Angiotensin II Antagonists – Therapeutic Benefits Spanning the Cardiovascular Disease Continuum From Hypertension to Heart Failure and Diabetic Nephropathy

By Ribeiro, Artur Beltrame

Key words: Angiotensin II antagonists * Cardiovascular disease * Diabetes mellitus * Elderly * End-stage renal disease * Heart failure * Hypertension * Isolated systolic hypertension * Losartan * Myocardial infarction * Pediatric * Stroke

ABSTRACT

Background: The cardiovascular benefits of angiotensin II antagonists (AIIAs) have been evaluated not only in terms of their ability to lower blood pressure but also on their ability to prevent strokes, cardiac events, and target organ damage. This review summarizes the body of evidence-based data demonstrating the efficacy of AIIAs across the spectrum of cardiovascular disease.

Methods: A PubMed/MEDLINE search of English-language articles (1990 to September 2005) was used to identify articles describing clinical studies, particularly outcome trials, or mechanisms of therapeutic action pertinent to the therapy of cardiovascular disease or nephropathy.

Findings: The antihypertensive efficacy of AIIAs is apparent across a wide spectrum of hypertensive patients, including black and Asian patients and patients with isolated systolic hypertension. More importantly, large outcome-based studies have demonstrated the efficacy of AIIAs across the continuum of cardiovascular disease, including hypertension, heart failure, post-myocardial infarction, and diabetic nephropathy. The Losartan Intervention For Endpoint reduction in hypertension study (LIFE), Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus with the All Antagonist Losartan (RENAAL), and the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT) indicate that AllAs confer cardiovascular and renal protective effects beyond their ability to lower blood pressure. These bloodpressure independent protective benefits of AIIAs may arise not only by blocking the deleterious effects of All mediated via the AT^sub 1^-receptor but may also be due to beneficial molecule-specific effects. As a class, AIIAs are well tolerated with an overall adverse event profile generally comparable to placebo and superior to that typically seen with calcium channel blockers, ACE inhibitors, diuretics, and beta-blockers.

Conclusions: By utilizing the body of clinical trial evidence as a guide to rational prescribing of AIIAs, practitioners can expect to deliver clinical benefits to their patients in terms of survival, prognosis, and quality of life.

Introduction

Angiotensin II receptor antagonists (AIIAs) are the newest class of antihypertensive agents that have been demonstrated to reduce cardiovascular (CV) events. Losartan, the first member of this class, was initially introduced for the treatment of hypertension. However, since that time, a wealth of clinical trial data has accumulated demonstrating the usefulness of this and other AIIAs not only in treating hypertensive patients with widely disparate demographics but also in treating left ventricular hypertrophy (LVH) and heart failure, as well as preventing or delaying progression of diabetic nephropathy.

The CV benefits of AIIAs have been carefully evaluated not only in terms of their ability to lower blood pressure across a broad spectrum of patient types, but also in their ability to prevent cardiac events, strokes and target organ damage. Indeed, unlike older types of antihypertensive agents such as diuretics and betablockers, AIIAs have been evaluated in terms of hard clinical endpoints almost from the inception of their clinical development.

This article reviews the large body of data demonstrating the efficacy of AIIAs across the spectrum of cardiovascular disease, including hypertension, heart failure, post-myocardial infarction (post-Mi), and diabetic and non-diabetic nephropathy, as well as summarizing the possible mechanisms to explain the observed cardiovascular benefits. Relevant studies were identified through a PubMed/MEDLINE search of English-language articles published between 1990 and September 2005. The search strategy included combining the terms angiotensin II antagonists, angiotensin receptor blockers, losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan or valsartan with each of the following terms: hypertension, systolic hypertension, isolated systolic hypertension, heart failure, post-myocardial infarction, diabetic nephropathy, non- diabetic nephropathy, end-stage renal disease, safety, or adverse events. Separate sub-searches were also performed using the above terms in combination with elderly, Caucasian, white, Asian, African- American, or black. To identify possible pharmacological mechanisms of action, additional searches were also conducted by combining angiotensin II antagonists, angiotensin receptor blockers, losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, or valsartan with the terms left ventricular hypertrophy, carotid artery hypertrophy, fatty streaks, atrial fibrillation, endothelial function, platelet aggregation, plasminogen activator inhibitor (PAI- 1), uric acid, serum creatinine, proteinuria, albuminuria, transforming growth factor-β, oxidative stress, glomerular and tubulointerstitial structure, or glomerular membrane pore size. A total of 11 157 articles were identified using the initial search terms, of which a total of 162 were included in this review. Articles describing clinical studies, particularly outcome trials, or mechanisms of therapeutic action pertinent to the therapy of cardiovascular disease (CVD) or nephropathy were, in the opinion of this author, appropriate for review.

Table 1. Summary of clinical trials demonstrating the antihypertensive efficacy of AIIAs in a variety of patient types with hypertension

Hypertension

Antihypertensive efficacy

Currently, seven AIIAs are available for the treatment of hypertension (losartan, candesartan, eprosartan, irbesartan, olmesartan, telmisartan, and valsartan)1-7 and each is available as a fixed-dose combination with a thiazide diuretic. As summarized in Table 1 numerous studies have reported the blood pressure (BP)- lowering effects of AIIAs in a wide spectrum of hypertensive patients, including those with mild-to-moderate/severe essential hypertension and isolated systolic hypertension (ISH), as well as those who are Asian or black8-50. Since losartan was the first member of the AIIA class, it is not surprising that this AIIA possesses the most comprehensive body of clinical trial evidence across various patient groups.

The ability of AIIAs to impact systolic blood pressure (SBP) is particularly important since systolic hypertension, particularly ISH, represents a powerful risk factor for CVD, stroke, and end- stage renal disease (ESRD) and is especially common in elderly individuals51-57. A major goal in hypertension management, therefore, is the prevention, detection, and control of elevated SBP58-60. AIIAs represent an attractive therapeutic option for the management of systolic hypertension, especially since SBP is often difficult to control with other antihypertensive agents in clinical practice61-63.

Compared with white persons, individuals who are black not only suffer from a greater incidence of hypertension but also tend to have more severe hypertension, more resistant to effective therapy64. Although several studies have demonstrated the efficacy of AIIAs in reducing BP in black hypertensive patients (Table 1), there is evidence from a sub-analysis of the Losartan Intervention for Endpoint reduction (LIFE) study suggesting that black patients with hypertension and LVH may not respond as favorably as white patients in terms of CV outcome benefits (see below)65.

Outcome studies

As noted in a recent review by Conlin, the efficacy of an antihypertensive agent must be viewed not only in terms of its ability to reduce BP but also in its impact on relevant clinical outcomes, including stroke, coronary heart disease (CHD), and left ventricular failure66. With respect to AIIAs, several large outcome studies have been conducted in patients with hypertension (Table 2) – LIFE, Valsartan Antihypertensive Long-term Use Evaluation (VALUE), and Study on Cognition and Prognosis in the Elderly (SCOPE)67-69. The objective of the LIFE study was to compare the effects of losartanbased therapy with atenolol-based therapy, a standard antihypertensive drug with proven CV benefits, on the primary composite endpoint of CV mortality, stroke (fatal and nonfatal), and MI in hypertensive patients (aged 55 to 80 years) with LVH67. Compared with an atenolol-based regimen, a losartan-based regimen gave rise to a 13.0% relative risk reduction in the primary composite endpoint of death, MI, or stroke (p = 0.021), a 24.9% relative risk reduction in fatal or non-fatal stroke (p = 0.001), and a 25% lower incidence of newonset diabetes (p = 0.001)67. There were no significant differences in CV mortality or MI between the losartan and atenolol groups. BP fell by 30.2/16.6mmHg and 29.1/ 16.8mmHg in the losartan and atenolol groups, respectively. A lower rate of study drug discontinuation also occurred in the losartan- based group compared with the atenolol-based group (13.1% vs. 18.1%, p < 0.001). This finding may have important ramifications with respect to patients continuing with antihypertensive regimens over the long term (see safety section below).

The LIFE study was sufficiently large to permit evaluati\on of the impact of losartan on CV events in several subsets of patients, including black patients and those with either diabetes or ISH65,70,71. Although black patients with hypertension and LVH did not appear to respond as favorably as white patients in terms of the primary composite end point of CV, death, stroke, and MI, the findings of the main LIFE study were essentially mirrored in diabetes and ISH sub-analyses.

The results of LIFE are especially notable since they indicate for the first time that, despite the absence of clinically meaningful differences in attained BP, greater CV protective benefits of one antihypertensive regimen exceed those observed with another established antihypertensive therapy. This outcome-based study provides a solid foundation for an evidence-based approach for utilizing losartan in clinical practice. The stroke benefits of losartan could potentially have a farreaching impact on public health, especially since stroke occurs with greater frequency than MI in patients with hypertension72. Indeed, if the benefits of losartan over atenolol in preventing stroke are projected to the EU population who meet the eligibility criteria of LIFE, it has been estimated that the use of losartan over atenolol in hypertensive patients with LVH would prevent 125 000 first strokes over a 5.5- year period73.

The greater CV benefits of losartan compared with atenolol observed in LIFE have been attributed, in part, to decreases in LVH74. However, other potential mechanisms may also be involved, including decreased carotid artery hypertrophy75 and fatty streaks76, decreased risk of stroke in patients with atrial fibrillation77, improvement in endothelial function and structure78, inhibition of thromboxane A2-dependent platelet aggregation79, and decreased levels of plasma plasminogen activator inhibitor type-1 antigen80. A lower incidence of new onset diabetes mellitus in patients receiving losartan compared with atenolol may also have contributed to the overall CV benefits67.

Compared with diuretics, beta-blockers, or calcium channel blockers, a consistently lower incidence of type 2 diabetes in hypertensive patients has been observed following treatment not only with AIIAs but also with ACE inhibitors81. The underlying mechanisms involved in this effect are not fully understood but may involve: (A) improved blood flow to skeletal muscles, thereby enhancing insulin and glucose delivery to the insulinsensitive tissues; (B) facilitation of insulin signaling at the cellular level; and (C) improved secretion of insulin from the beta cells81. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial and ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET)82 are currently ongoing and designed, in part, to investigate further the effect of AIIAs in preventing diabetes as well as the impact on CV morbidity and mortality.

SCOPE compared the effects of candesartan with placebo on CV events, cognitive decline, and dementia in elderly hypertensive patients (Table 2)68. Patients were randomly assigned to receive candesartan or placebo, both in combination with as-needed, open- label, conventional antihypertensive therapy to attain BP goals. In the placebo group, approximately 84% received open-label antihypertensive therapies that included diuretics, ACE inhibitors, beta-blockers, or calcium channel blockers. Although candesartan produced a 27.8% reduction in non-fatal stroke compared with usual antihypertensive treatment, no significant differences were apparent between candesartan and control groups for the primary endpoint (CV death, non-fatal MI, or non-fatal stoke), for the secondary endpoint measures of all stroke, fatal stroke, MI, CV mortality, or for the proportion of patients with cognitive decline/dementia. Unlike the LIFE study, however, small differences in BP (3.2/1.6mmHg) in favor of the candesartan group may have contributed, at least in part, to the stroke benefit seen in patients receiving a candesartan-based therapy.

Table 2. Outcome studies involving AIIAs in patients with hypertension

VALUE investigated the hypothesis that, in hypertensive patients at high risk of cardiac events, valsartan would be more effective than amlodipine in preventing cardiac morbidity and mortality for an equivalent degree of BP lowering69,83. The study revealed no difference in the primary composite endpoint of cardiac morbidity and mortality or in the all-cause mortality outcome between the valsartan and amlodipine groups (Table 2). However, more valsartan patients than amlodipine patients experienced MIs (hazard ratio [HR] = 1.19, p = 0.02). As observed in SCOPE, dissimilarities in achieved BP occurred between the two study groups, a difference that was particularly apparent during the first 6 months of therapy. In fact, at both the beginning and throughout the trial, patients receiving amlodipine had better BP control than those receiving valsartan. For example, more amlodipine-treated patients than valsartan-treated patients achieved the combined systolic/diastolic BP target of < 140/ 90mmHg (62% vs. 56%, respectively).

Additional insight into the value of AIIAs in hypertensive patient populations at high risk of clinical events is expected from the telmisartan Programme of Research tO show Telmisartan End-organ proteCTION (PROTECTION) program84. This extensive clinical development program comprises a number of randomized clinical trials comparing telmisartan with valsartan, losartan, amlodipine, and ramipril on end-organ protective effects in patients at high risk of renal, cardiac, and vascular damage. Two trials with telmisartan are specifically designed to study the role of AIIAs alone or together with an ACE inhibitor in high-risk populations with controlled hypertension (i.e., patients with coronary, peripheral, or cerebrovascular disease, or diabetes with end-organ damage)82.

Heart failure

The prognosis of patients with heart failure remains poor despite advances in our understanding of the pathophysiology and treatment of this disease over the past decade. Indeed, patients with heart failure have a survival rate that is worse than that reported for many common cancers, such as bowel cancer in men and breast cancer in women85. Activation of the reninangiotensin-aldosterone system (RAAS) is recognized as playing a key pathophysiological role in the development of heart failure86. Not surprisingly, therefore, RAAS blockade using ACE inhibitors has been shown to reduce morbidity and mortality in patients with heart failure87,88. However, management of heart failure using ACE inhibitors is far from optimal. Concerns about potential adverse effects have led, in part, to an underutilization of ACE inhibitors89,90. Blockade of the RAAS at the level of the AT^sub 1^-receptor not only provides an opportunity for more complete inhibition (by blocking AII regardless of its source) but is also a way of obtaining the benefits of ACE inhibitors without their common side effects, particularly cough85.

Over the last 5 years, several large randomized clinical trials91- 97 have shed light on a potential role for AIIAs in the treatment of chronic heart failure (Table 3), including ELITE (Evaluation of Losartan In The Elderly), ELITE II (Evaluation of Losartan In The Elderly II), VaI-HeFT (Valsartan Heart Failure Trial), RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction), and Candesartan in Heart Failure Assessment of Reduction in Mortality and Mortality (CHARM).

ELITE, the first major randomized trial of an AIIA in patients with heart failure, was designed to compare losartan with captopril on the incidence of renal dysfunction (primary endpoint)92. Although no difference between study groups was noted in the primary endpoint, losartan was unexpectedly found to decrease all-cause mortality significantly compared with ACE inhibitor treated patients (p = 0.035), an effect attributable primarily to a reduction in the risk of sudden cardiac death92. The results of the ELITE trial, suggesting that losartan could be superior to captopril in patients with heart failure, prompted further studies of AIIAs in patients with heart failure. Since ELITE did not include mortality as the primary endpoint, a second study (ELITE II) was conducted to corroborate (or actually disprove) the findings of ELITE I in a larger number of patients, and to specifically evaluate the effect of losartan on all-cause mortality and sudden death93. In contrast to ELITE, however, ELITE II failed to demonstrate significant differences between the losartan and captopril groups with respect to all-cause mortality, all-cause hospitalization, or sudden death. Nevertheless, while failing to demonstrate that AIIAs are not superior to ACE inhibitors in patients with heart failure, ELITE II showed that administration of losartan to heart failure patients was efficacious and well tolerated. It should be borne in mind, however, that losartan, is not approved by the United States Food and Drug Administration (FDA) for the treatment of heart failure.

The RESOLVD study, study, which compared the effects of candesartan, enalapril, and their combination in patients with symptomatic heart failure, also showed no significant difference between AIIA and ACE inhibitor91. All three study groups were similar with respect to 6 minute walking time, NYHA-FC, quality of life, or ejection fraction91. However, patients receiving candesartan alone or enalapril alone did show greater increases in end-diastolic and end-systolic volumes compared with combination therapy (p < 0.01). Combination therapy significantly decreased aldosterone (p < 0.05) at 17 but not 43 weeks and brain natriuretic peptide (p < 0.01) vs. candesartan or enalapril alone. Although not designed to directly assess mortality, RESOLVD was stopped prematurely after an increased \number of deaths and hospitalizations was observed in patients receiving candesartan (alone or in combination with enalapril) compared with enalapril alone91.

Table 3. Outcome studies involving AIIAs in patients with heart failure

Table 3. Outcome studies involving AIIAs in patients with heart failure

Later trials in patients with heart failure (Val-HeFT94 and CHARM95-98) provided more consistent evidence of benefit of AIIAs in patients with heart failure. In VaIHeFT, the combined endpoint of all-cause mortality plus morbidity was 13.2% lower with valsartan vs. placebo (p = 0.009), an effect predominantly due to fewer hospitalizations for heart failure (p < 0.001)94. However, there was no significant difference in all-cause mortality between valsartan and placebo groups (which comprised usual therapy, including diuretics and ACE inhibitors). A subgroup analysis found that, compared with placebo, patients receiving triple therapy (valsartan, ACE inhibitor, and beta-blocker) had an increased risk of all-cause mortality (relative risk [RR] = 1.42) and the combined endpoint of death from any cause, cardiac arrest with resuscitation, hospitalization for worsening heart failure, or therapy with intravenous inotropes or vasodilators (RR = 1.18). These findings initially raised some concerns over excessive neurohormonal inhibition in heart failure patients.

CHARM, the most recent of the AIIA outcome trials in patients with heart failure, provides convincing evidence of benefit for AIIAs in all patients with chronic heart failure regardless of ejection fraction, age, and sex. CHARM consisted of three trials; CHARM-Added, CHARM-Alternative, and CHARM-Preserved96-98. CHARM- Added involved patients with ejection fractions of ≤ 0.40 who were receiving optimum doses of chronic ACE inhibitor treatment; CHARM-Alternative involved heart failure patients with ejection fractions ≤ 0.40 who were intolerant of ACE inhibitors; and CHARM-Preserved involved patients with symptomatic failure and preserved systolic function (ejection fraction > 0.40). An integrated analysis of all results (CHARMOverall)95 showed that candesartan was associated with a 9% reduction in all-cause deaths (p = 0.055), a 12% reduction in CVmortality (p = 0.012), a 21% reduction in hospitalizations for heart failure (p < 0.0001), and a 16% reduction in CV deaths or hospitalization for heart failure (p < 0.0001). The benefits of candesartan occurred in addition to those achieved with other concomitant conventional therapies, including ACE inhibitors and beta-blockers. Importantly, unlike the findings of the VaI-HeFT study, CHARM-Added failed to show any deleterious effects associated with triple therapy (AIIA, ACE inhibitor, and beta-blocker).

When viewed together, these endpoint trials indicate that AIIAs are an appropriate alternative to ACE inhibitors in patients with heart failure who are intolerant of ACE inhibitors. When all available clinical trial data in patients with heart failure are analyzed together in a meta-analysis99, it was shown that AIIAs reduced allcause mortality and heart failure hospitalizations vs. placebo and produced similar reductions in all-cause mortality and heart failure hospitalizations vs. ACE inhibitors. In addition, a combination of AIIA and ACE inhibitor reduced heart failure hospitalizations compared with ACE inhibitors alone but had similar effects on allcause mortality. However, further studies are needed to clarify the use of AIIAs in patients with normal LV systolic function and to further define a potential role for AIIAs as part of a combination therapeutic regimen that includes ACE inhibitors and beta-blockers. At this time, valsartan and candesartan are the only AIIAs approved by the FDA for the treatment of heart failure. In addition, candesartan is PDA-approved for use in combination with an ACE inhibitor in patients with heart failure [based upon the results of CHARMAdded).

Post-MI

Clinical data from a number of large, randomized outcome trials, including Studies of Left Ventricular Dysfunction (SOLVD)100, Survival And Ventricular Enlargement (SAVE)101, Acute Infarction Ramipril Efficacy (AIRE)102, the Gruppo Italiano per lo Studio della Soprawivenza nell'infarto Miocardico (GISSI-3)103, and Survival of Myocardial Infarction Long-Term Evaluation (SMILE)104, clearly demonstrate that ACE inhibitor therapy following an MI produces beneficial effects on cardiac remodeling and development of heart failure and also affects the incidence of recurrent ischemic events and improves patient survival. The mechanisms by which ACE inhibitors provide benefits to post-Mi patients are not completely delineated, but it is apparent that these agents influence multiple pathophysiological processes in ischemic heart disease and heart failure, including inhibition of myocyte fibrosis and apoptosis, inhibition of the cardiac adrenergic nervous system, and direct anti- atherosclerotic and anti-ischemic effects105-108. In particular, the positive influence of ACE inhibitors on heart failure progression and mortality is likely to be related to the beneficial effects of these agents on the ventricular remodeling process. As evidenced by the results of SOLVD, ACE inhibitor treatment prevents continued remodeling for years after the initial MI109.

In light of the ability of ACE inhibitors to improve survival and reduce morbidity in patients with acute MI and evidence of heart failure or left-ventricular dysfunction, two studies (Table 4)110,111 have evaluated whether selective antagonism of the AT^sub 1^-receptor would provide an alternative pharmacologie approach to ACE inhibition. OPTIMAAL110 and VALIANT111 investigated whether AIIAs are similar to, or more effective than, ACE inhibitors in managing patients with acute MI. The results of OPTIMAAL, which compared losartan with captopril, were disappointing, with no significant differences between study groups with respect to all- cause mortality, sudden or resuscitated cardiac death, and fatal/ nonfatal re-infarction but a significant difference in favor of captopril for CV deaths (13.3% vs. 15.3%, p = 0.032). In VALIANT, valsartan was found to be non-inferior to captopril in post-Mi patients. VALIANT compared the effect of adding valsartan, valsartan plus captopril, or captopril alone to conventional therapy on death from any cause in patients with acute MI. Over a 24-month follow up period, no significant mortality difference was observed among groups (HR in valsartan patients vs. captopril patients was 1.00, p = 0.98; HR in the valsartan-and-captopril patients vs. captopril patients was 0.98, p = 0.73). Based on the results of OPTIMAAL and VALIANT, it is perhaps appropriate at this juncture to view AIIAs as effective alternatives to ACE inhibitors in post-Mi patients.

Diabetic nephropathy

Antihypertensive therapy reduces the rate of decline in renal function and delays ESRD in patients with diabetic nephropathy and, thus, represents a cornerstone of treatment for any diabetic patient with high BP112,113. Although capable of impeding the progression of renal disease in patients with type 1 diabetes and nephropathy, ACE inhibitors produce variable effects on proteinuria and renal function in patients with type 2 diabetic nephropathy and have not shown superiority over other antihypertensive agents in terms of delaying the progression to ESRD114-126. In the MicroHOPE study, ramipril significantly decreased the combined primary outcome (MI, stroke, or CV death) vs. placebo in hypertensive type 2 diabetic patients with microalbuminuria (after adjustment for BP effects)114. However, the results of this study are misleading because of imbalances in CV risk between groups at baseline; the placebo group in the diabetes cohort contained an excess of patients who were male and who had CHD, peripheral vascular disease, and cerebrovascular disease127. Only AIIAs have been shown to consistently produce favorable mortality and morbidity outcomes in endpoint trials in patients with type 2 diabetes (Table 5), as evidenced by the findings of RENAAL (Reduction of Endpoints in Non-insulin-dependent Diabetes Mellitus with the All Antagonist Losartan), IDNT (Irbesartan Type 2 Diabetic Nephropathy Trial), and IRMA 2 (Irbesartan in Hypertensive, Microalbuminuric, Type 2 Diabetic Patients)71,128-130. However, results from the DETAIL (Diabetics Exposed to Telmisartan and Enalapril) study suggest that enalapril and telmisartan have comparable long-term renoprotective effects and mortality benefits in patients with mild-to-moderate hypertension and diabetic nephropathy126.

Table 4. Outcome studies involving AIIAs in patients with MI

RENAAL compared the effects of losartan with placebo (both administered in addition to conventional antihypertensive therapy, including calcium channel blockers, diuretics, alpha-blockers, beta- blockers, and centrally acting agents) in patients with type 2 diabetes and nephropathy, defined as a urinary albumin: creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0mg/ dL130. The primary endpoint was a composite of the time to first event of doubling of serum creatinine, ESRD, or death, with secondary endpoints of CV events, progression of renal disease, and changes in proteinuria. Patients treated with losartan demonstrated a 16% reduction (p = 0.02) in the composite endpoint, a 25% risk reduction in doubling of serum creatinine (p = 0.006), a 28% reduction in the risk of ESRD (p = 0.002), and a 20% risk reduction in the composite endpoint of ESRD and death (p = 0.01), compared with patients receiving placebo. However, losartan was not associated with a significant reduction in the death rate. Losartan- treated patients also experienced a 35% decrease in proteinuria, as shown by a significant fall in the urine albumin/creatinine ratio (p < 0.001) Losartan did not impact on the composite endpoint of CV morbidity or mor\tality but did reveal evidence of cardioprotection, as evidenced by a 32% reduction in risk of first hospitalization for heart failure (p = 0.005). Both study groups had similar trough systolic and diastolic BPs throughout the study, a finding that indicates that the renoprotective effects of losartan were attributable to effects beyond BP control.

In the LIFE diabetes substudy, losartan was superior to atenolol in terms of impacting the primary composite endpoint of CV morbidity and mortality (CV death, stroke, or MI) (RR 0.76, p = 0.031]71. In addition, fewer losartan patients died from CV disease (RR 0.63, p = 0.028) or all causes (RR 0.61, p = 0.002) compared with atenolol, despite similar decreases in BP PB (17/11 mmHg in losartan patients and 19/11 mmHg in atenolol patients).

Similar renoprotective effects were obtained with irbesartan in the IDNT and IRMA 2 studies. IDNT, which compared irbesartan with amlodipine on the progression of nephropathy in patients with Type 2 diabetes, showed that irbesartan was associated with a lower risk of the primary composite end point of doubling of the base-line serum creatinine concentration, the development of ESRD, or death from any cause (20% lower risk vs. placebo, p = 0.02; 23% lower risk vs. amlodipine, p = 0.006), a lower risk of doubling of serum creatinine concentration (33% lower risk vs. placebo, p = 0.003; 37% lower risk vs. amlodipine p = 0.001), and a lower relative risk of ESRD although not statistically significant (23% vs. either group, p = 0.07)128. The study groups were similar with respect to all-cause mortality and the secondary composite endpoint of CV events. The serum creatinine concentration also increased more slowly in patients receiving irbesartan (24% more slowly vs. placebo, p = 0.008; 21% more slowly vs. amlodipine p = 0.02). As with RENAAL, the overall benefits favoring AIIA occurred despite the fact that BP control was generally comparable among the study groups. However, mean arterial pressure was significantly higher by 3.3 mmHg in placebo group vs. other two treatment groups (p = 0.001 for both comparisons), although this did not appear to influence the results after statistical analysis was performed.

Table 5. Outcome studies involving AIIAs in patients with diabetic nephropathy

IRMA 2 demonstrated that irbesartan reduced the rate of progression of microalbuminuria to clinical albuminuria compared with placebo (conventional antihypertensive treatment) in patients with type 2 diabetes and hypertension129. The primary endpoint of time to onset of diabetic nephropathy was reached in 5.2% of patients receiving 300mg irbesartan, 9.7% of patients receiving 150mg irbesartan, and 14.9% in patients receiving placebo (HR, 0.30 p < 0.001 and 0.61, p = 0.081, for the two irbesartan groups, respectively). Normoalbuminuria occurred in 34% of patients receiving irbesartan 300mg (p < 0.006 vs. placebo), 24% in the irbesartan 150mg group, and 21% in the placebo group. Over the course of the study, however, BP was significantly higher in the placebo group (144/83 mmHg) than in either the 150mg (143/83mmHg) or 300mg irbesartan groups (141/83 mmHg) group (p = 0.004, placebo vs. combined irbesartan groups). Similar findings were obtained with valsartan in the MARVAL study, which compared the effects of valsartan and amlodipine on urinary protein excretion in patients with type 2 diabetes and microalbuminuria with or without hypertension131. Despite similar reductions in BP in the two study groups, more valsartan patients than amlodipine achieved normoalbuminuria at week 24 (29.9% vs. 14.5%,p < 0.001).

Potential mechanisms of renoprotection beyond blood pressure control

In patients with diabetes, All is believed to play a central role in the progression of renal damage not only through hemodynamic effects but also non-hemodynamic effects including stimulation of growth factors and cytokines, and alterations in extracellular matrix metabolism132,133. All gives rise to glomerular hypertension and can. alter the filtration properties of the glomerular basement membrane, leading to proteinuria133,134. All can also produce glomerular sclerosis via stimulation of transforming growth factor- β, endothelin, and vascular endothelium growth factor, and modulation of extracellular matrix132,133.

In addition to the favorable impact of AIIAs on hypertension and renal hemodynamics, AIIAs may block All’s growth-promoting, profibrotic, nonhemodynamic effects, and this too may contribute to the observed renoprotection. For example, losartan may produce renoprotective benefits by lowering the fibrogenic cytokine TGF- β135, reducing proteinuria, the hallmark of renal injury136,140, decreasing renal oxidative stress141, preserving glomerular and tubulointerstitial structure142, and reducing the glomerular membrane pore size134.

Non-diabetic nephropathy

Losartan has been shown to reduce proteinuria not only in non- diabetic patients with renal disease but also in patients with renal transplant138-140,143. For example, in hypertensive patients with renal disease, losartan decreased urinary protein excretion, lowered BP, and elevated renal plasma flow to a degree comparable to that seen with enalapril143. Similar antiproteinuric effects in non- diabetic renal disease have been reported for candesartan144 and telmisartan145. At this time, however, no large, randomized outcome studies have been conducted in this patient population.

It has been hypothesized that co-administration of an ACE inhibitor and an AIIA may potentially produce greater antiproteinuric and nephroprotective effects than either agent alone146. According to this hypothesis, an AIIA would produce complete blockade of the RAAS (blocking AII generated by both ACE and nonACE pathways) as well as stimulate the vasodilating and non- proliferative actions of AII via the AT^sub 2^ receptor; on the other hand, ACE inhibitors would inhibit kinin metabolism, increasing the level of the vasodilator bradykinin146. The Combination Treatment of Angiotensin-II Receptor Blocker and AngiotensinConverting-Enzyme Inhibitor in Non-diabetic Renal Disease (COOPERATE) trial conducted in Japan has investigated the renal outcome benefits associated with combination therapy with ACE inhibitor and AIIA. In this study, losartan and trandolapril administered together resulted in significantly fewer patients reaching the combined primary endpoint of a doubling of serum creatinine concentration or ESRD at 3 years compared with either losartan alone (11% vs. 23%, p < 0.018) or trandolapril alone (11% vs. 23%, p = 0.016)147.

Safety

As a class, AIIAs are generally well tolerated both as monotherapy and in combination with other antihypertensive drugs. The tolerability profile when used in combination regimens is an important consideration given that most patients with hypertension will require the administration of multiple agents to adequately control BP. The overall adverse event profile of AIIAs is generally comparable to placebo in randomized clinical trials and superior to that seen with many other types of antihypertensive agents, including calcium channel blockers, ACE inhibitors, diuretics, and betablockers148,149. In a global tolerability assessment of losartan for the treatment of hypertension, the overall incidence of any reported adverse event for losartan was similar to that observed for placebo (15.3% vs. 15.5%)150. Furthermore, the same excellent tolerability profile was observed in special populations of patients, such as those with heart failure or renal or hepatic impairment, and was uninfluenced by age, race, or gender150. Similar adverse event profiles have been reported for other AIIAs including candesartan, valsartan, irbesartan, olmesartan, telmisartan, and eprosartan1,2,7,151,153.

As observed with ACE inhibitors, however, AIIAs may be associated with renal dysfunction in some patients and may give rise to hyperkalemia, especially in patients with altered potassium homeostasis, such as those with renal failure or high potassium intakes, or those receiving potassium-sparing diuretics154. There have also been recent suggestions that AIIAs after long-term use may be associated with angioedema, a well-recognized side effect of ACE inhibitors155,156. Although angioedema occurs much less frequently in patients receiving AIIA than those receiving ACE inhibitors156, it is suggested that AILAs should be used cautiously in patients with a history of angioedema, particularly that due to the use of ACE inhibitors.

The low incidence of adverse events observed with AIIAs may be particularly important with respect to patient compliance and persistence with therapy. Since the only effective antihypertensive therapy is the one the patient will take and continue to take long term, it is important to choose an antihypertensive therapy that most patients can tolerate, thereby reducing the need for switches in medication. This is particularly important in the light of findings from Saskatchewan showing that any changes in therapeutic regimens, such as the addition of a new drug or a switching to one or more other drugs, markedly decrease persistence with antihypertensive therapy157. In an analysis of prescription refill behavior of hypertensive patients in the US, hypertensive patients receiving losartan as initial therapy were most likely to stay on therapy after 1 year (64%) compared with patients treated with ACE inhibitors (58%), calcium channel blockers (50%), betablockers (43%), or thiazide diuretics (38%)158. Thus, more patients may be able to realize the full benefit of sustained BP control by improving patient compliance through the initial selection of antihypertensive medications with fewer side effects.

The issue of an AIIA class effect

The AIIA trials discussed above indicate that, compared with conventional antihypertensive therapy, some AIIAs are associated with an improvement inmorbidity and mortality outcomes in patients with hypertension and LVH (losartan) and type 2 diabetes (losartan, irbesartan) whereas others (candesartan, valsartan) are not. Given that these agents all belong to the same class, the question arises: what is the basis for these outcome differences?

There is evidence to suggest that pharmacological differences do exist among AIIAs, particularly with respect to basic pharmacokinetic parameters (half life, bioavailability, etc), mode of ATt-receptor antagonism (competitive or insurmountable binding), relative AT^sub 1^-receptor binding affinity, rate of dissociation from AT^sub 1^-receptor, and need for conversion of the parent molecule to an active metabolite159-161. The clinical relevance, if any, of these pharmacological differences is unclear. However, as recently reviewed in detail by Reid162, some AIIAs (losartan, irbesartan, telmisartan, valsartan, and eprosartan) have been shown to possess molecule-specific effects, including, for example, antagonism of the thromboxane A2-receptor, inhibition of platelet aggregation, induction of peroxisome proliferator-activated receptor gamma (PPARgamma) activity, and reduction of serum uric acid levels. These molecule-specific effects could potentially contribute to a therapeutic advantage of one agent over another. As noted by Reid162, the possibility of a link between a moleculespecific effect and a beneficial impact on cardiovascular risk is best illustrated to date by a treatment-induced decrease in serum uric acid levels produced by losartan. Regardless of the underlying mechanism of action, it is apparent that an AIIA class effect most likely does not exist with respect to outcomes, and physicians should evaluate the efficacy of each agent on its own merit.

Conclusions

Clinical studies demonstrating sustained efficacy and tolerability identify AIIAs as a rational choice of antihypertensive therapy for the prevention of stroke, CHD and target organ damage in a wide range of patients. Several large-scale, prospective controlled trials, including LIFE, RENAAL, and IDNT, have revealed that the AIIAs confer CV and renal protective effects beyond their ability to lower BP. AIIAs have a wide variety of vascular, cardiac, and renal benefits beyond BP reduction, including beneficial molecule-specific effects independent of the AT^sub 1^-receptor. These effects may offer possible explanations for recent clinical trials suggesting that AIIAs may help reduce mortality and morbidity associated with hypertension and renal disease to a greater extent than that achieved with older antihypertensive agents. However, many detrimental effects of AII on the CV and renal systems take place over a period of time much longer than that of typical clinical trials and, thus, the full extent of the CV benefits of AIIAs may only be fully realized following continuous therapy over an extended time frame. By utilizing the large body of clinical trial evidence as a guide to rational prescribing of AIIAs, practitioners can expect to deliver meaningful benefits to their patients in terms of survival, prognosis, and quality of life.

Acknowledgments

Declaration of interest: This article was supported by Merck & Co., Inc., Whitehouse Station, NJ. The author thanks Jan S. Redfern, PhD, for writing and editorial support.

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