Reports

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MEDICAL OPTIONS Cardiovascular Risk Factors

February 2008

The Essence of RAS Inhibition in Hypertension

Dr. Lyall Higginson, Royal Jubilee Hospital

The Renin-angiotensin System in Diabetes

Dr. Sheldon Tobe, University of Toronto

Maximizing Nephroprotection: The Role of RAS Inhibition

Dr. Paul René de Cotret, Université Laval

Reviewing RAS Inhibition in Heart Failure

Dr. Haissam Haddad, University of Ottawa

Exploring Stroke Prevention in Hypertension

Dr. Victor Huckell, University of British Columbia

Editorial Overview:

Lyall A. J. Higginson, MD, FRCPC, Head of Cardiology, Royal Jubilee Hospital, Victoria, British Columbia

Inhibitors of the renin-angiotensin system (RAS) have proven to be potent antihypertensive agents. The antihypertensive activity of both ACE inhibitors and angiotensin receptor blockers (ARBs) is attributed to their ability to block the effects of angiotensin II, a potent vasoconstrictor. Inhibition of angiotensin II has been associated with blood pressure (BP)-independent effects in individuals with left ventricular dysfunction and renal impairment, but the relative advantage of RAS inhibition as initial therapy in hypertension to prevent late-stage events has yet to be proven. This has not hindered speculation that RAS inhibitors do confer such relative advantages. In trials conducted in late stage disease, RAS inhibitors have been associated with protection against new onset diabetes, cardiac and vascular hypertrophy and proteinuria. The possibility that RAS inhibitors provide protection against fundamental pathophysiologic processes of vascular disease has been further suggested by the association of an ARB with protection from hypertension in patients with pre-hypertension. These findings provide a rationale for considering a RAS inhibitor in initial combination therapy for BP control.

The modification of treatment guidelines for essential hypertension to accept antihypertensive agents other than diuretics and betablockers as first-line therapy has been relatively recent. One reason to encourage use of diuretics or beta-blockers as first-line therapy was that these are effective for BP reductions, and they are inexpensive. Despite speculation that the mechanism by which BP is reduced may be important to risk reduction independent of BP control, supportive data were lacking. Many of the most recent guidelines still emphasize diuretics and betablockers as first-line treatment, particularly in individuals under 60 years of age, but these typically further suggest that the majority of patients will require combination therapy and that agents other than diuretics and betablockers may be reasonable in individuals with comorbidities, such as renal impairment.

Of ACEs and ARBs

ACE inhibitors were the first commercially available antihypertensive agents to control BP by inhibiting RAS. Although ACE inhibitors also prevent degradation of bradykinin, a vasodilator, their primary mechanism of action is attributed to their ability to block one of the major pathways of synthesis of angiotensin II. The development of ARBs followed. For inhibiting angiotensin II, these appear to have a more specific mechanism of action by blocking the effects of this hormone at the AT1 receptor, which is the final common pathway of the deleterious effects of angiotensin II. This specificity of action is likely to explain the reduced risk of adverse events, particularly cough. In controlled trials, ARBs typically demonstrate a side effect profile similar to placebo.

However, the inhibition of the effects of angiotensin II may not explain all of the clinical effects of either ACE inhibitors or ARBs. The aforementioned ability of ACE inhibitors to preserve bradykinin is not shared by ARBs, while ARBs, by blocking the AT1 receptor rather than reducing the amount of circulating angiotensin II, may increase stimulation of the AT2 receptor, which has been linked to antiproliferative effects. Either may influence downstream signalling that may explain some of the relative BP-independent benefits that have now been observed in multiple controlled trials.

For example, the ACE inhibitor ramipril was not only associated with a large reduction in clinical events despite only a modest reduction in BP in the HOPE (Heart Outcomes Protection Evaluation) trial, those randomized to the ACE inhibitor had a 34% reduction in new-onset diabetes relative to those randomized to placebo. In the overall CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity) trial program, candesartan was associated with a 22% reduction in new-onset diabetes despite the fact that part of the CHARM population was already taking an ACE inhibitor.

Continuous Disease Process Theory

The relevance of BP-independent benefits from RAS inhibitors observed in patients with vascular diseases, including nephropathies, to patients with essential hypertension is the premise that elevated BP is the earliest manifestation of a continuous disease process. This theory, proposed by Drs. Eugene Braunwald and Victor Dzau almost 20 years ago, outlines a pathophysiologic progression which begins with endothelial dysfunction induced by an imbalance between vasoconstrictors, including angiotensin II, and vasodilators. The inability of the endothelium to maintain a healthy homeostasis allows fatty streaks to form on vessel walls, the first step in atherosclerosis. In addition, angiotensin II generates vascular and left ventricular hypertrophy, which progresses slowly but inexorably to advanced stages and risk of clinical events, such as myocardial infarction, stroke and cardiac arrhythmias.

Prospective studies demonstrating that early use of a RAS inhibitor for treatment of hypertension will reduce the risk of late events may never be completed because of the expense

of following a sufficient number of patients for a prolonged period. Retrospective analyses, such as the one conducted by Kjeldsen and Julius (Am Heart J 2004;148:747-54), have attempted to demonstrate BP-independent benefits from RAS inhibitors through meta-analyses or cohort assessments, but these can only be hypothesis-generating. Yet including one of these agents into a first-line combination is attractive because they do offer effective BP control, they are generally well tolerated, and their ability to provide protection against latestage renal impairment and vascular disease progression by mechanisms unrelated to their effect on BP may be relevant in early disease.

Altering Disease Progression

One possible demonstration of the ability of RAS inhibitors to alter the trajectory of disease progression was provided by TROPHY (Trial for Preventing Hypertension) (Julius et al. N Engl J Med 2006;354:1685-97). In this study, 409 patients with pre-hypertension, defined as a systolic BP of 130 to 139 mm Hg and a diastolic BP of 89 mm Hg or lower, were randomized to candesartan or placebo for a two-year period. At the end of two years, those randomized to the ARB had a 66.3% (P<0.001) reduction in developing stage I hypertension relative to those randomized to placebo despite instruction on lifestyle changes in both groups. At the end of four years of follow-up, despite discontinuation of therapy after two years, those initially randomized to active treatment still had a 15.6% (P<0.007) reduction in risk of stage I hypertension relative to those initially randomized to placebo.

Although TROPHY did not include an active control with a non-RAS inhibitor antihypertensive agent, the authors indicated that untreated hypertension is “a self-accelerating condition” involving endothelial dysfunction. They noted that animal studies have associated brief RAS inhibitor treatment with lifelong protection against hypertension that, as the condition progresses, becomes driven by neuroendocrine stimulation and structural changes. According to the authors, TROPHY supports the underlying hypothesis that RAS inhibitor treatment in the pre-hypertension stage has the potential to change the natural history of hypertension.

One of the first and most compelling demonstrations that antihypertensive mechanism of action is important in event reduction was provided by the LIFE (Losartan Intervention For Endpoint reduction) trial. In LIFE, the ARB losartan was associated with a 13% reduction (P=0.021) in risk of major cardiovascular (CV) events relative to atenolol, a beta-blocker. At the time of the trial, beta-blockers were identified a
reatment guidelines.

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While this study was conducted in high-risk patients, differences in protection against events have been observed in patients with lower baseline risk. One example is the SCOPE (Study on Cognition and Prognosis in the Elderly) trial. Although the 11% reduction in the primary end point of major CV events for candesartan relative to other BP-lowering strategies did not reach statistical significance, the ARB was associated with a 28% reduction (P=0.041) in non-fatal stroke. Average BP was 3.2/1.6 mm Hg lower in the candesartan arm, but the elderly population had mild hypertension and no history of CV disease at baseline.

Summary

A substantial proportion of patients who require pharmacologic treatment to control BP will need more than one antihypertensive agent to reach their goal. While treating to goal deserves to be a priority concern, there is increasing evidence to suggest that drug mechanism does make a difference even in patients with uncomplicated hypertension. Such combinations as a RAS inhibitor with a diuretic are attractive because of their efficacy in reducing BP with the potential for BP-independent benefits. Proof that differences in mechanism of action are clinically important in uncomplicated hypertension is missing, but there is also little evidence to contest the potential for BP-independent benefits to favourably affect outcome.

Editorial Overview:

Sheldon Tobe, MD, FRCPC, Staff Nephrologist, Sunnybrook Health Sciences Centre, Associate Professor of Medicine, University of Toronto, Toronto, Ontario

Diabetes is a systemic disorder, responsible for promoting target organ damage including heart disease, stroke, blindness and neuropathy, and is the most common cause of end-stage kidney disease. The prevalence of diabetes is increasing dramatically in our population, almost doubling to over 9% in the last 10 years (Lipscombe LL, Hux JE. Lancet 2007; 369(9563):750-6).

The renin-angiotensin system (RAS) plays a role in the progression of diabetes-induced target organ damage, and disruption of the RAS results in improved renal outcomes even independent of blood pressure (BP) control (Brenner et al. N Engl J Med 2001;345(12):861-9). It is possible that use of ACE inhibitors or angiotensin receptor blockers (ARBs) can prevent diabetes in some population groups. Angiotensin II is a promoter of target organ damage at the molecular level and through the hemodynamic changes resulting from hypertension. Early use of RAS inhibitors may offer an opportunity to blunt the effects of vascular diseases on target organs in individuals with diabetes. The potential of these agents to reduce the risk of new-onset diabetes mellitus suggests that these agents may inhibit fundamental pathogenic processes leading to target organ damage. Most clinical practice recommendations include ACE inhibitors and ARBs as part of initial therapy for all people with diabetes and hypertension and recommend these agents specifically in the setting of renal target organ damage with albuminuria. Preventing new-onset diabetes will confer all the benefits of avoiding this condition, including prevention of late-stage diseases associated with diabetes, such as progressive nephropathy and cardiovascular (CV) disease, the most common cause of death in patients with diabetes.

Preventing New-onset Diabetes

The ability of RAS inhibitors to provide protection from new-onset diabetes has been observed in numerous trials. The first largescale study to associate a RAS inhibitor with protection from new-onset diabetes was HOPE (Heart Outcomes Protection Evaluation). In this study, patients randomized to the ACE inhibitor ramipril had a 34% reduction in risk of developing diabetes when compared to placebo (Yusuf et al. JAMA 2001;286:1882-5). Several subsequent studies with ARBs have demonstrated similar protection. In CHARM-Overall (Candesartan in Heart Failure Assessment. Reduction of Mortality and Morbidity), there was a 22% relative reduction, even though a portion of the patients were already taking an ACE inhibitor (Yusuf et al. Lancet 2003;362:777-81). In a meta-analysis of 10 trials, of which five were with ARBs and five were with ACE inhibitors, the mean relative reduction in new-onset diabetes was 22% (P<0.00001) (Scheen AJ. Diabetes Metab 2004;30:487-96). Based on these observations, the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication) study tested this hypothesis amongst a relatively healthy and young population with impaired fasting glucose levels or impaired glucose tolerance and found that the use of ramipril for three years did not significantly reduce the incidence of diabetes or death (N Engl J Med 2006;355(15):1551-62). However, there was a significant increase in regression to normoglycemia.

Addressing Renin Upregulation

The mechanism by which RAS inhibitors might prevent diabetes is unclear, but there are substantial data that these agents offer target organ protection greater than that explained by BP control. In fact, some of the initial benefit of BP-independent benefits was derived from the use of ACE inhibitors in type 1 diabetes patients. In an initial landmark study, captopril was associated with a 50% reduction in risk of the combined end point of death, dialysis or transplantation relative to placebo (Lewis et al. N Engl J Med 1993;329:1456-62). In type 2 diabetics, the same protection has now been observed with ARBs. In the IDNT (Irbesartan Diabetic Nephropathy Trial), for example, the risk of the composite end point of death, end-stage renal disease (ESRD) or doubling of serum creatinine was reduced by 24% in those receiving irbesartan relative to those receiving the calcium channel blocker amlodipine despite comparable BP control (Lewis et al. N Engl J Med 2001;345:851-60).

RAS inhibitors are effective for BP control because they address the consequences of renin upregulation. However, ACE inhibitors and ARBs do not block the effects of upregulated renin in the same way and despite the use of ACE inhibitors, angiotensin II levels climb back toward baseline over time, possibly through other non-ACE pathways such as chymase. While ACE inhibitors prevent conversion of angiotensin I to angiotensin II by blocking one of the converting enzymes, ARBs block the AT1 receptor, which is the final common pathway. Although the benefits of RAS inhibitors were once attributed to preventing the vasoconstriction mediated by angiotensin II, these agents are now associated with other important systemic effects, including prevention of vascular smooth muscle proliferation, neurohormone activation and progression of cardiac hypertrophy.

The Guideline Rationale

It is still unclear whether ARBs and ACE inhibitors offer comparable or dissimilar target organ protection. On a theoretical basis, it has been suggested that ARBs might offer greater protection from RAS upregulation for several reasons. The most important is that ACE inhibitors exert most of their effect by diminishing systemic angiotensin II production. In contrast, by blocking angiotensin II on target organ receptors, ARBs may provide better protection against local pathogenic processes, such as proteinuria and cardiac remodelling. A large number of clinical studies in diabetes have sought to compare ACE inhibitors with ARBs for the prevention of progression of diabetic nephropathy. Virtually all of these are small studies and have been confounded by a concomitant drop in BP with the combination therapy compared to either agent alone. This suggests that the maximal recommended dose of each of these agents is below the highest dose that leads to target organ protection.

If greater RAS blockade is the key to protection from diabetic nephropathy, another potential advantage of ARBs is that they may offer a better and more consistent dose response, and because they are not associated with a dose-dependent risk of cough, they are more likely to be better tolerated. Thus, for patients with severe target organ damage from diabetes with persistent proteinuria of >1 g/day despite the use of maximally recommended doses of ARBs, a high-dose ARB offers the potential for improved renal protection independent of BP control. Results of the recently presented SMART (Supra Maximal Atacand Renal Trial) demonstrated a stepwise increase in control of proteinuria when once-daily candesartan doses of 16 mg, 64 mg and 128 mg were compared. There was a 33% mean reduction (P<0.0001) in urinary proteinuria for the highest doses vs. candesartan 16 mg/day in an intention-to-treat (ITT) analysis. There were only small differences in BP between treatment groups. Importantly, the 128-mg dose was well tolerated with no relative increases in serum potassium.

Strategies to Improve Outcomes

Ultimately, determining whether ARBs or ACE inhibitors are better for the treatment of diabetic nephropathy in either type 1 or type 2 diabetic patients may be less important than determining whether outcomes can be improved with combinations of these classes or with higher doses of either class. Several studies have already been conducted to that end. In one such study, dual blockade with irbesartan/enalapril was superior to enalapril plus placebo for reducing BP and proteinuria (Jacobson et al. Kidney Int 2003;63:1874-80). The first CALM (Candesartan and Lisinopril Microalbuminuria) study also associated a dual blockade of RAS (candesartan/lisinopril) with greater reductions in BP than either RAS inhibitor alone, but CALM II, which was conducted over a longer period, did not show a greater reduction in BP with candesartan 16 mg/lisinopril 20 mg when compared to lisinopril 40 mg alone. Both treatments stabilized urinary albumin excretion rates.

Other combination trials are underway. In ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), patients have been randomized to an ARB, an ACE inhibitor, or the combination of both at maximally recommended doses. Although the primary end point is a composite of CV death, myocardial infarction, stroke or hospitalization for heart failure, an evaluation of renal function has been included among substudies. With more than 25,000 patients randomized, the study will not only provide new data about dual RAS inhibition but it may also provide insight about how ACE inhibitors and ARBs differ, if at all, for specific types of events, such as stroke, myocardial infarction or end-stage renal failure.

The combination of an ARB and an ACE inhibitor is being pursued for the opportunity to provide more complete RAS inhibition, but each may contribute other benefits. For example, while ACE inhibitors inhibit breakdown of bradykinin, a potent vasodilator, ARBs can increase angiotensin II available for stimulation of the AT2 receptor, which mediates antiproliferative effects. However, if either therapy is used alone, one advantage of ARBs over ACE inhibitors is their relatively benign sideeffect profile. In many controlled studies, the side-effect profile of the ARB has been indistinguishable from placebo.

While control of diabetic nephropathy is an important goal, the effects of therapy should also be evaluated in the context of other risks of diabetes, such as microvascular complications. RASS (Renin-Angiotensin System Study) is observing the role of RAS blockade in type 1 diabetes without microvascular disease; in an abstract recently reported at the American Society of Nephrology, researchers found no difference between ACE inhibitors and ARBs and placebo in renal progression but did find that RAS blockade was beneficial at preventing progression of retinopathy. This study was likely confounded by excellent blood glucose control in all groups with little chance for progressive diabetic renal disease. The DIRECT Diabetic Retinopathy Candesartan Trials) programme, a large ongoing study, will address this issue. The primary objective is to evaluate RAS blockade with an ARB to prevent diabetic retinopathy in normoalbuminuric and normotensive type 1 and 2 diabetic patients, and the trial will also hopefully be able to correlate such outcomes as retinopathy with changes in urinary albumin excretion rate, something that has not yet been definitively shown. Such studies are important for demonstrating the interrelationship of risks.

Summary

ACE inhibitors and ARBs not only provide protection against adverse outcomes in diabetic patients but may also reduce the risk of developing diabetes. Although more data are needed to evaluate RAS inhibitors in preventing diabetes, there are now large studies confirming that ARBs can prevent diabetes complications, particularly prevention of progressive kidney disease to ESRD. The relative benefits of ARBs and ACE inhibitors for risk reduction require more study and the ONTARGET study will help to raise awareness and interest in the concept of combining RAS inhibitors toward the goal of achieving better target organ protection than is currently achieved with either agent alone. With the recent presentation of the SMART study, for patients with severe target organ damage manifested by nephropathy resistant to the usual maximally recommended dose of ARBs, high-dose ARBs may provide an important new therapeutic option for the underlying pathophysiology of diabetic nephropathy independently of their effect on BP control.

Editorial Overview:

Paul René de Cotret, MD, FRCPC, Associate Professor of Medicine, Université Laval, Quebec City, Quebec

Impaired renal function, a growing problem linked to increasing rates of diabetes and an aging population, is an independent predictor of death, cardiovascular (CV) disease and hospitalization. These risks correlate closely with increasing severity of chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73m2. In one study, all-cause mortality increased 17% in patients with an eGFR of 45 to 59 mL/min/1.73 m2 relative to a higher eGFR and by nearly 600% in those with an eGFR <15 mL/min/1.73 m2 (Go et al. N Engl J Med 2004;351:1296-306).

Proteinuria, another clinical sign of renal impairment, is also an important predictor of CV events as well as end-stage renal disease (ESRD) in patients with and without diabetes. In the same cohort of individuals, it was an independent predictor of death, CV events and hospitalization at an adjusted hazard ratio of between 1.3 and 1.4. As a key risk factor in renal disease progression, one of the main goals in CKD management is to reduce urinary protein excretion to target levels of <1 g/day.

A Current View of RAS Inhibition

On the basis of a series of landmark trials, angiotensin receptor blockers (ARBs) and ACE inhibitors are considered first-line treatment for CKD. While initial studies associated RAS inhibitors with protection from ESRD, it is now clear that they can also exert a favourable impact on CV risk. Although ARBs and ACE inhibitors are effective, their relative mechanisms of protection may differ. More data are needed to determine whether optimal risk reductions are achieved with one drug class relative to the other or both together.

Current guidelines indicate that inhibition of the renin-angiotensin system (RAS) is the most effective nephroprotective strategy in patients with renal impairment associated with diabetes or other causes. Both ACE inhibitors and ARBs produce greater reductions in proteinuria than other antihypertensive agents for the same levels of blood pressure (BP) control. Most current guidelines recommend an ACE inhibitor or an ARB for treatment of CKD, but many patients on standard doses of agents from either class often have persistent proteinuria. As a result, there is increasing interest in determining whether it is possible to raise doses of these agents to achieve renal protection independent of BP control, to combine ACE inhibitors and ARBs to achieve a more complete RAS inhibition, or to pursue both.

Exploring High Doses of ARBs for Renoprotection

An early clue that high doses of RAS inhibitors may improve renoprotection was provided by a study with just 10 patients that demonstrated an inverse relationship between mean urinary protein excretion levels and dose of the ARB candesartan (Weinberg et al. JRAAS 2001;2[suppl1]:S196-S198). Specifically, mean urinary protein excretion levels dropped from a baseline of 4.4 g/day to 2.8 g/day on candesartan 16 mg, to 2.7 g/day on 32 mg and to 1.1 g/day on 96 mg. The reduction in urinary protein excretion with increasing doses was achieved without major changes in BP. No increases in serum potassium and only slight increases in serum creatinine were observed once the dose was titrated up to 96 mg/day. This set the stage for several larger studies including DROP (Diovan Reduction of Proteinuria) and the recently completed SMART (Supra Maximal Atacand Renal Trial).

In DROP, 391 type 2 diabetic patients with high levels of urinary protein (urinary albumin excretion rate 20-700 mg/min) initiated therapy on valsartan 160 mg for four weeks (Hollenberg et al. J Hypertens 2007;25:1921-6). They were then randomly assigned to either remain on that dose, increase to 320 mg or to increase to 640 mg for 26 more weeks. At the end of four weeks, there was a highly significant reduction in albuminuria (P<0.001). Over the subsequent 26 weeks, there was modest additional change among those who remained on 160 mg (P=0.03), but a highly significant further reduction on either 320 mg or 640 mg (P<0.001). At week 30, twice as many patients returned to normal albuminuria with valsartan 640 mg vs. 160 mg (24% vs. 12%; P<0.01). The higher doses were well tolerated with slightly more reported dizziness and headache and were not associated with increased risk of hypotension or hyperkalemia.

In the SMART study, as presented at Renal Week 2007 (Burgess et al.), 269 patients with persistent proteinuria were enrolled. After an eight-week run-in period of candesartan 16 mg/day, participants were randomized to remain on 16 mg, increase to 64 mg or to 128 mg. Median urinary protein excretion rate at baseline was 2.66 g/24 hr while the median eGFR was 49.9 mL/min/1.73 m2. After 30 weeks of treatment, there was a 33% greater mean reduction in urinary protein excretion in the intent-to-treat population on supramaximal doses of candesartan compared with the 16-mg group (P<0.0001) despite similar BP control. In the per-protocol analysis, there was a 44.3% greater mean reduction in proteinuria among patients assigned to 128 mg compared with those on standard dose (P<0.0001). A non-significant 16.9% greater reduction in urinary protein excretion was seen in patients assigned to 64 mg vs. those in the 16-mg group. The incidence of adverse events was not significantly different in the three dosage groups.

RENAAL Revisited

New strategies to improve the benefits of RAS inhibitors are needed because of the overwhelming evidence that uncontrolled proteinuria is a major risk factor of ESRD. In a re-analysis of data from RENAAL (Reduction in Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), initial antiproteinuric response to losartan and the degree of residual proteinuria at six months were found to be significant predictors of poor renal outcomes (De Zeeuw et al. Kidney Int 2004;65:2309-20). Specifically, the strongest predictor of all baseline risk parameters for renal outcome was the level of albuminuria prior to initiation of treatment. A baseline albuminuria of 3.0 g/g creatinine was associated with a 5.2-fold increased risk of reaching a renal end point, and a 8.1-fold in
ge.php?id=1351" />ssing to ESRD compared to a baseline albuminuria of <1.5 g/g.

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<img1352|center> In fact, every 50% reduction in albuminuria seen in the first six months of therapy was associated with a 36% reduction in risk for patients reaching a renal end point, and a 45% reduction in risk for ESRD during later followup. RENAAL confirmed that the renoprotective effect of losartan was largely attributable to its effect on albuminuria, not on BP, and that reduction of residual albuminuria to the lowest achievable level should be considered for future renoprotective strategies. Very similar data were generated by the IRMA (Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria) trial, which randomized 590 diabetic patients to placebo, irbesartan 150 mg and 300 mg (Parving et al. N Engl J Med 2001;345:870-8). Although there were no differences in BP in the three arms, the 150-mg dose was associated with a 44% reduction (P=0.05) in the risk of diabetic nephropathy, while the 300-mg dose was associated with a 68% reduction (P<0.001)

Combination RAS Inhibitors

While increasing doses of ARBs is one strategy that appears effective for increasing control of proteinuria, another is combining ARBs with an ACE inhibitor. In one randomized study of 90 non-diabetic patients with renal disease, baseline urinary excretion values fell from 1.78 g/day to 0.62 g/day at year 1, to 0.56 g/day at year 2, and to 0.55 g/day at year 3 when the ARB candesartan at a dose of 2 to 12 mg/day was added to background ACE inhibitor (Kanno et al. Clin J Am Soc Nephrol 2006;1:730-7). In the group randomized to ACE inhibitor alone, urinary protein excretion rates fell from a baseline of 1.61 g/day to 1.21 g/day at year 3. At year 3, a significant difference in serum creatinine increase was observed between the ARB and the ACE inhibitor from baseline at 3.02 mg/dL to 3.38 mg/dL in the candesartan group compared with 3 mg/dL at baseline to 4.48 mg/dL in the ACE inhibitor group (P<0.01). Large studies are underway to evaluate the benefits of an ARB/ACE inhibitor combination for a variety of end points, including renoprotection.

Summary

Even an optimized regimen of an ACE inhibitor, an ARB or both does not always reduce proteinuria to the desired range. Several strategies are being pursued to build on the benefits already observed with ACE inhibitors. This includes employing very high doses of ARBs as well as combining ARBs with ACE inhibitors. Data so far indicate that both strategies may offer important additional nephroprotective benefits over antihypertensive doses of these agents. With greater reductions in proteinuria and better preservation of renal function, it is reasonable to expect greater protection against progressive renal damage. More data are needed to confirm that these strategies reduce final progression to ESRD or affect the risk of CV events, a common cause of death in patients with renal failure.

Editorial Overview:

Hassaim A. Haddad, MD, FRCPC, FACC, Director, Heart Failure Program Medical Director, Heart Transplant Program, Ottawa Heart Institute, Associate Professor of Medicine, University of Ottawa, Ottawa, Ontario

Renin angiotensin system (RAS) inhibitors have been a standard component of optimal therapy for heart failure since SOLVD (Studies of Left Ventricular Dysfunction) confirmed a mortality benefit for ACE inhibitors 15 years ago. Subsequent studies with angiotensin receptor blockers (ARBs), such as Val-HeFT (Valsartan Heart Failure Trial) and the CHARM (Candesartan in Heart Failure Assessment and Reduction in Mortality and Morbidity) program, have indicated that ARBs also reduce the risk of events in patients with heart failure. In CHARM, the ARB was associated with a 12% reduction in cardiovascular (CV) death and a 9% borderline significant reduction in total mortality. Although the protection from RAS inhibitors is presumed to be largely due to the ability of these agents to block the effects of angiotensin II, the mechanisms by which ARBs and ACE inhibitors block the activities of this hormone differ. Moreover, the potential benefits of combination therapy, although addressed in both CHARM and Val-HeFT, remain incompletely evaluated. Differences in the adverse-effect profiles of ACE inhibitors and ARBs are a consideration for therapeutic selection.

Slowing Heart Failure Progression: Associated Benefits of RAS Inhibition

The benefits of RAS inhibitors and beta-blockers, both of which block neurohormonal activation in heart failure, have been well established by a series of large, well-controlled multicentre studies. In joint treatment guidelines from the American College of Cardiology and the American Heart Association, both RAS inhibitors and beta-blockers are recommended in all patients who have a history of myocardial infarction (MI) regardless of left ventricular ejection fraction (LVEF) as well as in all patients with a reduced LVEF. According to these guidelines, substitution of an ACE inhibitor for an ARB in patients who are ACE inhibitor-intolerant, usually because of cough or angioedema, is supported by level A evidence. The bulk of that evidence is derived from the CHARM trials program. In one of these studies, CHARM-Added, additional benefit from adding an ARB to an ACE inhibitor led the authors of the guidelines to characterize this strategy as having level B support. RAS inhibition in heart failure is attributed to protection against ventricular enlargement and worsening heart failure driven by upregulation of angiotensin II. In CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study), there was a 50% reduction in progressive heart failure for patients with severe congestive heart failure (CHF) who were randomized to enalapril relative to placebo. This was associated with a 27% reduction in mortality (P=0.003). In SOLVD, which did not require patients to have severe heart failure but did require a baseline LVEF =35%, an ACE inhibitor was associated with a 16% reduction in total death (P=0.004) and an 18% reduction in CV death (P<0.002) relat
tudies also documented a reduction in hospitalizations for heart failure, further reinforcing the ability of RAS inhibition to slow heart failure progression.

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The Case for ARBs

The first ARB trial in heart failure patients, VAL-HeFT (Valsartan Heart Failure Trial), also randomized patients with moderate to severe heart failure (New York Heart Association class II, III and IV). There was a 13% (P=0.009) reduction in the primary composite end point of mortality or cardiac arrest with resuscitation, hospitalization for heart failure, or receipt of intravenous inotropic or vasodilator therapy for at least four hours. There was no significant mortality benefit, but valsartan in this study was added on top of optimal therapy, which included an ACE inhibitor in 93% of patients and a beta-blocker in 35%. When those who did not receive an ACE inhibitor were assessed separately, there was a 44% reduction in the primary end point (P=0.003) and a 33% reduction in mortality (P=0.012).

In the CHARM program, there was a more ambitious effort to evaluate the effect of an ARB on heart failure both with and without ACE inhibitors. In this program, there were three component trials: CHARM-Alternative evaluated candesartan in heart failure patients who were intolerant to ACE inhibitors; CHARM-Added evaluated the ARB in heart failure patients with LVEF =40% already taking an ACE inhibitor; CHARM-Preserved evaluated the agent in patients with a LVEF >40% regardless of whether they were also taking an ACE inhibitor. There were more than 7500 patients enrolled. While candesartan was associated with the greatest benefits in CHARM Alternative and CHARM-Added, a reduction in disease progression in the form of an 18% reduction in hospitalizations for heart failure (P=0.017) was observed in CHARM-Preserved.

A combined data analysis from the CHARM program (Solomon et al. Circulation 2004;110: 2180-3) has confirmed that its benefit in reducing morbidity and mortality was generated by its ability to prevent heart failure progression. In particular, when deaths were reviewed by a blinded adjudication committee, the ARB was associated with a 15% reduction in sudden cardiac death (P=0.036) and a 22% reduction in death (P=0.008) due to worsening heart failure. The reductions were greatest in those with LVEF =40%.

In a meta-analysis of 24 trials with more than 38,000 patients, ARBs were associated with a 17% reduction in all-cause mortality relative to placebo, a reduction that trended for significance (95% CI, 0.69-1.00) but a 36% reduction in heart failure hospitalizations (P<0.001) (Lee et al. Ann Intern Med 2004; 141:693-704). When added to an ACE inhibitor, there was a marginal and non-significant 3% reduction in the risk of mortality, but a 23% reduction (95% CI, 0.69-0.87) in heart failure hospitalizations. When directly compared to an ACE in
difference in all-cause mortality or heart failure hospitalizations.

Different Mechanisms, Different Hypotheses

The reductions in progression of heart failure are consistent with a reduction in

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neurohormonal activation with favourable effects on sympathetic tone, ventricular dilatation and cardiac remodelling. Each would be expected to prevent ventricular enlargement that leads to unfavourable changes in hemodynamics and a vicious cycle of disease progression. Although the mechanism by which RAS inhibitors prevent sudden death has been less clearly demonstrated, it is presumed that protection from progression prevents the electrical instability that promotes arrhythmias. Both ARBs and ACE inhibitors are potassium-sparing, which might also reduce risk of arrhythmias. It is notable that reductions in sudden death have been observed with spironolactone and eplerenone, which block aldosterone, another hormone upregulated by RAS.

Due to the ability of ARBs to block angiotensin II at its receptor, the last common pathway to the effects mediated by this hormone, it has been speculated that ARBs would be more effective than ACE inhibitors in the treatment of heart failure. ACE inhibitors block the most important but not the only enzyme involved in synthesis of angiotensin II and therefore might be expected to provide less protection against RAS upregulation. However, ACE inhibitors also prevent breakdown of bradykinin, a potent vasodilator, and may have other activities favourable to protection against heart failure progression. Similarly, ARBs have other activities, such as stimulation of the AT2 receptor, which has demonstrated antiproliferative effects in experimental studies. Regardless of hypotheses, clinical trials are the only valid approach to comparing relative bene fits. So far, no ARB has surpassed an ACE inhibitor for clinical protection, but several studies have indicated similar protection.

Can Combination Therapy Provide Greater Benefit?

One of the most pressing questions in heart failure treatment is whether an ARB and an ACE inhibitor can be combined to provide better protection against events than either alone. The 15% relative reduction in the primary end point of CV death or hospitalization for the management of worsening chronic heart failure in CHARM-Added has provided support for an additive effect, but confirmatory studies would be helpful for reinforcing this benefit and for evaluating whether the relative dose is important for optimal benefit. In CHARM-Added, patients were permitted to take any ACE inhibitor at a dose prescribed by their physician along with candesartan 32 mg. Higher doses have been demonstrated to be safe and may provide added benefit, particularly if combined with a full dose of an ACE inhibitor. However, clinical trials are needed to address these issues.

Summary

RAS inhibitors are now a standard part of heart failure therapy but there may be opportunities to build on the proven benefits of these treatments. While many guidelines accept ARBs as a reasonable substitute for ACE inhibitors in patients who are intolerant to ACE inhibitors, several large studies indicate that ARBs may be just as effective while better tolerated. There is also a potential for combinations of ARBs and ACE inhibitors to improve protection against heart failure progression when compared to either therapy alone. Higher relative doses of ARBs to achieve better RAS blockade may further reduce disease progression and events associated with heart failure, including sudden death, one of the most important causes of mortality in this patient population.

Editorial Overview:

Victor F. Huckell, MD, FRCPC, FASH, Clinical Professor of Medicine, University of British Columbia, Vancouver, British Columbia

The tight correlation between rising blood pressure (BP) and increasing risk of stroke makes BP control the single most important goal in both primary and secondary stroke prevention. However, there is a growing pool of data indicating that antihypertensive agents are not interchangeable for stroke prevention at the same BP control.

The best examples are LIFE (Losartan Intervention for Endpoint Reduction) and MOSES (Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine in Secondary Prevention), both of which associated an angiotensin receptor blocker (ARB) with greater protection from stroke than an active comparator. Experimental evidence suggesting neuroprotective effects from blockade of the angiotensin AT1 may explain some of the relative benefit from ARBs. In the ACCESS (Acute Candesartan Cilexetil Therapy in Stroke Survivors) trial, which evaluated the safety of early treatment of stroke with an ARB, recruitment was ended prematurely because of the reduced risk of events in those receiving the ARB rather than placebo.

Differences in Risk Reduction

Of the substantial clinical data suggesting that antihypertensive therapies may not be interchangeable for prevention of stroke, only two large, double-blind multicentre trials have demonstrated a difference in risk reduction between treatment arms when each provided the same BP control. In LIFE, a primary prevention study, the ARB losartan was associated with a 24.9% (P=0.001) reduction in stroke relative to the beta-blocker atenolol (Dahlof et al. Lancet 2002;359:995-1003). In MOSES, a secondary prevention study, the ARB eprosartan was associated with a 25% (P=0.03) reduction in recurrent cerebrovascular events relative to the calcium channel blocker (CCB) nitrendipine (Scharder et al. Stroke 2005;35:1218-24). The relative benefit in MOSES may be particularly noteworthy, because previous studies such as ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) and NORDIL (Nordic Diltiazem Study) have suggested that CCBs as a drug class might be superior to older antihypertensive drugs such as diuretics for stroke prevention (although neither ASCOT nor NORDIL demonstrated superiority at the same BP control).

All of the currently available antihypertensive medications are effective for reducing BP but the mechanisms of action differ. The hypothesis that these mechanisms may affect relative protection against vascular events independent of BP control is several decades old. In stroke, retrospective analyses of several large studies, such as ALLHAT Antihypertensive and Lipid Lowering for Prevention of Heart Attack Trial), which suggested that initiating therapy with a CCB provided greater stroke prevention than initiating therapy with a diuretic, have reinforced these hypotheses.

Neuroprotection: A Rationale for ARBs

Currently, the best data suggesting differences between antihypertensive drug strategies for stroke prevention has been generated by studies with ARBs. This not only includes LIFE and MOSES but also such studies as SCOPE (Study on Cognition and Prognosis in the Elderly), which has supported experimental evidence that ARBs may be neuroprotective.

In SCOPE, the primary objective was to test the hypothesis that the ARB candesartan can reduce the risk of stroke in elderly patients with isolated systolic hypertension. Unlike LIFE or MOSES in which patients were randomized to one of two antihypertensive agents, SCOPE randomized 4964 elderly patients (age >70 years) with isolated systolic hypertension to the ARB candesartan or to placebo and open-label BP treatment with an agent other than an ARB (mostly thiazide diuretics). After a median follow-up of 3.7 years, findings indicated that there was a 42% relative reduction (P=0.05) in fatal and non-fatal strokes in the ARB group (Papademetriou et al. J Am Coll Cardiol 2004;44:1175-80). In this study, there was a 2 mm Hg greater reduction (22 mm Hg vs. 20 mm Hg) in systolic BP in those receiving candesartan, but the authors asserted that the BP difference could not account for the increased relative protection against stroke, which they believed should be at least partially credited to vascular protective effects of AT1-receptor blockade.

Cognitive function did not differ between those who received the ARB relative to those who did not. This was a disappointment in the context of experimental evidence suggesting that ARBs may be neuroprotective, but a posthoc analysis was able to show that there was an advantage for the ARB for preventing stroke and progressive dementia in patients with reduced brain function at baseline. The authors speculated that the median 3.7 years of follow-up was not enough to show protection against cognitive loss in patients with normal brain function at entry.

Although
oke and vascular events are the most commonly employed end points in secondary prevention studies, relative protection against the consequences of stroke, such as disability and dementia, are also important outcomes with which to compare strategies.

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In the cardiovascular (CV) system, upregulation of the renin-angiotensin system (RAS) is associated not only with vasoconstriction but also stimulation of inflammatory, proliferative and thrombotic processes. In the cerebrovascular system, the major peptide of upregulated RAS, angiotensin II, has been associated with some of these same BP-independent changes, including, at least in an animal model, structural changes in cerebral arterioles (Baumbach et al. Hypertension 2001; 41:50-5). Importantly, brain RAS may be regulated independently of systemic RAS, explaining why ARBs may have a role in neuroprotection not shared by ACE inhibitors (Culman et al. J Human Hypertens 2002;16:S63-S71). In the brain, the AT2 receptor, which opposes many of the activities of AT1, such as vasoconstriction, has been implicated in neuronal regeneration. Unlike ACE inhibitors, which reduce angiotensin II production, ARBs block binding of angiotensin II to the AT1 receptor to increase stimulation of the AT2 receptor.

Whether or not ARBs are neuroprotective, there are data demonstrating that agents in this class are beneficial even in acute stroke. Although the ACCESS study was designed to evaluate the safety of candesartan in acute stroke, the study was stopped early because of an imbalance in outcomes favouring the ARB (Schrader et al. Stroke 2003;34:1699-703). ACCESS had a planned enrolment of 500 acute stroke patients who were to be randomized to the ARB or placebo immediately after meeting inclusion criteria for an acute ischemic stroke (hemorrhagic strokes were excluded). Recruitment ended at 342 patients due to an imbalance in events favouring the candesartan arm. At the end of 12 months of follow-up, ARB treatment was associated with a 52.5% reduction (P=0.0261) in vascular events, including a 32% reduction in cerebrovascular events. There were no significant safety issues associated with early candesartan treatment. The authors speculated that neurohormonal inhibition was a likely factor in the relative protection of the ARB in this study.

BP Control Is the Primary Goal

Large studies are underway to further explore the protection of ARBs relative to other antihypertensive strategies for stroke protection. This includes PRoFESS (Prevention Regimen for Effectively Avoiding Secondary Strokes), which has randomized more than 20,000 stroke survivors in a 2x2 factorial design to receive the ARB telmisartan or placebo and clopidogrel or ASA/extended-release dipyridamole. While this study will also help clarify which of the currently available antiplatelet strategies is most effective for clinical risk reduction, the ARBvs.- placebo component of the study should provide insight about relative neuroprotection. The design of the study is to evaluate the effects of the ARB independent of BP control. A substudy of the PRoFESS study will include an evaluation of cognitive outcome.

If relative protection against stroke and its consequences does differ between antihypertensive therapies, this will not diminish the importance of BP control as a primary objective in clinical management. The risks of both cerebrovascular and CV events are closely interrelated, so that failure to favourably influence one is likely to obscure any favourable influence on the other. For example, authors of the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial, which was unable to demonstrate an advantage for the ARB valsartan relative to the CCB amlodipine for the primary composite end point of CV events or for stroke, was considered to be unevaluable as a result of the greater BP control in the CCB arm. These and other data suggest that it is essential to first achieve effective BP lowering before considering the potential of any strategy relative to another for stroke prevention.

Summary

The only multicentre, randomized, doubleblind studies to demonstrate a relative advantage for one antihypertensive strategy over another for stroke prevention at the same BP control has been achieved with ARBs. The relative benefit has been observed in both primary and secondary prevention. One of the key issues going forward will be to determine whether the experimental evidence that ARBs offer neuroprotection has relevance in clinical management. The ability to reduce the impairments incurred by stroke, such as dementia, as well as the events themselves will, if confirmed, represent a major clinical advance.