Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04217135 |
| Other study ID # |
EMRP18106N |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2017 |
| Est. completion date |
July 31, 2022 |
Study information
| Verified date |
January 2022 |
| Source |
Kaohsiung Veterans General Hospital. |
| Contact |
Yu-Miao Hsiao, MD |
| Phone |
886-7-6150011 |
| Email |
r10202[@]edah.org.tw |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
Description:
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.
Methods Study population: 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. 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. According to our prior
experience of acute HF control, the most patients could tolerate this dose well with
acceptable peripheral perfusion and blood pressure. This process will follow by or
simultaneously use evidence-based medications including ACEI/ARB, beta-blocker, and MRA.
Exclusion criteria include any history of the following: 1) cancer or other significant
co-morbid diseases with expected life span less than 3 years, 2) any sign of inadequate
preload such as poor skin turgor, severe thirsty feeling, evidence of gastrointestinal tract
bleeding or sepsis, 3) adverse effects of hydralazine, 4) surgical interventions of mitral
regurgitation will be done in follow-up period which change the course of native condition,
5) other valvular conditions other than mitral regurgitation with severity more than or equal
to moderate degree, particularly mitral stenosis, and aortic regurgitation/stenosis, or 6)
lack of written informed consent. Signs of inadequate peripheral perfusion including downhill
consciousness level, decreased urine output, and prerenal azotemia will be assessed
routinely. Histories of hyperlipidemia, hypertension, diabetes and smoking are recorded. The
endpoints for the current study are in-hospital mortality, 3-year HF rehospitalization and
3-year all-cause mortality. All participants will give written informed consent to
participate in the study, and the study had been approved by the institutional review board.
Measurement of hemodynamic change after high-dose hydralazine: Thirty patients in each group
will be arranged for admission to intensive care unit for severe HF control, and they will
receive invasive hemodynamic monitor by Swan-Ganz catheter routinely for 1 week. Hydralazine
will be up-titrated to maximal tolerable dose in hydralazine group at first 7 days and the
target dose will be 300-400 mg per day. Echocardiographic measurements including stroke
volume, left ventricular ejection fraction, left atrial size, mitral regurgitation severity,
mitral regurgitant volume, pulmonary artery systolic pressure, tissue Doppler parameters, and
left ventricular filling pressure estimated by left atrial expansion index, will be done at
day 1 and day 7.
Maintenance of high-dose hydralazine: 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. Regarding the initial negative inotropic
effect of beta blockers, it will be titrated slowly. While any reasons induce postural
hypotension, the investigator will reduce the dose of hydralazine first and try to keep the
ordinary dose of other evidence-based medications as possible. If participants would admit
for recurrent heart failure or other non-cardiovascular problems, ordinary regimen of
high-dose hydralazine will be maintained unless low blood pressure combined with low cardiac
output occurs.
Monitor adverse effect of high-dose hydralazine: Antinuclear antibody, hematogram and CXR
will be checked per 6 months. Signs of lupus-like syndrome, serositis, joint pain, skin rash,
liver biochemical and hematological studies will be monitored regularly. For patients with
coronary artery disease and ischemic HF, the investigators will take care of any signs of
worsening myocardial ischemia if chest pain occurs or HF worsens.
High-dose captopril will replace hydralazine if any adverse effects of high-dose hydralazine
are suspected. Echocardiographic measurements: Basic echocardiographic measurements including
left ventricular ejection fraction, pulmonary artery systolic pressure, left atrial size, and
tissue Doppler imaging will be done. Echocardiography is performed in all patients. The
severity of mitral regurgitation will be evaluated quantitatively by regurgitant volume.
Heart failure patients are admitted with left ventricular ejection fraction less than 35% and
mitral regurgitant volume more than 45 ml will be enrolled if they are willing to participate
in. Left atrial volume measurements were calculated using the biplane area-length method
immediately before mitral valve opening. In all participants, the left atrial volumes were
indexed to the body surface area. The mitral regurgitation volume is calculated as follows:
regurgitation volume = (stroke volume of mitral annulus) - (stroke volume of left ventricular
outflow tract), where the stroke volumes of the mitral annulus and left ventricular outflow
tract were obtained by multiplying the cross-sectional area by the respective time-velocity
integral. The mitral regurgitant volumes will be assessed at enrollment, at discharge, and at
least once per year during follow-up period. Based on our prior studies, the change of LVFP
assessed by left atrial expansion index will be examined during the course of admission.
Biochemical studies and biomarker measurements: Blood samples will be obtained during index
hospitalization and per 3 months after discharge. The measurements of B-type natriuretic
peptide, anti-nuclear antibodies, renal function, liver function and hematogram will be done
regularly.
Follow up: The median follow-up will be 3 years and the end-points will be in-hospital
mortality, 3-year HF rehospitalization and 3-year all-cause mortality. 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. These clinical signs and symptoms might
have represented a clear change from the normal clinical state of the patient and might have
been accompanied by either failing cardiac output, as determines by peripheral hypoperfusion,
or peripheral or pulmonary edema requiring treatment with intravenous diuretics, inotropes,
or vasodilators. Supportive documentation of a decreased cardiac index, an increased
pulmonary capillary wedge pressure, decreasing oxygen saturation, and end organ
hypoperfusion, if available, are included in the adjudication. Follow-up includes medical
record reviews and patient interviews. Medical assistants will check medical records once per
3 months. The certification of death is based on death records, death certificates, and
hospital medical records.
Statistical analysis: The SPSS software will be used for all statistical analyses. All
continuous variables are presented as means ± standard deviation. A p value of < 0.05 is
considered statistically significant. Comparisons of clinical characteristics are performed
by chi-square analysis for categorical variables. Acute hemodynamic changes after high-dose
hydralazine will be assessed and comparisons of Swan-Ganz and echocardiographic data before
and after high-dose hydralazine will be performed. Otherwise, comparisons of hemodynamic
changes between conventional treatment group and hydralazine will also be done. Kaplan-Meier
curve will be performed to assess the cumulative event-free rate according to different
treatment strategies. Cox proportional regression analysis of hazard ratio after adjusting
significant covariates in univariate analyses will be done. Otherwise, multivariate analysis
will be done to identify the independent prognostic indicators of in-hospital, 3-year HF
rehospitalization, and 3-year all-cause mortality. ROC curve analysis is also performed to
assess the sensitivity and specificity of the cut-off points of covariates for predicting
those events. The frequency of adverse effects of high-dose hydralazine, including positive
antinuclear antibody, lupus-like syndrome, serositis, arthritis, hematogram change, and
worsening myocardial ischemia will be assessed. If the strategy of high-dose hydralazine
combined with conventional evidence-based medications was proved to have prognostically
beneficial effect, the prognostic impact according to maximal tolerable dose of hydralazine
will be analyzed. Additionally, high dose of hydralazine will compress the use of other
evidence-based medications and it is assumed that, compared to conventional treatment group,
up-titration of those medications becomes difficult in high-dose hydralazine group. The
effect of counter-balance between high-dose hydralazine and relatively low doses of ACEI,
ARB, beta blocker and MRA will be assessed by multivariate analysis.
