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In adults with CKD does the risk:benefit ratio of ACE inhibitors or ARBs change with increasing age?

Ref ID: 771
ReferenceStudy type/Evidence levelNumber of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
Nakamura T, Kanno Y, Takenaka T et al. An angiotensin receptor blocker reduces the risk of congestive heart failure in elderly hypertensive patients with renal insufficiency. Hypertension Research. 2005; 28(5):415–423.RCT, open- label

1 +

E-COST- R Trial (Efficacy of Candesartan on Outcome in Saitama Trial in Renal Disease)

Multi-centre trial, Japan
N =141

ITT not stated
Inclusion: E-COST-R Study: people age 60–75 years with hypertension (SBP > 140 mm Hg and DBP > 90 mm Hg) and renal insufficiency (serum creatinine > 1.2 mg/dl and < 2.0 mg/dl)

Exclusion: diabetes, secondary hypertension, patients on dialysis, renal transplantation recipients, corticosteroid hormone use, MI or stroke within previous 6 months, angina pectoris requiring treatment with beta blockers or calcium channel blockers, heart failure or LVEF < 40%.

Baseline population characteristics: NS difference between those randomised to candesartan or conventional treatment. Mean age was 66.8 years in candesartan treated people with past CVD history and 67.4 years in candesartan treated people without past CVD history.
Mean age was 67.2 years in conventionally treated people with past CVD history and 66.1 years in conventionally treated people without past CVD history.
Mean eGFR was 44 ml/min in each group.
Candesartan (past history of CVD) N= 33

Candesartan (without past history of CVD) N= 36

Protocol:
Patients were randomised to receive candesartan or conventional-based regimens to reach a BP goal of SBP < 130 mm Hg and DBP < 80 mm Hg.
Mean dose of candesartan was 7. 12 mg/d in people with past history of CVD and 6.99 mg/day in those without a past history of CVD. SBP and DBP were determined at baseline and throughout study GFR was estimated with Cockcroft Gault equation. Patients were stratified by those with a previous history of cardiovascular events and those without.
Conventional (past history of CVD) N= 38

Conventional (without past history of CVD) N= 34

Protocol: as for intervention
Mean follow-up 3.1 yrsHospitalisation due to stroke, MI, or congestive heart failure

Serum creatinine levels

Change in GFR

All-cause mortality
Not stated
Effect size
All-cause mortality
No deaths occurred in the people without past history of cardiovascular events (treated with candesartan or conventional therapy).
4 deaths occurred in the group with a past history of CVD treated with candesartan.
4 deaths occurred in the group with a past history of CVD treated with conventional therapy.

Cardiovascular Events:
In people with a previous history of CVD, candesartan treatment (20/33) significantly decreased the incidence of cardiovascular events compared with conventional treatment (32/38, p< 0.05).

Stroke:
In people with a previous history of CVD, there was NS difference between candesartan and conventional treatment for the incidence of stroke.
In people without a previous history of CVD, there was NS difference between candesartan and conventional treatment for the incidence of stroke.

MI:
In people with a previous history of CVD, there was NS difference between candesartan and conventional treatment for the incidence of MI.
In people without a previous history of CVD, there was NS difference between candesartan and conventional treatment for the incidence of MI.

Congestive Heart Failure:
In people with a previous history of CVD, candesartan treatment (4/33) significantly decreased the incidence of congestive heart failure compared with conventional treatment (13/38, p< 0.05).
In people without a previous history of CVD, there was NS difference between candesartan and conventional treatment for the incidence of congestive heart failure.

Change in serum creatinine:
No significant changes in serum creatinine were observed in people treated with candesartan, regardless of previous CVD history.
In people without a past history of CVD and treated with conventional therapy, there were no significant changes in serum creatinine.
In people with a past history of CVD and treated with conventional therapy, serum creatinine significantly increased from baseline (1.50 mg/dl) to 3 years follow-up (1.89 mg/dl, p<0.05)

Change in GFR
No significant changes in estimated GFR were observed in people treated with candesartan, regardless of previous CVD history.
In people without a past history of CVD and treated with conventional therapy, there were no significant changes in GFR.
In people with a past history of CVD and treated with conventional therapy, GFR significantly decreased from baseline (43.6 ml/min) to 3 years follow-up (34.3 ml/min, p<0.05).

Note: Authors acknowledge limitations: no concealment (open label), the cause of renal disease was predominantly nepherosclerosis (not glomerulonephritis) as trial was conducted in general practice, Japanese people have a lower incidence of CVD, diabetes was excluded, study was terminated at 3 years (instead of 5 years as planned) when patients in the conventional treatment group were switched to ARBs (including candesartan).
Ref ID: 3677
ReferenceStudy type/Evidence levelNumber of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
Frances CD, Noguchi H, Massie BM et al. Are we inhibited? Renal insufficiency should not preclude the use of ACE inhibitors for patients with myocardial infarction and depressed left ventricular function. Arch Intern Med. 2000; 160(17):2645–2650.Retrospective cohort using medical record data

2+

US Cooperative Cardiovascular Project
Total N=20902

N serum creatinine > 3 mg/dl (265 micromol/L) = 1582

N serum creatinine ≤ 3 mg/dl (265 micromol/L) = 19320
Inclusion: Cohort of Medicare beneficiaries ≥ 65 years of age admitted to hospital from Feb. 1, 1994 to July 30, 1995 with documented LVEF < 40% (measured by echocardiography, radionuclide scintigraphy, angiography) following confirmed acute MI. Acute MI was diagnosed as a creatine kinase-MB > 5% or a 2-fold elevated LDH-2 or the patient met 2 of the 3 following criteria: chest pain, creatine kinase level at least 2-fold greater than normal, or evidence of acute MI confirmed by electrocardiography.

Exclusion: patients transferred to another hospital, those who died during hospitalisation

Baseline population characteristics:
Received an ACE inhibitor at hospital discharge

N= 525 serum creatinine > 3 mg/dl

N= 11892 serum creatinine ≤ 3 mg/dl

Protocol: Medical records were reviewed to determine one-year survival rates for patients who received or did not receive an ACE inhibitor at hospital discharge following an acute MI.
Patients were stratified by renal function: > 3 mg/dl (265 micromol/L) or ≤ 3 mg/dl (265 micromol/L).
Did not receive an ACE inhibitor at hospital discharge

N= 1057 serum creatinine > 3 mg/dl

N= 7428 serum creatinine ≤ 3 mg/dl

Protocol: as for intervention
Not applicableOne-year survivalHealth Care Financing Administration and National Institute on Ageing, NIH
Serum creatinine > 3mg/dlSerum creatinine ≤ 3mg/dl
ACENo ACEACENo ACE
N5251057118927428
Serum creatibnine, mg/dl5.35.61.41.5
Mean age, years72.174.775.475.9
%Fe male37.936.644.641.9
% Black17.713.28.06.1
% Diabetes57.146.136.730.5
Effect size

Only 33% (525/1582) of people with poor renal function (serum creatinine > 3 mg/dl) received ACE inhibitor at hospital discharge compared with 62% (11892/19320) who had better renal function (serum creatinine ≤ 3 mg/d).

1-year survival
Univariate analysis: People with poor renal function (serum creatinine > 3 mg/dl, mean age 72) had a 20% lower 1-year survival compared with people with better renal function (serum creatinine ≤ 3 mg/d, mean age 75).

Multivariate analysis: the receipt of an ACE inhibitor at hospital discharge was associated with a 37% increase in 1-year survival for patients with poor renal function (serum creatinine > 3 mg/dl), N=1582, mean age 72). [HR for 1–year mortality 0.63, 95% CI 0.48 to 0.84, p value not stated)]

Multivariate analysis: the receipt of an ACE inhibitor at hospital discharge was associated with a 16% increase in 1-year survival for patients with better renal function (serum creatinine ≤ 3 mg/dl, N=19320, mean age 75) [HR for 1–year mortality 0.84, 95% CI 0.77 to 0.92, p value not stated)]

Patients with serum creatinine > 3 mg/dl who did not receive ACE had the lowest survival rates. Advanced age, female sex, comorbid conditions, increased severity of illness were all associated with lower survival.

Note: limitations as noted by authors: serum creatinine may not be reliable markers of renal function. They did not determine whether ACE inhibitors treatment was maintained after discharge from hospital and dosage, consistency of use data was lacking. Other confounding variables?? Although ACE inhibitors were beneficial to people with poor renal function who suffered MI, caution should still be used when prescribing ACE (lower ACE dosage, monitor serum creatinine, K, avoid NSAIDS)
Ref ID: 3661
ReferenceStudy type/ Evidence levelNumber of patientsPatient characteristicsInterventionComparisonLength of follow-upOutcome measuresSource of funding
Winkelmaye r WC, Zhang Z, Shahinfar S et al. Efficacy and safety of angiotensin II receptor blockade in elderly patients with diabetes. Diabetes Care. 2006; 29(10):2210–2217.Post-hoc of double blind RCT

2+

Reduction of Endponts in NIDDM with the Angiotensin II Antatgonist Losartan-RENAAL)

Multinational trial
N=1513 total

N = 505 age ≤ 57 years

N= 587 age > 57 to 65 years

N= 421 age > 65 years

The oldest participant was 74 years.
Inclusion: RENAAL Study: Type 2 diabetes with nephropathy (presence on 2 occasions of urinary albumin:creatinine ratio of at least 300 mg/g (800 mg/day), serum creatinine between 1.3 and 3.0 mg/dl, with a lower limit of 1.5 mg/dl for male participants weighing more than 60 kg

Exclusion: none stated

Baseline population characteristics: Compared to the younger age groups, the group > 65 years were predominantly white (57.5%) males (64.8%) and more likely to have a history of angina or past MI, lower GFR (38.8 ml/min per 1.73 m2), higher SBP (154 mm Hg), lower DBP (80 mm Hg).
Losartan Age ≤ 57 years N=259

Losartan Age > 57 to 65 years N= 288

Losartan age > 65 years N=204

Protocol: Patients were stratified by baseline proteinuria (< 2000 mg/g or ≥ 2000 mg/g) and then randomised to receive losartan potassium (N=751; 50 mg/d) or placebo (N=762; usual care). BP target was < 140/90 mm Hg. To achieve target BP study drugs were up-titrated, followed by additional open-label antihypertensive therapy. SBP and DBP were determined at baseline and throughout study

Post-hoc analysis: Participants stratified by age: age ≤ 57 years, age > 57 to 65 years, age > 65 years. Due to insufficient statistical power within each stratum, tests for interaction between age and losartan treatment (P interaction) were used. The objective was to look for consistent treatment effects rather than efficacy in subgroups.
Placebo Age ≤ 57 years N=246

Placebo Age > 57 to 65 years N= 299

Placebo age > 65 years N=217

Protocol: as for intervention
Mean follow-up 3.4 yrsPrimary endpoint: time to doubling of serum creatinine, ESRD, or death

Death

Adverse Events

Hyperkalaemia

Drug discontinuation
American Heart Association
Effect size
Testing for interaction between losartan and age (P interaction).

Primary endpoint: time to doubling of serum creatinine, ESRD, or death
The treatment effect of losartan on the primary endpoint did not significantly differ by age (P interaction = 0.662 adjusted for treatment group, region, proteinuria, albumin, creatinine, haemoglobin).

Death
The treatment effect of losartan on risk of death did not significantly differ by age (P interaction = 0.695 adjusted for treatment group, region, proteinuria, albumin, creatinine, haemoglobin).

In the total population (N=1513), there was NS difference in risk of death between losartan or placebo. In people ≤ 57 years (N=505), there was NS difference in risk of death between losartan or placebo. In people age > 57 to 65 years (N=587), there was NS difference in risk of death between losartan or placebo. In people age > 65 years (N=421), there was NS difference in risk of death between losartan or placebo.

Drug Discontinuation
Drug discontinuation was not significantly affected by increasing age (P interaction = 0.921).

In the total population (N=1513), there was NS difference in drug discontinuation between losartan or placebo.
In people ≤ 57 years (N=505), there was NS difference in drug discontinuation between losartan or placebo.
In people age > 57 to 65 years (N=587, there was NS difference in drug discontinuation between losartan or placebo.
In people age > 65 years (N=421), there was NS difference in drug discontinuation between losartan or placebo.

Adverse Events (acute renal failure or ESRD)
Older patients were no more susceptible to experiencing adverse events from losartan than younger people (P interaction for the entire follow-up = 0.762; P interaction for the first 14 days after randomisation = 0.242; P interaction for the first 30 days after randomisation = 0.752 )

In all three age groups (people ≤ 57 years, age > 57 to 65 years, or > 65 years) there was NS difference in incidence of adverse events between losartan or placebo.

Hyperkalaemia
Losartan was associated with a greater rate of hyperkalaemia. This effect was present in all age ranges. Thus, increasing age did not significantly increase the risk of hyperkalaemia from losartan (P interaction = 0.402)

In people ≤ 57 years (N=505), more people receiving losartan (26.6%) developed hyperkalaemia than those receiving placebo (11.0%), p=0.000.
In people age > 57 to 65 years (N=587), more people receiving losartan (25.7%) developed hyperkalaemia than those receiving placebo (15.5%), p=0.002.
In people > 65 years (N=421), more people receiving losartan (19.6%) developed hyperkalaemia than those receiving placebo (9.7%), p=0.004.

Note: Authors acknowledge study limitations: tight monitoring schedule of a trial may not reflect typical practice setting, the oldest participant was 74, therefore no data on older people > 74 years. Limited power may explain why there was NS difference of age on losartan treatment.

From: Evidence Tables

Cover of Chronic Kidney Disease
Chronic Kidney Disease: National Clinical Guideline for Early Identification and Management in Adults in Primary and Secondary Care.
NICE Clinical Guidelines, No. 73.
National Collaborating Centre for Chronic Conditions (UK).
Copyright © 2008, Royal College of Physicians of London.

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