After completing this continuing education article, the pharmacist should be able to:
Individually, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have proven to be a versatile and critically important armamentarium for treating various cardiac and proteinuric kidney diseases (Table 1). Although both classes of drugs block the effects of the renin-angiotensinaldosterone system (RAAS), they exhibit complementary and additive effects by interrupting different sites of the RAAS cascade (Figure). In the past year, several landmark trials have been published in the literature, yet there is still limited and sometimes conflicting information regarding the combination use of the 2 classes. This article will review the available literature on clinical outcomes and how they may be applied in practice for 3 major medical conditions with high morbidity and mortality: systolic heart failure (HF), myocardial infarction (MI), and proteinuric nephropathy.
Whereas ACE inhibitor and ARB combination therapy has been studied in patients with hypertension, the results have been inconsistent.1-3 A review of this topic has recently been published,4 and the reader is referred to that reference for a more thorough discussion. Although we will not address hypertension therapy in this article, it is important to point out that the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) provided no recommendation on combination therapy, but it noted ARBs to be equivalent to ACE inhibitors for the treatment of hypertension.5 ARBs have favorable tolerability; clinical trials have found the incidence of side effects to be similar to that with placebo.
To understand the rationale for combination therapy, it is necessary to review the RAAS, including the alternative pathways for the production of angiotensin II, the major hormone of the RAAS (Figure). Angiotensin II is a potent vasoconstrictor, whereas the other important hormone, bradykinin, is a potent vasodilator. The reduction in circulating angiotensin II and elevated bradykinin levels are responsible for many of the observed benefits of ACE inhibitors.6 Angiotensin II is responsible for many harmful effects, including the promotion of hypertension, atherosclerosis, and hypertrophic changes in the blood vessels and the left ventricle.7,8 It has been demonstrated that levels of circulating angiotensin II return to pre-ACE inhibitor treatment values in patients receiving chronic ACE inhibitor therapy. This increase in angiotensin II levels, or "ACE escape,"is incompletely understood but thought to be associated with alternate synthesis pathways for angiotensin II. Enzymes such as cathepsin G and elastase are thought to directly convert angiotensinogen to angiotensin II, while chymases and cathepsin G are thought to provide an alternate pathway for conversion of angiotensin I to angiotensin II (Figure). In addition to being a potent vasodilator, bradykinin releases local tissue plasminogen activator (tPA), which is thought to provide beneficial antiischemic effects with long-term ACE inhibitor therapy.9 By targeting both the ACE and the angiotensin receptors, the goal of therapy is to completely block the RAAS cascade and to maintain a high level of bradykinin.
The activation of the RAAS occurs in response to a decrease in cardiac output, manifested as a decrease in renal perfusion or through sympathetic stimulation. As a compensatory mechanism, renin is released from the kidneys and is responsible for the conversion of angiotensinogen to angiotensin I. Angiotensin I is then further converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II stimulates the angiotensin receptors AT1 and AT2 , resulting in vasoconstriction and sympathetic activation, among other effects, as shown in the Figure. In addition, a feedback mechanism occurs at the adrenal gland, triggering the synthesis and release of aldosterone and leading to the retention of sodium and water. These activities ultimately lead to increased systemic blood pressure and cardiac output, a short-term hemodynamic benefit.
Whereas the actions of the RAAS are beneficial under certain conditions, chronic activation of this system more commonly results in deleterious effects for the patientnamely, hypertension, HF, kidney disease, and, if left untreated, death. When targeting the RAAS, clinicians currently have only a few major drug classes to select from: ACE inhibitors, ARBs, and the aldosterone antagonists (spironolactone and eplerenone). Mechanistically, there are 2 important distinctions between the ACE inhibitor and ARB classes: what point in the RAAS cascade each class is targeting and its effect on bradykinin. As described in the Figure, ACE inhibitors block the conversion of angiotensin I to angiotensin II and prevent degradation of bradykinin. ARBs, on the other hand, have little effect on bradykinin and work further downstream in the RAAS by blocking angiotensin II at the receptor site. Thus, by utilizing combination ACE inhibitor/ARB therapy, one would expect to gain broader and more complete blockade of the RAAS, potentially preventing or slowing the harmful effects of its continued stimulation.
HF is a progressive, debilitating, and often-fatal cardiac condition that afflicts a large number of individuals in the United States. During the past decade, there have been significant advances in the understanding of the pathology associated with the disease and, correspondingly, new treatment options. Despite considerable progress, HF remains one of the leading cardiovascular (CV) diseases in terms of morbidity, mortality, and economic burden.10 Recognizing the impact of HF and the rapid changes in therapeutic discoveries, influential organizations such as the American College of Cardiology/American Heart Association (ACC/AHA) and the Heart Failure Society of America (HFSA) have developed clinical practice guidelines to assist clinicians in providing optimal care to patients with HF. The guidelines undergo regular revisions; the HFSA update is scheduled for release later this year, whereas an ACC/AHA update is under way (release date unknown).
Pathophysiology of Systolic HF
HF is divided into 2 distinct types: systolic and diastolic. Although congestion symptoms are typically seen in both types, the left ventricle functions normally in diastolic HF (ejection fraction [EF] > 50%). The problem lies in the difficulty in filling the left ventricle due to high filling pressure; this condition is a common result of long-term hypertension. Generally, the long-term prognosis is much better than in patients stricken with systolic HF. Systolic HF signifies a failing left ventricle (EF<40%). This condition is commonly the result of acute myocardial infarction (AMI) or cardiomyopathy.
Experts now know that, in the setting of acute HF, compensatory mechanisms of the RAAS and sympathetic nervous system (SNS) are activated to enhance production of neurohormones, including angiotensin II, aldosterone, and norepinephrine. These neurohormones are effective in the short term at maintaining blood pressure and the perfusion of major organs through vasoconstriction and water retention, as well as producing positive inotropic and chronotropic effects.11 Unopposed activation of the RAAS and SNS for days and weeks, however, ultimately leads to remodeling of the ventricles, HF, and eventually death.12,13
Standard Medical Treatment of Systolic HF
The current "gold standard"of HF therapy is designed to interrupt the cycle of RAAS and SNS activation by using a combination of medications. Complementary to ACE inhibitor blockade of the RAAS, beta-blockers antagonize the harmful effects of norepinephrine produced during SNS activation. Trials have demonstrated therapeutic successes when combining medications that target different neurohormones using dosing targets that have proven beneficial.14-22 Table 2 outlines the current drug recommendations by the ACC/AHA and HFSA for the treatment of systolic HF. ACE inhibitors and beta-blockers have both been proven to reduce mortality in HF. On the other hand, ARBs have been shown only to reduce HF symptoms and hospitalization, but not mortality.23-25
Role of Combination Therapy with ACE Inhibitors and ARBs in Systolic HF
Despite the advancement of therapy and implementation of guidelines, morbidity and mortality from HF remain high. Even with ACE inhibitor therapy, left ventricular dysfunction continues to progress in most patients, and 1-year mortality approaches 35% to 40%.26 Clinical trials investigating the use of ACE inhibitors and ARBs in combination 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 in Heart Failure Assessment of Reduction in Morbidity and Mortality-Added)28 trials last year, only small short-term studies demonstrated beneficial suppression of neurohormone levels leading to blood pressure lowering, regression of ventricular remodeling, and improved exercise tolerance.29-32 Val-HeFT and CHARM-Added provided important information regarding the use of ACE inhibitor/ARB combination therapy and the reduction of HF-related morbidity and mortality.
The Val-HeFT trial compared the use of valsartan versus placebo on top of the background ACE inhibitor therapy and the effect on mortality. The study enrolled 5010 patients with moderate-to-severe HF, defined as New York Heart Association (NYHA) class II to IV. The use of valsartan 160 mg twice daily resulted in significant improvement in morbiditynamely, HF symptoms, left ventricular ejection fraction (LVEF), and hospital admission. All-cause mortality, however, was not significantly reduced when considered independently of morbidity. As a result of the study, valsartan became the first and only ARB to date to receive FDA indication for the treatment of HF in patients intolerant of ACE inhibitors.
Interestingly, a subgroup analysis of patients receiving an ACE inhibitor, a beta-blocker, and valsartan ("triple therapy") revealed an adverse effect on mortality that was statistically significant, as well as a trend toward an adverse effect on morbidity. However, this subgroup accounted for only 35% of the study population. Much larger databases from the CHARM-Added28 and VALIANT (Valsartan in Acute Myocardial Infarction Trial)33 studies refuted this finding.
Another landmark study examining the combination use of ACE inhibitors and ARBs is the CHARM-Added trial, a substudy in 2548 of the original 7601 NYHA class II to IV HF patients of the CHARM-Overall Programme.34 Patients in the CHARM-Added arm had an LVEF of ≤40% and had been taking an ACE inhibitor for at least 30 days prior to inclusion. Candesartan or placebo was added to the patient's stable HF regimen and was titrated by the individual investigator to a target dose of 32 mg daily as tolerated. The primary outcome studied was CV death or unplanned hospital admission for worsening HF management. Of note, 55% of the CHARM-Added population was receiving concurrent beta-blocker therapy.
Thirty-eight percent of patients in the candesartan arm experienced the primary outcome, compared with 42% in the placebo group, a difference that statistically favored the use of candesartan. Also, CV death was statistically different between the groups; 347 CV deaths occurred in the placebo group, compared with only 302 CV deaths in the candesartan group. From these data, one can infer that the combination of an ACE inhibitor and an ARB does provide morbidity and mortality benefit in HF patients who are still symptomatic despite being treated with HF regimens that meet currently accepted HF guidelines (Table 2). Similar to the finding from Val-HeFT, CHARM-Added reduced morbiditynamely, hospital admission for HF. CHARM-Added, however, is the first study to prove clearly the mortality reduction benefit with the addition of ARBs to ACE inhibitors.
Additional information on the benefit of combination ACE inhibitor/ARB therapy in HF will be available with the completion of the next large study, called the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) study.35 This will be the largest HF trial to date, evaluating the combination use of ACE inhibitors and ARBs in 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 guidelines are being revised. It is reasonable to expect that the new guidelines will incorporate the positive findings of the Val-HeFT and CHARM-Added studies. Of note, as of the time of this writing, candesartan had not received FDA approval for the treatment of HF. Based on the available information, several points can be made regarding ACE inhibitors and ARBs for treating HF:
Acute Myocardial Infarction
Parallel to the advances in the pharmacologic therapy of HF over the past 10 years, the treatment of AMI has seen similar progressive developments. Standard treatment protocols for AMI now include antiplatelet (aspirin, clopidogrel), anticoagulant (heparin, low-molecular-weight heparin), nitroglycerin, beta-blocker, ACE inhibitor, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapies. Depending on the type of AMI, thrombolytics or glycoprotein IIb/IIIa antagonists can be used.43 A more recent finding that has yet to appear in the guidelines is the use of eplerenone for HF in the setting of AMI.22
ACE inhibitors have shown mortality reduction benefit and have received FDA approval for treating AMI patients who are considered high-risk, defined as patients who show evidence of acute HF associated with AMI16,44,45 (Table 1). Due to an excellent tolerability profile and effectiveness in treating hypertension, and to a lesser extent HF and nephropathy, ARBs have been touted as potential replacements for ACE inhibitors for AMI. ARBs, however, have not demonstrated a benefit parallel to that from ACE inhibitors.
In 2002, a study called OPTIMAAL (Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan) enrolled high-risk AMI patients to take either losartan 50 mg daily or the gold standard ACE inhibitor captopril 50 mg 3 times daily. Losartan was found to be inferior to captopril in preventing death from CV causes. It has been suggested, however, that the losartan dose was too low to have shown benefit.23,46 Because ARBs and ACE inhibitors have demonstrated complementary effects, the most logical next question to ask is: Does the combination of these agents provide greater benefit in high-risk patients with AMI?
The recently published VALIANT33 trial helps answer that question. The VALIANT study enrolled more than 14,000 patients with HF, LV dysfunction, or both who had experienced AMI within the preceding 10 days. Patients were randomized to valsartan or captopril alone or the combination of the 2 drugs. The hypothesis was that valsartan added to captopril was not inferior to captopril monotherapy with regard to survival. Target doses of valsartan were 160 mg twice daily or 80 mg twice daily combined with captopril 50 mg 3 times daily. Valsartan was titrated from an initial dose of 20 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 population was taking a concomitant betablocker.
No significant mortality difference was seen across the 3 groups. The proportion and number of hospitalizations for MI or HF, however, favored the combination group over the captopril group. Although the study was widely perceived as a disappointment because the combination therapy failed to show superiority to either agent alone, it was the first large study to find equivalence between an ARB and the gold standard captopril for treating high-risk AMI.
Summary of AMI Treatment
As of the time of this writing, valsartan had not received FDA indication for the treatment of AMI. Based on the available information, there are several points that can be made regarding ACE inhibitors and ARBs for treating hig-hrisk AMI patients:
The incidence of chronic kidney disease (CKD) continues to rise in the United States, with an estimated 650,000 patients expected to require dialysis and transplantation by 2010.47,48 Whereas a large portion of end-stage renal disease (ESRD) is accounted for by diabetic patients, nondiabetic renal disease also contributes to the staggering number of patients with nephropathy who progress to chronic dialysis. Thus, the need to develop treatment strategies to impact albuminuria, preserve kidney function, and ultimately lengthen the time to dialysis dependence is widely recognized. In fact, by preserving kidney function for even an additional 10 to 12 months, an estimated $58,000 per patient could be saved in dialysis-associated health care dollars.47
Activation of the SNS and local RAAS leads to increased plasma volume, glomerular capillary hypertension, and irreversible nephron injury. Whereas the normally functioning nephron is not permeable to larger molecules such as proteins, the stressed nephron will experience excessive protein filtration until proteinuria results. Albuminuria, the first sign of nephropathy, has been shown to be an independent predictor of CV morbidity and mortality.49,50
Several studies have demonstrated that ACE inhibitors are useful in reducing the risk of ESRD in diabetic patients.51-53 Additionally, trials such as the IDNT (Irbesartan Diabetic Nephropathy Trial)54 and RENNAL (Reduction in End Points in Patients with Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan)55 have found that ARBs reduce microalbuminuria and proteinuria, slowing the progression of diabetic and nondiabetic kidney disease.
Despite the proven benefit of both ACE inhibitors and ARBs independently for the treatment of diabetic nephropathy, the role of combination therapy in attenuating renal function decline has not been elucidated definitively. Also, production of approximately 40% of tissue angiotensin II in the kidney occurs through ACE-independent pathways.56 Therefore, even with ACE inhibitor or ARB monotherapy, as recommended in the guidelines for diabetic nephropathy,57 the question still remains: Are clinicians matching pharmacology with pathophysiology?
Before discussing the available literature on combination ACE inhibitor/ARB therapy in patients with nondiabetic and diabetic kidney disease, the issue of optimal nephropathy doses of these agents must be addressed. Because the recommended doses of ACE inhibitors and ARBs are derived from hypertension trials, the lack of definition of optimal nephropathy doses is commonly cited as a limitation of nephropathy studies.
To address this topic, several trials investigated the doses of lisinopril, losartan, and candesartan. Optimal nephropathy doses were found to be losartan 100 mg daily, candesartan 16 mg daily, and lisinopril 40 mg daily.58,59
Nondiabetic Renal Disease
A few small trials examined the use of combination ACE inhibitor/ARB therapy in nondiabetic renally impaired patients.36,37,47 Results from these studies consistently showed a benefit in patients in the combination arm, compared with those with either monotherapy, for the primary outcomes of proteinuria and/or progression to ESRD (Table 3). The benefit of combination ACE inhibitor/ARB therapy was evident, regardless of baseline renal function and independent of blood pressure lowering.47
Diabetic Renal Disease
Diabetic nephropathy is present in an estimated 20% to 30% of all diabetic patients and is the leading cause of ESRD in the United States, accounting for approximately 40% of newly diagnosed ESRD.47,57 Given the benefits of ACE inhibitors51-53 and ARBs54,55 when used independently in diabetic nephropathy, there has been considerable interest in the use of combination therapy to help slow the progression of renal dysfunction. As in patients with nondiabetic nephropathy, the combination use of ACE inhibitors/ARBs in diabetic patients significantly decreases albuminuria more than does monotherapy.39-42
Summary of Nephropathy Treatment
Overall, the trials that examined proteinuric nephropathy were small. Also, the majority of work was performed in Caucasian patients, not an ethnicity traditionally considered at increased risk of nephropathy. Nevertheless, the results of these trials demonstrated the potential to slow the progression of renal dysfunction and delay the time to dialysis. Based on the results from published literature, the following conclusions can be made:
Side Effects and Monitoring
Adverse effects observed with combination ACE inhibitor/ARB therapy have been relatively mild. Most commonly reported are hypotension, dizziness, increased serum creatinine, and hyperkalemia. Many studies reported no significant increases in serum potassium or other parameters. Careful monitoring, especially of potassium, however, is necessary when using multiple agents associated with hyperkalemia. Also, renal function should be closely followed. Of note, the RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction),29 CHARM-Added,28 Val-HeFT,27 and VALIANT33 studies all found that significantly more patients in the combination therapy arm discontinued study medication due to adverse events or laboratory abnormalities. Although these findings underscore the need for prudent monitoring with the use of combination therapy targeting the RAAS, they should not deter one from using an ACE inhibitor together with an ARB if clinically indicated.
The Val-HeFT data27 initially raised some concerns over the safety of ACE inhibitor/ARB/beta-blocker triple therapy, but subsequent data from the VALIANT33 and CHARM28 trials convincingly proved no increased risk of harm. Finally, there has been conflicting information regarding the safety of ARBs in patients who developed angioedema with ACE inhibitors. The risk of developing angioedema with ARBs in patients who previously experienced this side effect while on ACE inhibitors was reported to be as high as 32%.60 In the CHARM-Alternative trial, the incidence occurred in 8% of patients (3 of 39), but in only 2.5% (1 of 39 patients) was it severe enough to require discontinuation of candesartan.61 Based on the low incidence of serious cross-sensitivity, ARBs are possibly an option for patients who experienced previous angioedema with ACE inhibitors.
Despite recent advances in pharmacologic therapy to treat disease states such as HF, AMI, and nephropathy, high rates of morbidity and mortality continue to prevail. Angiotensin II appears to be the main culprit in the progression of CV and related diseases. The phenomenon of ACE escape provides a plausible explanation to support the use of combination ACE inhibitor/ARB therapy. Although combination therapy has not yet garnered FDA approval for any disease state, there is strong evidence to support ARBs as adjunctive therapy in HF patients who are still symptomatic despite optimized medication regimens with an ACE inhibitor or a beta-blocker with or without a diuretic. There is also literature to support dual ACE inhibitor/ARB therapy in diabetic and nondiabetic renally impaired patients in delaying the progression to ESRD and dialysis. On the other hand, there is no literature to support combination therapy in AMI. Although the addition of an ARB to an ACE inhibitor has generally been shown to be safe when compared with monotherapy, prudent monitoring of serum potassium, in addition to blood pressure and renal function, is a necessity.
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: email@example.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?
2. Which of the following medications from the VALIANT (Valsartan in Acute Myocardial Infarction Trial) study was found to be as effective for myocardial infarction as an angiotensin-converting enzyme (ACE) inhibitor (captopril)?
3. ACE inhibitor/angiotensin receptor blocker (ARB) combination therapy reduces mortality in which of the following disease states?
4. Which of the following regarding systolic HF is false ?
5. Which of the following is a major hormone of the renin-angiotensin-aldosterone system?
6. The rationale for combination therapy in systolic HF is the following:
7. Which of the following regarding angiotensin II is false ?
8. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure suggests that ARBs are equivalent to ACE inhibitors in the treatment of which of the following conditions?
9. Which of the following does not increase as part of the compensatory mechanism in acute HF?
10. Which of the following should be considered for all stable systolic HF?
11. CHARM-Added (Candesartan in Heart Failure Assessment of Reduction in Morbidity and Mortality-Added) showed that adding which ARB to background ACE inhibitor therapy reduced heart failure-associated mortality?
12. Which of the following regarding ACE inhibitor/ARB combination therapy is true for the treatment of nephropathy?
13. When ACE inhibitor/ARB combination therapy is used, it is important to monitor which of the following?
14. Which statement regarding adding ARB to background ACE inhibitor and beta-blocker therapy (triple therapy) is true?
15. CHARM-Alternative found the risk of cross-sensitivity to ARBs with previous ACE inhibitor-associated angioedema to be present in what percentage of patients?
16. Which of the following drugs has been proven to decrease mortality in heart failure?
17. The recommended starting dose of carvedilol is as follows:
18. The next large study on combination ACE inhibitor/ARB therapy, the results of which are scheduled to be released in 2007, is called:
19. Which type of HF carries the worst prognosis?
20. Which ARB has an FDA indication for the treatment of nephropathy?
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
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