Rationale and Outcomes of Hydralazine-Nitrate Combination in Heart Failure

Mr. Gene D’aMeTi, a 53-year-old African American man with ischemic cardiomyopathy and heart failure with reduced ejection fraction (LVEF 30-35%), is recently admitted with acutely decompensated heart failure and acute kidney injury on chronic kidney disease stage III. His outpatient regiment includes sacubitril-valsartan 97-103mg BID, carvedilol 25mg BID, and hydralazine 50mg TID.

Sacubitril-valsartan was held because of worsening renal function. Despite symptomatic improvement with diuresis, his renal function continues to decline. He is otherwise well perfused & with preservation of other end organ function.

Throughout this hospitalization, he has steadily become more hypertensive with blood pressures persisting in the 170s/90s mmHg. What would be an appropriate adjustment to his medication regimen at this time?

A

Resume Losartan only

B

Start Amlodipine

C

Increase current Hydralazine dose

D

Start Isosorbide dinitrate therapy

E

Both C & D

Explanation

The correct answer is E – both increasing the current hydralazine dose (C) and starting isosorbide dinitrate therapy (D).

Although ACEI/ARB therapy (choice A) has shown a mortality and morbidity benefit in HFrEF, caution should be used in patients with renal insufficiency. In this patient with ongoing decline in renal function, RAAS-inhibiting therapies (ACEi, ARB, ARNI, MRA) should be avoided. In this case, as his RAAS-I has been stopped, it would be reasonable to increase current therapies to target doses (or nearest dose tolerated), as these demonstrated both safety and efficacy in trials (Class 1, LOE A). Considering that his high dose ARNI was stopped, it is unlikely that either hydralazine or isosorbide dinitrate alone, even at maximal doses, would be sufficient to control his blood pressure (Options C and D, respectively). Interestingly, in the original study by Massie et. Al (1977), the decision was made to combine these therapies as the result was thought to be superior to either medication alone. ISDN would provide preload reduction, while Hydralazine would decrease afterload. Consequently, we do not have data looking at the individual benefit of either medication in isolation.

In self-identified African Americans with NYHA class III or IV HFrEF already on optimal GDMT, the addition of hydralazine & isosorbide dinitrate is recommended to improve symptoms and reduce mortality and morbidity (Class 1, LOE A). In this case, as the patient has evidence of progressive renal disfunction, we are limited in using traditional RAAS-I, such as ACEI, ARB, or ARNI. In patients with current or previously symptomatic HFrEF who cannot be given first-line agents (like ARNi, ACEi, ARB) due to intolerance or renal insufficiency, combination therapy of hydralazine & isosorbide dinitrate might be considered to reduce morbidity and mortality (Class 2b, LOE C-LD).

Dihydropyridine calcium channel blockers such as Amlodipine (choice B) are not recommended for treatment of HFrEF (COR 3, LOE A), though may be considered for treating elevated blood pressure despite optimization of GDMT.

Main Takeaway

In self-identified African Americans, the addition of hydralazine & isosorbide dinitrate to GDMT has additional mortality & morbidity benefits.

Should a patient have drug intolerances or renal dysfunction that precludes the use of ACEi/ARB/ARNi, hydralazine & isosorbide dinitrate is a reasonable alternative.

Guideline Loc.

·       Section 7.3.5-8

·       Table 14, Table 15