Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04736329 |
| Other study ID # |
MS-352-2020 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
February 1, 2021 |
| Est. completion date |
October 31, 2022 |
Study information
| Verified date |
June 2023 |
| Source |
Cairo University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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.
