The Prognostic Impact of Using High-dose Hydralazine in Severe Systolic Heart Failure With Hemodynamically Significant Mitral Regurgitation

Background:

The investigator team had focused on heart failure (HF) treatment for many years and tried to develop non-invasive guide for HF treatment. Initially, the investigators had dedicated to use echocardiography to simulate Swan-Ganz and performed validation for non-invasive Swan-Ganz (echo Swan-Ganz). Although this method wasn't successful in assessing the full spectrum of Swan-Ganz data, the estimates of stroke volume and left ventricular filling pressure (LVFP) were reliable and well-validated by comparing with invasive measurements. Based on those two data, the investigators could control severe HF patients better and conducted a HF special outpatient clinic. Guiding HF treatment by this model was on-going. Due to lack of nitroprusside in Taiwan for more than 8 years, some cases with terminal HF combined with severe mitral regurgitation or aortic regurgitation were more complicated and troubled for management since it might present as even more reduction of forward flow with more low cardiac output and high LVFP. High-dose of hydralazine, a direct vasodilator, was the solution of our team and it was used to a substitute of nitroprusside. According to the preliminary results of previous studies, rapid up-titration of hydralazine to maximal tolerable dose, then combined with evidence-based medications, was very effective in patients with severe systolic HF and hemodynamically significant mitral regurgitation, especially in acute pulmonary edema with critical and unstable conditions. This method is useful for reducing regurgitation volume and promoting forward flow after afterload reduction and the counterbalance between increasing forward flow and pressure-lowing effect of vasodilator brings stable blood pressure without obvious hypotension or poor peripheral perfusion. Therefore, it increases the possibility of extubation and reduces the in-hospital mortality in those cases. Additionally, the risk of lupus-like syndrome, arthritis, and positive result of ANA are relatively lower than those in The East population. However, the exact short-term and long-term benefits of high-dose hydralazine in Taiwanese with severe systolic HF and significant mitral regurgitation are unknown. The investigators conduct this study to confirm our previous observation.

Introduction Heart failure, either acute or chronic, is a clinical syndrome caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. This means two major components associated with HF symptoms are inadequate cardiac output and high filling pressure. Although many categories of medications have been approved as therapeutic interventions for HF, including beta-blockers, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARB), mineralocorticoid receptor antagonists (MRA), ivabradine, and entresto, the prognosis of HF remains poor, even worse than that of most cancers. Up-titration of evidence-based medications to maximal tolerable dosages has been recommended, but loop diuretics remain the main stream of HF treatment despite lack of evidence of prognostic benefit. In daily practice, diuretics resolve respiratory distress with reduction preload and LVFP, but overdiuresis with postural hypotension, renal function decline and worsening low cardiac output is not uncommon. Decompensated HF with low blood pressure is always difficult to manage, and most evidence-based medications have blood-pressure-lowing effect at initiation of treatment. Many physicians do not up-titrate those medications to maximal dosages for fear of more reduction of blood pressure, which potentially induces adverse events or complications. Therefore, many eligible patients don't reach suggested dosage according to guidelines, which may adversely affect prognosis. It points out a blind spot of HF treatment that relatively low blood pressure would avoid up-titration of evidence-based medications in daily practice of the majority of cardiologists. Regarding severe systolic HF with hemodynamically significant mitral regurgitation (MR), it is an even more complicated situation because regurgitation will bring much lower stroke volume and higher LVFP, which blood pressure becomes low enough to let physicians withdrawing any medications with blood-pressure-lowering effect, including evidence-based medications. The nitroprusside with powerful vasodilating and short-active (rapid conversion after stopping infusion) effects are the solution of this critical situation. Unfortunately, this medication was unavailable for more than 8 years in Taiwan.

Many short-active medications with vasodilator effect such as captopril and hydralazine have potential to be a substitute of nitroprusside in this situation and are suitable for rapid up-titration because short half-life brings to achieve steady blood concentration soon. Compared to hydralazine, captopril decreases the mortality of advanced HF, mainly sudden death, in line with enalpril. But only the form of captopril 25 mg per tab is available in Taiwan and one fourth tab three times per day is the common initial regimen.

Although ACEIs offer strong prognostic benefit in HF and favorable hemodynamic change, it is not so convenient to use in study cohort. Regarding hydralazine, three forms including 10, 25, and 50 mg are available. Animal study reveals that it is effective for treatment of mitral regurgitation with reduction of peripheral vascular resistance and LVFP, and increase of stroke volume and cardiac output. The effect of hydralazine is comparable to nitroprusside with a similar reduction in systemic vascular resistance but a slightly greater increase in cardiac index, with a lesser fall in mean arterial pressure, mean pulmonary arterial pressure, and pulmonary wedge pressure. Hydralazine combined with nitrate had been documented useful in chronic heart failure, especially in African or black population, according to many publications. Based on the hypothesis that initial low-dose hydralazine with rapid up-titration to maximal tolerable dose, following by or simultaneously using other evidence-based medications, in acute HF patients with low-cardiac-output and low-blood-pressure patients due to severe left ventricular systolic dysfunction and hemodynamically significant mitral regurgitation, would bring better outcome compared to conventional treatment, the investigators conduct this study to assess short-term and long-term prognostic change.