Cardiovascular Update: The Role of Combination ACE Inhibitors and Angiotensin II Receptor Blockers

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Review the renin-angiotensin-aldosterone system.
• Explain the common pathophysiology of heart failure (HF), myocardial infarction (MI), and nephropathy.
• Discuss currently accepted treatment guidelines for HF, MI, and nephropathy.
• Describe the rationale for combination angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy in HF, MI, and nephropathy.
• Describe common side effects and monitoring recommendations associated with combination therapy.

Individually, angiotensin-convertingenzyme (ACE) inhibitors andangiotensin II receptor blockers(ARBs) have proven to be a versatileand critically important armamentariumfor treating various cardiac andproteinuric kidney diseases (Table 1).Although both classes of drugs blockthe effects of the renin-angiotensinaldosteronesystem (RAAS), they exhibitcomplementary and additive effectsby interrupting different sites of theRAAS cascade (Figure). In the past year,several landmark trials have been publishedin the literature, yet there is stilllimited and sometimes conflictinginformation regarding the combinationuse of the 2 classes. This articlewill review the available literature onclinical outcomes and how they maybe applied in practice for 3 major medicalconditions with high morbidityand mortality: systolic heart failure(HF), myocardial infarction (MI), andproteinuric nephropathy.

Whereas ACE inhibitor and ARB combinationtherapy has been studied inpatients with hypertension, the resultshave been inconsistent.^1-3 A review ofthis topic has recently been published,⁴ and the reader is referred to that referencefor a more thorough discussion.Although we will not address hypertensiontherapy in this article, it is importantto point out that the SeventhReport of the Joint National Committeeon Prevention, Detection, Evaluation,and Treatment of High Blood Pressure(JNC 7) provided no recommendationon combination therapy, but it notedARBs to be equivalent to ACE inhibitorsfor the treatment of hypertension.5ARBs have favorable tolerability; clinicaltrials have found the incidence of sideeffects to be similar to that with placebo.

Renin-Angiotensin-Aldosterone System

To understand the rationale for combinationtherapy, it is necessary toreview the RAAS, including the alternative pathways for the production ofangiotensin II, the major hormone ofthe RAAS (Figure). Angiotensin II is apotent vasoconstrictor, whereas theother important hormone, bradykinin,is a potent vasodilator. The reductionin circulating angiotensin II and elevatedbradykinin levels are responsiblefor many of the observed benefits ofACE inhibitors.⁶ Angiotensin II isresponsible for many harmful effects,including the promotion of hypertension,atherosclerosis, and hypertrophicchanges in the blood vessels and theleft ventricle.^7,8 It has been demonstratedthat levels of circulatingangiotensin II return to pre-ACEinhibitor treatment values in patientsreceiving chronic ACE inhibitor therapy.This increase in angiotensin II levels,or "ACE escape,"is incompletelyunderstood but thought to be associatedwith alternate synthesis pathwaysfor angiotensin II. Enzymes such ascathepsin G and elastase are thoughtto directly convert angiotensinogen toangiotensin II, while chymases andcathepsin G are thought to provide analternate pathway for conversion ofangiotensin I to angiotensin II (Figure).In addition to being a potent vasodilator,bradykinin releases local tissueplasminogen activator (tPA), which isthought to provide beneficial antiischemiceffects with long-term ACEinhibitor therapy.⁹ By targeting boththe ACE and the angiotensin receptors,the goal of therapy is to completelyblock the RAAS cascade and to maintaina high level of bradykinin.

The activation of the RAAS occurs inresponse to a decrease in cardiac output,manifested as a decrease in renalperfusion or through sympatheticstimulation. As a compensatory mechanism, renin is released from the kidneysand is responsible for the conversionof angiotensinogen to angiotensinI. Angiotensin I is then furtherconverted to angiotensin II by angiotensin-converting enzyme. AngiotensinII stimulates the angiotensinreceptors AT₁ and AT₂ , resulting invasoconstriction and sympathetic activation,among other effects, as shownin the Figure. In addition, a feedbackmechanism occurs at the adrenalgland, triggering the synthesis andrelease of aldosterone and leading tothe retention of sodium and water.These activities ultimately lead toincreased systemic blood pressure andcardiac output, a short-term hemodynamicbenefit.

Whereas the actions of the RAAS arebeneficial under certain conditions,chronic activation of this system morecommonly results in deleterious effectsfor the patient—namely, hypertension,HF, kidney disease, and, if left untreated,death. When targeting the RAAS,clinicians currently have only a fewmajor drug classes to select from: ACEinhibitors, ARBs, and the aldosteroneantagonists (spironolactone andeplerenone). Mechanistically, there are2 important distinctions between theACE inhibitor and ARB classes: whatpoint in the RAAS cascade each class istargeting and its effect on bradykinin.As described in the Figure, ACEinhibitors block the conversion ofangiotensin I to angiotensin II and preventdegradation of bradykinin. ARBs,on the other hand, have little effect onbradykinin and work further downstreamin the RAAS by blockingangiotensin II at the receptor site.Thus, by utilizing combination ACEinhibitor/ARB therapy, one would expectto gain broader and more completeblockade of the RAAS, potentiallypreventing or slowing the harmfuleffects of its continued stimulation.

Heart Failure

HF is a progressive, debilitating, andoften-fatal cardiac condition thatafflicts a large number of individualsin the United States. During the pastdecade, there have been significantadvances in the understanding of thepathology associated with the diseaseand, correspondingly, new treatmentoptions. Despite considerable progress,HF remains one of the leadingcardiovascular (CV) diseases in termsof morbidity, mortality, and economicburden.10 Recognizing the impact ofHF and the rapid changes in therapeuticdiscoveries, influential organizationssuch as the American College ofCardiology/American Heart Association(ACC/AHA) and the Heart FailureSociety of America (HFSA) have developedclinical practice guidelines toassist clinicians in providing optimalcare to patients with HF. The guidelinesundergo regular revisions; theHFSA update is scheduled for releaselater this year, whereas an ACC/AHAupdate is under way (release dateunknown).

Pathophysiology of Systolic HF

HF is divided into 2 distinct types:systolic and diastolic. Although congestionsymptoms are typically seen inboth types, the left ventricle functionsnormally in diastolic HF (ejection fraction[EF] > 50%). The problem lies inthe difficulty in filling the left ventricledue to high filling pressure; this conditionis a common result of long-termhypertension. Generally, the long-termprognosis is much better than inpatients stricken with systolic HF. SystolicHF signifies a failing left ventricle(EF<40%). This condition is commonlythe result of acute myocardial infarction(AMI) or cardiomyopathy.

Experts now know that, in the settingof acute HF, compensatory mechanismsof the RAAS and sympatheticnervous system (SNS) are activated toenhance production of neurohormones,including angiotensin II,aldosterone, and norepinephrine.These neurohormones are effective inthe short term at maintaining bloodpressure and the perfusion of majororgans through vasoconstriction andwater retention, as well as producingpositive inotropic and chronotropiceffects.11 Unopposed activation of theRAAS and SNS for days and weeks,however, ultimately leads to remodelingof the ventricles, HF, and eventuallydeath.^12,13

Standard Medical Treatment of Systolic HF

The current "gold standard"of HFtherapy is designed to interrupt thecycle of RAAS and SNS activation byusing a combination of medications.Complementary to ACE inhibitorblockade of the RAAS, beta-blockersantagonize the harmful effects of norepinephrineproduced during SNS activation.Trials have demonstrated therapeuticsuccesses when combiningmedications that target different neurohormonesusing dosing targets thathave proven beneficial.^14-22 Table 2 outlinesthe current drug recommendationsby the ACC/AHA and HFSA forthe treatment of systolic HF. ACEinhibitors and beta-blockers have bothbeen proven to reduce mortality in HF.On the other hand, ARBs have beenshown only to reduce HF symptoms andhospitalization, but not mortality.^23-25

Role of Combination Therapy with ACE Inhibitors and ARBs in Systolic HF

Despite the advancement of therapyand implementation of guidelines,morbidity and mortality from HFremain high. Even with ACE inhibitortherapy, left ventricular dysfunctioncontinues to progress in most patients,and 1-year mortality approaches 35%to 40%.²⁶ Clinical trials investigatingthe use of ACE inhibitors and ARBs incombination are listed in Table 3.^{3,17,27-29,31,33,35-42}

Before the publication of the Val-HeFT (Valsartan Heart Failure Trial)²⁷ and CHARM-Added (Candesartan inHeart Failure Assessment of Reductionin Morbidity and Mortality-Added)²⁸ trials last year, only small short-termstudies demonstrated beneficial suppressionof neurohormone levels leadingto blood pressure lowering, regressionof ventricular remodeling, andimproved exercise tolerance.^29-32 Val-HeFT and CHARM-Added providedimportant information regarding theuse of ACE inhibitor/ARB combinationtherapy and the reduction of HF-relatedmorbidity and mortality.

The Val-HeFT trial compared the useof valsartan versus placebo on top ofthe background ACE inhibitor therapyand the effect on mortality. The studyenrolled 5010 patients with moderate-to-severe HF, defined as New YorkHeart Association (NYHA) class II to IV.The use of valsartan 160 mg twice dailyresulted in significant improvementin morbidity—namely, HF symptoms,left ventricular ejection fraction(LVEF), and hospital admission. All-causemortality, however, was not significantlyreduced when consideredindependently of morbidity. As a resultof the study, valsartan became the firstand only ARB to date to receive FDAindication for the treatment of HF inpatients intolerant of ACE inhibitors.

Interestingly, a subgroup analysis ofpatients receiving an ACE inhibitor, abeta-blocker, and valsartan ("tripletherapy") revealed an adverse effect onmortality that was statistically significant,as well as a trend toward anadverse effect on morbidity. However,this subgroup accounted for only 35%of the study population. Much largerdatabases from the CHARM-Added28and VALIANT (Valsartan in AcuteMyocardial Infarction Trial)³³ studiesrefuted this finding.

Another landmark study examiningthe combination use of ACE inhibitorsand ARBs is the CHARM-Added trial, asubstudy in 2548 of the original 7601NYHA class II to IV HF patients of theCHARM-Overall Programme.³⁴ Patientsin the CHARM-Added arm had anLVEF of &#8804;40% and had been taking anACE inhibitor for at least 30 days priorto inclusion. Candesartan or placebowas added to the patient's stable HFregimen and was titrated by the individualinvestigator to a target dose of32 mg daily as tolerated. The primaryoutcome studied was CV death orunplanned hospital admission forworsening HF management. Of note,55% of the CHARM-Added populationwas receiving concurrent beta-blockertherapy.

Thirty-eight percent of patients inthe candesartan arm experienced theprimary outcome, compared with 42%in the placebo group, a difference thatstatistically favored the use of candesartan.Also, CV death was statisticallydifferent between the groups; 347CV deaths occurred in the placebogroup, compared with only 302 CVdeaths in the candesartan group. Fromthese data, one can infer that the combinationof an ACE inhibitor and anARB does provide morbidity and mortalitybenefit in HF patients who arestill symptomatic despite being treatedwith HF regimens that meet currentlyaccepted HF guidelines (Table 2). Similarto the finding from Val-HeFT,CHARM-Added reduced morbidity—namely, hospital admission for HF.CHARM-Added, however, is the firststudy to prove clearly the mortalityreduction benefit with the addition ofARBs to ACE inhibitors.

Additional information on the benefitof combination ACE inhibitor/ARBtherapy in HF will be available with thecompletion of the next large study,called the ONTARGET (OngoingTelmisartan Alone and in Combinationwith Ramipril Global EndpointTrial) study.³⁵ This will be the largestHF trial to date, evaluating the combinationuse of ACE inhibitors and ARBsin approximately 23,400 patients.Enrollment began in late 2001, and follow-up is projected to end in 2007(Table 3).

Summary of HF Treatment

The ACC/AHA and HFSA guidelinesare being revised. It is reasonable toexpect that the new guidelines willincorporate the positive findings of theVal-HeFT and CHARM-Added studies.Of note, as of the time of this writing,candesartan had not received FDAapproval for the treatment of HF. Basedon the available information, severalpoints can be made regarding ACEinhibitors and ARBs for treating HF:

• All stable systolic HF patients should receive ACE inhibitors(along with beta-blockers), unless contraindicated
• If the patient is intolerant of an ACE inhibitor (eg, experiencing asevere cough), an ARB—specifically,valsartan or candesartan—is a viable alternative
• An ARB (valsartan or candesartan) can be added to an HF regimencontaining an ACE inhibitor and a beta-blocker for further symptomrelief, and possibly mortality reduction

Acute Myocardial Infarction

Parallel to the advances in the pharmacologictherapy of HF over the past10 years, the treatment of AMI has seensimilar progressive developments. Standardtreatment protocols for AMI nowinclude antiplatelet (aspirin, clopidogrel),anticoagulant (heparin, low-molecular-weight heparin), nitroglycerin,beta-blocker, ACE inhibitor, and3-hydroxy-3-methylglutaryl coenzymeA reductase inhibitor (statin) therapies.Depending on the type of AMI, thrombolyticsor glycoprotein IIb/IIIa antagonistscan be used.⁴³ A more recent findingthat has yet to appear in theguidelines is the use of eplerenone forHF in the setting of AMI.²²

ACE Inhibitors

ACE inhibitors have shown mortalityreduction benefit and have receivedFDA approval for treating AMI patientswho are considered high-risk, definedas patients who show evidence of acuteHF associated with AMI^16,44,45 (Table 1).Due to an excellent tolerability profileand effectiveness in treating hypertension,and to a lesser extent HF andnephropathy, ARBs have been toutedas potential replacements for ACEinhibitors for AMI. ARBs, however,have not demonstrated a benefit parallelto that from ACE inhibitors.

ARBs

In 2002, a study called OPTIMAAL(Optimal Trial in Myocardial Infarctionwith the Angiotensin II AntagonistLosartan) enrolled high-risk AMIpatients to take either losartan 50 mgdaily or the gold standard ACE inhibitorcaptopril 50 mg 3 times daily.Losartan was found to be inferior tocaptopril in preventing death from CVcauses. It has been suggested, however,that the losartan dose was too low tohave shown benefit.^23,46 Because ARBsand ACE inhibitors have demonstratedcomplementary effects, the most logicalnext question to ask is: Does thecombination of these agents providegreater benefit in high-risk patientswith AMI?

The recently published VALIANT³³ trial helps answer that question. TheVALIANT study enrolled more than14,000 patients with HF, LV dysfunction,or both who had experiencedAMI within the preceding 10 days.Patients were randomized to valsartanor captopril alone or the combinationof the 2 drugs. The hypothesis was thatvalsartan added to captopril was notinferior to captopril monotherapy withregard to survival. Target doses of valsartanwere 160 mg twice daily or80 mg twice daily combined with captopril50 mg 3 times daily. Valsartanwas titrated from an initial dose of20 mg twice daily in a stepwise fashion.Doses could be adjusted, however,at the individual investigator's discretion,based on clinical response. Also,approximately 70% of the study populationwas taking a concomitant betablocker.

No significant mortality differencewas seen across the 3 groups. The proportionand number of hospitalizationsfor MI or HF, however, favoredthe combination group over the captoprilgroup. Although the study waswidely perceived as a disappointmentbecause the combination therapy failedto show superiority to either agentalone, it was the first large study tofind equivalence between an ARB andthe gold standard captopril for treatinghigh-risk AMI.

Summary of AMI Treatment

As of the time of this writing, valsartanhad not received FDA indicationfor the treatment of AMI. Based on theavailable information, there are severalpoints that can be made regarding ACEinhibitors and ARBs for treating hig-hriskAMI patients:

• ACE inhibitors should be considered first-line therapy for patients with AMI
• If a patient is intolerant of ACE inhibitors (eg, experiencing asevere cough), an ARB, specifically valsartan, is a viable alternative
• Combination therapy with ACEinhibitors/ARBs is not recommended for treating AMI

Nephropathy

The incidence of chronic kidney disease(CKD) continues to rise in theUnited States, with an estimated650,000 patients expected to requiredialysis and transplantation by2010.^47,48 Whereas a large portion ofend-stage renal disease (ESRD) isaccounted for by diabetic patients,nondiabetic renal disease also contributesto the staggering number ofpatients with nephropathy whoprogress to chronic dialysis. Thus, theneed to develop treatment strategies toimpact albuminuria, preserve kidneyfunction, and ultimately lengthen thetime to dialysis dependence is widelyrecognized. In fact, by preserving kidneyfunction for even an additional 10to 12 months, an estimated $58,000per patient could be saved in dialysis-associatedhealth care dollars.⁴⁷

Activation of the SNS and local RAASleads to increased plasma volume,glomerular capillary hypertension, andirreversible nephron injury. Whereasthe normally functioning nephron isnot permeable to larger molecules suchas proteins, the stressed nephron willexperience excessive protein filtrationuntil proteinuria results. Albuminuria,the first sign of nephropathy, has beenshown to be an independent predictorof CV morbidity and mortality.^49,50

Several studies have demonstratedthat ACE inhibitors are useful in reducingthe risk of ESRD in diabeticpatients.^51-53 Additionally, trials such asthe IDNT (Irbesartan DiabeticNephropathy Trial)⁵⁴ and RENNAL(Reduction in End Points in Patientswith Non-Insulin-Dependent DiabetesMellitus with the Angiotensin II AntagonistLosartan)⁵⁵ have found that ARBsreduce microalbuminuria and proteinuria,slowing the progression of diabeticand nondiabetic kidney disease.

Despite the proven benefit of bothACE inhibitors and ARBs independentlyfor the treatment of diabetic nephropathy,the role of combination therapy inattenuating renal function decline hasnot been elucidated definitively. Also,production of approximately 40% of tissueangiotensin II in the kidney occursthrough ACE-independent pathways.⁵⁶ Therefore, even with ACE inhibitor orARB monotherapy, as recommended inthe guidelines for diabetic nephropathy,⁵⁷ the question still remains: Are cliniciansmatching pharmacology withpathophysiology?

Before discussing the available literatureon combination ACE inhibitor/ARB therapy in patients with nondiabeticand diabetic kidney disease, theissue of optimal nephropathy doses ofthese agents must be addressed.Because the recommended doses ofACE inhibitors and ARBs are derivedfrom hypertension trials, the lack ofdefinition of optimal nephropathydoses is commonly cited as a limitationof nephropathy studies.

To address this topic, several trialsinvestigated the doses of lisinopril,losartan, and candesartan. Optimalnephropathy doses were found to belosartan 100 mg daily, candesartan 16mg daily, and lisinopril 40 mg daily.^58,59

Nondiabetic Renal Disease

A few small trials examined the useof combination ACE inhibitor/ARBtherapy in nondiabetic renallyimpaired patients.^36,37,47 Results fromthese studies consistently showed abenefit in patients in the combinationarm, compared with those with eithermonotherapy, for the primary outcomesof proteinuria and/or progressionto ESRD (Table 3). The benefit ofcombination ACE inhibitor/ARB therapywas evident, regardless of baselinerenal function and independent ofblood pressure lowering.⁴⁷

Diabetic Renal Disease

Diabetic nephropathy is present inan estimated 20% to 30% of all diabeticpatients and is the leading cause ofESRD in the United States, accountingfor approximately 40% of newly diagnosedESRD.^47,57 Given the benefits ofACE inhibitors^51-53 and ARBs^54,55 whenused independently in diabetic nephropathy,there has been considerableinterest in the use of combination therapyto help slow the progression ofrenal dysfunction. As in patients withnondiabetic nephropathy, the combinationuse of ACE inhibitors/ARBs indiabetic patients significantly decreasesalbuminuria more than does monotherapy.^39-42

Summary of Nephropathy Treatment

Overall, the trials that examined proteinuricnephropathy were small. Also,the majority of work was performed inCaucasian patients, not an ethnicitytraditionally considered at increasedrisk of nephropathy. Nevertheless, theresults of these trials demonstrated thepotential to slow the progression ofrenal dysfunction and delay the timeto dialysis. Based on the results frompublished literature, the following conclusionscan be made:

• Treat to goal blood pressure of lessthan 130/80 mm Hg in CKD or diabetes
• Screen for microalbuminuria amongdiabetics, also among nondiabeticsat increased risk for CKD and CVdisease, to detect early nephropathy
• Combination therapy has beenshown to reduce albuminuria,compared with monotherapy, inpatients with nondiabetic and diabeticrenal disease
• Optimal nephropathy doses shouldbe targeted to obtain maximumbenefit
• Further large-scale studies shouldbe performed to determine the roleof combination ACE inhibitor/ARBtherapy in CKD

Side Effects and Monitoring

Adverse effects observed with combinationACE inhibitor/ARB therapyhave been relatively mild. Most commonlyreported are hypotension, dizziness,increased serum creatinine, andhyperkalemia. Many studies reportedno significant increases in serum potassiumor other parameters. Careful monitoring,especially of potassium, however,is necessary when using multipleagents associated with hyperkalemia.Also, renal function should be closelyfollowed. Of note, the RESOLVD (RandomizedEvaluation of Strategies forLeft Ventricular Dysfunction),²⁹ CHARM-Added,²⁸ Val-HeFT,²⁷ andVALIANT³³ studies all found that significantlymore patients in the combinationtherapy arm discontinued studymedication due to adverse events orlaboratory abnormalities. Althoughthese findings underscore the need forprudent monitoring with the use ofcombination therapy targeting theRAAS, they should not deter one fromusing an ACE inhibitor together withan ARB if clinically indicated.

The Val-HeFT data²⁷ initially raisedsome concerns over the safety of ACEinhibitor/ARB/beta-blocker triple therapy,but subsequent data from theVALIANT³³ and CHARM²⁸ trials convincinglyproved no increased risk ofharm. Finally, there has been conflictinginformation regarding the safety ofARBs in patients who developedangioedema with ACE inhibitors. Therisk of developing angioedema withARBs in patients who previously experiencedthis side effect while on ACEinhibitors was reported to be as high as32%.⁶⁰ In the CHARM-Alternative trial,the incidence occurred in 8% ofpatients (3 of 39), but in only 2.5% (1of 39 patients) was it severe enough torequire discontinuation of candesartan.⁶¹ Based on the low incidence ofserious cross-sensitivity, ARBs are possiblyan option for patients who experiencedprevious angioedema with ACEinhibitors.

Summary

Despite recent advances in pharmacologictherapy to treat disease statessuch as HF, AMI, and nephropathy,high rates of morbidity and mortalitycontinue to prevail. Angiotensin IIappears to be the main culprit in theprogression of CV and related diseases.The phenomenon of ACEescape provides a plausible explanationto support the use of combinationACE inhibitor/ARB therapy.Although combination therapy hasnot yet garnered FDA approval for anydisease state, there is strong evidenceto support ARBs as adjunctive therapyin HF patients who are still symptomaticdespite optimized medicationregimens with an ACE inhibitor or abeta-blocker with or without a diuretic.There is also literature to supportdual ACE inhibitor/ARB therapy indiabetic and nondiabetic renallyimpaired patients in delaying the progressionto ESRD and dialysis. On theother hand, there is no literature tosupport combination therapy in AMI.Although the addition of an ARB toan ACE inhibitor has generally beenshown to be safe when comparedwith monotherapy, prudent monitoringof serum potassium, in addition toblood pressure and renal function, is anecessity.

Kelley Chiaventone, PharmD, Pharmacy Practice Resident, Mayo Clinic College of Medicine. Narith Ou, PharmD, BCPS, Pharmacotherapy, Coordinator-Cardiology, Mayo Clinic College of Medicine .

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@mwc.com.

CE REVIEW QUESTIONS

(Based on the article starting on page 92.) Choose the 1 most correct answer.

1. Which of the following differentiates systolic heart failure (HF) from diastolic HF?

• Systolic HF is caused by chronic hypertension.
• Systolic HF is associated with an ejection fraction of<40%.
• Systolic HF is associated with an ejection fraction of > 50%.
• Systolic HF has a better prognosis.

2. Which of the following medications from the VALIANT (Valsartan in AcuteMyocardial Infarction Trial) study was found to be as effective for myocardialinfarction as an angiotensin-converting enzyme (ACE) inhibitor (captopril)?

• Candesartan
• Losartan
• Irbesartan
• Valsartan

3. ACE inhibitor/angiotensin receptor blocker (ARB) combination therapyreduces mortality in which of the following disease states?

• Acute myocardial infarction (AMI)
• HF
• Nephropathy
• Hypertension

4. Which of the following regarding systolic HF is false ?

• There have been significant advancements in the understanding of the pathology.
• There have been significant advances in treatment options.
• HF is no longer considered one of the leading cardiovascular diseases in terms of morbidity, mortality, and economic burden.
• The American College of Cardiology/American Heart Association and the Heart Failure Society of Americahave developed guidelines to assist clinicians in treating HF.

5. Which of the following is a major hormone of the renin-angiotensin-aldosterone system?

• Bradykinin
• Angiotensin I
• Norepinephrine
• Angiotensin II

6. The rationale for combination therapy in systolic HF is the following:

• Complete blockade of angiotensin II
• Increased bradykinin
• Increased cardiac output
• Increased diuresis

7. Which of the following regarding angiotensin II is false ?

• It is a potent vasoconstrictor.
• It promotes the development of hypertension, atherosclerosis, and left ventricular dysfunction.
• The goal in HF treatment is to decrease its production.
• It provides beneficial effect as a potent vasodilator.

8. The Seventh Report of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High Blood Pressure suggests that ARBsare equivalent to ACE inhibitors in the treatment of which of the following conditions?

• AMI
• HF
• Hypertension
• Angina

9. Which of the following does not increase as part of the compensatory mechanism in acute HF?

• Angiotensin II
• Norepinephrine
• Aldosterone
• Bradykinin

10. Which of the following should be considered for all stable systolic HF?

• ACE inhibitors and beta-blockers
• Digoxin and diuretics
• Spironolactone and ARBs
• ACE inhibitors and ARBs

11. CHARM-Added (Candesartan inHeart Failure Assessment of Reduction inMorbidity and Mortality-Added) showedthat adding which ARB to backgroundACE inhibitor therapy reduced heart failure-associated mortality?

• Candesartan
• Valsartan
• Losartan
• No ARB has shown benefit in decreasing mortality when added to an ACE inhibitor.

12. Which of the following regarding ACE inhibitor/ARB combination therapy is true for the treatment of nephropathy?

• Combination therapy is effective only in the treatment of diabetic nephropathy.
• Combination therapy is effective only in the treatment of nondiabetic nephropathy.
• Combination therapy is effective for both diabetic and nondiabetic nephropathy.
• Combination therapy is not effective in the treatment of nephropathy.

13. When ACE inhibitor/ARB combination therapy is used, it is important to monitor which of the following?

• Serum potassium alone
• Blood pressure alone
• Renal function alone
• All of the above

14. Which statement regarding adding ARB to background ACE inhibitor and beta-blocker therapy (triple therapy) is true?

• All studies found increased risk of harm.
• All studies found no increased risk of harm.
• The Val-HeFT (Valsartan Heart Failure Trial) found decreased harm with triple therapy.
• In the CHARM-Added and VALIANT studies, combination therapy found no increased harm.

15. CHARM-Alternative found the risk of cross-sensitivity to ARBs with previousACE inhibitor-associated angioedema to be present in what percentage of patients?

• 32%
• 50%
• 8%
• 2.5%

16. Which of the following drugs has been proven to decrease mortality in heart failure?

• Digoxin
• Diuretics
• ARBs
• Beta-blockers

17. The recommended starting dose of carvedilol is as follows:

• 3.125 mg bid
• 6.25 mg bid
• 12.5 mg bid
• 25 mg bid

18. The next large study on combination ACE inhibitor/ARB therapy, the results ofwhich are scheduled to be released in 2007, is called:

• ONTARGET (Ongoing TelmisartanAlone and in Combination withRamipril Global Endpoint Trial)
• CHARM-Again
• Val-HeFT
• RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction)

19. Which type of HF carries the worst&#160;prognosis?

• Diastolic HF
• Systolic HF
• Right HF
• All have equally poor prognosis.

20. Which ARB has an FDA indication&#160;for the treatment of nephropathy?

• Candesartan
• Losartan
• Telmisartan
• Valsartan

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