Is Bidil (hydralazine and isosorbide dinitrate) a suitable alternative for treating heart failure in patients with Chronic Kidney Disease (CKD) stage 3-4 and impaired renal function?

BiDil in Heart Failure with CKD Stage 3-4

BiDil (hydralazine-isosorbide dinitrate) is a reasonable alternative for heart failure in patients with CKD stage 3-4, particularly when ACE inhibitors or ARBs are contraindicated due to hypotension or renal insufficiency, though the evidence base is limited and primarily derived from African American populations. 1

Evidence for Use in CKD

Renal Safety Profile

• No formal dose adjustment is required for isosorbide dinitrate or isosorbide mononitrate in patients with renal impairment or those on dialysis according to American Heart Association guidelines 2

• Hydralazine-isosorbide dinitrate can be useful in patients with heart failure who have renal insufficiency and cannot tolerate ACE inhibitors or ARBs 2

• Hydralazine is renally excreted and can accumulate in patients with CKD, requiring monitoring 1

• Isosorbide combined with hydralazine has been shown to decrease mortality in patients with renal failure 1

Clinical Efficacy Data

• The combination is recommended as a Class I indication for self-identified African Americans who remain symptomatic despite optimal medical therapy with ACE inhibitors and/or beta blockers 1

• In the general CKD population with heart failure, a proof-of-concept randomized trial showed a trend toward improved 6-minute walk test distance (mean difference 27 meters) at 6 months, though this did not reach statistical significance 3

• The trial in CRS patients (eGFR 46 ± 15 ml/min/1.73 m²) demonstrated fewer heart failure hospitalizations and lower mortality with H-ISDN, despite higher rates of giddiness and hypotension 3

Practical Considerations for CKD Stage 3-4

When to Consider BiDil

Use BiDil when:

• ACE inhibitors or ARBs cause hypotension (systolic BP <90 mmHg) 4
• ACE inhibitors or ARBs cause worsening renal function (creatinine rise >20%) 1
• Hyperkalemia limits RAAS inhibitor therapy 1
• Patient is African American with persistent symptoms on standard therapy 1

Monitoring Requirements

• Frequent blood pressure monitoring is essential, especially during initiation and dose titration 4

• Monitor renal function (serum creatinine, eGFR) at baseline and with any clinical deterioration 1

• Implement a nitrate-free interval of at least 10 hours to minimize tolerance and side effects 4

Common Pitfalls and Adverse Effects

• Discontinuation rates are substantial: 27% of patients discontinued H-ISDN due to intolerance and poor compliance in the CRS trial 3

• Headache and gastrointestinal complaints are frequent, and many patients cannot continue treatment at target doses 1

• Avoid in patients with systolic BP <90 mmHg as vasodilators may reduce central organ perfusion 4

• Hydralazine can rarely cause drug-induced lupus, which can involve the kidneys leading to renal dysfunction 1

• Absolute contraindication when used with phosphodiesterase inhibitors (sildenafil, tadalafil) due to risk of profound hypotension 4

Positioning in Treatment Algorithm

First-Line Therapy Limitations in CKD 3-4

• Beta-blockers remain beneficial across all CKD stages, including dialysis, and should be continued 5, 6

• ACE inhibitors/ARBs were studied in patients with creatinine <2.5-3.0 mg/dl, excluding severe CKD 5

• Mineralocorticoid receptor antagonists increase hyperkalemia risk (RR 2.91,95% CI 2.03-4.17) in CKD 6

BiDil as Alternative

• BiDil should not be substituted for ACE inhibitors in patients tolerating them without difficulty 1

• The combination should not be used for treatment of HF in patients who have no prior use of an ACE inhibitor 1

• Consider BiDil when RAAS inhibitor therapy is limited by hypotension or renal insufficiency 4

Evidence Limitations

• Most pivotal randomized trials specifically excluded patients with severe renal dysfunction 7

• The primary efficacy data for H-ISDN comes from African American populations; whether this benefit extends to other patients with HF remains to be investigated 1

• Effects on worsening heart failure, kidney function, and quality of life in CKD populations are uncertain due to sparse data 6

• The 2022 AHA/ACC/HFSA guidelines identify the need for efficacy and safety studies of hydralazine-isosorbide in non-African American patients with HF and in African American patients already on GDMT 1