Key Facts

ACE inhibitors and ARBs are among the most important drug classes in cardiovascular medicine. They have proven mortality benefits in heart failure and post-MI, and are renoprotective in diabetic nephropathy.

Pharmacology

• RAAS pathway: renin (from kidney) → angiotensinogen → angiotensin I → ACE → angiotensin II → vasoconstriction + aldosterone release
• ACE inhibitors: block ACE → ↓ Ang II production + ↑ bradykinin (beneficial vasodilation but causes cough)
• ARBs: block AT1 receptor → block Ang II effects; no effect on bradykinin → no cough
• Both: ↓ afterload, ↓ preload, ↓ aldosterone, ↓ sympathetic activity, renal protective (↓ intraglomerular pressure)

Pathophysiology

• Heart failure: RAAS overactivation → vasoconstriction, sodium/water retention, cardiac remodelling → ACE-i/ARBs reverse this
• Diabetic nephropathy: Ang II → preferential efferent arteriolar constriction → ↑ intraglomerular pressure → proteinuria → ACE-i/ARBs reduce proteinuria by ↓ efferent tone
• Initial creatinine rise on starting: expected (up to 30%) due to ↓ efferent tone → ↓ filtration pressure; >30% suggests bilateral renal artery stenosis

Indications

• Hypertension: first-line in <55, non-Black (NICE NG136 Step 1)
• Heart failure (HFrEF): mortality benefit — SOLVD, CONSENSUS trials; start at low dose, uptitrate
• Post-MI: ramipril or enalapril — HOPE, AIRE trials; especially if LV dysfunction
• Diabetic nephropathy/proteinuria: renoprotective — reduce proteinuria and slow CKD progression
• CKD with proteinuria: ACE-i/ARB regardless of BP (NICE NG203)

Side Effects

• Dry cough (~10–15%): ACE-i only (bradykinin); switch to ARB
• Hyperkalaemia: reduced aldosterone → reduced K excretion; risk with CKD, K-sparing diuretics, K supplements
• First-dose hypotension: especially with diuretics, dehydration, elderly, heart failure
• AKI: reduced GFR from efferent arteriolar dilation; expected mild rise <30%; significant rise suggests renal artery stenosis
• Angioedema: rare, potentially life-threatening; more common in Black patients; ACE-i > ARB (ARB cross-reactivity ~2–17%)
• Teratogenic: CONTRAINDICATED in pregnancy

Red Flags

• Creatinine rise >30% after starting → suspect bilateral renal artery stenosis → stop and investigate
• K+ >5.5 mmol/L → stop ACE-i/ARB; treat hyperkalaemia
• Angioedema → stop permanently; consider ARB with caution if essential; NEVER re-challenge with ACE-i
• AKI during concurrent illness → sick day rules (temporarily stop ACE-i/ARB)

Before Starting

• U&Es: baseline creatinine and K+ — essential
• eGFR: dose adjust if renal impairment
• BP: baseline; caution if already low

Monitoring

• U&Es: 1–2 weeks after starting or dose change; then at least annually
• Creatinine rise <30%: expected and acceptable — continue
• Creatinine rise >30%: stop; investigate for renal artery stenosis
• K+: must remain <5.5 mmol/L; higher risk if also on spironolactone, K supplements, co-trimoxazole
• BP: postural BP in elderly; target per NICE NG136

Special Tests

• Renal artery imaging (USS Doppler, MRA): if creatinine rise >30% or resistant hypertension with flash pulmonary oedema
• Echocardiogram: assess LV function in heart failure

Hypertension

• Ramipril 1.25 mg OD → 10 mg OD (titrate every 2–4 weeks)
• Losartan 50 mg OD → 100 mg OD (if ACE-i not tolerated)
• First-line in <55 years, non-Black heritage (NICE NG136)

Heart Failure (HFrEF)

• Ramipril 1.25 mg OD → 10 mg OD: target dose; mortality benefit (SOLVD: 16% mortality reduction)
• Candesartan 4 mg OD → 32 mg OD: if ACE-i not tolerated
• Sacubitril/valsartan (Entresto): NICE TA388 — neprilysin inhibitor + ARB; superior to enalapril in HFrEF (PARADIGM-HF trial: 20% mortality reduction); replaces ACE-i

Post-MI

• Start ACE-i within 24 hours if tolerated; particularly if anterior MI, LV dysfunction, diabetes

Diabetic Nephropathy

• ACE-i/ARB regardless of BP if albuminuria detected
• Titrate to maximum tolerated dose

Sick Day Rules

• Temporarily stop during acute illness, dehydration, vomiting, diarrhoea → resume when recovered

Referral Criteria

• Cardiology: heart failure uptitration, consideration for sacubitril/valsartan
• Nephrology: significant renal impairment, suspected renal artery stenosis
• Allergy: angioedema management

• ACE-i in HFrEF (SOLVD): 16% relative mortality reduction
• Sacubitril/valsartan (PARADIGM-HF): 20% mortality reduction vs enalapril in HFrEF
• Ramipril (HOPE): 22% relative risk reduction in CV death/MI/stroke in high-risk patients
• Renoprotective: slow CKD progression and reduce proteinuria in diabetic nephropathy
• ACE-i cough: resolves within 1–4 weeks of switching to ARB
• Angioedema: may be delayed in onset (weeks–months after starting); can recur after switching to ARB (~2%)

Key Landmark Trials

ACE-i/ARB Monitoring Checklist