Telmisartan Versus Enalapril in Heart Failure With Reduced Ejection Fraction Patients With Moderately Impaired Kidney Functions

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.