Effect of Telmisartan on Renal Outcomes: A randomized trial Mann JF, Schmieder RE, Dyal L, McQueen M

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Effect of Telmisartan on Renal Outcomes A
randomized trialMann JF, Schmieder RE, Dyal L,
McQueen MJ, Schumacher H, Pogue J, Wang X,
Probstfield JL, Avezum A, Cardona-Munoz E,
Dagenais GR, Diaz R, Fodor G, Maillon JM, Rydén
L, Yu CM, Teo KK, Yusuf S TRANSCEND (Telmisartan
Randomised Assessment Study in ACE Intolerant
SubjectsAnnals of Internal Medicine, 2009 July
7 151 (1-10)Daniel Fitelson, PGY 1July 28,
2009
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Diabetic Nephropathy

• Equal incidence in type 1 and 2 DM
• 20-30 microalbuminuria after 15 years of disease
• Less than ½ progress to overt nephropathy
• Mean duration of progression to macroalbuminuria
  is 10-20 years
• Tight glycemic control, aggressive blood pressure
  reduction, use of ACE/ARB has been shown to
  reduce rate of progression to diabetic nephropathy

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Diabetic Nephropathy

• Pathologic abnormalities evident prior to
  microalbuminuria
• 1) Glomerular basement membrane thickening
• 2) Mesangial expansion
• 3) Glomerular sclerosis
• 4) Kimmelstiel-Wilson lesion
• Hyaline expansion of glomerular arterioles

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Diabetic Nephropathy

• Elevated blood pressure and glomerular
  hyperfiltration implicated in development of
  microalbuminuria
• AGE
• Glycosylation of matrix proteins leading to
  mesangial expansion
• Up-regulation of PKC and heparanase lead to
  increased GBM permeability to albumin

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Role of ACE/ARB

• ACE/ARB Therapy
• Decrease blood pressure with concomitant decrease
  in intraglomerular pressure
• Shown to decrease urinary protein excretion
• Decreased rate of increase in serum creatinine
• Slower progression to ESRD and death

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ARB RCT

• RENAAL
• Losartan reduced the incidence of doubling of
  serum creatinine by 25 and incidence of ESRD by
  28 in patients with known diabetic nephropathy
• INDT
• Compared amlodipine or irbesartan vs placebo in
  patients with known diabetic nephropathy
• 23 reduction in doubling of serum creatinine and
  dialysis

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TRANSCEND

• Examined cardiovascular outcomes in ACE
  intolerant subjects with known vascular disease
  but not macroalbuminuria using telmisartan
  compared to placebo
• No statistically significant effect on primary
  cardiovascular outcome
• Renal outcomes were prespecified secondary
  outcomes

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Objective

• To examine long term renal effects of telmisartan
  vs placebo in adults with vascular disease but
  not macroalbuminuria

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Study Design

• Used data from TRANSCEND study with prespecified
  renal outcomes
• Randomized controlled trial
• 630 centers in 40 countries
• 5296 patients enrolled from November 2001 through
  May 2004
• Age 55 or older
• Intolerant of ACE inhibitors
• Coronary, cerebrovascular, peripheral vascular
  disease or DM with end organ damage

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Study Design

• Exclusion criteria
• Heart failure, valvular or cardiac outflow tract
  obstruction, unexplained syncope,
  revascularization in last 3 months, heart
  transplant, SAH, renal artery stenosis, serum cr
  gt 3.0, macroalbuminuia (gt300 mg/24hrs)
• ACE Intolerant
• Defined as having to stop therapy within 3 months
• 88 cough, 4 symptomatic hypotension, 1
  angioedema, 1 renal dysfunction

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Patient Characteristics
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Intervention

• 3-4 week run in phase
• Single blind placebo for 1 week followed by
  telmisartan 80mg for 2-3 weeks
• Randomly assigned Telmisartan 80mg or placebo
• Assigned by telephone using central automated
  system
• Participants and trial investigators blinded to
  randomized treatment
• Tablets identical in color, shape, and taste

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Outcome

• Primary composite outcome
• First occurrence of death, dialysis, renal
  transplantation, doubling of serum creatinine
• Secondary composite outcome
• Composite of dialysis or doubling of serum
  creatinine
• Estimated GFR
• MDRD formula
• UACR
• Progression of proteinuria

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Measurement

• Participants followed after 6 weeks and every 6
  months for mean of 56 months
• Analysis of prespecified subgroups using cox
  regression model
• Study groups compared using chi square and t
  tests for continuous variables
• UACR and GFR not normally distributed,
  log-transformed prior to statistical analysis,
  change analyzed using least squares linear
  regression
• Time to event approach
• Data displayed as hazard ratios with 95 CI

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Results

• Dialysis
• 0.24 (7) with telmisartan vs 0.34 (10) in
  placebo
• Not statistically significant
• HR 1.29, p 0.20
• Doubling of serum creatinine
• Telmisartan (1.9) more frequent than placebo
  (1.2)
• Occurred mainly in patients with baseline
  creatinine less than 1.0 (75 of cases)
• Composite outcome
• Telmisartan 14 (412) vs placebo 12.8 (381)
• Not statistically significant
• HR 1.1, CI (0.95 to 1.26), P 0.193

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Incidence of Main Outcomes
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Composite Renal Outcome
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Albuminuria

• Baseline microalbuminuria
• 287 patients in telmisartan group and 273 in
  placego group
• Telmisartan 9.8 and placebo 17.9 progressed to
  macroalbuminuria
• New incidence
• Telmisartan 11.4 vs placebo 14.8
• Statistically significant (p 0.001)

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UACR
Statistically significant reduction in UACR
compared at 2 years to baseline and final to
baseline (p lt 0.001)
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Estimated GFR

• GFR decreased more with telmisartan than placebo
• Most prominent during first 6 weeks of therapy
• Related to changes in systolic blood pressure
• Hypothesized to have long term protective benefit

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Main Outcomes in Subgroups

• Estimated GFR gt 60 or no microalbuminuria
• Telmisartan increased incidence of composite
  renal outcome
• Estimated GFR lt 60 or microalbuminuria
• Telmisartan decreased incidence of composite
  renal outcomes

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Discussion

• IRMA-2, ONTARGET, RENAAL have all proven benefits
  of ARB to reduce progression of microalbuminuria
  to overt diabetic nephropathy
• Compared to placebo, Telmisartan reduced urinary
  albumin excretion and progression of micro to
  macroalbuminuria
• No decrease in long term renal outcomes
• Did not show survival benefit seen in other
  studies

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Discussion

• Current Recommendations
• ACE or ARB on diagnosis of DM
• ACE or ARB in any patient with microalbuminuria
• To date, no large studies have shown a
  statistically significant benefit of ACE or ARB
  in patients without microalbuminuria
• Need for further trials to look at the effect of
  ACE/ARB on long term renal function in patients
  with no renal impairment

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Discussion

• Only 6 cases of dialysis depended acute renal
  failure
• 4 in placebo and 2 in telmisartan group
• ONTARGET
• Increased incidence of acute renal failure with
  ACE and ARB combination compared to placebo

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Discussion

• In concordance with ONTARGET results, suggest
  reduction in urinary albumin in patients with
  baseline albuminuria lt 300mg/24hrs may not be
  beneficial
• Decrease in UACR has been shown to correlate with
  a decrease in GFR and may not provide long term
  benefits

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Strengths

• Double blind design
• Large sample size, multi-ethnic population,
  multi-center
• Mean follow-up 56 months
• Minimal drop out rates

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Weaknesses

• Inclusion criteria based on cardiovascular
  outcomes
• Only patients with known vascular dysfunction and
  gt55 years old included
• Measurements made locally, inducing measurement
  bias
• Significant percentage of patients later found to
  have microalbuminuria at baseline
• Mean GFR 71 indicating population with
  significant renal dysfunction at baseline
• No wash-out period to evaluate effect on GFR and
  UACR
• Number of deaths related to renal causes not
  measured

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Limitations

• Reasons for dialysis and doubling of serum
  creatinine not specified
• Small number of patients in either group ended up
  on dialysis
• Not powered to detect significant differences in
  renal outcomes
• Patient selection based on vascular and not
  specifically renal risk factors

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Conclusion

• ARBs offer no significant benefit in ACE
  intolerant patients at high vascular risk but
  without macroalbuminuria
• Numerous studies including AMADEO and ONTARGET
  have show that ARBs decrease rate of progression
  to overt nephropathy in patients with known
  macroalbuminuria
• This study refutes the idea that ARBs have a
  beneficial effect on renal outcomes in patients
  without macroalbuminuria

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