Telmisartan Versus Enalapril in Heart Failure With Reduced Ejection Fraction Patients With Moderately Impaired Kidney Functions
Condition: Heart Failure With Reduced Ejection Fraction; Renal Insufficiency
MeSH terms: Renal Insufficiency; Heart Failure
Study type: Interventional

Summary: 
      Heart Failure (HF) poses a major health burden in various populations, with devastating
      annual rates of morbidity and mortality. It is estimated that 1%-to-2% of the general
      population suffer from the heart failure syndrome.

      HF with reduced ejection fraction (HFrEF) is the most studied among different strata of
      ejection fractions (compared to HFpEF and HFmrEF), and thus therapies with evidence based
      survival benefit are well identified.

      The syndrome of heart failure and the subsequent reduced cardiac output triggers activation
      of neurohormonal compensatory responses aiming to augment cardiac output and tissue
      perfusion, like upregulation of sympathetic nervous system and over-activation of the Renin
      Angiotensin Aldosterone System. Nevertheless, overshooting of such compensatory mechanisms
      have deleterious effects on heart failure in terms of aggravation of symptoms and reduction
      of survival.

      Angiotensin II acts primarily on type I receptors inducing the following:

        -  intense arteriolar vasoconstriction

        -  stimulates sodium reabsorption in the proximal convoluted tubules

        -  stimulates adrenal medulla to secrete catecholamines

        -  stimulates sympathetic nervous system, through facilitation of ganglionic stimulation

        -  modestly inhibits vagus (parasympathetic system)

        -  stimulates secretion of vasopressin/anti-diuretic hormone

        -  stimulates adrenal cortex to secrete aldosterone, which promotes sodium and water
           reabsorption and promotes potassium secretion at the distal convoluted tubules in
           addition to induction of myocardial remodeling and fibrosis

        -  constricts the glomerular efferent arteriole which increase filtration pressure and
           promotes proteinuria and nephron injury/loss.

      While, angiotensin type II receptors activation have beneficial effects like vasodilatation
      and promoting endothelial function.

      Accordingly, angiotensin converting enzyme inhibitors (ACEi), angiotensin-II receptor type I
      blockers (ARBs) or Angiotensin receptor blocker- neprilisin inhibitor (ARNI) are considered a
      cornerstone in HFrEF therapy for both: symptoms relief and improvement of survival. Yet,
      hypotension, hyperkalemia or worsening of renal function are potential side effects that
      occasionally may lead to ACEi/ARBs/ARNI intolerance and subsequent discontinuation with loss
      of their cardioprotective effects.

      On the other hand, cardiorenal syndrome is a recently introduced medical category due to the
      frequent association of cardiac and renal dysfunction in clinical practice. CardioRenal
      Syndrome CRS type I; acute cardiac dysfunction leading to renal dysfunction, is reported in
      25%-to-33% of acute heart failure patients, and this prevalence jumps to 70% in cases of
      cardiogenic shock. CRS type II; chronic cardiac dysfunction leading to renal dysfunction, was
      found in 45% of chronic heart failure patients.

      Despite the definite renoprotective and antiproteinuric effects of RAAS blockade in patients
      with chronic renal impairment, in cases when the glomerular filtration is critically
      dependent on angiotensin II-mediated efferent vasoconstriction such as in patients with heart
      failure and severe depletion of circulating volume-, ACEi/ARBs can lead to profound reduction
      of the glomerular filtration rate (GFR). The concerns about the safety of RAAS blockade in
      the presence of renal impairment has led to profound underutilization of these drugs in CHF
      patients with renal impairment.

      The very prevalent co-existence of heart failure and renal impairment prominently impairs
      patients' outcomes both by direct disease effects and indirectly due to the occasional but
      frequent enforced discontinuation of therapies with proven survival benefit.[6]

      Telmisartan is an ARB with peculiar pharmacodynamic properties. Unlike most of the ACEi/ARBs
      family, Telmisartan primarily depends on hepatic excretion and only a minority depends on
      renal excretion. Telmisartan has been proved in human and animal studies to be an effective
      agonist of the peroxisome proliferator-activated receptor gamma (PPAR ɣ) which potentiates
      its renoprotective effects being acting by dual mechanism.

      So, it can be hypothesized that Telmisartan might be better tolerated than standard ACEi/ARBs
      in HF patients with moderate renal impairment, guranteeing less frequent interruptions and
      more consistent cardioprotective and renoprotective effects. However, there is no wealth of
      data to support or deny this theory.
    

Detailed description: 
      Population of study & disease condition Chronic heart Failure patients with reduced ejection
      fraction, (LVEF <40%) associated with moderate impairment of renal functions, (eGFR by
      Cockroft-Gold equation 60-40 ml/min/m2).

      Patients will be randomized to receive either Enalapril (2.5 up to 20mg ) or Telmisartan (20
      up to 80mg) for RAAS inhibition, as part of their heart failure therapy.

      Objectives:

      - Compare efficacy, safety and tolerability of Telmisartan versus Enalapril in HFrEF patients
      with impaired renal function.

      • Methodology in details: HFrEF patients with moderate renal impairment as defined per
      protocol and after accepting participation to the study, will be randomly allocated into 2
      equal groups using closed envelopes randomization system based on web-based randomization
      tables. Group 1 will receive Enalapril (between 2.5 to 20mg daily) as tolerated. Group 2 will
      receive Telmisartan (between 10 to 80mg daily) as tolerated. Both groups will receive other
      guidelines directed medical therapy for HFrEF. Patients will be monitored for :-

        -  Improvement of NYHA class.

        -  Six-minutes walk test at baseline at 2, 6 and 12 months.

        -  Trends of changes in NT-BNP values from baseline and every 6 months.

        -  Changes in left ventricular dimensions and ejection fraction assessed by
           echocardiography at baseline, at 6 and 12 months.

        -  Rates of worsening kidney functions assessed by changes in serum creatinine and in eGFR
           from baseline.

        -  Rates of improvement in albuminuria and serum albumin assessed by urinary
           Albumin/Creatinine ratio and serum albumin levels respectively, at baseline at 2, 6 and
           12 months.

        -  Rates of discontinuation of / intolerance to the used agent for RAAS inhibition
           (enalapril/telmisartan)

        -  Rates of rehospitalization for decompensated heart failure.

        -  Rates of rehospitalization for any reason.

        -  Cardiac death.

        -  All-cause death.
    

Intervention name(s): Telmisartan
Intervention type(s): Drug
Intervention description(s): Telmisartan (20 up to 80mg) for RAAS inhibition, as part of heart failure therapy.
Intervention MeSH terms: Telmisartan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment