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Medscape J Med. 2008; 10(Supp): S5. Published online 2008 March 26. | PMCID: PMC2344120 |
Prospects for Renovascular Protection by More Aggressive Renin-Angiotensin System Control Luis Miguel Ruilope, MD, Professor Risk factors such as hypertension or diabetes result in a continuum of renal damage. Without intervention, initial subclinical endothelial damage progresses to incipient disease, identified by microalbuminuria. Glomerular filtration rate declines, macroalbuminuria develops, and eventually end-stage renal disease (ESRD) emerges. Because of the interrelationship between cardiovascular and renal disease and their common pathophysiologies involving angiotensin II, many patients die of cardiovascular disease before renal replacement therapy is needed. Blood pressure control is key to renoprotection, but blood pressure-independent mechanisms are also implicated. Targeting the renin-angiotensin system (RAS) using angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) is a logical approach to managing all at-risk patients. In advanced nephropathy, therapy aims at retarding progression to ESRD. For incipient nephropathy, ideal therapy should bring about microalbuminuria regression. In patients at risk of renal damage, preventing early target-organ damage is essential. Although evidence of ACE inhibitor benefit is limited, data show that ARBs provide renoprotection throughout the continuum and that this may be related to their cardioprotective effects. More aggressive RAS targeting by combination blockade is under investigation. Telmisartan is an ARB that delays progression of incipient and overt diabetic nephropathy and brings about regression from microalbuminuria to normoalbuminuria in hypertensive and normotensive patients. The ultimate proof of benefit will come from the ONTARGET trial, which will evaluate the cardiovascular and renal protective effects of the combination of telmisartan and ramipril. Angiotensin II generated by the RAS has direct pathophysiological effects on the heart and peripheral vasculature. There is now a considerable body of evidence from large-scale outcome trials that shows that blockade of the RAS confers cardiovascular benefit in terms of reducing nonfatal and fatal events. [1] As a result, both ACE inhibitors and ARBs are now widely accepted as providing effective management of hypertensive target-organ damage and cardiovascular protection. Due to their different mechanisms of action, a combination of an ARB with an ACE inhibitor may provide superior control of the RAAS (see Unger, in this supplement). This hypothesis is being tested in a major study (total 31,546 patients), the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET). [2] Among the patients recruited to ONTARGET are individuals with type 2 diabetes and organ damage, and the onset of nephropathy is a secondary endpoint. This review provides a background to the ONTARGET trial from a renal perspective, summarizing the pathological basis and wider clinical relevance of renal disease, as well as clinical evidence for the use of ARBs and their combination with ACE inhibitors to slow renal disease progression, with a particular emphasis on telmisartan. The Renal Continuum The concept of a chain of pathophysiological events – the cardiovascular continuum – was introduced in 1991, [3] and this concept can be equally applied to the kidney (). [4] The risk factors for chronic kidney disease (structural or functional abnormalities of the kidney, with or without decline in glomerular filtration rate to < 60 mL/minute/1.73 m 2) [5] are the same as those for cardiovascular damage and include components of the metabolic syndrome, such as hypertension. [6] The underlying pathophysiology involves glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis. [7] Damage to the renal endothelium, and resultant detrimental effects on renal function, bring about microalbuminuria and are thus precursors of chronic kidney disease. [8] Oxidative stress and associated endothelial dysfunction are increasingly recognized as important precursors of cardiovascular disease. [9]Renal damage is at first incipient and only identifiable by the presence of small amounts of albumin in the urine (ie, microalbuminuria [urinary albumin excretion rate 30 to 299 mcg/minute]). However, without intervention, the severity of injury to the kidney magnifies, glomerular filtration rate declines, and disease becomes overt with the emergence of macroalbuminuria (urinary albumin excretion rate ≥ 300 mcg/minute). Serum creatinine levels increase, and ESRD can ensue. Without renal replacement therapy in the form of dialysis or a kidney transplant, the final result is death. Interrelationship Between Cardiovascular and Renal Damage In patients with cardiovascular disease, renal damage often occurs in concert. Patients with cardiovascular disease are more susceptible to chronic kidney disease, and vice versa. For example, the incidence of coronary heart disease in patients with microalbuminuria and a high urinary albumin:creatinine ratio (≥ 17 mg/g creatinine in men and ≥ 25 mg/g creatinine in women) is approximately 3-fold greater than in patients without a high urinary albumin:creatinine ratio. [10] Furthermore, many outcome studies have shown that the incidence of renal dysfunction is relatively high in patients with cardiovascular disease ( Table). [11– 14] | TablePrevalence of Chronic Kidney Disease in Large-Scale Outcome Studies |
Modifiable risk factors for chronic kidney disease are similar to those for cardiovascular disease, [15] and the principal modifiable risk factor for ESRD in nondiabetic patients is hypertension. [16] The interrelationship between cardiovascular disease and chronic kidney disease risk factors, and the common pathophysiological role of sclerosis mediated by angiotensin II, explains the fact that many renal patients will die of a cardiovascular event before ESRD develops. [15]A strong and positive relationship between even low levels of kidney disease and increased risk for cardiovascular events has been demonstrated in a number of studies. The Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, for example, demonstrated the predictive value of albuminuria on all-cause mortality among > 40,000 subjects in the general population. [17] It is important to note that even at very low levels of albuminuria (10–20 mcg/minute), which many would regard as normal, the risk of dying in the 961-day median follow-up period of the study was increased. Similarly, even mild renal impairment can significantly increase mortality risk. In the VALsartan In Acute myocardial iNfarction Trial (VALIANT), in 14,527 patients with acute myocardial infarction complicated by clinical or radiologic signs of heart failure, left ventricular dysfunction, or both, mild renal impairment (defined as an estimated glomerular filtration rate [eGFR] ≥ 75 mL/minute/1.7 m 2) significantly increased the risk of death or the composite endpoint of death from cardiovascular causes, reinfarction, congestive heart failure, stroke, or resuscitation after cardiac arrest. [18] In patients with an eGFR rate < 81.0 mL/minute/1.73 m 2, each 10-point reduction in eGFR increased the hazard ratio for death and nonfatal cardiovascular outcomes by 1.10 (95% confidence interval [CI]: 1.08, 1.12). The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) demonstrated that more severe renal dysfunction (either proteinuria or high serum creatinine levels) was as potent a risk factor as prior myocardial infarction. [12] And in the Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study, baseline albuminuria was shown to be the strongest predictor of an adverse cardiovascular outcome, with a 1.92-fold (95% CI: 1.54, 2.38) increase in the composite cardiovascular endpoint in patients with albuminuria ≥ 3 g/g creatinine vs those with low albuminuria (< 3 g/g creatinine). [19] Longitudinal data (281 hypertensive patients with normal glomerular filtration rate at baseline were followed for a mean of 13.2 years) further support the interrelationship between renal impairment and cardiovascular risk. [20] In this study, the incidence of cardiovascular events in the patients who developed chronic kidney disease was 40% as opposed to 13.3% in those with normal renal function. RAS Blockade in Type 2 Diabetic Nephropathy Targeting the RAS is pivotal to the management of chronic kidney disease, [5] although currently there is no strong evidence for the use of ACE inhibitors in patients with type 2 diabetes and overt nephropathy, such as are included in the ONTARGET trial. Several clinical trials have, however, demonstrated the efficacy of ARBs in this patient population. The clinical significance of these beneficial effects of ARBs is acknowledged in current guidelines. For example, those of the American Diabetes Association advocate the use of ARBs for the management of patients with advanced stages of nephropathy as well as in those with microalbuminuria. [21]ARBs exert their beneficial effect by blood pressure reduction (especially in patients with hypertension) and by improving endothelial function and reducing oxidative stress. Analysis of the Irbesartan in Diabetic Nephropathy Trial (IDNT) has revealed the importance of both these factors. [22] Over a median follow-up period of 2.6 years, there was a 2.2-fold increase in the risk of doubling serum creatinine or ESRD in patients with systolic blood pressure (SBP) > 149 mm Hg compared with those with SBP < 143 mm Hg, regardless of the specifics of their treatment. However, in patients achieving comparable reductions in SBP, the incidence of renal endpoints was lower in patients receiving irbesartan compared with those receiving amlodipine. The early response to treatment is an important predictor of long-term protection. After 6 months of therapy in the RENAAL study, a 50% reduction in albuminuria reduced the risk of a renal endpoint by the end of the 3- to 4-year follow-up by 36%, and of ESRD by 45% (consisting of a doubling of serum creatinine or ESRD). [19] RENAAL also confirmed that regression of nephropathy by pharmaceutical intervention is linked to improved cardiovascular outcomes. For every 50% reduction in albuminuria achieved by pharmacological intervention in the first 6 months of the study, total cardiovascular risk was reduced by 18% and heart failure risk by 27%. RAS Blockade in Microalbuminuria/Early Chronic Kidney Disease Existing evidence for the beneficial effects of ACE inhibitors in similar populations is limited. A substudy of HOPE (MIcroalbuminuria, Cardiovascular and Renal Outcomes [MICRO-HOPE]) evaluated as a secondary endpoint the emergence of overt nephropathy in patients with type 2 diabetes. Ramipril was shown to reduce the onset of overt nephropathy by 22%. [13]The evidence for the beneficial effect of angiotensin receptor blockade, however, is more conclusive. In the IRbesartan in patients with type 2 diabetes and MicroAlbuminuria (IRMA-2) study, the time to the onset of diabetic nephropathy (defined as persistent albuminuria in overnight specimens, with a urinary albumin excretion rate > 200 mcg/minute and a ≥ 30% increase from baseline level) was determined in patients receiving placebo (n = 201), irbesartan 150 mg (n = 195), or irbesartan 300 mg (n = 194). [23] After a follow-up period of 2 years, only 5.2% of patients treated with irbesartan 300 mg progressed to overt nephropathy as opposed to 9.7% of those receiving irbesartan 150 mg and 14.9% of those receiving placebo. This represents a relative risk reduction with irbesartan 300 mg vs placebo of 79% and with irbesartan 150 mg of 39% vs placebo. The ability of an ARB to reduce the degree of microalbuminuria was shown in the MicroAlbuminuria Reduction with VALsartan (MARVAL) trial. [24] This study, which employed amlodipine 5 mg as the comparator, included both hypertensive and normotensive patients with type 2 diabetes and incipient nephropathy (persistent urinary albumin rate of 20 to 200 mcg/minute). In the overall patient population, valsartan 80 mg treatment for 24 weeks produced a reduction from baseline in the urinary albumin excretion of 92% (95% CI: 81.7, 103.7). This was significantly greater ( P < .001) than the 56% (95% CI: 49.6, 63.0) reduction from baseline with amlodipine. Reduction in albuminuria was similar in both the hypertensive and normotensive patients; because of this observation, it was concluded that valsartan conferred an antialbuminuric effect that was independent of blood pressure control. Prevention of Early Chronic Kidney Disease ONTARGET will include many patients at high risk of renal disease progression but without nephropathy, and thus will provide an excellent opportunity to assess the effect of RAS control in such patients. Use of the ACE inhibitor has been shown to prevent the emergence of persistent microalbuminuria in patients with type 2 diabetes and apparently normal urinary albumin levels (overnight values < 20 mcg/minute). [25] The BErgamo NEphrologic DIabetes Complications Trial (BENEDICT) compared the efficacy of the ACE inhibitor trandolapril with the nondihydropyridine calcium-channel blocker verapamil. In a study of 1204 patients followed for a median of 3.6 years, trandolapril proved more effective than verapamil, delaying the onset of microalbuminuria by a factor of 2.1 compared with placebo ( P = .01). Evidence on Telmisartan in Preventing and Treating Renopathy A number of studies have assessed the effects of telmisartan at several stages of the renal continuum. Two 1-year studies have compared telmisartan with other ARBs on proteinuria in patients with type 2 diabetes. The trial to inVestigate the efficacy of telmIsartan versus Valsartan in hypertensive type 2 DIabetic patients with overt nephropathy (VIVALDI) showed that the 2 ARBs provided comparable renoprotection. [26] After 1 year of treatment, reductions in proteinuria of 33% were achieved in patients treated with either telmisartan 80 mg or valsartan 160 mg. (At the time the study was initiated, these doses were the maximum recommended for the treatment of hypertension.) To ensure adequate blood pressure control, an alpha- or beta-blocker, calcium channel blocker, or diuretic could also be given. Notably, however, patients in the valsartan arm received more concomitant antihypertensives. A trial to compare 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) was a sister study to VIVALDI that compared telmisartan with losartan in 1566 patients. [27] Telmisartan significantly reduced proteinuria compared with losartan (29% reduction compared with 20%; P = .03), despite similar reductions in blood pressure (again due to the provision of concomitant antihypertensives). The INcipieNt to OVert: Angiotensin II receptor blocker, Telmisartan, Investigation On type 2 diabetic Nephropathy (INNOVATION) trial showed that telmisartan is able to prevent the transition to overt disease in Japanese patients after a mean follow-up of 1.3 years. [28] The relative risk of transition to overt nephropathy was reduced by 66% and 55%, respectively, with telmisartan 80 mg and telmisartan 40 mg compared with placebo in the overall patient population (). Thus, for every 3 patients treated, telmisartan 80 mg prevented 1 transition to overt nephropathy over the course of approximately 1 year. The renoprotective benefit of telmisartan was also apparent in patients who were normotensive at baseline (), which suggests that there is a blood pressure-independent effect. In addition, INNOVATION showed treatment of patients with telmisartan could bring about regression of incipient disease, with 21.2% and 12.8% of patients in the telmisartan 80 mg and 40 mg arms, respectively, becoming normoalbuminuric compared with 1.2% of patients receiving placebo (both doses P < .001). A head-to-head comparison of telmisartan with an ACE inhibitor was provided by the Diabetics Exposed to Telmisartan And EnalaprIL (DETAIL) study of patients who were predominantly microalbuminuric. [29] Over the 5-year study period, yearly changes in glomerular filtration rates with telmisartan 80 mg (n = 120) and enalapril 20 mg (n = 130) were comparable (). There were also comparable changes in mean serum creatinine and median urinary albumin excretion in the 2 treatment groups. The improvement in the glomerular filtration rate was less apparent after 3 years of treatment than initial marked impact. Based on the findings of DETAIL, it may be argued that a more aggressive approach to renoprotection may be required in the long term. A recently published study – Telmisartan versus Ramipril in renal Endothelial DYsfunction (TRENDY) – provides the first head-to-head comparison of an ARB and an ACE inhibitor on renal endothelial function. [30] TRENDY was performed in 96 patients with type 2 diabetes who had mild-to-moderate hypertension (seated SBP/diastolic blood pressure [DBP] 140 to 180/90 to 110 mm Hg), normo- or microalbuminuria, and glomerular filtration rate > 80 mL/minute/1.73 m 2. These patients, therefore, were at the very earliest stage of the renal continuum. They were treated with telmisartan 40 mg or ramipril 5 mg for 3 weeks, followed by telmisartan 80 mg or ramipril 10 mg for 6 weeks. Both telmisartan and ramipril improved nitric oxide activity (a measure of endothelial function), with a trend toward superiority of telmisartan. There was also a significant decrease in urinary albumin excretion from 9.0 to 7.3 mg/24 hours with telmisartan ( P = .022), whereas the change from baseline with ramipril was not significant. Possible Benefits of Dual RAS Control The clinical evidence strongly supports the hypothesis that targeting the RAS is important at all stages of chronic kidney disease, not simply by controlling blood pressure but also by blood pressure-independent effects. With more aggressive blockade of the RAS, it may be possible to achieve better renoprotection than currently reported. In theory, there are a number of ways in which this could be achieved. These include: use of a combination of an ACE inhibitor and an ARB; use of doses of an ARB that are higher than those employed to treat hypertension; use of an ACE inhibitor or an ARB together with an aldosterone antagonist; or use of a renin inhibitor. Some of these options have been investigated in small-scale studies. Some data suggesting that a combination of losartan and trandolapril reduces the risk of renal failure in patient with nondiabetic renal disease come from the COmbination treatment Of angiotensin II recePtor blockER and AngioTensin-converting Enzyme inhibitor in non-diabetic renal disease (COOPERATE) study. [31] A total of 336 patients were randomized to treatment with losartan 100 mg, trandolapril 3 mg, or a combination of losartan and trandolapril. The patients were monitored over 36 months for the emergence of a doubling of serum creatinine or ESRD. Among the patients receiving combination therapy, 10 (11%) reached the composite endpoint compared with 20 (23%) receiving trandolapril monotherapy (hazard ratio 0.38; 95% CI: 0.18, 0.63; P = .018) and 20 (23%) of 86 receiving losartan (hazard ratio 0.40; 95% CI: 0.17, 0.69; P = .016). The main evidence for the beneficial effect of more aggressive management of renal disease in diabetic patients by combination RAS blockade comes from the Candesartan And Lisinopril Microalbuminuria (CALM) study. [32] There was a significantly greater reduction in the urinary albumin:creatinine ratio in the 49 patients treated with the combination therapy compared with that achieved in the 49 patients receiving candesartan ( P = .003) and the 46 receiving lisinopril ( P = .005). However, the combination therapy produced a significantly greater ( P ≤ .05) reduction in DBP (16.3 mm Hg) than either monotherapy (candesartan reduction 10.4 mm Hg, lisinopril reduction 10.7 mm Hg); thus, the role of blood-pressure independent effects is unclear. Combination therapy with telmisartan and lisinopril has also been found to significantly reduce albuminuria compared with either monotherapy. [33] The effects of a doubled dose of telmisartan has been studied in 78 hypertensive patients with nondiabetic nephropathies – telmisartan 80 mg was given once or twice daily for 18 months. [34] Despite similar blood pressure control, the decline in estimated creatinine clearance was significantly less in patients treated twice daily than in the patients treated once daily (). Twice-daily telmisartan also brought about a significantly greater reduction in proteinuria than did once-daily telmisartan. Clinical studies performed on patients at different stages in the renal continuum show that targeting the RAS is beneficial in terms of renal function. However, because of the nature of the studies, and in particular the duration of treatment and the numbers of patients evaluated, we cannot establish whether these interventions have a long-term beneficial effect on cardiovascular outcomes and the prevention of renal events, including the emergence of microalbuminuria in patients at risk. Moreover, the optimal approach for the provision of more complete RAS blockade has yet to be identified. ONTARGET is designed to provide answers to these questions, among others. [2] Based on the results of the findings of HOPE, [13] ramipril has come to be regarded as a highly effective treatment in the management of cardiovascular risk, including the reduction of proteinuria in these high-risk patients. As discussed above, there is currently evidence from a number of trials that telmisartan is effective at various stages of the renal continuum, from the earliest stage of renal endothelial dysfunction to the later stages of proteinuria. The renal studies to date suggest that the renal benefit of telmisartan and ramipril is due not only to control of blood pressure, but also to blood pressure-independent mechanisms. These mechanisms will be particularly important in ONTARGET as the majority of patients enrolled had well-controlled blood pressure or did not have a diagnosis of hypertension at baseline. [2] ONTARGET will provide a unique opportunity to examine the effects of the study drugs on progression of renal disease in a diverse population, and also on the link with cardiovascular outcomes. Writers employed by PAREXEL MedCom drafted the manuscripts, based on the authors' slide presentations and the audio from the symposium. 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