What medications can be added to a regimen of a calcium channel blocker and isosorbide mononitrate (Isordil) for heart failure management?

Medication Options for Heart Failure Management

For a patient already on a calcium channel blocker and isosorbide mononitrate, the most appropriate additions depend critically on whether this is heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF), and which type of calcium channel blocker is being used.

Critical Initial Assessment

If the patient has HFrEF and is on a non-dihydropyridine calcium channel blocker (verapamil or diltiazem), this medication must be discontinued immediately as these agents are contraindicated and cause harm in HFrEF 1. Non-dihydropyridine calcium channel blockers have significant negative inotropic effects and worsen heart failure outcomes 1.

For Heart Failure with Reduced Ejection Fraction (HFrEF)

First-Line Guideline-Directed Medical Therapy to Add:

The following medications should be initiated sequentially if not already prescribed:

• ACE inhibitors or ARBs (if ACE inhibitor intolerant) - Class I recommendation to improve outcomes and reduce mortality 1

• Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) - Class I recommendation, proven to reduce mortality 1

• Aldosterone receptor antagonists (spironolactone or eplerenone) - Class I recommendation for patients who remain symptomatic despite ACE inhibitor and beta-blocker therapy 1, 2

• Loop diuretics - for volume management if signs of congestion are present 1, 2

Special Consideration for Hydralazine/Isosorbide Dinitrate Combination:

Since the patient is already on isosorbide mononitrate (a nitrate), adding hydralazine to create the proven combination therapy is strongly recommended in specific populations:

• For self-described African American patients with NYHA class III-IV HFrEF: Class I recommendation to add hydralazine to the existing nitrate regimen when on optimal therapy with ACE inhibitors and beta-blockers 1

• For non-African American patients with HFrEF: Class IIa recommendation - the combination can be useful to reduce morbidity and mortality 1

• For patients intolerant of ACE inhibitors or ARBs: Class IIa recommendation - this combination serves as an alternative when renin-angiotensin system inhibitors cannot be used due to hypotension, renal insufficiency, or drug intolerance 1

The hydralazine/isosorbide dinitrate combination has demonstrated mortality reduction in landmark trials, with particular efficacy in African American patients where it reduced both mortality and hospitalizations when added to standard therapy 1.

For Heart Failure with Preserved Ejection Fraction (HFpEF)

If the patient has HFpEF, the medication approach differs:

• ACE inhibitors, ARBs, or beta-blockers are reasonable for blood pressure control (Class IIa) 1

• ARBs specifically may be considered to decrease hospitalizations 1

• Diuretics for symptom management if volume overload is present 1

Important caveat: A 2015 randomized trial found that isosorbide mononitrate in HFpEF patients actually decreased daily activity levels and did not improve quality of life or exercise capacity compared to placebo 3. This raises questions about the appropriateness of continuing the nitrate in HFpEF.

Medications to Avoid

The following must be avoided or discontinued in HFrEF patients:

• Non-dihydropyridine calcium channel blockers (verapamil, diltiazem) - Class III Harm recommendation 1

• NSAIDs - worsen heart failure symptoms through sodium/water retention and should be avoided 1

• Thiazolidinediones - increase risk of worsening heart failure and hospitalizations 1

• Alpha-adrenergic blockers (doxazosin) - should be avoided except as last resort for blood pressure control 1

• Class IC antiarrhythmics and dronedarone - increase mortality risk 1

Regarding the Current Calcium Channel Blocker

If the patient has HFrEF:

• Dihydropyridine calcium channel blockers (amlodipine, felodipine) have no proven benefit but are not harmful and may be continued only for blood pressure control if needed after optimizing guideline-directed medical therapy 1
• Consider discontinuing if blood pressure is controlled with other agents

If the patient has HFpEF:

• Calcium channel blockers are reasonable for blood pressure control 1

Practical Implementation Algorithm

1. Confirm heart failure type (HFrEF vs HFpEF) and ejection fraction
2. Identify which calcium channel blocker is being used
3. If non-dihydropyridine CCB + HFrEF: Discontinue immediately
4. Initiate core HFrEF therapy if not already prescribed: ACE inhibitor/ARB → beta-blocker → aldosterone antagonist
5. Add hydralazine to the existing isosorbide mononitrate to create the proven combination, particularly for African American patients or those intolerant of ACE inhibitors/ARBs
6. Optimize diuretics for volume management
7. Monitor closely for hypotension given multiple vasodilators 4

Common Pitfalls

• Do not assume all calcium channel blockers are equivalent - the distinction between dihydropyridine and non-dihydropyridine is critical for safety 1, 5
• Do not continue nitrates in HFpEF without reassessing benefit given negative trial data 3
• Monitor for excessive hypotension when combining multiple vasodilators (nitrate + hydralazine + ACE inhibitor) 4
• Ensure adequate hydration status before adding vasodilators to avoid severe hypotension 4
• The combination of hydralazine/isosorbide dinitrate should not replace ACE inhibitors in patients tolerating them well 1