Parameters
Yes
No
Comment
Validity
Is the randomization procedure well described?
+1
The protocol was fully described in a prior publication [5]
2 × 2 factorial design aimed at investigating:
Impact of different [5] low-protein diets
Low-protein diet (0.58 g/kg/day) and very low protein intake (0.28 g/kg/day) supplemented with keto-amino acids
And
Different [5] levels of BP control
Mean arterial pressure, 92 and 107 mmHg
Double blinded?
−2
Blinding dietary interventions is difficult to achieve. But compliance and dietary protein intake were estimated by the measurement of urinary urea nitrogen excretion
Is the sample size calculation described/adequate?
+3
Study 1 = 585
Study 2 = 255
Does it have a hard primary end point?
+1
Yes; the decline in measured GFR (radiolabeled-Iothalamate clearance)
Is the end point surrogate?
0
Is the follow-up appropriate?
+1
36 months
Was there a Bias?
+2
Is the drop out >25 %?
+1
Is the analysis ITT?
+3
Utility/usefulness
Can the findings be generalized?
+1
Mainly to CKD 3 and 4
GFR between 25 and 55 mL/min
Note that the large percentage (25 %) of ADPKD in the MDRD study population is not representative (overestimate) of their distribution prevalence in CKD
Was NNT <100?
Not applicable, as the study was negative
Score
73 %
Discussion
A number of studies investigated the impact of dietary protein restriction on the progression of CKD in the 1970s and 1980s. While suggesting a beneficial effect, they were largely flawed and consequently inconclusive [6], primarily because of the reliance on changes in serum creatinine parameters to evaluate the impact of the intervention on the progression of CKD; this was clearly unacceptable in view of the fact that a dietary protein restriction impacts serum creatinine levels through other mechanisms, independent of the changes in GFR, not the least a reduction in protein intake, creatine/creatinine intake, and metabolism, as well as possible confounders, such as malnutrition and sarcopenia [6].
The MDRD study was therefore the first and only RCT that investigated the impact of dietary protein restrictions on the progression of CKD, as measured by the clearance of radiolabeled-Iothalamate. MDRD study was a 2 × 2 factorial designed study to investigate the impact of two levels of dietary protein intake and two levels of BP control on the progression of CKD over a 36-month observation period. It proved negative on both outcomes.
An equally large European study had previously also proved negative in terms of the effect of low-protein diet on CKD progression, albeit by measuring changes in serum creatinine and in the face of issues relating to adherence/compliance to the prescribed diet and limited difference in dietary protein intake between the groups [7]. Subsequent meta-analyses, combining a heterogeneous number of studies with different types of dietary protein restrictions and different methods of measuring CKD progression, mostly relying on changes in serum creatinine estimation, continued to claim otherwise and justify the dietary protein restriction to delay the progression of CKD to end-stage renal disease (ESRD) [8].
MDRD also failed to show an impact of lower BP control (MAP = 92 mmHg) compared to usual control (MAP = 107 mmHg) on the progression of CKD.
Disappointingly, the interpretation of the results of the MDRD studies and outcomes has been confounded by a number of factors:
1.
The high percentage of patients with ADPKD (25 %) included in the study; these patients usually have a fast and relentless rate of decline in kidney function. This also impacts the utility of the study as it may be less representative of common CKD populations where the percentage of ADPKD tends to be lower (<10 %).
2.
The high rate of prescription of ACE inhibitors, thus potentially impacting independently the rate of GFR decline and thus confounding the predicted differences between the group and consequently the power of the study to detect such a difference.
3.
The complicated interpretation and potential impact of the initial, 4 months, faster decline in GFR in patients treated with a low-protein diet and those assigned to the low-BP group. Dietary protein restriction and lower BP, or related increased ACE inhibition, may have had in this study the anticipated early impact on reducing GFR (first 4 months), thus negatively impacting the overall data analysis, while the analysis based on the 4–36 months seemed more positive and potentially protective.
4.
The heterogeneity of the CKD population studies, including some with low and others with high levels of proteinuria, leading to different impacts of the lower BP intervention on the different populations; slower rate of GFR decline upon lower BP control in those with high proteinuria levels compared to those with low proteinuria levels. Also, different responses were noted between black and white patients. However, subgroup analyses can only be hypothesis-generating rather than providing conclusive evidence.
5.
Blood pressure measurement relied on casual office estimation and not on the preferable daytime and nighttime recordings of BP or its 24 h ambulatory BP monitoring (ABPM). The latter appear to correlate better with outcomes [9].
Finally, this study calls upon investigators to measure GFR when studying the rate of decline of kidney function in CKD and also have a careful preplanned/specified anticipation of possible breakpoints in GFR decline slopes due to the impact of a given intervention on renal physiology and pathophysiology. MDRD led the way in the thorough evaluation of renal function decline in RCTs by iothalamate clearance measurement, but sadly very few studies followed that lead.
Conclusions
It was a well-designed and well-conducted RCT that showed no substantial benefit of dietary protein restriction on the progression of CKD. It also failed to show a benefit of a lower BP compared to usual BP control. This was more or less the end of dietary protein restrictions to slow CKD progression. On the other hand, MDRD was the first to examine the impact of more intensive BP control on CKD progression.
Angiotensin-Converting Enzyme (ACE) Inhibition Studies
AIPRI Trial
N Engl J Med. 1996 Apr 11;334(15):939–45.
Effect of the angiotensin–converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin–Converting Enzyme Inhibition in Progressive Renal Insufficiency Study Group.
Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P.
Abstract
Background: Drugs that inhibit angiotensin-converting enzyme slow the progression of renal insufficiency in patients with diabetic neuropathy. Whether these drugs have a similar action in patients with other renal diseases is not known. We conducted a study to determine the effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of renal insufficiency in patients with various underlying renal diseases.
Methods: In a 3-year trial involving 583 patients with renal insufficiency caused by various disorders, 300 patients received benazepril and 283 received placebo. The underlying diseases included glomerulopathies (in 192 patients), interstitial nephritis (in 105), nephrosclerosis (in 97), polycystic kidney disease (in 64), diabetic nephropathy (in 21), and miscellaneous or unknown disorders (in 104). The severity of renal insufficiency was classified according to the baseline creatinine clearance: 227 patients had mild insufficiency (creatinine clearance, 46–60 mL/min), and 356 had moderate insufficiency (creatinine clearance, 30–45 mL/min). The primary end point was a doubling of the baseline serum creatinine concentration or the need for dialysis.
Results: At 3 years, 31 patients in the benazepril group and 57 in the placebo group had reached the primary end point (P < 0.001). In the benazepril group, the reduction in the risk of reaching the end point was 53 % overall (95 % CI, 27–70 %), 71 % (95 % CI, 21–90 %) among the patients with mild renal insufficiency, and 46 % (95 % CI, 12–67 %) among those with moderate renal insufficiency. The reduction in risk was greatest among the male patients; those with glomerular diseases, diabetic nephropathy, or miscellaneous or unknown causes of renal disease; and those with baseline urinary protein excretion above 1 g/24 h. Benazepril was not effective in patients with polycystic disease. Diastolic pressure decreased by 3.5–5.0 mmHg in the benazepril group and increased by 0.2–1.5 mmHg in the placebo group.
Conclusions: Benazepril provides protection against the progression of renal insufficiency in patients with various renal diseases.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | −1 | Randomization procedure was not well described beyond the fact that it was aimed to match the control and intervention groups based on the disease severity in each center | |
Double blinded? | +2 | ||
Is the sample size calculation described/adequate? | +3 | Not described, but likely to be adequate: | |
Benazepril group: 300 patients | |||
Control: 283 patients | |||
Subsequently stratified into patients with mild CKD (Creatinine clearance: 60–45 mL/min) and moderate CKD (CrCl: 44–30 mL/min) | |||
Does it have a hard primary end point? | −1 | Doubling of serum creatinine or the need for dialysis (the need for dialysis [ESRD] definition not protocolized/prespecified) | |
Is the end point surrogate? | 0 | GFR not measured | |
ESRD not defined by a creatinine clearance, but instead by the need for dialysis | |||
Is the follow-up appropriate? | +1 | 3 years | |
Was there a Bias? | +2 | ||
Is the drop out >25 %? | +1 | ||
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | Nondiabetic CKD with CrCl between 60 and 30 mL/min | |
Was the NNT <100? | +1 | 11 treated with benazepril for 3 years to prevent one end point | |
Five patients treated for 3 years if proteinuria >3 g/24 h | |||
Score | 81 % | ||
Discussion
AIPRI was the first large RCT investigating the impact of ACE inhibition (benazepril) on the progression of nondiabetic CKD; <5 % had diabetic nephropathy. It followed the publication of the Captopril study that Lewis et al. undertook and published in 1993 and showed that the rate of progression of diabetic nephropathy in patients with type 1 diabetes mellitus (DM) was significantly slowed down by ACE inhibition [10].
AIPRI is a well-designed and well-conducted RCT that seemed to indicate that benazepril (ACE inhibition) slows the progression of CKD. It also showed a significant reduction in proteinuria. AIPRI led to a huge number of subsequent studies claiming similar beneficial outcomes for ACE inhibitors in nondiabetic CKD.
While plausible, the limitations of this RCT are manifold:
1.
Significant differences in systolic and diastolic BP between the treated and placebo groups cannot exclude a beneficial effect being solely due to lower BP and its possible impact on CKD progression. This was addressed in the study by statistical adjustment for changes in BP; however, a statistical correction for the biological effect of lower BP on CKD progression is difficult to achieve in order to exclude this major confounder.
2.
Also, differences in BP control between groups were ascertained by casual office BP recordings. This is less than optimal in a trial of an intervention that primarily lowers BP, bearing in mind that more frequent daytime and nighttime recordings as well as 24 h ABPM are nowadays thought to be more reliable and less subject to variability as well as more predictive of outcomes [11].
3.
CKD progression was to a very large extent (90 % of participants) evaluated by the doubling of serum creatinine, a commonly used progression parameter. This would be acceptable if ACE inhibition did not impact tubular secretion of creatinine [12, 13], thus confounding the interpretation and the validity of that end point in such trials. GFR was not measured.
Conclusions
This was undoubtedly a seminal trial in the field of CKD progression along with that of Lewis et al. in 1993 in patients with diabetic nephropathy [10]. Along with the REIN study that followed it [14], they set the trend of ACE inhibition in CKD.
Unfortunately, the AIPRI study shares many of the limitations of the entire literature on ACE inhibition in CKD, including the lack of measured GFR and rigor in BP measurements.
REIN Trial
Lancet. 1997 Jun 28;349(9069):1857–63.
Randomized placebo–controlled trial of effect of ramipril on the decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, nondiabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia)
Abstract
Background: In diabetic nephropathy, angiotensin-converting-enzyme (ACE) inhibitors have a greater effect than other antihypertensive drugs on proteinuria and the progressive decline in glomerular filtration rate (GFR). Whether this difference applies to the progression of nondiabetic proteinuric nephropathies is not clear. The Ramipril Efficacy in Nephropathy study of chronic nondiabetic nephropathies aimed to address whether glomerular protein traffic influences renal disease progression, and whether an ACE inhibitor was superior to conventional treatment, with the same blood pressure control, in reducing proteinuria, limiting GFR decline, and preventing end-stage renal disease.
Methods: In this prospective double-blind trial, 352 patients were classified according to baseline proteinuria (stratum 1: 1–3 g/24 h; stratum 2: ≥3 g/24 h), and randomly assigned ramipril or placebo plus conventional antihypertensive therapy targeted at achieving diastolic BP under 90 mmHg. The primary end point was the rate of GFR decline. Analysis was by intention to treat.
Findings: At the second planned interim analysis, the difference in decline in GFR between the ramipril and placebo groups in stratum 2 was highly significant (p = 0.001). The Independent Adjudicating Panel therefore decided to open the randomization code and do the final analysis in this stratum (stratum 1 continued in the trial). Data (at least three GFR measurements including baseline) were available for 56 ramipril-assigned patients and 61 placebo-assigned patients. The decline in GFR per month was significantly lower in the ramipril group than the placebo group (0.53 [0.08] vs. 0.88 [0.13] mL/min, p = 0.03). Among the ramipril-assigned patients, percentage reduction in proteinuria was inversely correlated with the decline in GFR (p = 0.035) and predicted the reduction in risk of doubling of baseline creatinine or end-stage renal failure (18 ramipril vs. 40 placebo, p = 0.04). The risk of progression was still significantly reduced after adjustment for changes in systolic (p = 0.04) and diastolic (p = 0.04) BP, but not after adjustment for changes in proteinuria. Blood pressure control and the overall number of cardiovascular events were similar in the two treatment groups.
Interpretation: In chronic nephropathies with proteinuria of 3 g or more per 24 h, ramipril safely reduces proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of BP lowering.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | Randomization code allocated by Hoescht research institute | |
Double blinded? | −2 | Study was unblinded at 27 months, in view of publication of a study showing a beneficial effect of ACE inhibition. The study continued unblended for an additional 3 years as open label | |
Is the sample size calculation described/adequate? | −3 | Assumptions of progression and protection by ACE inhibitor were made based on the studies of patients with progressive diabetic nephropathy | |
This may not be translatable to nondiabetic CKD | |||
No, in view of the small number of patients included in the study (50 % of the total randomized: 177 of 352) and the even smaller number of those whose data was analyzed by measured GFR: 117 of 166 in strata 2 (proteinuric) | |||
Does it have a hard primary end point? | +1 | Rate of decline in measured GFR measured by the clearance of nonradioactive iohexol clearance | |
Is the end point surrogate? | 0 | However, GFR was measured in a percentage of patients (117 of 166 = ~70 %) enrolled, and ESRD was not protocolized and well defined. The last point is all the more relevant since the study was unblinded to the investigators from the 27th month and for a duration of the three following years | |
Is the follow-up appropriate? | +1 | 42 months | |
Was there a Bias? | +2 | ||
Is the drop out >25 %? | −1 | Only 50 % of those enrolled had a GFR-based analysis | |
Is the analysis ITT? | −3 | Only those who had measured GFR were analyzed, although the authors state that the study was an ITT-based analysis | |
Utility/usefulness | |||
Can the findings be generalized? | +1 | To patients with proteinuric CKD3 | |
Was the NNT <100? | +1 | ||
Score | 0 % | ||
Discussion
REIN is undoubtedly the single most important RCT on the impact of ACE inhibition (ramipril) on the progression of nondiabetic CKD. It is certainly the most cited. It has led to a tsunami of ACE inhibition prescription to patients with proteinuric CKD and even to those without the same severity of proteinuria (>3–4 g/24 h). It has considerably informed subsequent guidelines on the management of hypertension in patients with CKD [15, 16].
It also claimed that the changes in the measured GFR were independent from comparable BP control in both groups but dependent on the changes in proteinuria that decreased in the ramipril group.
The REIN study has significant limitations:
1.
It is undoubtedly underpowered as the sample size of the stratum [16], analyzed in the publication under discussion, is half the total study randomized population (177 of 352); those with lower level proteinuria showed no beneficial effect of ACE inhibition on progression, and had the total population been included in the analysis, there would have been no overall effect of ramipril on CKD progression.
2.
Overall, only 177 of 352 patients in the REIN study had measured GFR. The sample of the study population who had the evaluation of the primary end point measured GFR, in the strata/substudy 2 (proteinuric patients), was even smaller – 56 of 78 (ramipril-treated) and 61 of 88 (controls). Consequently, this was a per-protocol study analysis, although the authors state otherwise (ITT).
3.
Blood pressure control was comparable in both groups, but it can be argued that measuring casual/office blood pressure is no longer considered an accurate enough reflection of overall blood pressure control; 24 h ambulatory blood pressure monitoring (24 h ABPM) is considered more reliable [17]. In fact, in another study on the impact of ramipril on cardiovascular outcomes, differences in outcome proved to be associated with better nighttime BP control and 24 h BP control in the ramipril group, an effect that would have been overlooked if only office BP was measured [18].
4.
The use of ESRD and start of dialysis as an end point without prior defined protocolization with clear specification of the level at which ESRD would be determined is unsatisfactory, all the more so in an unblinded study such as REIN.
Conclusions
Unfortunately, REIN is an underpowered study with an inadequate sample size, insufficiently large to draw firm and irrefutable conclusions.
REIN Follow-Up Trial
Lancet. 1999 Jul 31;354(9176):359–64.
Renoprotective properties of ACE inhibition in nondiabetic nephropathies with nonnephrotic proteinuria
Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G.
Abstract
Background: Stratum 2 of the Ramipril Efficacy in Nephropathy (REIN) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, angiotensin-converting enzyme (ACE) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF) found in controls on placebo plus conventional antihypertensives. In REIN stratum 1 reported here, 24 h proteinuria was 1 g or more, but less than 3 g/24 h.
Methods: In stratum 1 of this double-blind trial, 186 patients were randomized to a ramipril or a control (placebo plus conventional antihypertensive therapy) group targeted at achieving a diastolic blood pressure of less than 90 mmHg. The primary end points were changed in glomerular filtration rate (GFR) and time to ESRF or overt proteinuria (≥53 g/24 h). Median follow-up was 31 months.
Findings: The decline in GFR per month was not significantly different (ramipril, 0.26 [SE 0.05] mL/min/1.73 m2; control, 0.29 [0.06]). Progression to ESRF was significantly less common in the ramipril group (9/99 vs. 18/87) for a relative risk (RR) of 2.72 (95 % CI, 1.22–6.08); so was the progression to overt proteinuria (15/99 vs. 27/87, RR 2.40 [1.27–4.52]). Patients with a baseline GFR of 45 mL/min/1.73 m2 or less and proteinuria of 1.5 g/24 h or more had more rapid progression and gained the most from ramipril treatment. Proteinuria decreased by 13 % in the ramipril group and increased by 15 % in the controls. Cardiovascular events were similar. As expected, the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2.
Interpretation: In nondiabetic nephropathies, ACE inhibition confers renoprotection even to patients with nonnephrotic proteinuria.
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | Randomization code allocated by the Hoescht Research Institute | |
Double blinded? | −2 | Study was unblinded at 27 months and subsequently pursued for 3 years as open label | |
Is the sample size calculation described/adequate? | −3 | Assumptions of progression and protection by ACE inhibitor were made based on the studies of patients with progressive diabetic nephropathy | |
This may not be translatable to nondiabetic CKD | |||
Study likely to be underpowered, in view of the small number of patients included in the study – 186 of 352 (Strata 1 = ~50 % of the total randomized). The number of patients whose data was analyzed by measured GFR is not specified and is likely to be an even smaller number | |||
Does it have a hard primary end point? | Rate of decline in measured GFR and ESRD (the latter could be a subjective decision regarding initiation of RRT by investigators who had unblinded information) | ||
Is the end point surrogate? | 0 | ||
Is the follow-up appropriate? | +1 | Median follow-up = 31 months | |
Was there a Bias? | +2 | Baseline GFR was higher in the ramipril group | |
Is the drop out >25 %? | +1 | Number of those who had a measured GFR is unclear but those who reached ESRD is given | |
Is the analysis ITT? | Number of those who had a measured GFR is unclear but those who reached ESRD is given | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | To nondiabetic patients with CKD3 and proteinuria <3 g/24 hour | |
Was the NNT <100? | +1 | ||
Score | 12.5 % | ||
Discussion
This is the other half of the REIN study (strata 1) evaluating the impact of ACE inhibition with ramipril on the progression of nondiabetic CKD with nonnephrotic range proteinuria (<3 g/24 h).
It suffers the same limitations as the main REIN study (stratum 2 in nephrotic patients).
But, in addition, it has the following limitations:
1.
The overall end point result relating to the decline in the measured GFR, 0.26 mL/min/month, is identical between the two groups, ramipril and placebo. It is only when a subgroup analysis is undertaken of those with GFR lesser or greater than 45 mL/min that those with GFR < 45 mL/min seem to benefit from ramipril treatment. Subgroup analysis is at best hypothesis-generating and not concluding evidence.
2.
Intriguingly, while there was no difference in the GFR rate of decline, there was a higher percentage of patients reaching ESRF in the placebo group. Starting RRT was a clinical decision and not one based on reaching a prespecified protocolized cutoff GFR. This was confounded by the fact that the investigators by that stage of the study were no longer blinded, as the study was unblended at 27 months.
Conclusions
Overall, this is a negative albeit underpowered study. Subgroup analysis claims to show a benefit in those with GFR < 45 mL/min, but this would be at best hypothesis-generating, as the study was not powered to answer the question of the level of GFR that responded best to ACE inhibition.
RAS Inhibition in Advanced CKD4–5
N Engl J Med. 2006 Jan 12;354(2):131–40.
Efficacy and safety of benazepril for advanced chronic renal insufficiency.
Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, Jiang JP, Liang M, Wang GB, Liu ZR, Geng RW.
Abstract
Background: Angiotensin-converting enzyme inhibitors provide renal protection in patients with mild-to-moderate renal insufficiency (serum creatinine level, 3.0 mg/dL or less). We assessed the efficacy and safety of benazepril in patients without diabetes who had advanced renal insufficiency.
Methods: We enrolled 422 patients in a randomized, double-blind study. After an 8-week run-in period, 104 patients with serum creatinine levels of 1.5–3.0 mg/dL (group 1) received 20 mg of benazepril per day, whereas 224 patients with serum creatinine levels of 3.1–5.0 mg/dL (group 2) were randomly assigned to receive 20 mg of benazepril per day (112 patients) or placebo (112 patients) and then followed for a mean of 3.4 years. All patients received conventional antihypertensive therapy. The primary outcome was the composite of a doubling of the serum creatinine level, end-stage renal disease, or death. Secondary end points included changes in the level of proteinuria and the rate of progression of renal disease.
Results: Of 102 patients in group 1, 22 patients (22 %) reached the primary end point, as compared with 44 of 108 patients given benazepril in group 2 (41 %) and 65 of 107 patients given placebo in group 2 (60 %). As compared with placebo, benazepril was associated with a 43 % reduction in the risk of the primary end point in group 2 (P = 0.005). This benefit did not appear to be attributable to BP control. Benazepril therapy was associated with a 52 % reduction in the level of proteinuria and a reduction of 23 % in the rate of decline in renal function. The overall incidence of major adverse events in the benazepril and placebo subgroups of group 2 was similar.
Conclusions: Benazepril conferred substantial renal benefits in patients without diabetes who had advanced renal insufficiency. (ClinicalTrials.gov number, NCT00270426.)
Critical Appraisal
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | Computer-generated randomization | |
Double blinded? | +2 | ||
Is the sample size calculation described/adequate? | +3 | Although an assumption of 60 % progression to ESRD in the group not treated with ACE inhibitors may be incorrect, the assumption that ACE inhibition would slow progression by 40 % is questionable. The sample size calculation assumption raises concern about the power of the study | |
Does it have a hard primary end point? | −1 | Composite end points including doubling of serum creatinine, ESRD, and start of RRT or death | |
GFR was not measured | |||
Is the end point surrogate? | −2 | Serum creatinine parameters, and nonprotocolized and prespecified ESRD cutoff point make these end points soft | |
Is the follow-up appropriate? | 3.4 years | ||
Was there a Bias? | −2 | Only one control group with CKD4 and none for those with higher GFR (group 1) | |
Is the drop out >25 %? | −1 | Large number (>35 %) of randomized, but not analyzed, patients in all groups: | |
326 of 422 analyzed | |||
Is the analysis ITT? | −3 | >30 % not analyzed | |
Utility/usefulness | |||
Can the findings be generalized? | −1 | Applicable to Chinese with CKD4 and 5 | |
Was the NNT <100? | +1 | ||
Score | 0 % | ||
Discussion
This study took the use of ACE inhibitors a step further and into patients with CKD stage 4. This has encouraged a trend of the prescription of this class of antihypertensive agents to all CKD patients, even those with GFRs < 20 mL/min.
The study concluded that benazepril treatment was capable of considerably improving outcomes (by 50 %) even in advanced CKD – stage 4.
The study and its design have a number of limitations and inconsistencies:
1.
GFR was not measured as a gold standard to evaluate CKD progression at this advanced stage of CKD.
2.
A composite end point of interrelated end points, doubling of serum creatinine, ESRD, or death, was used with the serious limitations of such an approach and without clarification of the end point with the highest impact and meaning. This calls for cautious interpretation of results [19].
3.
The design of this RCT is complicated, with one placebo group with a lower GFR for two benazepril groups of different GFRs: 26 and 37 mL/min.
4.
Blood pressure was claimed to be the same between groups, although one received placebo and the other two benazepril. Also, casual 3-monthly office BP recording leaves a lot to be desired in RCTs, where the intervention is primarily an antihypertensive strategy; day and night BP recordings as well as 24 h ABPM would have been more conclusive [20].
5.
Some inconsistencies such as identical values for creatinine clearance and GFR at baseline, when it is well known that at CKD stage 4, creatinine clearance can exceed GFR by as much as 50 % due to increased tubular secretion of creatinine.
6.
Study power and sample size as well as benazepril dosage differed in this study from a parallel publication of the same study by the same group in a Chinese journal [21]. This warrants clarification and justification.
Conclusions
Critical appraisal highlights numerous limitations to this RCT, raising concern that such a study has been adopted by many without careful evaluation of data, justifying the prescription of RAS inhibitors to patients with advanced renal insufficiency at the risk of further decline in kidney function.
REIN 2 Trial
Lancet. 2005 Mar 12–18;365(9463):939–46.
Blood pressure control for renoprotection in patients with nondiabetic chronic renal disease (REIN–2): multicenter, randomized controlled trial.
Ruggenenti P, Perna A, Loriga G, Ganeva M, Ene-Iordache B, Turturro M, Lesti M, Perticucci E, Chakarski IN, Leonardis D, Garini G, Sessa A, Basile C, Alpa M, Scanziani R, Sorba G, Zoccali C, Remuzzi G; REIN-2 Study Group.
Abstract
Background: In chronic nephropathies, inhibition of angiotensin-converting enzyme (ACE) is renoprotective, but can further renoprotection be achieved by reduction of blood pressure (BP) to lower than usual targets? We aimed to assess the effect of intensified versus conventional BP control on progression to end-stage renal disease.
Methods: We undertook a multicenter, randomized controlled trial of patients with nondiabetic proteinuric nephropathies receiving background treatment with the ACE inhibitor ramipril (2.5–5 mg/day). We randomly assigned participants, either conventional (diastolic < 90 mmHg; n = 169) or intensified (systolic/diastolic < 130/80 mmHg; n = 169) BP control. To achieve the intensified BP level, patients received add-on therapy with the dihydropyridine calcium channel blocker felodipine (5–10 mg/day). The primary outcome measure was the time to end-stage renal disease over 36 months’ follow-up, and analysis was by intention to treat.
Findings: Of 338 patients who were randomized, 3 (2 assigned intensified and 1 allocated conventional BP control) never took study drugs, and they were excluded. Over a median follow-up of 19 months (IQR, 12–35), 38/167 (23 %) patients assigned to intensified BP control and 34/168 (20 %) allocated conventional control progressed to end-stage renal disease (hazard ratio, 1.00 [95 % CI 0.61–1.64]; p = 0.99).
Interpretation: In patients with nondiabetic proteinuric nephropathies receiving background ACE inhibitor therapy, no additional benefit from further BP reduction by felodipine could be shown.
Parameters | Yes | No | Comment |
|---|---|---|---|
Validity | |||
Is the randomization procedure well described? | +1 | ||
Double blinded? | −2 | Patients and investigators were aware of the allocation | |
Is the sample size calculation described/adequate? | +3 | Early termination may have affected the study power | |
Does it have a hard primary end point? | −1 | Time to ESRD over 36 months, although ESRD was neither protocolized nor specified | |
Is the end point surrogate? | −2 | Time to ESRD in an unblinded study with no prespecified ESRD cutoff point is a soft end point | |
Is the follow-up appropriate? | Terminated early for futility | ||
Was there a Bias? | +2 | ||
Is the drop out >25 %? | +1 | ||
Is the analysis ITT? | +3 | ||
Utility/usefulness | |||
Can the findings be generalized? | +1 | CKD3 patients with variable levels of proteinuria < div class='tao-gold-member'>
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