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

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ClinicalTrials.gov Identifier: NCT04217135
Recruitment Status : Recruiting
First Posted : January 3, 2020
Last Update Posted : January 7, 2020
Sponsor:
Collaborator:
E-DA Hospital
Information provided by (Responsible Party):
Shih-Hung Hsiao, Kaohsiung Veterans General Hospital.

Brief Summary:

Background: Severe systolic heart failure would be complicated with low cardiac output and high left ventricular filling pressure and the clinical presentations would be low blood pressure, poor peripheral perfusion, and pulmonary edema. Severe systolic heart failure with hemodynamically significant mitral regurgitation brings even more challenged since the obvious elevation of left atrial pressure induces more pulmonary congestion and backward flow of regurgitation in cases with already low cardiac output and poor peripheral perfusion complicates more severe of low cardiac output. Surgical interventions in those cases aren't strongly recommended due to very high operation risk. In the era of lack of nitroprusside in Taiwan (more than 7 years), hydralazine, a direct vasodilator, is a potential substitute for treatment of those cases. The advantages of hydralazine include 1) different dosage forms are available (10 mg, 25 mg, and 50 mg); 2) short half-life makes it reaching steady blood concentration in short period and allow to up- titrate rapidly and also recover fast while adverse reaction occurs; 3) it is much cheaper than other evidence-based medications. In this study, the investigators try to use rapid up-titration of hydralazine to maximal tolerable dose, almost up to 300-400 mg per day, combined with other evidence-based medications in cases with left ventricular ejection fraction less than 35% and mitral regurgitation severity more than moderate degree and assess the prognostic impact.

Objective: Four hundred of patients with severe systolic dysfunction and hemodynamically significant mitral regurgitation, who were admitted for intensive care unit for acute decompensated heart failure, will be enrolled and the participants will be divided into two groups according 1 to 1 randomization process. Control group will receive conventional treatment with tolerable maximal dose of evidence-based medications and study group will use hydralazine with rapid up-titration, if no clinical adverse responses were noted, following by or simultaneously using evidence-based medications. The end-points include in- hospital mortality, 3-year all-cause mortality and heart failure rehospitalization.

During follow-up period, any adverse response of high-dose hydralazine including lupus-like syndrome and arthritis will be monitored.


Condition or disease Intervention/treatment Phase
Systolic Heart Failure Stage D (Disorder) Mitral Regurgitation Drug: evidence-based medications vs. high-dose hydralazine + evidence-based medications Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This prospective study will recruit 400 patients aged 18 years or older, and hospitalization to E-Da Hospital for acute decompensated heart failure due to severe left ventricular systolic dysfunction combined with hemodynamically significant mitral regurgitation. Severe systolic dysfunction and hemodynamically significant mitral regurgitation are defined as left ventricular ejection fraction less than 35% and mitral regurgitant volume more than 45 ml (more than moderate degree), respectively. All participants will be randomly divided into two groups according to 1 to 1 fashion. One group will receive conventional evidence-based medication with up-titration to maximal tolerable dose and another group will receive low-dose hydralazine initially with rapid up-titration, if no adverse effect including hypotension with worsening low cardiac output sign, skin rash and joint pain occurred.
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: The Prognostic Impact of Using High-dose Hydralazine in Severe Systolic Heart Failure With Hemodynamically Significant Mitral Regurgitation
Actual Study Start Date : August 1, 2018
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Active Comparator: conventional treatment
This group will receive conventional evidence-based medications with up-titration to maximal tolerable dose. The evidence-based medications include angiotensin converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, mineralocorticoid receptor antagonist, ivabradine and entresto. Which evidence-based medications will be started first depends on the decision of in-charge doctors without strict regulation. However, all evidence-based medications should be up-titrated to maximal tolerable dose. (Excuse me! Up-titration of evidence-based medications in heart failure isn't multiple intervention. Those medications should be prescribed in each heart failure case if no contraindication was noted.)
Drug: evidence-based medications vs. high-dose hydralazine + evidence-based medications
randomized in 1 to 1 fashion After discharge, high-dose hydralazine is maintained except any adverse effect and up-titration of other evidence-based medications to maximal tolerable dose will be done. The dose of medications is adjusted by clinical signs, especially peripheral perfusion, not only simply by blood pressure. If participant had low blood pressure (for example, systolic blood pressure less than 90 mmHg) but no sign of postural hypotension, or low cardiac output (cold limbs, decreased urine output, dizzy), the investigators will keep up-titration of medications.

Active Comparator: high-dose hydralazine group
another group will receive low-dose hydralazine initially with rapid up-titration, if no adverse effect including hypotension with worsening low cardiac output sign, skin rash and joint pain occurred. Since the half-life of hydralazine is around 4-6 hours and 3-5 half-life achieves the steady blood concentration, up-titration of hydralazine will be done per 1-2 days. For example, initial dose of hydralazine would be 25 mg tid and the dose would be 50 mg bid next day if no adverse effect occurred. Following this rule, one week is enough to reach high-dose hydralazine with daily dose of 300-400 mg.
Drug: evidence-based medications vs. high-dose hydralazine + evidence-based medications
randomized in 1 to 1 fashion After discharge, high-dose hydralazine is maintained except any adverse effect and up-titration of other evidence-based medications to maximal tolerable dose will be done. The dose of medications is adjusted by clinical signs, especially peripheral perfusion, not only simply by blood pressure. If participant had low blood pressure (for example, systolic blood pressure less than 90 mmHg) but no sign of postural hypotension, or low cardiac output (cold limbs, decreased urine output, dizzy), the investigators will keep up-titration of medications.




Primary Outcome Measures :
  1. in-hospital mortality [ Time Frame: From date of randomization until the date of in-hospital death at indexed hospitalization, assessed up to 2 months ]
    death at indexed hospitalization

  2. 3-year heart failure (HF) rehospitalization [ Time Frame: From date of randomization until the date of first rehospitalization for heart failure or date of death from any cause, whichever came first, assessed up to 156 months ]
    Hospitalization for HF is defined as a hospital stay of at least 1 night for treatment of a clinical syndrome with at least two of the following symptoms: paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary rales, a third heart sound, cardiomegaly on chest radiography, or pulmonary edema on chest radiography.

  3. 3-year all-cause mortality [ Time Frame: From date of randomization until the date of date of death from any cause, assessed up to 156 months ]
    The certification of death is based on death records, death certificates, and hospital medical records



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • aged 18 years or older
  • acute decompensated heart failure due to severe left ventricular systolic dysfunction combined with hemodynamically significant mitral regurgitation. Severe systolic dysfunction and hemodynamically significant mitral regurgitation are defined as left ventricular ejection fraction less than 35% and mitral regurgitant volume more than 45 ml (more than moderate degree), respectively

Exclusion Criteria:

  • cancer or other significant co-morbid diseases with expected life span less than 3 years
  • adverse effects of hydralazine
  • surgical interventions of mitral regurgitation will be done in follow-up period which change the course of native condition
  • other valvular conditions other than mitral regurgitation with severity more than or equal to moderate degree, particularly mitral stenosis, and aortic regurgitation/stenosis
  • lack of written informed consent.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04217135


Contacts
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Contact: Yu-Miao Hsiao, MD 886-7-6150011 ext 5111 r10202@edah.org.tw

Locations
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Taiwan
E-Da hospital Recruiting
Kaohsiung, Taiwan, 817
Contact: Yu-Miao Hsiao, MD    886-7-6150011 ext 5111    r10202@edah.org.tw   
Sponsors and Collaborators
Kaohsiung Veterans General Hospital.
E-DA Hospital
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Responsible Party: Shih-Hung Hsiao, Staff of Cardiology, Principal Investigator, Clinical Associate Professor, Kaohsiung Veterans General Hospital.
ClinicalTrials.gov Identifier: NCT04217135    
Other Study ID Numbers: EMRP18106N
First Posted: January 3, 2020    Key Record Dates
Last Update Posted: January 7, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Shih-Hung Hsiao, Kaohsiung Veterans General Hospital.:
high-dose hydralazine
mitral regurgitation
severe systolic heart failure
heart failure rehospitalization
all-cause mortality
Additional relevant MeSH terms:
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Heart Failure
Mitral Valve Insufficiency
Heart Failure, Systolic
Heart Diseases
Cardiovascular Diseases
Heart Valve Diseases
Hydralazine
Antihypertensive Agents
Vasodilator Agents