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Abstract

For patients with hypertension, effective control of blood pressure (BP) reduces cardiovascular (CV), and renal risk. Antihypertensive agents that offer benefits that extend beyond those associated with BP reduction alone, to include tissue protective effects and effects on the vasculature, may be of benefit for many patients with increased CV risk due to comorbidities or prior history of CV events. Renin–angiotensin system (RAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)] are guideline-recognized, highly effective antihypertensive agents that exert their BP-lowering action through different mechanisms at different levels of the RAS. Large-scale clinical studies suggest that small, between-treatment differences in BP lowering do not account for observed outcome differences between RAS blockers and other antihypertensive agents. Analysis of data from seminal clinical studies and meta-analyses identify that, controlling for effects on BP control, RAS blockers may be more effective than calcium channel blockers (CCBs) in reducing risk of myocardial infarction and congestive heart failure; ARBs may be more effective than either ACEIs or β blockers in stroke prevention; CCBs may be more effective than RAS blockers in stroke prevention; and ARBs may be more effective than β blockers in reducing left ventricular hypertrophy. This review considers the rationale and evidence for benefits of RAS blockade beyond BP lowering, and highlights the differences between ARBs and ACEIs, and between agents within these drug classes.

Keywords

angiotensin II receptor blockers angiotensin-converting enzyme inhibitors beyond blood pressure cardiovascular events cerebrovascular events renal events

Introduction

Many patients with hypertension who achieve blood pressure (BP) control remain at high risk for cardiovascular (CV) events because of comorbidities such as type 2 diabetes, or because of a history of prior CV events. Clinical guidelines on the management of hypertension highlight the importance of choosing antihypertensive therapies taking into account the effect of drugs on CV risk factors and according to patients’ individual CV risk profile [Mancia et al. 2007]. Accordingly, renin–angiotensin system (RAS) blockers [angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)] and calcium channel blockers (CCBs) are commonly used in hypertension since these agents offer control of BP and have been shown to reduce the risk of CV events [Wong et al. 2004; Whitworth, 2003; Mancia et al. 2007]. Indeed, the clinical benefits of RAS blockers are considered to extend beyond those associated with BP reduction alone. These include effects on the vasculature and end organs that appear to be tissue protective, with resulting impact on CV morbidity and mortality [Schmieder et al. 2007b; Unger et al. 2007].

This paper describes the rationale and current evidence to support that antihypertensive treatment based on RAS blockade, offers the potential to reduce end-organ damage: both through mechanisms to reduce BP and through actions beyond BP lowering to prevent progression of the inflammatory disease processes that lead to atherosclerosis.

Mechanistic rationale for beyond-blood-pressure effects

The RAS has an established role in the regulation of BP and fluid–electrolyte balance. Disorders of this system contribute to the pathophysiology of hypertension, congestive heart failure (CHF), and renal disease [Dzau, 2001]. As well as an association with increased BP and salt retention, the RAS has direct effects on vascular endothelial and smooth muscle cells, and disorder of the RAS is associated with amplification of events that contribute to vascular disease, such as inflammation and plaque formation [Unger, 2002; Schmieder et al. 2007b; Dzau, 2001]. The principal effector of the RAS is angiotensin II, an eight-amino-acid active peptide formed in large part by ACEI cleavage of angiotensin I, which exerts its effects via two main receptor subtypes, AT₁ and AT₂, which have differing tissue distribution and differing properties. AT₁ receptors are widely expressed and implicated in mediating vasoconstriction, sympathetic nervous system activation, and CV remodeling, while activation of AT₂ receptors results in vasodilation, antiproliferative effects, and apoptosis [Probstfield et al. 2010; Unger et al. 2007]. Production of angiotensin I and II is not limited to the systemic circulation and these peptides may be generated in vascular and other tissues [Schmieder et al. 2007b].

While both ACEIs and ARBs have actions that effectively aim to block the actions of angiotensin II, these two classes of drugs act on the RAS at different levels and therefore would be expected to have different pharmacological effects [Schmieder et al. 2007a, 2007b]. For example, ACEIs do not affect the generation of angiotensin II by non-ACEI pathways, but stop the conversion of ACEI-generated angiotensin II, thus inhibiting the action of angiotensin II at both AT₁ and AT₂ receptors. ACEIs also inhibit kinase II, an enzyme responsible for the inactivation of bradykinin, and it is thought that increases in bradykinin during treatment with ACEIs contribute to the BP-lowering effects of this class of drugs, as well as to a common side effect of ACEI therapy: cough [Probstfield et al. 2010; Unger et al. 2007]. By contrast, ARBs preferentially block the effects of angiotensin II (of any origin) mediated through AT₁ receptors and leave the effects of angiotensin II on AT₂ receptors unopposed [Probstfield et al. 2010]. It has been suggested that these differing actions of ACEIs and ARBs contribute to the principal effect of these therapies, which is BP reduction, and to beyond-BP lowering actions of RAS blockade. Furthermore, the actions of ARBs and ACEIs are complementary, such that in combination these drugs may theoretically confer beyond-BP lowering cardiopreventive effects in high-risk patients [Unger et al. 2007].

Clinical outcomes and small differences in blood pressure reduction

Although BP reduction, especially for patients with high BP baseline levels, is critically important to reduce CV risk [Mancia et al. 2007], the clinical meaningfulness of relatively small between-treatment differences in mean BP reduction, or reasonably small incremental improvements in BP, beyond-BP targets, and towards a normotensive state, are unclear. It has previously been suggested that even a difference in systolic BP (SBP) as low as 2 mmHg may relate to a 10% lower mortality from stroke and a 7% lower mortality from ischemic heart disease [Lewington et al. 2002]. A number of studies have sought to determine whether small additional reductions in BP, in patients with a known high risk for CV events, can impact on clinical endpoint outcomes.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in over 4700 patients with type 2 diabetes at high risk for CV events was a randomized study designed to compare intensive antihypertensive therapy, targeting an SBP of less than 120 mmHg, with standard therapy, targeting SBP less than 140 mmHg [Cushman et al. 2010]. The primary endpoint was a composite of nonfatal myocardial infarction (MI), nonfatal stroke, or death from CV causes. After 1 year, the mean change in SBP and diastolic BP (DBP) from baseline in the intensive treatment group compared with the standard treatment group was considerable, 14.2 mmHg and 6.1 mmHg, respectively; however, at a mean follow up of 4.7 years, the annual rate of the primary outcome did not differ between treatment groups, despite this persisting difference in BP. ACCORD reported that the yearly incidence of nonfatal MI also remained consistent between the intensive BP control group (1.13%) and the standard BP control group (1.28%), although the incidence of any stroke [0.32% versus 0.53%; hazard ratio (HR) 0.59; 95% confidence interval (CI), 0.39–0.89; p = 0.01] and of nonfatal stroke (0.30% versus 0.47%; HR 0.63; 95% CI 0.41–0.96; p = 0.03) was lower in the intensively treated group [Cushman et al. 2010]. The ACCORD trial did not have a positive primary outcome and therefore did not provide definitive answers on the clinical value of additional BP reductions beyond recommended levels in high-risk patients. However, the use of a composite endpoint may dilute the association between BP reduction and risk of events if only one component of the composite, in this case stroke, shows a consistent association with the degree of BP reduction. Moreover, ACCORD was likely underpowered to determine a significant advantage of one BP target over the other, as prestudy power calculations were planned on a 4%/year event rate in the standard treatment group, while the actual event rate was 2.09%/year.

Another study, which (unlike ACCORD) had no prespecified BP goals, but which assessed intensified antihypertensive therapy in patients with type 2 diabetes and a history of major CV disease, was the Action in Diabetes and Vascular disease: preterAx and diamicroN MR Controlled Evaluation (ADVANCE) trial [Patel et al. 2007]. In this study, 11,140 patients were randomized to receive an ACEI plus diuretic (indapamide) or placebo, in addition to their current therapy. While subjects in the active treatment group had mean additional reductions in SBP/diastolic BP (DBP) of 5.6/2.2 mmHg, this improvement in BP was not associated with a significant reduction in the incidence of macrovascular events as assessed by a composite endpoint, including death from CV disease, nonfatal stroke, or non-fatal MI. The 8% relative risk (RR) reduction in major vascular outcomes was not statistically significant in either group despite significant reductions in the individual outcomes of renal and coronary events in the active treatment group [Patel et al. 2007].

The ONgoing Telmisartan Alone and in combination with Ramipril Global End-point Trial (ONTARGET) in patients at high risk of vascular events was designed to determine whether the ARB, telmisartan, was as effective as the ACEI, ramipril, in terms of prevention of CV morbidity and mortality in patients whose hypertension was mostly controlled. The study demonstrated the equivalence of the ARB, telmisartan, and the ACEI, ramipril, and also assessed the effects of these treatments and the combination of telmisartan plus ramipril in terms of BP reduction, and beyond that of BP reduction alone [Yusuf et al. 2008b]. Analysis of data from ONTARGET showed that, while combination therapy reduced SBP by 8.4 mmHg compared with 6.9 mmHg and 6.0 mmHg reductions for telmisartan and ramipril alone, there was no additional beneficial effect of BP reduction on the primary endpoint, a composite of death from CV causes, MI, stroke, or hospitalization for heart failure [Yusuf et al. 2008b]. There was evidence of a relationship between changes in SBP and the risk of stroke [risk ratio 0.93 (0.81–1.07)], and a J curve with nadir around 130 mmHg was evident for all outcomes except stroke [Sleight, 2009; Yusuf et al. 2008b].

These studies suggest that, in patients at high risk for CV events because of underlying athero-sclerotic disease, or due to diabetes with end-organ damage, the benefits of additional reduction in BP on composite clinical endpoints are driven mostly by a reduction in stroke risk.

Clinical study meta-analyses also provide insights into the impact of additional BP reductions on CV outcomes. Two recent meta-analyses in patients with diabetes identify a consistent relationship between BP reduction and reduction in the risk for stroke [Reboldi et al. 2011; Bangalore et al. 2011]. In a meta-analysis of 31 trials involving 73,913 high-risk patients, Reboldi and colleagues established a relationship between magnitude of BP reduction and the risk of stroke. Patients allocated to intensive BP control had a 31% reduction in risk of stroke and metaregression analysis determined that the risk of stroke decreased by 13% for each 5 mmHg reduction in SBP. There was no statistically significant effect of intensive BP reduction on MI; however, a J curve for coronary events was not observed and was effectively excluded down to a SBP of 120 mmHg and a DBP of 65–75 mmHg. Another meta-analysis that focused on data from 13 trials in the diabetic population and evaluated the impact of lowering BP beyond a threshold of 130 mmHg also supported the relationship between BP reduction and reduced rates of stroke, noting that although BP reduction of up to 130 mmHg reduced the odds of stroke by 47%, at BP lower than 130 mmHg there was a 40% increase in serious adverse events with no benefit on other outcomes [Bangalore et al. 2011].

These studies and meta-analyses highlight the difficulty of assessing the impact of additional BP reductions on clinical events. Indeed a recent meta-analysis of 30 trials and 221,024 patients highlighted the limitations of composite CV endpoints, identifying that when the differences in BP reduction between two treatment strategies are small (specifically less than 4.6/2.2 mmHg) any difference in the odds for the composite may be down to chance [Verdecchia et al. 2010]. By the same thinking, this suggests that when a treatment intervention is associated with differences in BP that are below this threshold, yet accompanied by a treatment effect on CV outcomes, there is evidence of a reduction in CV risk beyond that imparted by BP lowering alone.

Clinical trial evidence of beyond-blood-pressure effects of the renin–angiotensin system on cardiovascular and cerebrovascular outcomes

Other evidence of beyond-BP effects of RAS blockade or inhibition comes from a number of seminal studies in which, despite low or no difference in mean BP reductions achieved between treatment groups, there is evidence of differences in CV outcome for treatments targeting RAS compared with antihypertensive agents with different mechanisms of action. Many studies used composite endpoints as measures, which makes separating stroke from MI, or other CV outcomes, difficult.

For example, the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, comparing RAS inhibition with the β blocker atenolol, had a composite CV endpoint of death, MI, or stroke [Dahlof et al. 2002]. In patients with essential hypertension and left ventricular (LV) hypertrophy, both treatments effected a similar reduction in BP, yet treatment with losartan was associated with a 13% reduction in the RR of the composite endpoint (p = 0.021) and a 25% reduction in the RR of fatal and nonfatal stroke (p = 0.001). The ARB also induced significantly greater reductions in LV mass than atenolol [Dahlof et al. 2002]. Given the similar effects of the study treatments on BP, the findings of LIFE suggest that losartan had vascular protective benefits beyond those achieved by BP reduction alone.

Another outcome study, the Heart Outcomes Prevention Evaluation (HOPE) trial, also provides evidence of beyond-BP benefits from RAS inhibition. In that study, which involved treatment of high-risk patients with normal ejection fraction but evidence of vascular disease or diabetes plus at least one additional CV risk factor, ramipril was compared with placebo on top of standard care over a 5-year period. The primary endpoint was a composite of MI, stroke, or CV death. Treatment with the ACEI effected only a 3.3/1.4 mmHg reduction in BP, but led to greater than expected CV risk reductions. RAS inhibition was associated with a 22% reduction in the RR of the primary composite outcome of MI, stroke, or CV death (p < 0.001). Separately, these translated to a 26% reduction in the RR of CV death (p < 0.001), a 32% reduction in the RR of stroke (p < 0.001) and a 20% reduction in the RR of MI (p < 0.001) [Verdecchia et al. 2010; Galzerano et al. 2010; Yusuf et al. 2000].

These effects are far greater than would have been predicted from previous studies of antihypertensive therapy. Overviews of available data show that in studies comparing, for example, calcium antagonist-based therapy with diuretic therapy, BP reductions of this magnitude were associated with only a 13% reduction in stroke and extrapolations from other clinical studies would have predicted that the BP reductions achieved in HOPE would have resulted in an approximate 5% reduction in MI [Neal et al. 2000; Galzerano et al. 2010]. Indeed, in one analysis, the benefits seen in HOPE were calculated to be around three times greater than predicted on the basis of BP reductions alone [Sleight et al. 2001].

Two more recent studies, ONTARGET and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) also demonstrate CV prevention in beyond-BP reduction alone. In both studies BP was almost controlled at baseline. Consequently, only small BP reductions were observed in these studies, and in ONTARGET, the small additional BP reduction seen with dual RAS therapy (ramipril plus telmisartan combination) did not impart any further CV risk reduction compared with ramipril monotherapy or telmisartan monotherapy [Yusuf et al. 2008a, 2008b]. ONTARGET showed the ARB, telmisartan, to be clinically equivalent to the established standard of care ACEI, ramipril [Yusuf et al. 2008b]. TRANSCEND, which compared the ARB, telmisartan, with placebo in patients with CV disease or diabetes with end organ damage, showed a modest superiority of telmisartan over placebo (SBP/DBP reduction difference of 4.0/2.2 mmHg) with regard to BP reduction. Both groups were being treated and had BP controlled according to current standards of care. However, the control arm of TRANSCEND involved patients receiving more intensive background therapy than patients in the HOPE trial [Yusuf et al. 2000, 2008a]. In TRANSCEND, telmisartan was statistically superior on the secondary endpoint of CV death, MI, and stroke (HR 0.87; 95% CI 0.76–1.00; p = 0.048), which excluded hospitalization for heart failure and thus matched the primary endpoint of the HOPE trial [Yusuf et al. 2000]. In TRANSCEND, it was also found that the prevalence of LV hypertrophy was significantly reduced with telmisartan compared with placebo after 2 and 5 years due to a lower rate of new-onset LV hypertrophy (5.0% telmisartan versus 7.9% placebo; HR 0.62; 95% CI 0.50–0.78; p < 0.001) [Yusuf et al. 2008a]. The prevalence of LV hypertrophy at 2 and 5 years after randomization was seen to fall in patients receiving telmisartan over time [Verdecchia et al. 2011; Yusuf et al. 2008a]. Overall, telmisartan significantly reduced LV hypertrophy by 21% (p = 0.0017) versus placebo. New onset of LV hypertrophy was statistically reduced by 37% (p = 0.0001) in the telmisartan group versus placebo. Differences between groups were still significant after adjustment for achieved SBP change (p = 0.0001) [Verdecchia et al. 2009b].

The results of Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), a study terminated early because of a signal of superior efficacy for a RAS inhibitor plus CCB, highlights again that BP control is not the only driver of clinical endpoints in high-risk patients. In this study, benazepril plus amlodipine were more effective in reducing the six-component composite endpoint (death from CV causes, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization) than benazepril plus diuretic, despite similar BP control. For the secondary endpoint of death from CV causes, nonfatal MI, and nonfatal stroke, the HR was 0.79 (95% CI 0.67–0.92; p = 0.002). This study suggests that, for high-risk patients, the choice of a CCB combined with a treatment targeting RAS may affect outcomes [Jamerson et al. 2008].

Effects of renin–angiotensin system blockade and renal outcomes

Given the role of the RAS in regulating renal function, and the close relationship between CV risk factors and end organ damage, there has been great interest in studying the effects of RAS blockade and inhibition in patients with hypertension and CV risk factors that predispose towards chronic kidney disease (CKD) and end-stage kidney disease (ESKD). In patients with diabetes, albuminuria is a strong and independent predictor of progression of diabetic kidney disease and increased CV risk. Such a marker is extremely valuable in gauging the impact of therapies on progressive renal decline, particularly since many patients with CV risk factors such as hypertension and type 2 diabetes may experience CV events before there is frank evidence of ESKD.

The beneficial effects of RAS blockade in patients at high risk of CV and renal morbidity are well demonstrated in clinical studies that have included a number of recognized renal endpoints. As shown in the Telmisartan versus Ramipril in renal ENdothelial DYsfunction in type 2 diabetes (TRENDY) study, ARBs and ACEIs both effect improvements in renal endothelial function [Schmieder et al. 2007b]. Following 9 weeks of treatment with either telmisartan or ramipril, patients with diabetes and hypertension showed an increase in basal nitric oxide activity of the renal endothelium relative to baseline, which indicates an improvement from renal endothelial dysfunction, back towards more normal responses and function [Schmieder et al. 2007a, 2007b; Yusuf et al. 2008b].

ARBs and ACEIs are also similarly effective in reducing long-term renal decline, as shown in the Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial, in which both telmisartan and enalapril were equally effective in preventing progression of CKD as measured by changes in glomerular filtration rate (GFR) [Barnett et al. 2004]. In this study, telmisartan was also not inferior to enalapril in preventing an increase in baseline albuminuria.

The IRbesartan in patients with type 2 diabetes and MicroAlbuminuria (IRMA 2) study established the efficacy of ARBs in reducing the onset of diabetic nephropathy as determined by assessing albuminuria progression over a 2-year treatment period [Parving et al. 2001; Staessen et al. 2005; Turnbull, 2003]. In this study, patients with hypertension, type 2 diabetes mellitus, microalbuminuria, and normal renal function were randomized to receive either placebo or irbesartan at 150 or 300 mg daily. While both doses of the ARB were equally effective in improving BP control over placebo, the higher dose of treatment resulted in a 38% decrease in albuminuria compared with a 24% decrease in the lower-dose treatment arm and only a 2% decrease in the placebo arm (p < 0.001 compared with the combined treatment groups) [Parving et al. 2001]. Significantly (p = 0.006) more patients in the high-dose irbesartan group than in the placebo group experienced a regression from micro- to normoalbuminuria at the last study visit, suggesting a reduced progression toward overt nephropathy in the group taking the high-dose ARB.

There have also been studies comparing the effects of different ARBs on renal endpoints. A trial comparing telMisartan 40 mg titrated to 80 mg versus losArtan 50 mg titrated to 100 mg in hypertensive type 2 DiabEtic patients with Overt nephropathy (AMADEO) assessed the effects of two ARBs in terms of changes in urinary albumin (protein) to creatinine ratio (UPC) after 1 year on treatment [Bakris et al. 2008]. Although telmisartan and losartan allowed similar reductions in BP in patients with hypertension and type 2 diabetes, telmisartan was superior in terms of renoprotective effects. Both ARBs significantly reduced UPC, but the 29.8% reduction effected by telmisartan was significantly greater than that achieved with losartan (21.4%, p = 0.03). This study identifies that there are intraclass differences between ARBs in terms of their impact on intermediate endpoints with known links to progressive kidney disease. It has been shown in outcome trials that reductions of at least 30% in proteinuria correlate with slowed progression of kidney disease, and therefore the superior efficacy of telmisartan in reducing proteinuria demonstrated in AMADEO suggests renoprotective properties of this ARB which are beyond-BP lowering effects [Bakris et al. 2008].

Other studies that highlight the benefits of RAS blockade in patients with established nephropathy at high risk of ESKD include the Irbesartan type II Diabetic Nephropathy Trial (IDNT), which showed the superiority of an ARB over a CCB in terms of a 20% lower risk of achieving the composite endpoint of doubling of baseline serum creatinine, ESKD, or death from any cause. At 2.6 years of follow up, patients in the ARB group had a 23% lower RR of ESKD than in the CCB group (p = 0.07), and treatment differences could not be explained by differences in BP alone [Lewis et al. 2001]. An interesting post hoc analysis of the IDNT trial data along with the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial data reported a variable and discordant SBP and albuminuria response to RAS blockade. Indeed, after 6 months of follow up, a progressively lower CV risk was evident with lower albuminuria levels across all SBP categories, which was particularly notable at SBP levels approaching 130 mmHg. This study suggests the importance of monitoring albuminuria response in addition to BP in order to achieve optimal CV benefits [Holtkamp et al. 2011].

Recently, the BErgamo NEphrologic DIabetes Complications Trial (BENEDICT-B) showed that a combination of a CCB and ACEI did not improve outcomes over an ACEI alone [Ruggenenti et al. 2011]. This study showed that patients who regressed to normoalbuminuria were significantly less likely to experience CV events over a 4.5-year follow-up period. However, there was no difference between the CCB plus ACEI group and the ACEI monotherapy group in terms of percentage of patients who either progressed to macroalbuminuria or regressed to normoalbuminuria [Ruggenenti et al. 2011].

Given the potential additive effects of dual RAS blockade, investigations have also sought to determine whether the combination of an ACEI plus ARB might improve albuminuria more than either drug alone [Russo et al. 1999]. In a 12-week study in normotensive patients with nephropathy defined by proteinuria, treatment with ACEI monotherapy or ARB monotherapy significantly reduced proteinuria by 38% and 30%, respectively. Although no further reduction in proteinuria was achieved by doubling the dose of either the ACEI or the ARB alone, additive effects were seen when an ACEI and an ARB were combined, effecting a 73% reduction in proteinuria, which was independent of treatment-induced changes in BP and creatinine clearance [Russo et al. 1999]. Analysis of renal outcomes from the ONTARGET study showed less increase in urinary albumin excretion with telmisartan (p = 0·004) or with a combination of telmisartan and ramipril (p = 0·001) than with ramipril alone [Mann et al. 2008]. However, an increase in adverse events was noted, and these results indicate caution when using a combination of ACEI and ARB in patients at high CV risk [Yusuf et al. 2008b]. A further analysis showed no benefit for combination therapy even in patients with reduced GFR (<60 ml/min/1.73 m²) or with micro- or macroalbuminuria [Tobe et al. 2011], which supports the need for caution when using dual RAS blockade.

Meta-analyses of cardiovascular outcomes

Meta-analyses of multiple trials that adjust for achieved BP also provide good evidence of beyond-BP effects for antihypertensive drugs that affect the RAS. Such meta-analyses highlight, as individual studies also do, that some drugs and certain drug combinations are associated with more evident beyond-BP benefits than others.

As discussed earlier, beyond-BP effects of antihypertensive drugs are commonly masked in clinical outcome studies that employ a composite endpoint, but when individual CV outcomes are examined separately, either in pooled analyses or meta-analyses, the power to determine effects on specific CV outcomes is enhanced and differences between treatments can emerge [Reboldi et al. 2008; Verdecchia et al. 2005].

A meta-analysis of 31 trials, which included 225,764 high-risk patients treated with RAS blockers, CCBs, or other antihypertensive agents, showed that the risk of CHF decreases by 24% for each 5 mmHg reduction in SBP and that, after correction for BP effects, beyond-BP reduction showed a greater protective effect of ARBs and ACEIs than was seen for CCBs, in terms of reduced risk for CHF (Figure 1) [Verdecchia et al. 2009a].

Figure 1.

Meta-analysis shows angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are superior to calcium channel blockers (CCBs) in terms of congestive heart failure [Verdecchia et al. 2009a]. *The weighted systolic blood pressure (SBP) difference was calculated by weighting the difference observed in each contributing trial by the number of randomized subjects. Negative values indicate lower mean follow-up SBP in the first listed group (ACEIs, ARBs, and CCBs).

Extraction of data and metaregressional analyses of data from 28 outcome studies investigating the effects of ACEIs and CCBs on coronary heart disease and stroke have also shown that, independent of BP differences, ACEIs were superior to CCBs for prevention of coronary heart disease. This same analysis found that CCBs, independent of BP reduction, were superior to ACEIs in terms of stroke prevention [Verdecchia et al. 2005]. Indeed, there is good evidence from a number of meta-analyses and reviews of study data that CCBs confer a reduced risk of stroke when compared with other antihypertensive therapies [Costanzo et al. 2009; Staessen et al. 2005; Turnbull, 2003; Zhang et al. 2006;].

A meta-analysis of six large-scale studies comparing ACEIs and ARBs in terms of reduction in the risk of MI, stroke, and death suggests that ARBs and ACEIs may have differing effects on the outcome of stroke. While both ARBs and ACEIs effect similar changes in BP and provide similar reductions in risk of MI, CV mortality, and total mortality, the risk of stroke was significantly reduced (odds ratio 0.92; 95% CI 0.85–0.99; p = 0.037) with an ARB relative to an ACEI (Figure 2) [Reboldi et al. 2008].

Figure 2.

Meta-analysis showing angiotensin II receptor blockers (ARBs) allow an 8% lower risk of stroke than angiotensin-converting enzyme inhibitors (ACEIs) [Reboldi et al. 2008]. CI, confidence interval; DETAIL, Diabetics Exposed to Telmisartan and Enalapril; ELITE, Evaluation of Losartan in the Elderly; ONTARGET, Ongoing Telmisartan Alone and in combination with Ramipril Global End-point Trial; OPTIMAAL, OPtimal Trial In Myocardial infarction with the Angiotensin II Antagonist Losartan; OR, odds ratio; VALIANT, VALsartan in Acute Myocardial INfarcTion.

Thus, a review of contemporary meta-analyses and study overviews suggests that, after controlling for BP, there are distinct differences between the antihypertensive drug classes in terms of their potential CV protective effects. Among the key differences identified between therapies, the following beyond-BP effects have been highlighted: ARBs may be more effective than ACEIs in stroke prevention [Reboldi et al. 2008]; CCBs may be more effective than RAS blockers (both ACEIs and ARBs) in stroke prevention [Staessen et al. 2005; Turnbull, 2003; Zhang et al. 2006; Costanzo et al. 2009]; ARBs may be more effective than β blockers in stroke prevention [Zhang et al. 2006]; ARBs may be more effective than β blockers in reducing LV hypertrophy [Verdecchia et al. 2011]; ACEIs and ARBs may be more effective than CCBs in reducing risk of MI and CHF [Verdecchia et al. 2005, 2009b].

Intraclass differences in beyond-blood-pressure effects

Despite the value of meta-analyses in appraising available datasets, because these forms of data assessment generally combine studies relating to drugs within a particular drug class, they tend to offer an evaluation of the average effects of one class of drug rather than insights into differences between drugs of the same class. In all drug class systems, individual drugs can greatly differ from other members of the same broad class in terms of their pharmacology and pharmacokinetics. In the case of antihypertensive therapies, these differences can translate into differential effects on CV events. Within the ACEI class, for example, highly lipophilic ACEIs could be more effective in preventing CV events in patients with atherothrombotic disease. Agents that are more liposoluble, such as perindopril and ramipril, may have better tissue penetration than ACEIs, such as enalapril and captopril, which may affect tissue affinity and penetration of these agents into key sites such as atherosclerotic plaques [Ferrari et al. 2009].

Among the ARBs, telmisartan has a number of distinguishing properties, including a plasma half life of 24 h, the highest lipophilicity of agents in this class, thus the greatest volume of distribution, the highest affinity for the AT₁ receptor, the longest receptor dissociation half life, and the lowest half-maximal inhibitory concentration of any ARB, including the new ARB, azilsartan [Burnier, 2009; Ojima et al. 2011].

Adding to these distinguishing features, in patients with hypertension with the metabolic syndrome, telmisartan has been shown to decrease markers of inflammation such as C-reactive protein, and to increase adiponectin compared with valsartan [Yano et al. 2007]. There is also evidence from in vitro studies that telmisartan but not losartan or its active metabolite can reduce adhesion-molecule gene expression and reduce oxidative damage in human umbilical vein endothelial cells [Cianchetti et al. 2008]. Evidence from studies in animal models suggests that telmisartan reduces atherosclerotic lesion progression in mice and reduces the expression of inflammatory factors to a greater extent than the ACEI ramipril. This evidence of anti-inflammatory and antioxidant properties of telmisartan may contribute to the therapeutic properties of this agent and indicate the distinct properties of this ARB both within its class and within the RAS-blocking agents [Blessing et al. 2008]. There is also emerging evidence that telmisartan, in contrast to losartan, reduces progression of carotid artery thickening as assessed by carotid intima-media thickening in patients receiving treatment with ARBs [Hasegawa et al. 2011]. Finally, as described above, telmisartan was superior to losartan in reducing proteinuria, a known surrogate for renal dysfunction in patients with high CV risk, within the AMADEO trial [Bakris et al. 2008].

Conclusions

RAS blockade has clear and established direct effects on the processes driving CV disease, in addition to its proven effects to reduce and control BP in patients with hypertension and additional risk factors. There is a wealth of clinical trial evidence to support the benefits of RAS blockade beyond BP reduction. Even when modest or no differences from control therapy are seen in achieved BP, there is evidence that agents targeting the RAS provide beyond-BP lowering effects that translate into clinically relevant differences in CV outcomes. Trials with reasonably closely matched BP outcomes and similar composite endpoints (such as HOPE and ONTARGET) may be taken as evidence for a beyond-BP effect of RAS blockade. There are beyond-BP benefits associated with RAS blockade, including reduction in risks for stroke, MI, CHF, and progressive renal dysfunction. A number of rigorous meta-analyses support the view that RAS blockade can provide beneficial effects beyond BP reduction. However, these meta-analyses obscure differential effects between individual drugs within a class. Care should be taken to avoid assuming the mere existence of a class effect, but rather to consider individual agents on the basis of the available outcomes evidence and, therefore, their given indications. In conclusion, there is evidence that RAS blockade has end-organ protective effects, leading to improved clinical outcomes beyond improvements that may be expected from BP reduction alone.

Footnotes

Acknowledgements

Writing and editorial assistance was provided by Emma Fulkes, PhD, of PAREXEL, which was contracted by Boehringer Ingelheim International GmbH for these services. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE) and were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development.

The authors received no compensation related to the development of the manuscript.

The authors declare there is no conflict of interest.

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Beyond blood pressure: evidence for cardiovascular,cerebrovascular,and renal protective effects of renin–angiotensin system blockers

Abstract

Keywords

Introduction

Mechanistic rationale for beyond-blood-pressure effects

Clinical outcomes and small differences in blood pressure reduction

Clinical trial evidence of beyond-blood-pressure effects of the renin–angiotensin system on cardiovascular and cerebrovascular outcomes

Effects of renin–angiotensin system blockade and renal outcomes

Meta-analyses of cardiovascular outcomes

Intraclass differences in beyond-blood-pressure effects

Conclusions

Footnotes

Acknowledgements

References