What alternative antihypertensive medications can be used in patients who cannot tolerate Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs)?

Alternative Antihypertensive Medications for ACE Inhibitor/ARB Intolerance

For patients who cannot tolerate ACE inhibitors or ARBs, hydralazine-nitrate combination therapy is the recommended alternative, particularly in symptomatic heart failure patients, with beta-blockers and mineralocorticoid receptor antagonists (MRAs) serving as essential complementary therapies depending on the clinical context. 1

Primary Alternative: Hydralazine-Nitrate Combination

Hydralazine-nitrate therapy may be considered for symptomatic heart failure in patients who cannot tolerate (or have a contraindication to) ACE inhibitor or ARB therapy. 1 This combination has demonstrated favorable effects on survival in patients with mild to moderate symptoms who were not taking ACE inhibitors or beta-blockers. 1

Important Caveats

• Many patients experience headaches or gastrointestinal distress with these direct-acting vasodilators, which can prevent long-term treatment adherence. 1
• The utility of this vasodilator combination in patients with end-stage disease who are being given neurohormonal antagonists remains unknown. 1

Beta-Blockers: Essential Complementary Therapy

Beta-blockers are recommended for all patients with current or prior heart failure symptoms and should be considered even when ACE inhibitors/ARBs cannot be used. 1 Specifically, one of three beta-blockers should be prescribed: bisoprolol, carvedilol, or metoprolol succinate. 1

Beta-Blocker Advantages

• Beta-blockers have a modest effect on blood pressure but often lead to substantial improvement in ejection fraction. 1
• They are anti-ischemic and probably more effective in reducing the risk of sudden cardiac death. 1
• They lead to a striking and early reduction in overall mortality. 1

Critical Warnings for Beta-Blockers

• Do not initiate in patients with systolic blood pressure less than 80 mm Hg or signs of peripheral hypoperfusion. 1
• Do not start if patients have significant fluid retention or recently required intravenous positive inotropic agents. 1
• Beta-blockers may mask tachycardia occurring with hypoglycemia in diabetic patients. 2, 3
• Never abruptly discontinue in patients with coronary artery disease due to risk of severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias. 2, 3

Mineralocorticoid Receptor Antagonists (MRAs)

MRAs are recommended for patients who remain symptomatic despite treatment with beta-blockers, particularly those with NYHA class II-IV symptoms and ejection fraction ≤35%. 1

Critical Contraindications

• Preserved renal function is essential - MRAs can produce dangerous hyperkalemia in patients with impaired renal function. 1
• The evidence supporting MRA use has been derived in patients with preserved renal function. 1
• Avoid in patients already on ARBs with renal impairment due to unacceptable hyperkalemia risk. 4

Diuretics

Diuretic agents should be considered for fluid overload to reduce heart failure hospitalizations. 1 However, diuretics have not been shown to reduce mortality and should be used primarily for symptom management. 1

Caution with Diuretics

• Avoid adding another diuretic first in patients with renal impairment, as this significantly increases hyperkalemia risk. 4

Calcium Channel Blockers

Calcium channel blockers can be used for blood pressure reduction to target. 1 However, avoid non-dihydropyridine calcium channel blockers (verapamil, diltiazem) if adding a beta-blocker due to increased risk of bradycardia and heart block. 4, 2

Specific Warnings

• Bradycardia and heart block can occur when beta-blockers are administered with verapamil or diltiazem. 2
• Patients with pre-existing conduction abnormalities or left ventricular dysfunction are particularly susceptible. 2

Angiotensin Receptor-Neprilysin Inhibitor (ARNI)

ARNI (sacubitril/valsartan) is recommended to replace ACE inhibitor therapy in ambulatory patients who remain symptomatic despite optimal therapy. 1 However, this contains an ARB component (valsartan), so it would not be appropriate for patients intolerant to both ACE inhibitors AND ARBs. 1

Ivabradine

Ivabradine should be considered in patients with symptomatic heart failure despite treatment with beta-blockers (or in those with beta-blocker contraindication/intolerance). 1

What NOT to Do

Never combine an ACE inhibitor with an ARB - this increases adverse events without additional benefit. 4 This warning extends to patients already on ARNIs, as they contain an ARB component. 1

Clinical Algorithm for ACE Inhibitor/ARB Intolerant Patients

1. First: Optimize beta-blocker therapy (bisoprolol, carvedilol, or metoprolol succinate) unless contraindicated. 1

2. Second: Add hydralazine-nitrate combination for symptomatic relief, particularly in heart failure patients. 1

3. Third: Consider MRA if ejection fraction ≤35%, NYHA class II-IV, and renal function is preserved. 1

4. Fourth: Use diuretics as needed for fluid overload and symptom management. 1

5. Fifth: Add dihydropyridine calcium channel blocker if blood pressure remains uncontrolled. 1, 4

6. Consider ivabradine if heart rate remains elevated despite beta-blocker optimization or if beta-blockers are contraindicated. 1