Heart Failure With Preserved Ejection Fraction
Conditions
Brief summary
Determine if cilostazol improves symptoms and NTproBNP levels (heart failure blood marker) in heart failure with preserved ejection fraction (HFpEF) - a prevalent syndrome without targeted evidence-based treatment. This will be assessed in a prospective 1-month single blinded study with 2 cross-overs n-of-1 study design with placebo and cilostazol
Detailed description
Heart failure (HF) is the #1 reason for hospital admissions. About half of the patients with HF have a preserved ejection fraction (HFpEF). There is no targeted evidence-based treatment for HFpEF. We recently reported that elevating the heart rate with pacemakers conveys clinical benefits e.g. reduction in heart failure symptoms, lowering filling pressures and an increase in walk distance. Cilostazol is a PDE3 inhibitor that increases the heart rate by about 5-8 beats per minute and has other potentially beneficial HFpEF effects such as peripheral vasodilation, lusitropic effects and dromotropic effects. By activating proteinkinase A, cilostazol may also phosphorylate titin, which may reduce myocardial stiffness. n-of-1 study design using the standard dose cilostazol formulation of 100mg twice a day approved for peripheral vascular disease. The investigators and patients are blinded. The patients serve as their own controls with two crossovers (Week 1: cilostazol or placebo - Week 2: placebo or cilostazol - Week 3: cilostazol or placebo - Week 4: placebo or cilostazol).
Interventions
DRUGCilostazol 100Mg Tab
Cilostazol Twice a Day
DRUGPlacebo
Placebo
Sponsors
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
n-of-1 design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* \>18 yrs * LVEF ≥ 50% (on last assessment, \<2 years) * Diagnosis of HFpEF or Shortness of breath with NYHA Class ≥ 2 and one of the following: 1. pulmonary edema on chest imaging or documented on exam or on loop diuretics 2. NTproBNP \>400 ng/ml in the last 24 months 3. HFpEF\>50% hospitalization in the last 3 years 4. Qualitative echo: \> mild diastolic dysfunction on echo report and \> mild left ventricular hypertrophy and left atrial dilation or quantitative echo: left ventricular hypertrophy \[men ≥115 g/m², women ≥95 g/m² or relative wall thickness \>0.42 or any LV wall thickness \>1.2cm and has LA dilation (\>28ml/m2)
Exclusion criteria
* \<18yo * resting heart rate \>100/min * patients with LVEF \<50% * advanced end-stage heart failure, * symptomatic COPD on home O2, * uncontrolled severe HTN (SBP \>160/100 mmHg) * patients with life expectancy \<6 months, * end-stage liver cirrhosis, * more than moderate valve disease, * infiltrative myocardial disease * constrictive pericarditis or myocarditis, * patients unable to participate in follow up, * pregnant patients or patients without reliable contraceptive agent for the duration of study participation), * left ventricular outflow tract obstruction, * bleeding dyscrasias, blood dyscrasias, * Patients on oral ketoconazole, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, erythromycin, clarithromycin or azithromycin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| KCCQ-12 | 4 weeks | The Kansas City Cardiomyopathy Questionnaire contains 12 items that measure the effect of heart failure on health and quality of life. Total scores are scaled from 0 to 100 and frequently summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| NTproBNP | 1st and 3rd week | Blood marker of heart failure severity \[pg/mL\], average of 2 time points 1st and 3rd week |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cilostazol First, Then Placebo First week, Cilostazol 100mg twice a day
Second week, Placebo twice a day
Third week, Cilostazol 100mg twice a day
Forth week, Placebo twice a day
Cilostazol 100Mg Tab: Cilostazol Twice a Day
Placebo: Placebo | 11 |
| Placebo First, Then Cilostazol First week, Placebo twice a day
Second week, Cilostazol 100mg twice a day
Third week, Placebo twice a day
Forth week, Cilostazol 100mg twice a day
Cilostazol 100Mg Tab: Cilostazol Twice a Day
Placebo: Placebo | 12 |
| Total | 23 |
Baseline characteristics
| Characteristic | Cilostazol First, Then Placebo | Placebo First, Then Cilostazol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 11 Participants | 12 Participants | 23 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 10 Participants | 20 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 23 | 5 / 23 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 3 / 23 | 5 / 23 |
Outcome results
Primary
KCCQ-12
The Kansas City Cardiomyopathy Questionnaire contains 12 items that measure the effect of heart failure on health and quality of life. Total scores are scaled from 0 to 100 and frequently summarized in 25-point ranges, where scores represent health status as follows: 0 to 24: very poor to poor; 25 to 49: poor to fair; 50 to 74: fair to good; and 75 to 100: good to excellent
Time frame: 4 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilostazol | KCCQ-12 | 47 units on a scale |
| Placebo | KCCQ-12 | 39 units on a scale |
Secondary
NTproBNP
Blood marker of heart failure severity \[pg/mL\], average of 2 time points 1st and 3rd week
Time frame: 1st and 3rd week
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cilostazol | NTproBNP | 375 pg/mL |
| Placebo | NTproBNP | 448 pg/mL |