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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 1  |  Page : 24-28

Limitations in using angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the management of heart failure due to comorbidities: An Indian scenario


1 Department of Cardiology, Badr Al Samaa Hospital, Muscat, Oman and Former PhD Fellow in the Department of Cardiology, Kerala Institute of Medical Sciences, Trivandrum, Kerala, India
2 Department of Cardiology, Kerala Institute of Medical Sciences, Trivandrum, Kerala, India
3 Senior Registrar, Registrar in Department of Cardiology, Meditrina Hospital, Kollam, Kerala, India
4 Department of Cardiology and Medicine, Irkutsk State Medical University, Irkutsk, Russia

Date of Submission15-Apr-2018
Date of Decision14-Mar-2020
Date of Acceptance16-Mar-2020
Date of Web Publication16-Jun-2020

Correspondence Address:
Dr. Suman Omana Soman
Department of Cardiology, Kerala Institute of Medical Sciences, Trivandrum, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ACCJ.ACCJ_1_18

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  Abstract 


Background and Objectives: The essential drugs used in heart failure are angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers. Many trials had shown that these are the group of drugs with maximum benefits for the patients with heart failure. However, most of the patients were not receiving these drugs due to the negative impact of the comorbidities. Our study aims at identifying the limitations in giving ACE/angiotensin receptor blockers (ARBs) in chronic heart failure patients in our population. Methods: This is a prospective observational study conducted in a tertiary care center, over a period of 2 years from 2012. We selected 310 consecutive patients with the New York Heart Association (NYHA) Class 3 or 4 with various etiologies of heart failure. The patients with new-onset myocardial infarction, acute inflammatory conditions, septicemia, and end-stage renal disease with glomerular filtration rate (GFR) <30 were excluded from the study. Results: In our study population of 310 patients with various etiologies of heart failure, only 60.3% (187) of the patients received ACE/ARBs, in which 34.5% (107) received ACE inhibitors and 16.4% (n-51) received ARB s. Hence, we noticed that 39.7% (n-123) of the patients with heart failure could not receive these drugs due to renal failure (10.3%), hyperkalemia (13.5%), and hypotension (15.8%). Conclusion: We noticed that many of the patients (39.7%) with heart failure did not receive these drugs due to comorbidities. We found that many patients had moderate renal failure with a significant reduction in GFR. Hypotension may be due to reduced ejection fraction because of the patient selection of Class NYHA 3 or 4. Hypotension may reduce the GFR and hence the progressive rise of serum creatinine. Careful patient selection and detailed evaluation alone can improve the number of subjects to whom the above drugs can be given.

Keywords: Heart failure, hypotension, renal failure


How to cite this article:
Soman SO, Vijayaraghavan G, Muneer A R, Mujeeb A M, Ankudinov A S, Kalyagin A N. Limitations in using angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the management of heart failure due to comorbidities: An Indian scenario. Ann Clin Cardiol 2020;2:24-8

How to cite this URL:
Soman SO, Vijayaraghavan G, Muneer A R, Mujeeb A M, Ankudinov A S, Kalyagin A N. Limitations in using angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the management of heart failure due to comorbidities: An Indian scenario. Ann Clin Cardiol [serial online] 2020 [cited 2020 Jul 3];2:24-8. Available from: http://www.onlineacc.org/text.asp?2020/2/1/24/286469




  Introduction Top


Epidemiologic and experimental data suggest that the activation of the renin–angiotensin–aldosterone system has an important role in increasing the risk of cardiovascular events.[1] Unless contraindicated or not tolerated, angiotensin-converting enzyme (ACE) inhibitor therapy is recommended for all patients with systolic heart failure, irrespective of symptomatic severity or blood pressure.[2],[3],[4] Many trials had proven that these drugs increase longevity and improves the quality of life in patients with heart failure. However, many patients could not be given these drugs due to comorbidities. The incidence of renal failure increases with comorbidities such as diabetes, hypertension as well as with aging. Many patients with heart failure remain in renal failure or have symptomatic hypotension, and we were forced not to start these drugs or stop these drugs in the course of the illness.


  Methods Top


The essential drugs used in heart failure were ACE inhibitors, angiotensin II receptor blockers, aldosterone receptor antagonists, and beta-blockers. With increasing longevity of the Indian population, the incidence of heart failure is increasing with its attendant high mortality and morbidity. Moreover, it also affects relatively younger patients in this geographical location. The present study aims at identifying the limitations in giving ACE inhibitors and angiotensin II receptor blockers to chronic heart failure patients in our population.

This is a prospective observational study conducted in Kerala Institute of Medical Sciences, over a period of 2 years from June 1, 2012. We selected 310 consecutive patients with the New York Heart Association (NYHA) Class 3 or 4 with various etiologies of heart failure. The patients had coronary artery diseases, valvular heart diseases, cardiomyopathies, congenital heart diseases, cor pulmonale, etc., The patients with new-onset myocardial infarction, acute inflammatory conditions, septicemia, and end-stage renal disease with glomerular filtration rate (GFR) <30 were excluded from the study.

Definition

  • Renal failure – GFR <89 ml/min
  • Hypotension – Systolic blood pressure <90 mmHg.


Statistics

Data analysis was carried out using statistical software, STATISTICA.7.0 by Stat Soft. Categorical variables were described by absolute numbers and percentages and continuous variables as means with standard deviations. Chi-square test was applied to compare the variables, which were significant in the univariate analysis (P < 0.05).


  Results Top


In the cohort of 310 patients, 214 (69%) were male and 96 (31%) were female. The study population was divided into seven age groups ranging from 21 to 90 years [Table 1]. In both sexes, a majority of patients were in the age group of 60–69 years. Males were predominating up to the age of 69 years and females were predominating after the age of 70 years.
Table 1: Age- and sex-wise distribution of patients with heart failure

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Major etiologies of heart failure in our study

Among the study population of 310 patients, coronary artery disease was the leading cause of heart failure in our population, followed by idiopathic dilated cardiomyopathy, hypertensive heart disease, valvular heart disease, and other causes [Table 2]. Among the valvular heart diseases, rheumatic heart disease was found in 18 patients, degenerative aortic valve disease in 2 patients, and myxomatous mitral valve in 1 patient.
Table 2: Various etiologies of heart failure

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The other causes consisted of cor pulmonale in 13 (4.2%) patients, hypertrophic cardiomyopahty in 6 (1.93%) patients, primary pulmonary hypertension in 6 (1.93%) patients, drug-induced cardiomyopathy in 6 (1.93%) patients, mainly those who underwent chemotherapy for breast cancer, and congenital heart disease and restrictive cardiomyopathy in 3 (1%) patients each.

In the study population, 174 (58.7%) patients had diabetes, systemic hypertension was found in 171 (57%) patients, 132 (44%) had both diabetes and systemic hypertension, and 170 (56.7%) had dyslipidemia. One hundred and ten (41.33%) patients were smokers, 103 (34.0%) had chronic kidney disease, and 44 (16.24%) were hypothyroid.

The drugs mainly used in our study population were diuretics, ACE inhibitors, angiotensin II receptor blockers, aldosterone receptor antagonists, beta–blockers, and digoxin [Table 3].
Table 3: Drugs used in heart failure (n=310)

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Diuretics in heart failure patients

In our study, 271 (90.3%) patients received loop diuretics. Frusemide was used in 139 (46.3%) patients and torsemide in 132 (44.0%). Thiazide diuretics were used infrequently. Metolazone was used as an add-on drug in 64 (21.4%) patients who were on loop diuretics and they all had renal failure. Among the potassium sparing diuretics, spironolactone was used in 116 (38.6%) patients and eplerenone was used in 26 (8.7%) patients.

Angiotensin-converting enzyme inhibitors in heart failure patients

In our study population of 310 patients with various etiologies of heart failure, only 187 (60.3%) patients received ACE inhibitors or angiotensin II receptor blockers. Among them, 136 (43.9%) patients received ACE inhibitors and 51 (16.4%) patients received angiotensin II receptor blockers. A good number of patients, i.e., 123 (39.7%) could not be able to receive these drugs.

Among the 136 (43.9%) patients who received ACE inhibitors, ramipril was received by 76 (24.5%), perindopril by 28 (9.03%), enalapril by 23 (7.5%), and lisinopril by 9 (2.9%) patients. Of the 76 (24.5%) patients who received ramipril, only 8 (2.6%) patients received 10 mg of ramipril daily, 25 (8.1%) received 5 mg, 32 (10.3%) patients received 2.5 mg, and 11 (3.5%) patients received only 1.25 mg daily. The higher doses were not tolerated due to symptoms related to hypotension (systolic blood pressure <90 mmHg).

Angiotensin receptor blockers in heart failure patients

Angiotensin II receptor blockers were used only when patients were intolerant to ACE inhibitors. Angiotensin II receptor blockers were given to 51 (16.4%) patients, as they developed a persistent dry cough while using ACE inhibitors. Among the angiotensin II receptor blockers, losartan potassium was given to 29 (9.3%), valsartan to 13 (4.2%) patients, and telmisartan to 9 (2.9%) patients.

We noticed that many of the patients (39.7%) with heart failure did not receive these drugs due to comorbidities. We did a detailed analysis of patients with renal failure who did not receive ACE/angiotensin receptor blockers (ARBs) [Table 4]. Among the 34.0% (n – 103) of the patients with renal failure, 23.8% (n-74) could not receive ACE/ARBs. This group of patients has advanced renal failure. We found that the majority had a moderate renal failure with a significant reduction in GFR [Table 4]. Most of them had age >60 years and reduced ejection fraction (EF). Hyperkalemia found in 42 (13.5%) patients and progressive rise of serum creatinine in 32 (10.3%) and the rest of the 49 (15.8%) patients had hypotension [Figure 1].
Table 4: Analysis of Heart failure patients with renal failure

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Figure 1: Limitations in the use of angiotensin-converting enzyme/ angiotensin receptor blocker

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  Discussion Top


ACE inhibitors can reduce the mortality and morbidity in heart failure patients with reduced EF. The benefits of ACE inhibitors were seen in patients with mild, moderate, or severe symptoms of heart failure in patients with coronary artery disease as well as noncoronary artery diseases.

CONSENSUS study demonstrated a significant mortality reduction with enalapril with a dose up to 40 mg/day in patients with severe heart failure.[5] The SOLVD trial provided more evidence of mortality and morbidity reduction with enalapril up to 20 mg/day in patients with left ventricular dysfunction and mild-to-moderate heart failure.[6]

The Heart Outcomes Prevention Evaluation study showed that there was a significant reduction in major cardiovascular events and death by the use of 10 mg of ramipril daily for 4.5 years.[7] Acute Infarction Ramipril Efficacy study showed that ramipril reduces mortality and progression to resistant heart failure among patients with evidence of heart failure early after myocardial infarction.[8] In both the trials, patients received ramipril of 10 mg daily. However in our study among the 76 (24.5%) patients who received ramipril, only 8 (2.6%) could be given 10 mg ramipril daily. These fell short of the maximum dose of 10 mg ramipril which reduced mortality of the clinical trial patients. Our patients had low blood pressure (systolic blood pressure: <90 mmHg) or progressive renal failure on the introduction of ACE inhibitors. Hypotension may be due to reduced EF, because we selected patients in NYHA Class 3 or 4. Hypotension may reduce the GFR and hence the progressive raise of serum creatinine.

Angiotensin II receptor blockers were recommended in patients with heart failure with reduced EF who were ACE inhibitors intolerant, unless contraindicated.[9],[10],[11] The Val-HeFT trial showed that there was a significant reduction in the risk of hospital admissions in patients with heart failure by the use of valsartan compared to ACE inhibitors.[9] Maggioniet al. in a subset analysis of 366 patients, who were not receiving ACE inhibitors were randomly analyzed. At about 2 years, valsartan significantly reduced both all cause mortality (17% vs. 27%, and a combined mortality and morbidity end point (25% vs. 43%).[10]

VALIANT trial compared valsartan with captopril in systolic heart failure patients for a period of 2 years. There was no statistically significant difference in mortality as well as primary endpoint.[11] Many placebo-controlled studies demonstrated that the long-term therapy with angiotensin II receptor blockers produced hemodynamic, neurohormonal, and clinical effects because of the interference with the renin–angiotensin system.

ACE inhibitors are the preferable choice for inhibition of the renin–angiotensin system in systolic heart failure, but angiotensin II receptor blockers can now be considered as a reasonable alternative. However, their use is also limited by hypotension and progressive renal failure in a sizable percentage of the patient population. CHARM-Alternative trial showed that there was a reduction in mortality and morbidity in symptomatic heart failure patients who were on candisartan, those patients were intolerant to ACE inhibitors.[12]

Loop diuretics have emerged as the preferred diuretic agents for symptomatic relief of heart failure. Controlled trials have proven the ability of diuretic drugs to increase urinary sodium excretion and decrease physical signs of fluid retention in patients with heart failure.[13] Loop diuretics give symptomatic relief for the patient with heart failure. Controlled trials have shown that diuretics help to reduce fluid retention by increasing sodium excretion. By diuresis, there will be a decrease in left ventricular afterload and it improves the performance of the left ventricle, but there is no role in remodeling of the left ventricle.[14]

In the Randomized Aldactone Evaluation Study (RALES), when spironolactone compared with placebo, there was a 30% reduction in mortality.[15] Another study (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study [EPHESUS]) has shown that the addition of a selective aldosterone antagonist, eplerenone, to optimal medical therapy resulted in reduced morbidity and mortality among patients with post myocardial infarction along with left ventricular dysfunction.[16]

RALES study showed a 30% reduction in mortality with spironolactone compared with placebo.[15] EPHESUS trial also showed a reduction in morbidity and mortality among patients with post myocardial infarction with left ventricular dysfunction by the addition of a selective aldosterone antagonist, eplerenone, to optimal medical therapy.[16]


  Conclusion Top


ACE inhibitors stabilize patients with heart failure and increase their longevity. However, comorbidities became a handicap in using these drugs in many subjects, especially those with renal failure and hypotension. ACE/ARBs could not be given due to the following reasons – hypotension was found in 15.8% of patients and renal failure and hyperkalemia in 23.8%. Careful patient selection and detailed evaluation alone can improve the number of subjects to whom the above drugs can be given.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR, et al. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994;90:2056-69.  Back to cited text no. 1
    
2.
Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154-235.  Back to cited text no. 2
    
3.
Krum H, National Heart Foundation of Australia and Cardiac Society of Australia and amp; New Zealand Chronic Heart Failure Clinical Practice Guidelines Writing Panel. Guidelines for management of patients with chronic heart failure in Australia. Med J Aust 2001;174:459-66.  Back to cited text no. 3
    
4.
National Institute for Clinical Excellence. Chronic Heart Failure: Management of Chronic Heart Failure in Adults in Primary and Secondary Care. Clinical Guideline London: National Institute for Clinical Excellence; 2003.  Back to cited text no. 4
    
5.
CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;316:1429-35.  Back to cited text no. 5
    
6.
SOLVD Investigators, Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325:293-302.  Back to cited text no. 6
    
7.
Heart Outcomes Prevention Evaluation Study Investigators, Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145-53.  Back to cited text no. 7
    
8.
Cleland JG, Erhardt L, Murray G, Hall AS, Ball SG. Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J 1997;18:41-51.  Back to cited text no. 8
    
9.
Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667-75.5.  Back to cited text no. 9
    
10.
Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002;40:1414-21.  Back to cited text no. 10
    
11.
Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906.  Back to cited text no. 11
    
12.
Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003;362:772-6.  Back to cited text no. 12
    
13.
Faris RF, Flather M, Purcell H, Poole Wilson PA, Coats AJ. Diuretics for heart failure. Cochrane Database Syst Rev 2012;15:CD003838.  Back to cited text no. 13
    
14.
Wilson JR, Reichek N, Dunkman WB, Goldberg S. Effect of diuresis on the performance of the failing left ventricle in man. Am J Med 1981;70:234-9.  Back to cited text no. 14
    
15.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.  Back to cited text no. 15
    
16.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.  Back to cited text no. 16
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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