Hydralazine-nitrate combination for heart failure with a reduced ejection fraction – does formulation matter?

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Author: Michael Plazak, PharmD and Kristin Watson, PharmD, BCPS-AQ Cardiology

Prior to directly comparing the different formulations of hydralazine (HYD) and isosorbide dinitrate (ISDN), let us first revist the historical data for these therapies in patients with heart failure with reduced ejection fraction (HFrEF). The routine use of HYD and ISDN in patients with HFrEF dates back to the Vasodilator Heart Failure Trial (V-HeFT I) study published in 1986. Compared to placebo, HYD/ISDN titrated to a target dose of 40 mg and 75 mg, respectively, four times daily improved left ventricular ejection fraction at both 8 weeks and 1 year among patients with New York Heart Association (NYHA) Class II-III heart failure. However, these improvements did not translate into a reduction in mortality at a mean follow-up of 2.3 years.¹ In V-HeFT II, enalapril was associated with a lower risk of death at 2 years compared to HYD/ISDN in patients with primarily symptomatic HFrEF.² Following the publications of V-HeFT I and II, HYD/ISDN was recommended in patients with HFrEF who were unable to receive an angiotensin-converting enzyme inhibitor (ACEi) due to hypotension or renal insufficiency. A nitrate, alone or with hydralazine, could also be added to a regimen consisting of an ACEi, beta blocker, digitalis, and a diuretic.³

Sub-group analyses of V-HeFT I and II suggested that black patients may derive a mortality benefit from HYD/ISDN. These hypothesis-generating findings were confirmed in the African-American Heart Failure trial (A-HeFT) in which a new fixed-dose combination of HYD/ISDN (BiDil®) was shown to reduce the risk of death and heart failure hospitalization and improve quality of life when added to ACEi and beta blocker therapy in self-described black patients with NYHA Class III-IV heart failure.⁴ Current recommendations for the use of HYD/ISDN are provided in Table 1.

The use of guideline-directed medical therapy (GDMT) in patients with HFrEF remains suboptimal, and this is also true of HYD/ISDN. Despite the clear benefit of fixed-dose combination HYD/ISDN in black patients with NYHA Class III-IV HFrEF, there remains a disconnect in prescribing and overall usage.^7,8 The explanation for this dearth of prescribing is largely unknown, but may be related to adherence concerns with thrice daily dosing. To further compound this issue, the cost of BiDil® may be prohibitive as lack of insurance is a predictor of under-usage.⁷ While the manufacturer discount program can decrease the cost of BiDil® to $10 per month in patients with particular insurance plans and $50 per month in those without insurance coverage, the annual cost of therapy is still high (Table 2).¹¹ Patients are therefore commonly prescribed the individual components of HYD and ISDN, which requires administration of at least six tablets per day.

The results of the landmark A-HeFT trial and current prescribing trends prompt several questions. First, what are the pathophysiologic differences in black patients with HFrEF that result in improved response to vasodilator therapy? Second, does the formulation of nitrate therapy impact the pharmacokinetics, pharmacodynamics, and ultimately clinical outcomes?The use of extended-release ISMN has emerged as a potential alternative for ISDN potentially owing to its once daily dosing and that select doses are on discount prescription plans.¹⁰ However, in the 2017 American College of Cardiology Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment, the authors note that ISMN is not recommended by practice guidelines, and only the fixed-dose combination or separate combination of HYD/ISDN should be considered GDMT for heart failure.¹² Despite this, a retrospective analysis of black patients with HFrEF and Medicare Part D coverage indicated that 43.9% of outpatient prescriptions for HYD/nitrate therapy were for HYD/ISMN. This was complemented by only 26.8% of patients receiving the fixed-dose combination and 29.3% receiving the individual components of HYD and ISDN.¹³

In V-HeFT I, the utility of HYD/ISDN was thought to be secondary to a simultaneous improvement in preload by ISDN and afterload by HYD.¹ However, the progression of HFrEF has also been associated with dysregulation of the nitroso-redox balance. This ultimately results in excess oxidative stress, thus disrupting the maintenance of nitric oxide.¹⁴ ISDN and ISMN are organic nitrates, which fuel the continued signaling of nitric oxide. HYD acts synergistically by inhibiting the production of superoxide, which is also thought to reduce nitrate tolerance. Based on the results from the studies and subgroup analyses mentioned previously, the proposed mechanism for this phenomenon is that the renin-angiotensin system is thought to be less active and nitric oxide bioavailability is lower in this patient population.^4,15

There is data assessing the pharmacokinetics of the different HYD/ISDN formulations utilized in V-HeFT I, V-HeFT II, and A-HeFT. Healthy volunteers were randomized to receive identical doses of HYD capsule plus ISDN tablet (V-HeFT I formulation), HYD tablet plus ISDN tablet (V-HeFT II formulation), or fixed-dose HYD/ISDN (A-HeFT formulation). Compared to the V-HeFT I and V-HeFT II formulations of ISDN, the fixed-dose combination exhibited a higher ISDN C_max, but similar ISDN AUC’s. Additionally, the ISDN and HYD in the fixed-dose combination peaked at nearly the same time, whereas the other two formulations did not demonstrate this phenomenon. The authors ultimately concluded that the three formulations did not demonstrate bioequivalence; however, this was largely driven by differences in HYD pharmacokinetics.¹⁶ All of the patients in these pharmacokinetic studies were healthy volunteers and the majority were of Caucasian descent, therefore, it is not practical to extrapolate these results to any meaningful clinical impact in a black patient with HFrEF.

ISMN, the primary active metabolite of ISDN, was not used in any of these landmark studies and its role in HFrEF is not well-established. However, it does effectively increase nitric oxide signaling and conveys several unique pharmacologic benefits compared to ISDN. The extended-release formulation of ISMN does not undergo first-pass metabolism, is nearly 100% bioavailable, and is dosed once daily.¹⁷ ISDN on the other hand exhibits extensive first-pass metabolism, a bioavailability of 20-30%, demonstrates high peak concentrations between 30 and 60 minutes, and requires three to four doses per day.¹⁸

Only one publication has assessed clinical outcomes with fixed-dose combination HYD/ISDN (BiDil®) compared to HYD/nitrate therapies being prescribed separately (HYD+ISDN and HYD+ISMN). In this propensity-score matched analysis, black Medicare beneficiaries with heart failure and at least 80% 1-year adherence with HYD/nitrate therapy were included. Survival at 1-year was 87.9% with fixed-dose HYD/ISDN compared to 83.0% with HYD+ISDN (p=0.0024) and 88.2% with fixed-dose HYD/ISDN compared to 84.8% with HYD+ISMN (p=0.032).¹³ While this analysis demonstrated favorable survival at 1-year with fixed-dose HYD/ISDN, there was no means of differentiating patients with HFrEF from those with heart failure with preserved ejection fraction. Other limitations of this study are that prescription refill data does not necessarily provide accurate indications for therapy and 80% adherence with a thrice daily formulation is likely not replicable in clinical practice. Prospective studies are needed to confirm these results. Based on this paucity of data, it is prudent to rely on the results demonstrated in A-HeFT and the subgroup analyses from V-HeFT I and V-HeFT II.

Final Recommendations:

Despite the clear mortality benefit of HYD/ISDN demonstrated in black patients with NYHA Class III-IV HFrEF, utilization of this therapy in clinical practice remains inadequate. There must be greater efforts to improve prescribing of HYD/ISDN in this patient population as well as in those with HFrEF who can not take an ACEi, angiotensin II receptor blocker or angiotensin receptor-neprilysin inhibitor.
Pharmacokinetic data do not indicate any clear differences between nitrate exposure when comparing BiDil®, ISDN, or ISMN. However, no clinical outcome data exists to suggest that extended-release ISMN is an appropriate alternative. The substitution of ISMN for ISDN is not recommended.
In the absence of prospective comparator studies, it is likely appropriate to substitute the individual components of HYD and ISDN for brand name BiDil® especially if cost is of concern.

Michael Plazak, PharmD

At the time of this writing, Michael Plazak was a postgraduate year 2 (PGY2) cardiology pharmacy resident at the University of Maryland in Baltimore, MD.