The Role of Angiotensin Receptor Blockers in Treating Hypertension

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DOI
https://doi.org/10.15420/2006.3.2.28

The prevalence of hypertension is increasing. Most recently National Health and Nutrition Examination Survey (NHANES) 2003-2004 report showed that awareness of hypertension is quite high and increasing across all age and ethnic groups.1 Encouragingly, treatment and control are improving in the elderly population; however, treatment and control in younger age groups has not shown the same success. Thus the task of managing one of the most common diagnoses for an out-patient visits to a physician still remains a significant problem. Angiotensin receptor blockers (ARBs) were the last additions to the classes of antihypertensives. Since their introduction, these drugs have established an important role in treatment across the spectrum of hypertension.

Blood Pressure Reduction

The renin angiotensin system plays a fundamental role in hypertension and heart failure therefore blockade of this system is important to reducing blood pressure, and target organ damage. Currently, this class of agents consists of angiotensin converting enzyme inhibitors (ACEIs) and ARBs; however, trials are under way to investigate the treatment benefits of renin inhibitors. The mechanism of blood pressure reduction in ACEIs is largely through blockade of the formation of angiotensin II; however, there is some effect due to bradykinin upregulation. The mechanism of blood pressure reduction with ARBs is primarily through blockade of the AT1 receptor. In addition, there are benefits through binding at the AT2 receptor.2 Both agents effectively reduce blood pressure and cardiovascular morbidity and mortality.3,4 An advantage of ARBs is the side effect profile and tolerance. Overall, these agents are well tolerated and have the highest reported adherence rates for a single hypertensive drug. The most common side effect with ACEIs is cough, in addition there is a small risk of angioedema these effects are not necessarily dose dependent while these risks are minimal with ARBs.5

In uncomplicated hypertension, ARBs are an excellent choice of agent as initial or as second-line therapy. All of these agents successfully reduce blood pressure. In addition to effectiveness, tolerability, and adherence profile, the potential for target organ protection and vascular changes enhance the attractiveness of this class of agents.

In high-risk hypertensives, the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial showed that valsartan-based therapy reduced cardiovascular outcomes equivalently to amlodipine based therapy (Event rates: 10.6 valsartan, and 10.4 amlodipine; HR 1.04 p=0.490).A key feature emerging from this study is the blood pressure difference, which occurs early in the trial period favoring amlodipine during this period, event rates were also lower in the amlodipine group. This highlights the importance of proper dosing and prompt blood pressure control.6

Target Organ Protection

The ARB class has demonstrated benefits in organ protection in several clinical trials. First, in renal disease, ARBs reduce progression of proteinuria and the development of end-stage renal disease (ESRD) in patients with hypertension and renal insufficiency and particularly in high-risk populations such as type 2 diabetics.7-13 In the Reduction in Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial comparing losartan to placebo in type 2 diabetics with nephropathy, blood pressure was lowered from 152/82 vs 153/82 at baseline to 140/74 vs 142/74mmHg at the study end-point, with losartan and placebo, respectively.The primary end-point of doubling of serum creatinine, progression to ESRD or death was reduced by 16% in the intention to treat analysis and 22% in patients who remained on treatment. There was a 25% reduction in doubling of serum creatinine, and 28% reduction in ESRD with losartan. Despite the -4/- 2mmHg blood pressure difference at the end of year one between the losartan and placebo groups favoring losartan, the results remained statistically significant even after adjustment. Of note 87-90% of the subjects in this study on losartan were also treated with calcium channel blocker, which did not appear to adversely affect the benefits of the ARB treatment. Losartan prevented one case of ESRD for every 16 patients treated during the 3.5 years of the study.8

The Irbesartan Diabetic Nephropathy Trial (IDNT) investigated the effect of irbesartan compared to amlodipine on doubling of serum creatinine, progression to ESRD or death in 1,715 participants with type 2 diabetes, diabetic nephropathy, and hypertension proteinuria. This was a placebo-controlled study. The baseline blood pressure was 160/87mmHg. The blood pressure goal was 135/85mmHg; however, the achieved mean blood pressure was suboptimal in all three groups.

Blood pressure was similar in the two treatment groups but higher in the placebo group (140/77mmHg irbesartan group, 141/77mmHg amlodipine group and 144/80mmHg placebo group). The relative risk of the primary end-point, including doubling of serum creatinine, progression to ESRD or death, was reduced by 20% in the irbesartan group relative to the placebo group and 23% lower than the amlodipine group. There was no difference between the amlodipine and placebo groups. The unadjusted relative risk of doubling serum creatinine was 33% lower in the irbesartan group and 37% lower than the amlodipine group. The unadjusted relative risk of ESRD was 23% lower in the irbesartan group than in the amlodipine or placebo groups.There was no difference between amlodipine and placebo groups in doubling of serum creatinine or ESRD. These effects of irbesartan remain significant after adjustment for blood pressure differences in the groups. Based on this study, to prevent one patient from having a primary event, it is necessary to treat 15 patients with irbesartan 300mg or 10 patients to prevent one patient from doubling serum creatinine.These results suggest that the protective benefit of the ARB is independent of blood pressure reduction.7

Many of these patients will require combination therapy to achieve blood pressure goals. ARBs are an ideal component of the combination drug therapy. In this regard the side effect profile is an advantage of ARBs used in combination with other agents.

Second, is the effect of ARB therapy on left ventricular hypertrophy (LVH). The Losartan Intervention For Endpoints in Hypertension (LIFE) trial is the only clinical trial to show that treatment with an ARB reduces left ventricular mass and cardiovascular morbidity and mortality in patients with LVH and hypertension.14 In comparison to the beta-blocker atenolol, losartan reduced LV mass (Cornell voltage-duration product reduction: -290 versus 124mmXms, respectively, in losartan and atenolol groups). Similarly the rate of CVD events was reduced to a greater extent with losartan than atenolol (23.8% and 27.9%, respectively, p =0.02), despite similar blood pressure control (achieved blood pressure: 144/81mmHg losartan group; 145/80mmHg atenolol group). In the diabetic subgroup of the LIFE trial, these benefits were even greater than the overall population showing a 24% reduction in cardiovascular morbidity and mortality and 39% reduction in all cause mortality with losartan compared with atenolol.15

Although these effects were not clearly demonstrated in the African- American subgroup in this trial, the sample size in the original design limits to ability to make clear conclusions in African-Americans.16 Furthermore, there is no clear physiologic explanation for these findings, thus it is more likely that this is a statistical aberration. To date, these findings have not been replicated. Thus, ARBs have a clear role in the reduction of LVH in hypertensives and the subsequent cardiovascular consequences.

Third, is the protection these drugs offer against stroke. One of the interesting findings in the LIFE trial is the fact that the greatest reduction in outcomes was observed in strokes (stroke rate 10.8 and 14.5%, respectively in losartan and atenolol). Other studies of cerebrovascular and cognitive outcomes support this finding.The Study on Cognition and Prognosis in the Elderly (SCOPE) is a prospective, double-blind, randomized, parallel group study designed to assess whether candesartan-based therapy in elderly hypertensives confers a reduction in cardiovascular events, cognitive decline and dementia.17 This study included 4,964 patients aged 70-89 years with stage II hypertension with a Mini Mental State Examination (MMSE) score 24. Patients were assigned double-blinded to candesartan or placebo in addition to other open label antihypertensive medications. The blood pressure reduction in the study was 21.7/10.8mmHg in the candesartan group and 18.5/9/2mmHg in the control group a net difference of 3.2/1.6mmHg. The MMSE score was well maintained equally in both the candesartan and placebo groups. Although the reduction in cardiovascular events was not statistically significant, the reduction in nonfatal stroke was 27.8% (p=0.04) and in overall stroke 23.6% (p=0.056) with candesartan-based therapy.

More recently, the findings from the Morbidity and mortality after Stroke trial (MOSES) comparing eprosartan to nitrendipine demonstrate an effect of ARB treatment, which is independent of blood pressure reduction. Secondary strokes were reduced by 21% with eprosartan treatment compared to nitrendipine despite equivalent reduction in blood pressure.18

Another trial that may have further implications regarding the use of ARBs in the prevention of secondary stroke is the Prevention Regimen For Effectively avoiding Second Strokes Trial (PRoFESS). In this trial telmisartan is used in combination with antiplatelet agents versus placebo with antiplatelet agents to assess the most effective regimen for preventing recurrent stroke. This study will not be exclusively hypertensives; however, it is likely that many of the participants will be hypertensive.

The primary end-point of this trial is time to the first recurrent stroke over the course of the study. The study will be completed in 2007.19 This trial may be helpful in defining the role of ARBs with antiplatelet therapy in preventing secondary strokes. The evidence for a protective benefit of ARBs against cerebrovascular disease is strong furthermore this effect may be due to both blood pressure and other pleiotropic effects.

Fourth, ARBs have a role in the treatment of heart failure. The most recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines include ARBs as a component of the treatment paradigm.20 Three major trials of heart failure have investigated the role of ARB treatment. The ELITE I & II trials showed conflicting results with losartan treatment; however, the CHARM study with candesartan showed a reduction in all cause mortality, cardiovascular death, and heart failure hospitalizations in patients with congestive heart failure and left ventricular ejection fraction (LVEF) ≤40% when added to standard therapies.21-23 The Valsartan Heart Failure Trial (VAL-HeFT) demonstrated that valsartan in addition to standard heart failure treatment reduced mortality and morbidity by 13.2% compared with placebo. In the subgroup of the study participants who received valsartan without the addition of an ACEI, all-cause mortality and combined morbidity and mortality were significantly reduced compared with placebo (17.3% versus 27.1%, p=0.017 and 24.9% versus 42.5% p<0.001, respectively).24 These trials suggest that ARB therapy is beneficial in heart failure patients.

Most recently ARBs have been studied in the prevention of hypertension.The premise for this idea is based on the effect of angiotensin antagonism on vasculature leading to regression of vascular hypertrophy. The recent Trial of Preventing Hypertension (TROPHY) investigated the effect of two years of treatment with the ARB candesartan compared with placebo on the development of hypertension over four-year period in 809 individuals with prehypertension. The participants had prehypertensive blood pressures in the range of 130–139/85–89mmHg. The rate of progression to hypertension in the placebo group was 63% over four years. This rate is quite high relative to the previously observed rate of 40-50%.25,26 Early short-term treatment with candesartan resulted in a 66% reduction in relative risk at two years, and 15.8% reduction in relative risk of hypertension over the four-year period. This demonstrates that early angiotensin receptor blocker treatment can suppress or delay the development of hypertension in prehypertensives. In addition, there was no increase in adverse events in the treatment group compared with placebo thus ARB treatment in prehypertensives is safe and well tolerated.27 Whether this result is due to blood pressure reduction during the two-year treatment or the vascular effects of ARB requires further investigation.

Summary

In summary, ARBs are safe, well tolerated, and efficacious in blood pressure reduction across the spectrum of blood pressure elevation. This class of antihypertensives offers protection from renal disease progression, cardiovascular disease, and stroke, and delays progression to hypertension from prehypertension. There is evidence supporting beneficial effects that extend beyond blood pressure reduction alone. Thus ARBs are an excellent choice as initial or add-on therapy in the treatment of hypertension.

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