Feature Article
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Angiotensin Receptor Blocker Use for Hypertension Treatment in the Elderly Angiotensin receptor blockers (ARBs) are a new class of drug that has entered the hypertension market within the last five years. This class, although similar to angiotensin converting enzyme (ACE) inhibitors in their renal cardiovascular effects, has a different mechanism of action. By directly blocking the receptor, ARBs can have specific effects on systems that are affected by angiotensin II . Because of this differential effect, this class of drugs is better tolerated by patients, as is evident in lower side-effect profiles with ARB use when compared with ACE inhibitors. This article reviews the data from all available, well-designed studies in the elderly with regard to ARB use related to hypertension and renal disease.
(Annals of Long-Term Care 1999;7[8]:305-308)
Introduction
Our understanding of the renin-angiotensin-aldosterone system (RAS) has evolved since the discovery of renin some 100 years ago. The delineation of renin's role in the physiology of this system subsequently led to the discovery of angiotensin converting enzyme (ACE) inhibitors in the 1970s. This class of agents was heralded on the market with the introduction of captopril in 1981. The first ACE inhibitors, although designed and approved as antihypertensive agents, were soon proven in clinical trials to reduce mortality in both heart failure and the postmyocardial infarction period, as well as during the slow progression to end-stage renal disease. It was noted, however, that angiotensin II levels in the plasma returned to baseline within weeks of starting an ACE inhibitor, yet the antihypertensive effect persisted. This finding led to the concept of tissue ACE activity. However, it also signaled the presence of alternative pathways that generated angiotensin II, specifically the chymase pathway. Thus, after a period of a month or more, angiotensin II levels are not significantly lower than baseline while patients have good blood pressure control on ACE inhibitors.
Because of these and related observations, the need for the development of an angiotensin receptor antagonist was clear. With improved assaying techniques and intensive research, the development of specific receptor antagonists to further our understanding of the RAS has occurred. Angiotensin receptor blockers (ARBs) became available to clinicians in 1993, when losartan was released for use as an antihypertensive agent. This class of antihypertensive agents is different from ACE inhibitors in mechanism of action and tolerability (Table). Unlike ACE inhibitors, ARBs block the angiotensin I receptor, one of four receptors with which angiotensin II can interact to cause changes in the cell.1 This review summarizes the evidence for ARB use in cardiovascular diseases of the elderly.
Classification of ARBs
Presently there are five drugs from the ARB class on the U.S. market. In the order of Food and Drug Administration approval and release onto the market, these agents are as follows: losartan, valsartan, irbesartan, candesartan, andtelmisartan. As can be seen, the suffix "-sartan" distinguishes this class from the ACE inhibitors, which have the suffix "-pril." ARBs differ somewhat in their chemical structure, potency, bioavailability, plasma half-life (telmisartan has the longest half-life; losartan, the shortest), and metabolism. Unlike ACE inhibitors, none of the ARBs act as prodrugs (ie, inactive until converted by the liver to active agents, such as enalapril). Losartan, however, has an active metabolite that also serves to extend the duration of drug action.
All ARBs are indicated as once-a-day medications for blood pressure reduction. However, clinical practice suggests that some agents should be used twice a day to achieve adequate blood pressure goals as outlined by The Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.2 This class of antihypertensive drugs is very well tolerated, with side-effect profiles comparable to those with placebo. Moreover, no dosage adjustment is necessary with respect to age, gender, renal impairment, or timing of the meal.
Clinical Uses
The use of ARBs in hypertension and in heart failure will be discussed.
Use in Hypertension
ARBs effectively lower both systolic and diastolic blood pressure in patients with hypertension. This antihypertensive effect is sustained for periods over one year in duration.3 Results from studies of African-Americans suggest that the efficacy of low-dose ARBs is comparable to that of low-dose ACE inhibitors. For example, blood pressure is not reduced as effectively as with higher doses of these drug classes. Moreover, the addition of a diuretic to low doses of these agents significantly potentiates their effectiveness at lowering blood pressure. The diuretic stimulates the activity of the RAS through intrarenal mechanisms. Consequently, blood pressure becomes increasingly dependent on angiotensin II, and the hypotensive effect of the ARB is, therefore, accentuated. In our opinion, neither race nor age should preclude consideration of ARB therapy in patients who could truly benefit.
To improve compliance and efficacy with the ARBs, several--including losartan and valsartan--are available as a fixed-dose combination with a diuretic. Additionally, a fixed-dose combination with two other agents is expected to be released in the near future. It should be noted, however, that the addition of a diuretic to ARBs might yield the same consequence (ie, hypotension) in the elderly as its addition to an ACE inhibitor. Thus, before starting this therapy, fluid status needs to be assessed and volume depletion corrected in order to avoid profound hypotension after the first dose.
Lastly, ARBs, like ACE inhibitors and calcium antagonists, have neutral effects on insulin resistance, a risk factor associated with the development of cardiovascular disease, diabetes, and hypertension. This is in contrast to moderate- to high-dose diuretics or beta-blockers that clearly increase insulin resistance and the tendency of an obese, nondiabetic patient to develop diabetes.
Use in Heart Failure
ACE inhibitors are known to improve symptomatic status in all grades of heart failure.1 These agents also reduce mortality associated with heart failure. Thus, certain ACE inhibitors that underwent the appropriate clinical trials carry an indication for their use in heart failure.
Unlike ACE inhibitors, however, the data in this area are not as plentiful with ARB. At least two short-term studies of 12 weeks' duration have evaluated losartan with respect to humoral and hemodynamic changes in patients with heart failure.4,5 The results showed a sustained hemodynamic effect at 12 weeks. Another study carried out over three months in 116 patients with heart failure revealed that losartan was generally well-tolerated and comparable to enalapril concerning improved exercise tolerance.6
The only large-scale trial, however, that has evaluated the effects of an ARB in elderly patients with heart failure is the Evaluation of Losartan in the Elderly (ELITE) trial.3 This trial randomized 722 ACE inhibitor–naive subjects over 65 years of age who had Class II-IV heart failure to an ACE inhibitor or to losartan. The primary endpoint in this trial was the degree of elevation in serum creatinine. Secondary endpoints included death related to heart failure or hospital admission, total mortality, severity of heart failure (New York Heart Association [NYHA] class), and admission for myocardial infarction or unstable angina.
The results demonstrated that both groups enjoyed similar improvement in NYHA class. Moreover, there was no difference between groups in the frequency of admissions for heart failure or rise in serum creatinine. Interestingly, sudden death was lower in the ARB group. Since the trial was not intended to look at sudden death, a second trial was designed to address this issue--ELITE II. We must await the results of this and other ongoing trials to answer this question definitively.
It is important to realize that although definitive data are not available on the question of cardiovascular mortality in heart failure, the RAS plays an important contributing role. Thus, until more data are available, it seems prudent to substitute an ARB to block angiotensin II effects in patients who cannot tolerate an ACE inhibitor.
In the ELITE trial, ACE inhibitors were generally not as well tolerated as the ARB. Overall, the results showed that the ARB drug was better tolerated than the ACE inhibitor, specifically as related to the areas of renal function, hyperkalemia, and cough.
Side Effects
Side effects to consider include worsening of renal function, cough and other adverse effects, and renal disease.
Worsening of Renal Function
The primary endpoint in this randomized, double-blind trial was the difference in serum creatinine elevation between losartan andcaptopril (more than 0.3 mg/dL). The data revealed that persistent increases in serum creatinine were the same for both drugs (10.5%). Less than 2% of subjects, however, had to discontinue their participation for this reason. Moreover, whereas hyperkalemia was present in 18.8% of patients treated with losartan and 22% of patients treated with captopril, less than 2% had to discontinue the drug.
Clinicians should also keep in mind that concomitant use of nonsteroidal anti-inflammatory agents or high intake of foods containing potassium (eg, fruits, potatoes) with ACE inhibitors markedly increases the likelihood of hyperkalemia in elderly patients. This result is especially true in elderly patients with serum creatinine levels greater than 1.3 mg/dL. This finding is due primarily to the higher proportion of such patients who may become volume-depleted in the presence of poor fluid intake and/or concomitant use of diuretics, and subsequently having a reduction in their already age-related decrease in renal function. ARBs, however, do not have the same tendency toward development of hyperkalemia. Although these agents will increase serum potassium in the aforementioned setting, the degree of increase is less, since these agents do not reduce aldosterone to the same degree as an ACE inhibitor.
Cough or Other Adverse Effects
Cough is a frequent side effect of ACE inhibitor therapy.7 It often necessitates discontinuation of therapy. In the ELITE trial, 14 out of 370 patients (3.8%) on captopril had to discontinue the drug; there were no discontinuations because of cough in the losartan group.
In addition, losartan was generally better tolerated, as fewer patients discontinued therapy because of adverse experience (12.2% for losartan versus 20.8% for captopril; P = .002). Despite a 10.5% incidence of persistent renal dysfunction, less than 2% of patients had to discontinue the drug for this reason.
Overall, significantly more patients withdrew from captopril than from losartan (21% versus 12%, P = .002), mainly due to the incidence of cough but also because of angioedema, rash, and taste disturbances, all of which are well-known to be ACE inhibitor- or captopril-related side effects.
Renal Disease
It is known that ACE inhibitors significantly reduce the loss of kidney function in diabetic nephropathy as well as a variety of other renal diseases (eg, glomerulopathies, interstitial nephritis). Such data are not yet available for evaluating ARBs in this role. A recent review concluded that it is too early to judge the clinical impact of ATI receptor blockers on nondiabetic renal disease.8 However, in hemodynamically mediated renal disease, emerging data show that ATI antagonists have efficacy similar to ACE inhibitors for preserving renal function and morphology.
Mortality
In the ELITE trial, the losartan group had fewer deaths or hospital admissions than did the captopril group (9.4% versus 13.2%). This difference trans lates into a 32% reduction in relative risk by losartan (95% confidence interval, -4% to 55%, P = .075). This finding was primarily due to a decrease in all-cause mortality, and in particular due to a decrease in sudden cardiac death in the losartan arm. Most of the decrease in mortality was seen in the first three months.
An interesting experiment has been performed on human atrial tissue obtained from patients undergoing coronary bypass grafting.9 It showed that the decrease in sudden cardiac death in the losartan group of the ELITE trial could be related to decreased concentrations of noradrenaline in the losartan-treated cardiac tissue as compared with captopril-treated tissue. This result helps to further establish the concept that agents that block angiotensin II action protect not only through this mechanism, but also through indirect blockade of the sympathetic nervous system.
Conclusion
In summary, ARBs are antihypertensive agents with efficacy comparable to that of ACE inhibitors. Some of the newer agents may have a more pronounced antihypertensive effect.10 These drugs are better tolerated than the ACE inhibitors, and the addition of a low-dose diuretic also increases efficacy.
Cough is not a class-specific adverse effect. In the elderly, discontinuation rates for elevation in serum creatinine or potassium are under 2% for either captopril or losartan. Approved as once-a-day agents, ARBs are convenient for use.
There is also potential for additional benefits from ARBs, such as a decrease in sudden death among elderly persons with systolic heart failure. Trials such as ELITE II, Losartan Intervention for Endpoint Reduction in Hypertension (LIFE), Reduction of Endpoint in Non-Insulin Dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan (RENAAL), Valsartan Antihypertensive Long-Term Use Evaluation (VALUE), and Valsartan Heart Failure Trial (VALHEFT) are well underway, and more outcomes data will be available in the near future.
References
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2. The Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157.
3. Pitt B, Segal R, Martinez FA, Meurers G. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747-752.
4. Gottlieb SS, Dickstein K, Fleck E, et al. Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation 1993;88:1602-1609.
5. Crozier I, Ikram H, Awan N, et al. Losartan in heart failure: Hemodynamic effects and tolerability. Circulation 1995; 91(3):691-697.
6. Lang RM, Elkayam U, Yellen LG, et al. Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. J Am Coll Cardiol 1997;30(4):983-991.
7. Pitt B, Chang P, Timmermans PBMWM, et al. Angiotensin II receptor antagonists in heart failure: Rationale and design of the Evaluation of Losartan in the Elderly (ELITE) Trial. Cardiovasc Drugs Ther 1995;9:693-700.
8. Tarif N, Bakris GL. Angiotensin II receptor blockade and progression of nondiabetic- mediated renal disease. Kidney Int 1997;52(suppl 63):S67-S70.
9. Rump LC, Oberhauser V, Schwertfeger E, Schollmeyer P. Experimental evidence to support ELITE. Lancet 1998;351:644-645.
10. Elliot HL. Angiotensin II antagonists: Efficacy, duration of action, comparison with other drugs. J Hum Hypertens 1998;12:271-274.
From the Rush University Hypertension/Clinical Research Center, Department of Preventive Medicine, Rush Presbyterian/St. Luke's Medical Center, Chicago, IL. Address for correspondence: George Bakris, MD, Rush Presbyterian/St. Luke's Medical Center, 1725 W Harrison St, Suite 117, Chicago, IL 60612. E-mail: gbakris@rush.edu. Annals of Long-Term Care - ISSN: 1524-7929 - Volume 7 - Issue 08 - August 1999 |