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ACE Inhibitors to Prevent End-Stage Renal Disease: When to Start and Why Possibly Never to Stop: A Post Hoc Analysis of the REIN Trial Results
PIERO RUGGENENTI,*† ANNALISA PERNA,* and GIUSEPPE REMUZZI*† on behalf of Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN)
*Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, “Aldo e Cele Dacco ` ” Villa Camozzi, Ranica, Italy; and †Unit of Nephrology, Ospedali Riuniti, Azienda Ospedaliera, Bergamo, Italy. (P Ͻ 0.0001), diastolic (P ϭ 0.02), and mean (P Ͻ 0.001) BP and proteinuria (P Ͻ 0.0001) but not by basal GFR (P ϭ 0.12). ESRD risk reduction was predicted by basal proteinuria (P Ͻ 0.01) and GFR (P Ͻ 0.0001) and was strongly dependent on treatment duration (P Ͻ 0.0001). Adverse events were comparable among the three tertiles and within each tertile in the two treatment groups. Thus, disease progression and response to ACE inhibition do not depend on severity of renal insufficiency. The risk of ESRD and the absolute number of events saved by ACE inhibition is highest in patients with the lowest GFR. However, renoprotection is maximized when ACE inhibition is started earlier and when longlasting treatment may result in GFR stabilization and definitive prevention of ESRD.
Abstract. In this post hoc, secondary analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, an angiotensin-converting enzyme (ACE) inhibition risk/benefit profile was assessed in 322 patients with nondiabetic, proteinuric chronic nephropathies and different degrees of renal insufficiency. The rate of GFR decline (⌬GFR) and the incidence of end-stage renal disease (ESRD) during ramipril or non–ACE inhibitor treatment were compared within three tertiles of basal GFR. ⌬GFR was comparable in the three tertiles, whereas the incidence of ESRD was higher in the lowest tertile than in the middle and highest tertiles. Ramipril decreased ⌬GFR by 22%, 22%, and 35% and the incidence of ESRD by 33% (P Ͻ 0.05), 37%, and 100% (P Ͻ 0.01) in the lowest, middle, and highest tertiles, respectively. ⌬GFR reduction was predicted by basal systolic
Since the first angiotensin-converting enzyme (ACE) inhibitor, captopril, was approved for the treatment of arterial hypertension, most doctors have been reluctant to offer such therapy to patients with renal failure. Reasons for potential concern have been acute renal function deterioration and hyperkalemia (1). This bias prevented patients with advanced renal failure from taking part in the prospective, large-scale clinical trials that eventually found ACE inhibitors to be a class of drugs that offer significant renal protection (2,3). As a consequence and somehow paradoxically, the risk/benefit profile of ACE inhibitor therapy in patients with advanced renal insufficiency is poorly defined so far. Even more disturbing, a large proportion of renal patients who might theoretically benefit from this treatment is not currently offered the only therapy that may delay progression of the disease to end-stage renal failure and need for dialysis. Actually, a recent review emphasized that even a transient increase in serum creatinine levels leads to
physician reticence to stay the course with ACE inhibitor therapy (4). This behavior is further encouraged by advice from some investigators to withhold these medications when creatinine levels exceed 3 mg/dl (5). The rationale for such an attitude remains elusive if one considers that ACE inhibition in animal models is remarkably antiproteinuric and provides renoprotection even when treatment is initiated late in the course of the disease (6). This is why the Ramipril Efficacy In Nephropathy (REIN) study–a randomized, prospective trial aimed at exploring the specific renoprotective effect of ACE inhibition therapy in proteinuric, chronic nephropathies (7,8)— did not use severe renal insufficiency as an exclusion criterion. This offered the investigators the unique opportunity for post hoc analyses on the impact of renal function (GFR, 10 to 100 ml/min per 1.73 m2) on disease progression and response to treatment. Results of these analyses form the basis of the present report.
Materials and Methods
Received May 21, 2001. Accepted October 1, 2001. Correspondence to Dr. Piero Ruggenenti, Clinical Research Center “Aldo e Cele Dacco ` ” Villa Camozzi, “Mario Negri” Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: 39-035-319.888; Fax: 39-035-319.331; E-mail: firstname.lastname@example.org 1046-6673/1212-2832 Journal of the American Society of Nephrology Copyright © 2001 by the American Society of Nephrology
A detailed description of the REIN study design and results has been published elsewhere (7,8). Study participants were patients of either gender, aged between 18 and 70 yr, with urinary protein excretion Ն1 g/24 h over at least 3 mo and creatinine clearance in the range of 20 to 70 ml/min per 1.73 m2, who had not received ACE inhibition therapy for at least 3 mo. Exclusion criteria were treatment with corticosteroids, nonsteroidal anti-inflammatory
108 were in the middle tertile. Thirty-four patients (11%) (19 on ramipril and 15 on placebo plus conventional treatment) had a concomitant.6%.J Am Soc Nephrol 12: 2832–2837. Risk reduction achieved statistical significance in the lowest (P Ͻ 0. 22%. and ineffective contraception.0 to 2. NC) was used for all statistical analyses. 322 patients who had at least three GFR evaluations (including baseline) entered into the study (median follow-up. there was a significant interaction of treatment effect with basal proteinuria (P Ͻ 0. Within each tertile. In each patient. 107 were in the lowest tertile. Only four patients (three on ramipril) were withdrawn because of persistent hyperkalemia (serum potassium Ն6 mEq/L). In no tertile did GFR significantly decrease after 1 or 3 mo of ramipril or conventional treatment (data not shown).05 versus 0. In patients already receiving antihypertensive agents. and 35%) and the incidence of ESRD (by 33%. P ϭ 0.. Statistical Analyses Data were analyzed on an intention-to-treat basis. pregnancy. evidence or suspicion of renovascular disease. respectively. with the only exception of a significantly higher prevalence of male patients on ramipril treatment in the middle tertile (Table 1).0004) and in the highest tertile (31 [26 to 52] mo. Ն3 g/24 h) and were then randomly assigned 1. patients had their GFR centrally evaluated at Mario Negri Institute for Pharmacological Research by the plasma clearance of nonradioactive iohexol (9). whereas—as expected—the incidence of events was significantly higher in the lowest (50. main baseline demographic.52 Ϯ 0. ACE inhibitors or antagonists to angiotensin II receptor could not be added to the study drugs during the study period. In time-to-event analysis of ESRD. 6 mo after randomization and every 6 mo thereafter. At study entry. 1. and 27% in the lowest. middle. the incidence of renal events (ESRD) was higher (32%) than in those with chronic glomerular disease (25%) and was not significantly affected by ACE inhibitor therapy. Details on the analyses of GFR decline and renal endpoints are given elsewhere (7. with only 5 patients (11%) in the control group progressing to ESRD. Within each tertile (Figures 1 through 3). diastolic (P ϭ 0. Patients were considered separately within three subgroups (tertiles) with progressively increasing basal GFR (lowest. respectively). The protocol of the REIN trial was approved by the ethics committee and the institutional review board of each of the 14 hospitals involved. Results Overall. breast-feeding. Median (IQ range) ramipril or conventional treatment duration was significantly shorter in the lowest tertile (24 [14 to 38] mo) than in the middle tertile (32 [24 to 51] mo.12) (Table 2). the study drug dose was increased and the dose of other antihypertensive agents progressively reduced to avoid symptomatic hypotension. 12.38 Ϯ 0. patients were separated before randomization into two strata (stratum 1.9 g/24 h. the overall incidence of ESRD was relatively low regardless of treatment allocation. obstructive uropathy. In the highest tertile. and highest tertiles (0.25-mg capsules of ramipril or placebo on a 1:1 basis within each stratum. only 54 (17%) of patients were already on ACE inhibitor therapy (11.0001 versus middle and highest tertiles) and middle tertiles (17.01) and GFR (P Ͻ 0.02). despite concomitant diuretic therapy. According to the Declaration of Helsinki.8).05) and highest (P Ͻ 0.0001) but not with basal GFR (P ϭ 0. and laboratory characteristics were comparable between the two treatment groups. 37%.01 versus highest tertile) as compared with the highest (4. middle. The incidence of major adverse events was comparable in the three tertiles (Table 3) and was comparable within each tertile in ramipril and conventionally treated patients. higher serum aminotransferase concentrations. Follow-up serum potassium levels were higher in ramipril than in conventionally treated patients. heart failure (New York Heart Association class III or higher). Cary. Data were expressed as mean Ϯ SD or median and interquartile (IQ) range. ramipril as compared with conventional treatment uniformly decreased ⌬GFR (by 22%. P ϭ 0. At baseline at 1. Antihypertensive agents (but not ACE inhibitors) were introduced. middle. or log-rank test as appropriate. written informed consent before study entry. 31 mo. The study drug dose was increased every 2 wk up to 2.0002). and highest tertiles. All P values were based on two-sided tests at Ͻ0.001) BP and proteinuria (P Ͻ 0. drug or alcohol abuse.05.73 m2 per mo. and mean (P Ͻ 0.5 mg/d or 5 mg/d until trough diastolic BP (measured in the morning before study drug administration) was reduced to Ͻ90 mmHg.0001). 21 to 49 mo). The main objective of the study was to compare the effect of the two study treatments (ramipril versus conventional) on ⌬GFR and progression to end-stage renal disease (ESRD) in patients with comparable levels of BP control and different underlying renal diseases.7%) tertile. and 100%) in the lowest. acute myocardial infarction or cerebrovascular accident in the previous 6 mo. the broad aim was to adjust the dose of the study drugs to achieve and maintain the target BP with the minimum dose of concomitant antihypertensive agents. and their doses were adjusted appropriately to achieve and maintain diastolic BP Ͻ90 mmHg. All of them had withdrawn from previous ACE inhibitor therapy for at least 3 mo before study entry. chronic cough. cancer. 2001 ACE Inhibition in Renal Insufficiency 2833 drugs. urinary tract infection. respectively. P Ͻ 0. diabetes type 1. in patients with adult polycystic kidney disease (APKD).5%.0001). According to baseline urinary protein excretion rate. and—in diabetic patients—intensified metabolic control.01) tertiles.08 versus 0. clinical. there was a significant interaction of treatment effect with the level of basal systolic (P Ͻ 0. Risk reduction was strongly dependent on treatment duration (P Ͻ 0.005 lowest or middle tertile versus highest tertile). and highest tertiles. 3. unless otherwise stated. all patients provided signed. IQ range.44 Ϯ 0. but differences between treatment groups were statistically significant only in the lowest tertile and never exceeded 0. Fisher exact test. and 107 were in the highest tertile. P Ͻ 0. severe uncontrolled hypertension (diastolic BP Ն115 mmHg and/or systolic BP Ն220 mmHg). Mean Ϯ SEM ⌬GFR was comparable in the lowest. Comparisons among tertiles and between the two treatment groups within each tertile were done by using Wilcoxon rank sum test. Overall. or immunosuppressive drugs. middle.07 ml/min per 1. P Յ 0.0001). optimized acid-base balance. The IQ range obtained using the first and third quartile of values distribution served as a measure of data dispersion that is less influenced than absolute range by extreme values. In slope-based analysis of ⌬GFR. stratum 2.5 . collagen disease. SAS version 8 (SAS Institute Inc. highest tertiles). chronic cardiovascular disease.
5 Figure 1.3 48.6 4.2 46 50.0 77% 144. only 12 patients (3.0 192.8 Ϯ 10.8 78% 143.8 92. Figure 2.11). proteinuric chronic nephropathies Lowest Parameter Conventional Ramipril Conventional Ramipril Conventional Ramipril Middle Highest Patients n GFR (ml/min per 1.6 Ϯ 2.4 Ϯ 0.7%) withdrew from the study due to serious (fatal in 4 cases) cardiovascular events (6 on ramipril and 6 on conventional treatment) during the follow-up period.9 67. and was remarkably safe.0 Ϯ 12.7 to 100.0 214.0 89.9 to 101.3 Ϯ 11.3 Ϯ 0.0 89. Consistent with previous findings (10.7 Ϯ 11.6 71% 147.8 Ϯ 68.1 243. chronic nephropathies according to treatment and tertiles of basal GFR.0 63.1 Ϯ 10.6 25.4 Ϯ 17.9 238.4 52.4 Ϯ 17.73 sqm) range mean Ϯ SD Clinical parameters age (yr) male gender (%) systolic BP (mmHg) diastolic BP (mmHg) mean BP (mmHg) Diagnosis glomerular disease (%) APKD or interstitial nephritis (%) other or unknown (%) Laboratory parameters serum creatinine (mg/dl) creatinine clearance (ml/min per 1.2 Ϯ 13.0 Ϯ 5.8 Ϯ 59.3 48.3 3. Within each tertile.8 Ϯ 10.3 245.7 23.3 3.8 60% 2% 38% 2.9 174.0 to 50. Altogether.9 Ϯ 216.0 90.0 89.6 109. 2001 Table 1.4 Ϯ 0.1 2.7 Ϯ 14.7 57% 2% 41% 1.9 31. There were no significant differences among the groups.1 Ϯ 20.2 4.5 Ϯ 0.0 46.8 90.5 56 32.3 Ϯ 12.2 49.8 Ϯ 11.3 Ϯ 14.6 107.2 168.7 52% 9% 39% 2.4 Ϯ 5.0 250.6 4.7 111.7 Ϯ 51.0 68% 87% 146.6 Ϯ 12.5 Ϯ 15.1 3.2 50% 10% 40% 3.6 4.5 Ϯ 16.3 Ϯ 12.8 Ϯ 14.9 4. This analysis establishes that the renoprotective effect exerted by ACE inhibition in chronic nephropathies is independent of the severity of renal failure.1 Ϯ 19.1 35% 11% 54% 3.7 Ϯ 133.5 61 51.6 41. Values are mean Ϯ SEM.1 Ϯ 18.9 Ϯ 54.9 142.5 Ϯ 12.8 Ϯ 126.6 4. chronic nephropathies according to treatment and tertiles of basal GFR.3 Ϯ 0.3 73% 149.7 Ϯ 2.5 237.2 52 13.3 71.3 Ϯ 13.4 48.1 Ϯ 2.4 Ϯ 0. Per tertile GFR baseline characteristics of 322 patients with nondiabetic.6 4.2834 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 2832–2837.7 to 50.6 to 32.7 29.0 Ϯ 12.7 Ϯ 0.5 Ϯ 11.2 Ϯ 2. ACE inhibition was dialysis-saving in all three subgroups of patients.5 Ϯ 0.3 50.2 Ϯ 9.5 107. the data also shows that renoprotection conferred by ACE inhibitors is time-depen- .4 172. follow-up hematocrit and hemoglobin concentrations were comparable in the two treatment groups (data not shown).4 46.9 Ϯ 96.8 41.8 Ϯ 2.73 sqm) proteinuria (g/24 h) total cholesterol (mg/dl) triglycerides (mg/dl) potassium (mEq/l) 55 10.1 108.1 Ϯ 3.4 Ϯ 53.8 Ϯ 14.0 Ϯ 0.4 Ϯ 9.0 Ϯ 10. Discussion mEq/L.1 Ϯ 5. including those with very severe renal dysfunction.0 Ϯ 13.4 Ϯ 94.0 Ϯ 12.0 Ϯ 0.2 52 33.0 64% 6% 30% 1.9 90.0 195.7 3.9 Ϯ 16. Incidence of end-stage renal disease (ESRD) in 322 patients with proteinuric.2 Ϯ 94.0 Ϯ 5.5 to 32.1 Ϯ 0.0 Ϯ 83.3 67. GFR decline in 322 patients with proteinuric.2 Ϯ 0.0 247.
ACE inhibition uniformly slowed GFR decline and progression to ESRD within each tertile of basal GFR. this is the first large study that definitely demonstrates that ACE inhibitors are worth using even in very advanced forms of renal failure. Another one found an effect on events but not on GFR (15). despite less risk reduction.02 Ͻ0. . had their GFR decline decreased by 22% and risk of ESRD reduced by 33%. previous analyses of the REIN study found that ramipril decreased renal events less effectively in male than in female patients (16).92 0. Thus. To the best of our knowledge.08 0. as compared with conventionally treated patients. patients who might benefit most from ACE inhibitors are actually the ones not offered treatment. dialysis risk reduction was actually lower in the lowest tertile as compared with the middle or highest GFR tertiles. according to our present analyses.001 0. translated into a higher absolute number of dialyses saved in the 10 to 30 ml/min GFR category than in higher GFR categories. Findings that the rate of GFR decline in patients recruited into the REIN study was comparable within each tertile indicate that in proteinuric. On the other hand.0001 0.0001 0.23 0. patients with more advanced renal insufficiency experienced a remarkably higher incidence of events.31 0. probably because of the high prevalence of male patients on ramipril treatment. Indeed. despite comparable ⌬GFR reduction in the three tertiles.32 Ͻ0.14).13 0.0001 0. which.56 0. two previous studies (13.17 Ͻ0.J Am Soc Nephrol 12: 2832–2837. even in patients quite closed to terminal renal failure (basal GFR. a finding that further reinforces the current concept that systolic hypertension should be considered as an important target for antihypertensive treatment that is targeted at improving the outcome of chronic nephropathies. This observation is remarkably consistent with previous analyses that show that faster GFR decline in chronic renal disease is significantly predicted by higher arterial BP and proteinuria but not by basal GFR (12). In particular.73 m2). ramipril therapy had a consistent renoprotective effect. did not have the power for finding differences in event rates. Consistent with previous studies (12).08 0.12 0. Table 2. Risk reduction failed to achieve the statistical significance in the middle tertile. chronic nephropathies according to treatment and tertiles of basal GFR.71 0. Indeed.01 Ͻ0. Actually. 2001 ACE Inhibition in Renal Insufficiency 2835 Figure 3. 10 to 30 ml/min per 1. This can be reconciled by considering that ramiprilassociated risk reduction was a function of treatment duration and that patients in the lowest tertile had been treated for a shorter period compared with patients with more preserved GFR. We found that. That men are at increased risk of progression is consistent with the results of the RENAAL study in patients with type 2 diabetes with overt nephropathy (17). nondiabetic chronic nephropathies the disease progresses independently of the severity of renal dysfunction and rather suggest that the higher risk of terminal renal failure seen in patients with more depressed GFR is just the consequence of more advanced renal disease. Univariate analysis of the interaction between treatment effect on ⌬GFR or end-stage renal disease (ESRD) and baseline patients characteristics Parameter ⌬GFR ESRD Age Gender Systolic BP Diastolic BP Mean BP Diagnosis Proteinuria GFR Total cholesterol Triglycerides 0. even response to ramipril treatment was not dependent on the severity of renal excretory dysfunction. systolic more than diastolic BP predicted progression to ESRD and response to ACE inhibitor therapy.37 Ͻ0. Kidney survival in 322 patients with proteinuric. Of note.23 dent and that treatment started at earlier stages of the disease considerably stabilizes renal function and prevents the need of dialysis.48 0. which indeed found a trend to slower GFR decline in ACE inhibitor versus conventionally treated patients. who.
because none of the above trials were designed and powered to detect a significant effect of ACE inhibitor therapy on major cardiovascular events. Chichester. Indeed. The comparable incidence of events in the two treatment groups was consistent with previous evidence that. including chronic glomerular diseases. Hypertension and Related Diseases.5 mEq/L and had no appreciable effects on patients’ hematocrit or hemoglobin concentrations. even when GFR approximates levels requiring replacement therapy. Furthermore. 2001 Table 3. Milan. angiotensin II receptor antagonists and calcium channel blocking agents: A review of potential benefits and possible adverse reactions. given the fact that it can be estimated that Ͻ20% of patients in need are currently offered this renoprotective treatment. Sixth European Meeting on Hypertension. These findings. Bain RP. among and within tertiles no differences were recorded in the incidence of major side effects between treatment groups. Motolese M. ACE inibitors failed to exert any appreciable cardioprotective effect (19). 1996 4. Treatment is also renoprotective for levels of renal function between 10 and 30 ml/min. Serious adverse events leading to patient withdrawal Lowest Tertile Conventional Ramipril Middle Tertile Conventional Ramipril Highest Tertile Conventional Ramipril Death Cardiovascular events Worsening of renal function Hyperkalemia Cough Uncontrolled BP Cancer Other Total 0 2 2 1 1 0 0 1 7 1 0 1 2 1 1 0 1 7 1 1 1 0 0 2 2 1 8 1 1 0 1 0 0 2 1 6 0 2 0 0 1 0 0 2 5 1 2 0 0 1 1 0 2 7 Finding more events and less benefit from ramipril therapy in patients with APKD than in those with chronic glomerulonephritis was consistent with previous evidence that APKD carries a worse prognosis and is less responsive to renoprotective treatments—including low protein diet and intensified BP control (18)—than other chronic nephropathies. 1993. These findings. Mann JF. Remuzzi G: Angiotensin converting enzyme inhibition in patients with impaired renal function: helpful or harmful? In: ACE Inhibition. The incidence of serious (fatal and nonfatal) cardiovascular events was remarkably lower in the REIN study than in previous trials on ACE inhibitor therapy in patients with or without chronic renal disease. Thus. Ponticelli C. Bakris GL. N Engl J Med 34: 939 –945. Zucchelli P: Effect of the angiotensinconverting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. Rohde RD for the Collaborative Study Group: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. 1997 . Maschio G. near end-stage renal failure. those with a serious cardiovascular event in the 3 mo before basal evaluation) were not selected for study participation and because those in the trial had their risk minimized by optimal BP control (according to the guidelines of the early 1980s) and by uniform adherence to a Mediterranean diet. must be taken with caution. Locatelli F. 2000 5. Ruggenenti P. Alberti D.e. ACE inhibition therapy should be offered to all patients with proteinuric chronic nephropathies. Media Medica Publications Ltd. UK. References 1. J Am Coll Cardiol 29: 1414 –1421. a nonsignificant trend to more withdrawals because of worsening renal function or hyperkalemia was observed in patients with lowest GFR at study entry. June 8. edited by Unger T. 1993 3. As predicted. Ramipril therapy was tolerated well. regardless of renal function. Lewis EJ. even in patients with very severe. including those in the lowest GFR tertile. clearly document an excellent tolerability profile. Janin G. the risk of acute renal function deterioration was most likely prevented by temporary diuretic withdrawal before randomization and exclusion of patients with clinical suspicion of volumedepletion or renovascular disease (3). Maximal renoprotection is achieved when the treatment is started early in the course of the disease (GFR Ͼ50 ml/min). combined with the evidence that ramipril therapy resulted in an average increase in serum potassium that never exceeded 0. Is this a cause for concern? Arch Intern Med 160: 685– 693. pp 27– 40 2. in virtually all trials in nondiabetic chronic nephropathies.. indicating the need not to withhold ACE inhibitors. Weir MR: Angiotensin converting enzyme inhibitor associated elevations in serum creatinine. This was probably because patients at highest risk (i. Dal Palu ` C. these events were extremely uncommon (Ͻ3 cases observed in every 100 patients) and equally reported in ramipril and conventionally treated patients. however. Equally reassuring was the evidence that.2836 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 2832–2837. Ritz E. N Engl J Med 329: 1456 –1462. Overall incidence of major adverse events was comparable in ramipril and conventional treatment groups. even in the lowest tertile. a figure that decreases to 11 to 12% if the GFR is severely impaired. However. Hunsicker LG. no short-term GFR decrease was observed in ramipril-treated patients. at variance with previous reports in diabetic nephropathy. This message will never be emphasized enough. Moser M: Angiotensin-converting enzyme inhibitors.
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