Effects of Telmisartan Added to Angiotensin Converting Enzyme Inhibitors on Mortality and Morbidity in Hemodialysis Patients With Chronic Heart Failure - Telmisartan in Hemodialysis Patients With Chronic Heart Failure

Nov 09, 2010
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Second University of Naples
Date Published:
01/01/2010
Date Updated:
11/09/2010
Original Posted Date:
11/09/2010
References

Description:

Chronic heart failure (CHF) is highly prevalent in patients with end-stage renal disease (ESRD). Data in this patient population are sparse, and are usually extrapolated from data in nonuremic patients. The current trial sought to study the safety and efficacy of telmisartan added to angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers in patients with systolic CHF who were on hemodialysis.

Hypothesis:

Telmisartan would be superior to placebo in patients with systolic CHF who were on hemodialysis, and were on ACEIs and beta-blockers.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

  • Adult hemodialysis patients with CHF
  • NYHA class II or III
  • Ejection fraction ≤40%
  • Therapy with ACEI individually optimized and unchanged for ≥30 days before randomization

    Number of screened applicants: 351
    Number of enrollees: 332
    Duration of follow-up: 3 years
    Mean patient age: 63 years
    Percentage female: 46
    Ejection fraction: 30%
    NYHA class: II (33.3%), III (66.6%)

Exclusions:

  • Hypotension during dialysis
  • Atrial fibrillation
  • Intolerant to low dose of telmisartan

Primary Endpoints:

  • All-cause mortality
  • Cardiovascular mortality
  • Hospitalization for worsening CHF

Secondary Endpoints:

  • Acute nonfatal MI
  • Cardiovascular mortality + nonfatal MI
  • Cardiovascular hospital admission
  • Nonfatal stroke
  • Coronary revascularization
  • Premature treatment withdrawals

Drug/Procedures Used:

During a preliminary “run-in” phase, all patients received telmisartan (20 mg/day) for 2 weeks to determine, before randomization, whether any of the patients had a low tolerance to small doses of the drug. Patients tolerating the low dose were then randomized to receive either telmisartan or matching placebo. The dose of the study drug was doubled, as tolerated, every 2 weeks while aiming for the target dose of 80 mg/day.

Concomitant Medications:

ACEIs (100%), beta-blockers (61%), aspirin (64%), nitrates (48%), digitalis (51%), and statins (68%)

Principal Findings:

A total of 332 patients were randomized, 165 to telmisartan and 167 to placebo. Baseline characteristics were fairly similar between the two arms. About 29% had diabetes mellitus, and 57% had a history of myocardial infarction (MI). The majority of patients had symptomatic (New York Heart Association [NYHA] class III: 66%) systolic left ventricular (LV) dysfunction (mean left ventricular ejection fraction [LVEF] 30%). The mean time on dialysis was 94 months. Predialysis systolic blood pressure (125 mm Hg) and diastolic blood pressure (81 mm Hg) were also similar.

The primary endpoint of all-cause mortality was significantly reduced at 3 years in the telmisartan arm compared with placebo (35.1% vs. 54.4%, p < 0.001). Cumulative 3-year median survival was low in both arms, but significantly higher in the telmisartan arm (30.6 months vs. 24.2 months, p < 0.001). Cardiovascular mortality was also significantly reduced in the telmisartan arm (30.3% vs. 43.7%, p < 0.001). The number of pump failure deaths and sudden cardiac deaths was significantly reduced in patients receiving telmisartan (20.6% vs. 31.1%; p < 0.01 for both). There was no difference in the incidence of nonfatal MI and noncardiovascular deaths between the two arms. Hospital readmissions were also significantly reduced in the telmisartan arm (33.9% vs. 55.1%, p < 0.0001).

More patients treated with telmisartan compared with placebo showed an improvement in NYHA functional class (37.4% vs. 32.6%) (p < 0.001). Echocardiographic parameters including change in LV diastolic diameter from baseline (-0.12 vs. -0.04 cm/m2, p < 0.0001) and change in LVEF from baseline (+5.8% vs. +3.1%, p < 0.001) were both superior in the telmisartan arm.

There was a higher rate of dropout due to adverse effects in the telmisartan arm (16.3% vs. 10.7%, p < 0.01). The incidence of hypotension was also higher. Hyperkalemia leading to drug discontinuation was numerically higher in the telmisartan arm (3% vs. 1%).

Interpretation:

The results of this trial indicate that: 1) patients with CHF on hemodialysis have very high mortality at 3 years (rates even in the telmisartan arm were 35.4%), and 2) telmisartan in addition to an ACEI is superior to ACEI alone in hemodialysis patients with symptomatic systolic CHF in reducing all-cause mortality, cardiovascular mortality, and hospital readmissions. From an echocardiographic perspective, there is evidence that at least some of the benefit was due to remodeling, as evidenced by greater reduction in LV diastolic diameter and an increase in mean LVEF at the end of follow-up. The rate of dropout due to adverse effects of telmisartan, including hyperkalemia, was moderately low.

These are important findings since data in this group of patients are limited, and are often extrapolated from data in nonuremic patients. Moreover, this group of patients is usually excluded from most CHF trials. The CHARM-Added trial had noted an improvement in hemodynamic measurements in patients with CHF who received candesartan, in addition to an ACEI, as compared with placebo. However, there was no mortality benefit in that trial. Given the small sample size of the current trial, these findings will need to be replicated in a larger cohort before a dual angiotensin-receptor blocker/ACEI combination can be considered as standard of care in these patients.

References:

Cice G, Di Benedetto AA, D’Isa S, et al. Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure: a double-blind placebo-controlled trial. J Am Coll Cardiol 2010;56:1701-8.

Keywords: Myocardial Infarction, Follow-Up Studies, Kidney Failure, Chronic, Receptors, Angiotensin, Standard of Care, Hypotension, Blood Pressure, Hyperkalemia, Tetrazoles, Benzoates, Renal Dialysis, Angiotensin II Type 1 Receptor Blockers, Benzimidazoles, Patient Readmission, Heart Failure, Stroke Volume, Death, Sudden, Cardiac, Diabetes Mellitus


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