Introduction
Heart failure (HF) is one of the most pressing global health concerns, affecting more than 64 million people worldwide. Despite significant advances in therapy, it remains associated with high morbidity, mortality, and healthcare costs. Among the pharmacological treatments developed, angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) have been pivotal in improving outcomes for patients with HF, particularly those with heart failure with reduced ejection fraction (HFrEF).
These drugs target the renin–angiotensin–aldosterone system (RAAS), a major driver of pathophysiological changes in HF such as vasoconstriction, sodium retention, fluid overload, and cardiac remodeling. ACE inhibitors and ARBs have been proven in large-scale clinical trials to reduce mortality, hospitalizations, and progression of disease.
This article explores the mechanism of action, landmark clinical trials, guideline recommendations, and limitations/adverse effects of ACE inhibitors and ARBs in the context of HF.
1. Mechanism of Action
1.1 The Renin–Angiotensin–Aldosterone System (RAAS)
The RAAS plays a central role in cardiovascular regulation.
- Renin, secreted by the juxtaglomerular cells of the kidney, converts angiotensinogen to angiotensin I.
- Angiotensin-converting enzyme (ACE) then converts angiotensin I to angiotensin II.
- Angiotensin II is a potent vasoconstrictor and stimulates aldosterone secretion, leading to sodium and water retention.
In HF, the RAAS is chronically overactivated, contributing to increased afterload, preload, and ventricular remodeling.
1.2 ACE Inhibitors
- ACE inhibitors (e.g., enalapril, lisinopril, captopril, ramipril) block the conversion of angiotensin I to angiotensin II.
- Effects:
- Reduced vasoconstriction → decreased afterload.
- Reduced aldosterone secretion → decreased sodium and water retention.
- Reduced sympathetic activation.
- Increased bradykinin levels → vasodilation and improved endothelial function (but also cough/angioedema).
- Inhibition of remodeling: Slows progression of LV dilation and fibrosis.
1.3 ARBs
- ARBs (e.g., losartan, valsartan, candesartan, irbesartan) selectively block angiotensin II type 1 receptors (AT1R).
- Effects:
- Prevent vasoconstriction and aldosterone release.
- Unlike ACE inhibitors, they do not increase bradykinin → lower risk of cough and angioedema.
- Provide alternative RAAS blockade in patients intolerant to ACE inhibitors.
1.4 Key Differences Between ACE Inhibitors and ARBs
| Feature | ACE Inhibitors | ARBs |
|---|---|---|
| Mechanism | Block conversion of Ang I → Ang II | Block AT1 receptor |
| Bradykinin effect | Increased (vasodilation, cough, angioedema) | No effect |
| Side effects | Cough, angioedema | Rare cough, rare angioedema |
| Clinical use | First-line in HFrEF | Alternative if ACEI not tolerated |
2. Clinical Trials and Guidelines
2.1 Landmark ACE Inhibitor Trials
- CONSENSUS Trial (1987)
- Population: Severe HF (NYHA IV).
- Intervention: Enalapril vs placebo.
- Results: 40% reduction in mortality at 6 months.
- Significance: Established ACE inhibitors as lifesaving therapy.
- SOLVD-Treatment Trial (1991)
- Population: Symptomatic HF (LVEF ≤35%).
- Intervention: Enalapril vs placebo.
- Results: 16% reduction in mortality, 26% reduction in hospitalizations.
- Significance: Cemented ACE inhibitors as standard of care.
- SOLVD-Prevention Trial
- Population: Asymptomatic LV dysfunction.
- Intervention: Enalapril vs placebo.
- Results: Reduced incidence of symptomatic HF and hospitalizations.
- Significance: Preventive benefit even in asymptomatic patients.
- SAVE Trial (1992)
- Population: Post-MI with LV dysfunction.
- Intervention: Captopril vs placebo.
- Results: 19% reduction in mortality.
- Significance: Established role after myocardial infarction.
2.2 Landmark ARB Trials
- ELITE Trial (1997)
- Losartan vs captopril in elderly patients.
- Suggested lower mortality with losartan, but not definitive.
- ELITE II Trial (2000)
- Larger study, losartan vs captopril.
- Results: No mortality benefit; ARBs were non-inferior to ACE inhibitors.
- Val-HeFT Trial (2001)
- Valsartan vs placebo in HF.
- Results: Reduced hospitalizations, modest effect on mortality.
- CHARM-Alternative (2003)
- Candesartan in patients intolerant to ACE inhibitors.
- Results: 23% reduction in CV death or hospitalization.
- Significance: ARBs as effective alternatives.
- CHARM-Added (2003)
- Candesartan + ACE inhibitor vs ACE inhibitor alone.
- Results: Reduced morbidity and mortality, but increased risk of renal dysfunction/hyperkalemia.
2.3 Guidelines (ESC 2021, ACC/AHA/HFSA 2022)
- ACE inhibitors:
- First-line in patients with HFrEF (LVEF ≤40%) to reduce mortality and morbidity.
- Class I recommendation.
- ARBs:
- Recommended in patients intolerant to ACE inhibitors (cough, angioedema).
- Class I recommendation.
- Combination therapy:
- ACE inhibitor + ARB generally not recommended due to adverse effects (ONTARGET trial showed more harm).
- Exception: Selected patients under specialist supervision.
- ARNI (sacubitril/valsartan):
- Now preferred over ACE inhibitors in HFrEF (PARADIGM-HF trial).
- Guidelines: Start ARNI in place of ACEI if tolerated.
3. Limitations and Adverse Effects
3.1 Limitations
- Not all patients tolerate ACE inhibitors or ARBs.
- Limited effectiveness in HF with preserved EF (HFpEF) (trials show neutral outcomes).
- Slow titration required to minimize side effects.
- Contraindicated in pregnancy and bilateral renal artery stenosis.
3.2 Adverse Effects of ACE Inhibitors
- Cough
- Occurs in ~10–20% of patients.
- Due to increased bradykinin and prostaglandin levels.
- Management: Switch to ARB.
- Angioedema
- Rare but potentially life-threatening.
- Risk higher in African and Asian populations.
- Hyperkalemia
- Due to reduced aldosterone.
- Risk increased with CKD, potassium-sparing diuretics, MRAs.
- Hypotension
- Especially after first dose in volume-depleted patients.
- Renal dysfunction
- Modest rise in creatinine is expected.
- Severe rise indicates bilateral renal artery stenosis.
3.3 Adverse Effects of ARBs
- Generally better tolerated than ACE inhibitors.
- Cough and angioedema rare.
- Can still cause hyperkalemia, hypotension, renal impairment.
- Headache and dizziness reported.
3.4 Comparative Safety
- ACE inhibitors: More robust evidence, but higher incidence of cough/angioedema.
- ARBs: Safer in terms of tolerability, but evidence base slightly smaller.
- Both require monitoring of renal function and potassium.
4. Clinical Practice Considerations
- Start at low dose, titrate upward every 2–4 weeks as tolerated.
- Monitor:
- Blood pressure
- Renal function (creatinine, eGFR)
- Serum potassium
- Avoid combination with potassium supplements unless indicated.
- Reassess after dose adjustments.
5. Future Directions
- ARNIs (angiotensin receptor-neprilysin inhibitors) have surpassed ACEIs/ARBs in many HFrEF guidelines, but ACE inhibitors and ARBs remain foundational where ARNI is not accessible.
- Personalized medicine: Pharmacogenomics may help identify patients at higher risk for side effects (e.g., angioedema).
- Combination with SGLT2 inhibitors and MRAs: Form the modern quadruple therapy in HFrEF.
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