Heart Failure With Preserved Ejection Fraction
Conditions
Keywords
HFPEF, Heart Failure, HF w/ preserved EF, Preserved EF, Preserved Ejection Fraction, Diastolic Dysfunction
Brief summary
The purpose of this study is to determine whether treatment with Ranolazine will improve exercise capacity in patients with Heart Failure with preserved left ventricular ejection fraction, or HFPEF.
Detailed description
Denise Barnard, M.D., and her associates, are conducting a research study to find out more about ways to improve symptoms in patients with Heart Failure with Preserved Ejection Fraction (HFPEF). Heart failure with preserved ejection fraction is a condition where the heart squeezes well but is stiff. This stiffness in the heart muscle makes the heart unable to fill, leading to shortness of breath and decreased exercise tolerance. Subjects with HFPEF are asked to participate in this study. There will be approximately 40 participants enrolled in this study. The purpose of this study is to investigate the effects of Ranolazine (Ranexa) in patients with HFPEF. The study is sponsored by the manufacturers of the drug, Gilead Pharmaceuticals. Ranolazine is a drug that affects the ion channels in the heart. In patients with heart failure, these ion channels do not work properly, and contribute to make the heart stiff. A stiff heart leads to the symptoms of shortness of breath which patients with HFPEF experience. Due to its properties, Ranolazine may improve this stiffness. Ranolazine could improve subject's shortness of breath and ability to exercise. Currently, ranolazine carries FDA approval for the treatment of chronic angina only. We intend to study ranolazine in patients with HFPEF, in the absence of documented ischemia, to determine whether the drug's lusitropic properties can improve exercise capacity in HFPEF patients. Previous trials of ranolazine in patients with chronic angina found that there was a dose-dependent relationship between improvements in exercise capacity and ranolazine. However, there did appear to be a plateau in which 1500 mg of ranolazine twice daily improved exercise capacity only slightly more than 1000 mg of ranolazine given twice daily. Additionally, there was a substantially higher rate of adverse events (mainly nausea, dizziness, and asthenia) with the higher dose. Given the desire to maximize benefit and minimize the risk of adverse events, ranolazine 1000 mg by mouth twice daily was chosen as the target dose. To properly evaluate the effects of Ranolazine, this research study is set up as a double blind, placebo controlled study. Subjects will be randomly assigned (like rolling a dice) to either Ranolazine or placebo (inactive substance). Subjects will have a 50% chance of getting the study drug and 50% chance of getting placebo.
Interventions
DRUGRanolazine
Patients with be given 500 mg by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period)
DRUGPlacebo
Patients will be given 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period)
Sponsors
Gilead Sciences
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
I. Inclusion Criteria * Age \> 18 years old * Diagnosis of Heart Failure (HF) with Preserved Ejection Fraction (PEF) * Signs or symptoms of heart failure (breathlessness, pulmonary congestion, edema, fatigue), NYHA (New York Heart Association) Class II-III HF AND * LVEF (Left Ventricular Ejection Fraction) \> 45% AND * Evidence of elevated LV filling pressures 1. E/e-prime (E/e') mitral ratio \> 8. Mitral E/e' ratio has been proposed as a noninvasive measure of left ventricular filling pressure. 2. Brain natiuretic peptide (BNP) \> 80 pg/mL. BNP is biomarker of ventricular wall stress. * Pulmonary Artery systolic pressure estimated at \> 35 mm Hg on echocardiography * Stable medical management for at least 1 month II.
Exclusion criteria
* Inability to perform 6 minute walk (6MW) test or 6 minute walk distance \> 550 meters at baseline * Inability to perform the Naughton protocol exercise test, or an absolute contraindication to exercise testing * Decompensated heart failure * Clinically significant valvular disease or congenital cardiac defects * Clinical diagnosis of Chronic obstructive pulmonary disease (COPD) or significant lung pathology * Prior treatment with ranolazine * Percutaneous coronary intervention within the past 6 months or planned intervention during the study period * Acute coronary syndrome within the prior 2 months * Presence of uncorrected perfusion defects on stress testing * Presence of angina * Any rhythm other than sinus * Electrocardiogram measured QTc interval \> 500 msec * Clinically significant hepatic impairment (ALT/AST \> 3x upper limit of normal) * Participation in another investigational drug or device study within 1 month prior to screening * Females of childbearing potential * Current treatment with potent inhibitors of hepatic cytochrome P450 (CYP) enzyme complex pathways affecting drug metabolism (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir) * Current treatment with CYP3A and/or P-Glycoprotein (Pgp) inducers (e.g. rifampin, rifampicin, carbamazepine, St. John's wort) * Any other conditions that in the opinion of the investigators are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Exercise Capacity at 6 Weeks | 6 weeks | Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks. |
| Change in Oxygen Consumption (VO2) at 6 Weeks | 6 weeks | Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Quality of Life (QOL) Score | 6 weeks | The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points. |
| Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e') | 6 weeks | Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is \< 8; and of abnormal filling pressure when E/e' is \> 15. The percent change is reported. |
Countries
United States
Participant flow
Recruitment details
Between 12/2011 and 3/2013, the UCSD Echo database of \>4500 patients (pts) and their electronic medical records were screened. Of the 1200 pts with left ventricular (LV) ejection fraction (EF) \>45%, only 60 pts met all inclusion criteria. Informed consent was obtained from 10 pts who were subsequently randomized and completed study protocols.
Pre-assignment details
Pts meeting all inclusion criteria were most often excluded due to the presence of atrial fibrillation, being unable to perform the minimum exercise effort required, or walked \> 550 meters on the 6MW test. The remaining pts were excluded for acute heart failure (HF) decompensation, baseline QTc \> 500 ms or participation in another clinical trial .
Participants by arm
| Arm | Count |
|---|---|
| Ranolazine Group Patients with be given 500 mg Ranolazine by mouth twice a day for three days, and then the dose will be increased to 1000 mg by mouth twice daily thereafter. (patients who concurrently take moderate CYP3A inhibitors including diltiazem, verapamil, aprepitant, erythromycin, and fluconazole will continue to 500 mg by mouth twice a day for the entire dosing period) | 6 |
| Placebo Group Patients will be given Placebo matching the appearance of Ranolazine as 1 tab twice a day for 3 days, then increasing to 2 tabs twice a day thereafter (patients who concurrently take moderate CYP3A inhibitors, will be given 1 tab twice daily for the entire dosing period) | 4 |
| Total | 10 |
Baseline characteristics
| Characteristic | Ranolazine Group | Placebo Group | Total |
|---|---|---|---|
| 6MW test distance | 382.5 meters STANDARD_DEVIATION 88.2 | 298.2 meters STANDARD_DEVIATION 76.3 | 348.8 meters STANDARD_DEVIATION 83.4 |
| Age, Continuous | 79.5 years | 75.5 years | 77.9 years |
| BNP | 111.7 pg/mL STANDARD_DEVIATION 86.4 | 184.8 pg/mL STANDARD_DEVIATION 87.1 | 140.9 pg/mL STANDARD_DEVIATION 86.6 |
| Exercise Duration | 608.6 seconds STANDARD_DEVIATION 253.1 | 328.8 seconds STANDARD_DEVIATION 128.8 | 496.7 seconds STANDARD_DEVIATION 206.5 |
| Peak Oxygen Uptake (VO2) | 15.9 mL O2/kg/min STANDARD_DEVIATION 2.3 | 15.7 mL O2/kg/min STANDARD_DEVIATION 2.1 | 15.8 mL O2/kg/min STANDARD_DEVIATION 2.3 |
| Quality of Life (QOL) Score | 36.7 units on a scale STANDARD_DEVIATION 20.3 | 48.8 units on a scale STANDARD_DEVIATION 36.3 | 41.5 units on a scale STANDARD_DEVIATION 26.7 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Septal E/e' Doppler velocity ratio | 16.2 unitless STANDARD_DEVIATION 3.2 | 17.0 unitless STANDARD_DEVIATION 5.8 | 16.5 unitless STANDARD_DEVIATION 4.2 |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 4 |
| other Total, other adverse events | 1 / 6 | 1 / 4 |
| serious Total, serious adverse events | 0 / 6 | 0 / 4 |
Outcome results
Primary
Change in Exercise Capacity at 6 Weeks
Exercise capacity in terms of exercise duration (time in seconds) as described for the baseline value, is repeated at 6 weeks.
Time frame: 6 weeks
Population: Entire study population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine Group | Change in Exercise Capacity at 6 Weeks | 659.9 seconds | Standard Deviation 284.5 |
| Placebo Group | Change in Exercise Capacity at 6 Weeks | 300.5 seconds | Standard Deviation 92.4 |
p-value: 0.47t-test, 2 sided
Primary
Change in Oxygen Consumption (VO2) at 6 Weeks
Oxygen consumption (VO2) as described at baseline is remeasured after 6 weeks of drug vs placebo.
Time frame: 6 weeks
Population: Entire study population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine Group | Change in Oxygen Consumption (VO2) at 6 Weeks | 17.8 ml/kg/min | Standard Deviation 3.4 |
| Placebo Group | Change in Oxygen Consumption (VO2) at 6 Weeks | 13.5 ml/kg/min | Standard Deviation 4.1 |
p-value: 0.009Wilcoxon (Mann-Whitney)
Secondary
Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e')
Doppler echo allows non-invasive evaluation of diastolic cardiac function. The mitral inflow velocity (E) correlates with LV filling pressure, but is influenced by myocardial relaxation time (RT) and filling pressure. The early diastolic septal mitral annular tissue velocity (e') varies with RT alone. The unitless ratio of the E to e' velocities (E/e') is considered a reliable surrogate of LV filling pressure. Prediction of normal diastolic filling pressure is most reliable when E/e' is \< 8; and of abnormal filling pressure when E/e' is \> 15. The percent change is reported.
Time frame: 6 weeks
Population: Entire Study Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine Group | Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e') | -15 percent change | Standard Deviation 35 |
| Placebo Group | Change in Doppler Echocardiographic Parameters, Septal E/e' Ratio (E/e') | -1 percent change | Standard Deviation 9.4 |
p-value: 0.49Wilcoxon (Mann-Whitney)
Secondary
Change in Quality of Life (QOL) Score
The Minnesota Living with Heart Failure (HF) Questionnaire was re-administered at the 6 week time point. The total quality of life (QOL) scores were compared to the baseline score. The well-validated Minnesota Living with Heart Failure questionnaire is self-administered, has 21 questions and takes 5-10 minutes to complete. The test measures perceived health-related QOL. Each question is scored from 0 to 5 on the Likert scale, where 0 is 'none', and 5 is 'very much'. QOL scores range from 0 to 105; a lower score represents a better quality of life. After an intervention, a decrease in score reflects an improvement in QOL. A minimally important difference in the total score is 5 points.
Time frame: 6 weeks
Population: The analysis population is comprised of the 10 patients who were eligible and consented for participation in the trial. Six patients were assigned to the Ranolazine group and four to the placebo group, randomization was by chance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine Group | Change in Quality of Life (QOL) Score | 38.2 units on a scale | Standard Deviation 24.7 |
| Placebo Group | Change in Quality of Life (QOL) Score | 50.9 units on a scale | Standard Deviation 65.5 |
p-value: 0.74t-test, 2 sided