ACE inhibitor dosages were substantially higher in VALIANTthan in CHARM-Added or Val-HeFT.

The increased frequency of adverse events with addition of an ARB to ACE inhibitor therapy is worth noting, since these events can negatively affect quality of life and reducetreatment adherence. Patients receiving both an ARB and an ACE inhibitor for chronicheart failure were at significant risk for worsening renal function (number needed to harm[NNH] 56), hyperkalemia (NNH 36), and symptomatic hypotension (NNH 111). Adverseeffects caused by the ARB – ACE inhibitor combination also reduced drug compliance(NNH 25) versus ACE inhibitors alone.[27] Patients with the greatest potential for experiencing adverse events from the addition of an ARB to an ACE inhibitor remainunidentified.

The increased mortality and morbidity seen in Val-HeFT among those taking concomitantvalsartan, an ACE inhibitor, and a β-blocker caused concern over the safety of the tripletherapy combination, with its potentially excessive neurohormonal inhibition. Conversely,a small study with heart failure surrogate end points suggested that candesartan was safeand effective when was used in combination with enalapril and metoprolol.[28] TheCHARM-Added study also found candesartan to provide significant cardiovascular mortality and morbidity benefits regardless of background therapy. These results removedconcerns over providing ARBs to patients receiving ACE inhibitors and β-blockers.Accordingly, updated guidelines favor the addition of ARBs to conventional treatmentregimens for heart failure in some circumstances. The 2005 guideline update of theAmerican College of Cardiology – American Heart Association (ACC-AHA) recommendsadding an ARB to persistently symptomatic patients who already receive conventionaltherapy.[29] More recently updated guidelines from the Heart Failure Society of America(HFSA) state that ARBs should be considered in patients with heart failure due to systolicdysfunction who have persistent symptoms or progressive worsening despite optimizedtherapy with an ACE inhibitor and a β-blocker.[30] These guidelines go on to state thatARBs should be considered in patients with heart failure due to systolic dysfunction whoare unable to tolerate a β-blocker and have persistent symptoms or progressive worseningdespite optimized therapy with an ACE inhibitor. Although the guidelines do not single outa specific ARB, candesartan is the only ARB whose package insert lists a heart failureindication when used with an ACE inhibitor.

Aldosterone Antagonists



Decades before the Randomized Aldosterone Evaluation Study (RALES) was completed,clinical observations suggested a role for aldosterone inhibition in patients with heartfailure. Patients experiencing an acute decompensation of their heart failure were observedto have higher serum aldosterone levels than those with chronic systolic heart failure.[31] Inthe first Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), plasma

aldosterone levels were lower in survivors than in subjects who died during the trial.

[12]

Like angiotensin II, aldosterone is briefly suppressed by ACE inhibition but rapidly returnsto pre – ACE inhibition levels.[9,10] This suggests that aldosterone production may bestimulated by alternative means (escape pathways) that are independent of angiotensin II.Based on these findings, investigators proposed that patients with heart failure might benefit from the combination of an ACE inhibitor with a drug that directly antagonizesaldosterone. Spironolactone and its chemical derivative, eplerenone, both block the effectsof aldosterone at the cortical collecting tubule and late distal tubule by directlyantagonizing mineralocorticoid receptors. Eplerenone has greater selectivity for thealdosterone receptor than spironolactone. Aldosterone antagonists are thought to improveoutcomes in patients with heart failure through several mechanisms: reduced ventricular fibrosis and hypertrophy; increased vascular compliance; and improved heart ratevariability, serum potassium levels, fibrinolysis, and myocardial norepinephrineuptake.[7,32,33]

The RALES began in March 1995 and was terminated early in August 1998 due to thesignificant mortality benefit seen in the spironolactone group compared with the placebogroup.[34] All participants had moderate-to-severe heart failure with a recent LVEF less than35%, and all were receiving standard therapy at baseline, which at the time primarilyconsisted of ACE inhibitors, loop diuretics, and digoxin. Patients with serum creatinineconcentrations above 2.5 mg/dl or serum potassium levels above 5.0 mEq/L at baselinewere excluded.

Baseline pharmacotherapy consisted of ACE inhibitors (>90% of patients), loop diuretics(100%), digoxin (73%), and β-blockers (10%). The relatively small percentage of patientstaking β-blockers was consistent with clinical practice for patients with moderate-to-severeheart failure at the time of the study. The mean ± SD age of participants was 65 ± 12 years;70% were characterized at baseline with NYHA class III heart failure, whereas 30% had NYHA class IV. Mean LVEF was 25% at baseline. Patients in the treatment group receivedspironolactone 25 mg/day. This dosage could be reduced to every other day if hyperkalemiadeveloped; alternatively, it could be increased to 50 mg/day after 8 weeks in patients withworsening heart failure without hyperkalemia. Serum potassium levels were monitoredevery 4 weeks for the first 12 weeks, then every 3 months for 1 year, and finally every 6months until completion of the study. The primary end point was death from any cause.

After a mean follow-up of 24 months, the mean spironolactone dose in the treatment groupwas 26 mg/day. At that time, 386 (46%) deaths had occurred in the placebo groupcompared with 284 (35%) deaths in the spironolactone group, showing a benefit of spironolactone with an NNT of 9. Median concentrations of both serum creatinine and potassium increased by a relatively small amount in the spironolactone group; this wasstatistically significant in comparison with the placebo group. The authors did not consider these increases to have clinical importance, and the two groups were not significantly



different with regard to severe hyperkalemia (1% and 2% for placebo and treatment groups,respectively, p = 0.42).

A more recent trial, the Eplerenone Post-Acute Myocardial Infarction Heart FailureEfficacy and Survival Study (EPHESUS) addressed the benefits of eplerenone in heart

failure. All participants had experienced an acute myocardial infarction in the past 3 – 14days, had an LVEF less than 40% after the myocardial infarction, and had clinical signs of heart failure (presence of pulmonary rales, pulmonary venous congestion on chestradiograph, or third heart sound) and/or diabetes mellitus.[35] As in RALES, patients wereexcluded if they had a baseline serum creatinine concentration above 2.5 mg/dl, potassiumlevel above 5.0 mEq/L, or were taking potassiumsparing diuretics. The mean ± SD age was64 ± 12 years. Serum potassium levels were monitored frequently (48 hrs after starting drugor placebo; at weeks 1, 4, and 5, and then every 3 months; and within 1 week after anydosage change). In contrast to the baseline characteristics seen in RALES, 85% of patientsin EPHESUS were receiving ACE inhibitors, 60% were taking diuretics, and 75% were prescribed β-blockers. The mean LVEF was 33% at baseline. Primary outcomes were all-cause mortality and cardiovascular mortality or hospitalization.

After a mean follow-up of 16 months, 478 patients (14.4%) in the eplerenone group haddied, versus 554 (16.7%) in the placebo group. This showed a benefit of eplerenone with a NNT of 44 patients. A statistically significant difference was also seen in bothcardiovascular mortality and cardiovascular-related hospitalizations. Safety end pointsrevealed a significantly smaller increase in blood pressure in the eplerenone group versusthe placebo group, and a significantly higher increase in both serum creatinine and potassium levels compared with corresponding values for the placebo group. Serum potassium levels were monitored more frequently in EPHESUS than in RALES. Serioushyperkalemia (6.0 mEq/L) was more prevalent in the eplerenone group than in the placebogroup (5.5% vs 3.9%, p = 0.002). In contrast, RALES did not show a significant differencein severe hyperkalemia rates between the two study groups.

When applying evidence to clinical practice, it is imperative to recognize differences between inclusion criteria and the actual study patients' baseline characteristics. Thesecharacteristics better reflect the patients to whom evidence should be applied and maydiffer significantly from a trial's stated inclusion criteria. For example, most patients in bothRALES and EPHESUS had a baseline serum creatinine concentration below 1.5 mg/dl,even though the inclusion criteria allowed patients with concentrations up to 2.5 mg/dl.Five years after the results of RALES were published, a populationbased, time-seriesanalysis of health care databases indicated that spironolactone use in heart failure resultedin increased hospitalizations for hyperkalemia.[36] However, the patients described in thatreview were not consistent with those in the RALES trial. Thus, the database analysis provides an example of evidence-based medicine being applied to unsuitable patients, ashas been reported in the literature.[37,38]

The low percentage of patients prescribed β-blockers (~10%) in RALES also represents acommon problem in large clinical trials, which is that new evidence may change standardsof care by the time a study's results are published. In EPHESUS, published 4 years after RALES, 75% of patients were receiving β-blockers at baseline. Although the mortality



benefit of eplerenone seemed diminished in patients taking concurrent β-blockers, theseresults must be interpreted cautiously since the study was not powered to detect differencesamong subgroups. The RALES and EPHESUS study populations also differed in baselinemean LVEF. This parameter was 25% in RALES versus 33% in EPHESUS; moreover; itmay have improved after baseline in EPHESUS due to interventions for acute myocardial

infarction. These differences may account for the lower overall mortality rate seen inEPHESUS versus RALES.

Current ACC-AHA guidelines do not recommend widespread prescribing of either spironolactone or eplerenone for patients with heart failure, nor do they differentiate between the two drugs in any of their recommendations.[29] Instead, the guidelines call for prescribing the drugs judiciously to specific patients who closely match those patientsstudied in clinical trials (RALES and EPHESUS).

The HFSA guidelines advise clinicians to consider adding an aldosterone antagonist to thedrug therapy of patients with systolic heart failure with persistent symptoms or disease progression despite optimized therapy with ACE inhibitors and β-blockers.[30] In addition,the guidelines call for clinicians to consider providing an aldosterone antagonist to patientswho are receiving optimized therapy with an ACE inhibitor but are unable to tolerate a β- blocker.

Isosorbide Dinitrate Plus Hydralazine

Specific patient populations may differ with regard to the prevalence and causes of heartfailure. Pathophysiologic differences, such as an apparent reduction in renin-angiotensinsystem activity and lower bioavailability of nitric oxide due to decreased production, have been found in patients self-identified as African descent compared with patients self-

identified as Caucasian.

[39-41]

Lower levels of plasma norepinephrine have also beenobserved in African-Americans versus Caucasians. These differences are most pronouncedin patients with hypertension. Impaired bioavailability of nitric oxide translates to increasedoxidant stress, which contributes to cardiac remodeling. Many observations of differences between African- Americans and Caucasians are from clinical trials that were performed before the benefits of ACE inhibitors and β-blockers were known. Until recently, it wasunclear whether the benefits seen in African-Americans treated with isosorbide dinitrate plus hydralazine in past trials would persist if isosorbide dinitrate plus hydralazine wasgiven in conjunction with neurohormonal inhibitors (ACE inhibitors and β-blockers).

The original Vasodilator Heart Failure Trial (VHeFT I), published in 1986, compared

isosorbide dinitrate plus hydralazine with placebo in 642 men with mild-to-severe heartfailure.[42] Baseline therapy consisted only of diuretics and digitalis and did not include anyneurohormonal inhibitors, as those had no proven benefit in heart failure at that time. Two-year mortality was significantly lower in the isosorbide dinitrate plus hydralazine treatmentgroup than in the placebo group (25.6% vs 34.3%, p = 0.028). A retrospective analysisrevealed that African- American patients in the isosorbide dinitrate plus hydralazine groupshowed a significant survival benefit when compared with African-American patients in the placebo group. In contrast, no treatment effect was seen in Caucasian patients.



The second Vasodilator Heart Failure Trial (VHeFT II), published in 1991, comparedisosorbide dinitrate plus hydralazine with enalapril in 804 men with mild-to-severe heartfailure.[43] A trend toward an interaction between race and treatment group was observed.Patients identified as African-American had similar mortality rates regardless of whether they were in the enalapril group or the isosorbide dinitrate plus hydralazine group. In

contrast, a statistically significant decrease in mortality was seen in Caucasian patients inthe enalapril group versus Caucasians in the isosorbide dinitrate plus hydralazine group.Since there was no placebo group, it was difficult to tell whether the racial differencesreflected a reduced effect of ACE inhibitors in the African-American population or agreater response of the African-American population to isosorbide dinitrate plushydralazine.

The African-American Heart Failure Trial (AHeFT) began in June 2001 and wasterminated early in July 2004, due to a significantly higher mortality rate in the placebogroup.[44] This study randomized 1050 patients self-identified as African-American with NYHA class III or IV heart failure for at least 3 months to either isosorbide dinitrate plushydralazine or placebo. All participants received standard heart failure therapy. The mean ±SD age of participants was 56 ± 13 years, and approximately 95% had NYHA class IIIheart failure at baseline, with an LVEF of 24 ± 7%. Baseline pharmacotherapy for systolicheart failure consisted of diuretics (89%), ACE inhibitors (69%), β-blockers (74%), digoxin(59%), spironolactone (39%), and ARBs (17%). The primary end point was a compositescore that included death from any cause, heart failure – related hospitalization, and changesin quality of life. Secondary end points included all primary end points separately, as wellas cardiovascular mortality and other morbidity end points.

The trial was stopped early; 54 patients (10.2%) in the placebo group had died comparedwith 32 (6.2%) in the isosorbide dinitrate plus hydralazine group, representing an NNT of 25. Other individual end points used for the composite score were also significantly better in the isosorbide dinitrate plus hydralazine group than in the placebo group. These includeda significant reduction in first hospitalization for heart failure (16.4% for isosorbidedinitrate plus hydralazine vs 24.4% for placebo, p = 0.001) and a significant improvementin quality of life for the isosorbide dinitrate plus hydralazine group as reflected in scores onthe Minnesota Living with Heart Failure questionnaire.[45] Both headache and dizzinessoccurred more frequently in the isosorbide dinitrate plus hydralazine treatment group thanin the placebo group. Mean duration of follow-up was 10 months, and 68% of patients inthe treatment group reached the target doses of isosorbide dinitrate 120 mg/day andhydralazine 225 mg/day.

Evidence supporting isosorbide dinitrate plus hydralazine in heart failure is distinctive inthat A-HeFT targeted a specific demographic of patients with heart failure rather than aheterogeneous population. The combination formulation of the two drugs is the first suchcombination to be specifically approved by the FDA for a particular race. The morbidityand mortality benefits seen in A-HeFT support the addition of isosorbide dinitrate plushydralazine to baseline therapy of ACE inhibitors and β-blockers in African-Americanswith heart failure. This observation is especially important due to the disproportionatemortality rate among African-Americans versus Caucasians with heart failure.



Baseline therapy in A-HeFT included the cornerstones of systolic heart failure therapy:ACE inhibitors and β-blockers. This helped resolve uncertainties from previous trials(VHeFT I and II), where limited background therapy made it unclear whether apparentracial differences were due to a reduced effect of neurohormonal therapy or a greater response to isosorbide dinitrate plus hydralazine. Thus, the A-HeFT findings appear to

confirm that the benefit of isosorbide dinitrate plus hydralazine in African-American patients with heart failure is independent of background therapy. Unfortunately, A-HeFTleaves some questions unanswered. By enrolling only African-American patients, the studydid not compare various racial or ethnic groups with regard to the effects of isosorbidedinitrate plus hydralazine. Moreover, race is a poorly defined marker and provides noinformation about clinically relevant genetic variations.

The 2005 ACC-AHA practice guidelines advise clinicians to consider using isosorbidedinitrate plus hydralazine combination therapy in African- American patients. However,they stress that this therapy should not substitute for an ACE inhibitor in patients who haveeither not tried an ACE inhibitor or are currently tolerating ACE inhibitor therapy.[29] The2006 HFSA guidelines recommend prescribing isosorbide dinitrate plus hydralazine toAfrican-Americans with left ventricular dysfunction, in addition to ACE inhibitors and β- blockers. The guidelines further call for clinicians to consider the isosorbide dinitrate plushydralazine combination for patients of other race-ethnicities who have left ventricular dysfunction and remain symptomatic despite provision of optimized therapy.[30] TheAHeFT did not prove that the benefit of isosorbide dinitrate plus hydralazine is specificonly to patients of African descent, although it is unclear whether the benefits are as greatin patients of other race-ethnicities as they are in African- Americans. Finally, the HFSAguidelines identify isosorbide dinitrate plus hydralazine as an option in patients with heartfailure of any ethnicity who are unable to tolerate ACE inhibitors or ARBs.[29,30]

Comparison of Drug Therapies

The improved outcomes seen with addition of ARBs, aldosterone antagonists, andisosorbide dinitrate plus hydralazine to standard therapy are consistent with evidence thateach of these drug classes intensifies neurohormonal suppression, reduces cardiacremodeling, and improves functional and exercise capacity. There appears to be a definiterole for these agents in patients with left ventricular systolic dysfunction whose heartfailure remains symptomatic after receiving standard therapy. In this population, ARBs,aldosterone antagonists, and isosorbide dinitrate plus hydralazine can reduce the risk of cardiovascular death, heart failure – related hospitalization, and other indexes of heart failure progression. Because ARBs, aldosterone antagonists, and isosorbide dinitrate plushydralazine have not been subject to comparative trials, it is difficult to directly comparethese drug classes. When selecting one of these agents, clinicians should take intoconsideration study outcomes, results in specific patient populations, background drugs,safety and tolerability, cost, and dosing frequency.

Study Outcomes



Data from trials of aldosterone antagonists, ARBs, and isosorbide dinitrate plus hydralazinesuggest different benefits for these agents. The aldosterone antagonists and isosorbidedinitrate plus hydralazine showed dramatic reductions in all-cause mortality. The ARB benefit was driven mainly by improvements in heart failure – related morbidity, butreductions in all-cause mortality were not shown.

Patient Populations

Table 1 compares the treatment groups of Val- HeFT, RALES, CHARM-Added, and A-HeFT.[23,24,34,44] Spironolactone and isosorbide dinitrate plus hydralazine were evaluated ina more symptomatic patient population (NYHA class III and IV) than ARBs (NYHA classII and III). This may account for the some of the variation in all-cause mortality outcomes.This accords with subgroup analyses of Val-HeFT and CHARM-Added, which suggestedthat ARBs provide greater benefits to patients with advanced, symptomatic disease than tothose with less severe heart failure. Aldosterone antagonists have not been well studied in patients with mild-to-moderate heart failure in the absence of recent myocardial infarction.There is strong evidence for isosorbide dinitrate plus hydralazine in the African-American population. Unfortunately, African-Americans were underrepresented in studies of ARBsand aldosterone antagonists. Thus, the evidence for use of these agents in African-Americans is limited. There is also a lack of evidence for use of isosorbide dinitrate plushydralazine in patients who are not of African descent. Current assumptions about drug benefits in Caucasians versus African-Americans may reflect oversimplification of geneticdifferences in patients' responses to pharmacotherapy. Future research may shed more lighton this issue and allow clinicians to prescribe based on genotype rather than phenotype.

Table 1. Baseline Characteristics of Patients in the Treatment Groups of Large-Scale

Heart Failure Trials



Background Drugs

Clinicians must also consider how a particular study's background drugs, particularly β- blockers, fit with today's standard of care. As shown in Table 2 ,[23,24,34,44] the ARB(CHARMAdded and Val-HeFT) and isosorbide dinitrate plus hydralazine (A-HeFT) trials provided a better fit with present treatment strategies than the RALES study of spironolactone, which had limited β-blocker use. One can speculate that if background useof β-blockers had been as extensive in RALES as it was in CHARM-Added and A-HeFT,RALES might not have found such a substantial impact of spironolactone on mortality. Onthe other hand, eplerenone, another aldosterone antagonist, reduced mortality in a treatmentgroup in which most participants received β-blockers.

Table 2. Background Therapy of Patients in the Treatment Groups of Large-Scale

Heart Failure Trials



Safety and Tolerability

Aldosterone antagonists are associated with substantial risk for hyperkalemia and renaldysfunction, necessitating monitoring of any patients who receive them. The ACC-AHAguidelines provide a rigorous monitoring regimen for potassium levels in patients receivingthese agents and call for renal function to be checked 3 days and 1 week after the start of treatment, then at least monthly for the first 3 months.[29] In patients taking an ARB,recommended monitoring is less stringent, with guidelines advising reassessment of potassium levels and renal function 1 – 2 weeks after the start of treatment and after dosagechanges.[29] Clinicians must consider whether frequent monitoring of potassium levels andrenal function will be feasible when starting either agent.

Patients prescribed the combination of isosorbide dinitrate plus hydralazine will likelyexperience relatively mild adverse effects, such as headache, dizziness, and gastrointestinalupset. These patients do not require laboratory monitoring but need to have their blood pressure monitored.

Cost and Dosing Frequency

When providing add-on therapy for patients, clinicians should consider drug cost andfrequency of administration. The least expensive add-on therapy is spironolactone, whichcosts approximately $13/month.[46] In contrast, the other available aldosterone inhibitor,eplerenone, costs approximately $110/month.[46] Both aldosterone inhibitors are

administered once/day. The ARBs vary in cost from approximately $60/month for candesartan, which is also a once-daily therapy, up to approximately $100 – 130/month for valsartan, which requires twice-daily dosing.[46] The most expensive option is thecombination formulation of isosorbide dinitrate plus hydralazine, which costsapproximately $180/month; however, the cost increases to $360/month at maximallytitrated doses.[46] In addition, this combination requires 3 times/day dosing.



The separate components of the combination formulation of isosorbide dinitrate plushydralazine are available as generic formulations but have not been evaluated in recenttrials. Some clinicians may consider substituting the generic formulations for cost savings, but they should be mindful of the even greater pill burden required to achieve the dosagesstudied in AHeFT. When generic formulations of isosorbide dinitrate and hydralazine are

combined, the cost decreases from $360/month to $100 – $200/month at maximally titrateddoses.[46] Each patient should be assessed for barriers to compliance and payment beforeselecting and individualizing therapy for heart failure.

Conclusion

Heart failure is an increasing and often misunderstood epidemic. Knowledge about the pathophysiology and treatment of heart failure is continually growing; however, gapsremain in the evidence needed to maximize pharmacotherapy. Beyond the core treatmentregimen of ACE inhibitors and β-blockers, several therapeutic options are available to theclinician. These include aldosterone antagonists, ARBs, and isosorbide dinitrate plus

hydralazine. Direct comparisons among these agents are needed. When selecting theappropriate pharmacologic class for individual patients, clinicians should consider thefollowing: clinical trial results for specific patient populations, background drugs, safetyand tolerability, cost, and dosing frequency. The benefits of these agents can also beaugmented with nonpharmacologic treatments, such as implantable cardiac defibrillatorsand cardiac resynchronization therapy. New pharmacologic treatments for heart failure thatare on the horizon show therapeutic potential. The task of developing a heart failuretreatment plan is growing increasingly complex and will continue to evolve.

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Pharmacotherapy. 2008;28(7):920-931. © 2008 Pharmacotherapy PublicationsCopyright © 1999, Pharmacotherapy Publications, Inc., All rights reserved.

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