Dilated Cardiomyopathy, Heart Failure
Conditions
Keywords
n-3 PUFAs, Heart Failure, Dilated cardiomyopathy, Ejection Fraction, Exercise Capacity
Brief summary
The purpose of this study is to test the hypothesis that n-3 PUFAs improve left ventricular systolic function in patients with stable chronic HF secondary to nonischemic dilated cardiomyopathy (NICM).
Detailed description
The results of the GISSI-HF trial indicate that in patients with chronic HF on evidence-based medical therapy and New York Heart Association (NYHA) functional class II-IV, long term treatment with n-3 PUFAs 1 g daily reduces mortality and hospitalizations for cardiovascular reasons. Several potential mechanisms may underlie the beneficial effects of n-3 polyunsaturated fatty acids (PUFAs) in HF patients, including, but not limited to, antiarrhythmic, and hemodynamic actions. The current investigation was therefore designed to test the hypothesis that treatment with n-3 PUFAs improves LV systolic function expressed as EF in patients with stable chronic HF secondary to a nonischemic dilated cardiomyopathy (NICM). Additionally, we sought to determine if n-3 PUFAs also exert positive effects on LV diastolic function assessed by echocardiography; functional capacity assessed by cardiopulmonary stress testing (CPET); and New York Heart Association (NYHA) functional class.
Interventions
DRUGn-3 PUFAs
1.0 g gelatin capsules containing 850 to 882 mg of EPA and DHA ethyl esters in the average ratio EPA/DHA of 0.9:1.5 The treatment dose was five capsules daily for the first month followed by two capsules daily for the rest of the study.
DRUGPlacebo
1.0 g gelatin capsules containing olive oil. The treatment dose was five capsules daily for the first month followed by two capsules daily for the rest of the study
Sponsors
Università degli Studi di Brescia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* patients with a diagnosis of non ischemic cardiomyopathy (the absence of coronary artery disease,defined as the absence of stenosis \> 50%, was confirmed by angiography performed at the time of the diagnostic workup of the cardiomyopathy) * LV systolic dysfunction (defined as an EF \< 45%) * Stable clinical conditions with minimal or no symptoms for at least three month * Evidence-based medical treatment at maximum tolerated target doses for at least six month
Exclusion criteria
* presence of symptoms or evidence of CAD diagnosed through noninvasive tests; * peripheral arterial disease; * presence of congenital or primary valvular heart disease; * persistent atrial fibrillation; * inability to perform bicycle ergometry for noncardiac causes; * moderately to severely reduced functional capacity; * NYHA functional class IV; * poor acoustic windows limiting the ability to assess echocardiographic measurements; * chronic lung disease; * advanced renal disease (eGFR \< 30 mL/min/1.73 m2); * advanced liver disease; * any disease limiting life expectancy to one year or less; * contraindications to study drugs; * concomitant participation in other research studies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Left Ventricular (LV) Systolic Function Expressed as Left Ventricular Ejection Fraction (LVEF) Between Baseline and 12-month Follow-up | one year | The primary end point of the study was the change in LV systolic function expressed as LVEF between baseline and 12-month follow-up. The following parameters were measured according to the professional standards defined by the American Society of Echocardiography and the European Association of Echocardiography |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| LV Diastolic Function | one year | Change in LV diastolic function assessed by echocardiography: mitral diastolic inflow velocities (peak velocity of early ventricular filling \[E-wave\], peak velocity of late ventricular filling \[A-wave\], E/A ratio, and E-wave deceleration time), diastolic function score (graded on a scale from 1 to 4) were used. |
| Functional Capacity (Change in Peak Oxygen Uptake, VO2) | one year | Change in functional capacity expressed as a peak oxygen uptake (VO2), that was acquired breath-by-breath by pneumotachograph (with bidirectional differential pressure) during cardiopulmonary exercize testing. |
| Change in Mean New York Heart Association (NYHA) Functional Class Between Baseline and 12th Month Follow up. | one year | NYHA class I: No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs, etc... NYHA class II: Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. NYHA class III: Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest NYHA class IV: Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. |
Countries
Italy
Participant flow
Recruitment details
Potential participants were recruited consecutively from the Heart Failure (HF) outpatient clinic of the University of Brescia. The first patient was enrolled on November 5, 2007, and the last patient completed the study on June 30, 2009.
Pre-assignment details
458 patients were assessed for eligibility. 235 patients were excluded: 251 not meeting inclusion criteria; 74 refused to participate. A total of 133 patients took part in the study.
Participants by arm
| Arm | Count |
|---|---|
| n-3 PUFAs 1.0 g gelatin capsules containing 850 to 882 mg of EPA and DHA ethyl esters in the average ratio EPA/DHA of 0.9:1.5 The treatment dose was five capsules daily for the first month followed by two capsules daily for the rest of the study. | 67 |
| Placebo 1.0 g gelatin capsules containing olive oil. The treatment dose was five capsules daily for the first month followed by two capsules daily for the rest of the study | 66 |
| Total | 133 |
Baseline characteristics
| Characteristic | n-3 PUFAs | Placebo | Total |
|---|---|---|---|
| Age Continuous | 61 years STANDARD_DEVIATION 11 | 64 years STANDARD_DEVIATION 9 | 62.9 years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 3 Participants | 10 Participants | 13 Participants |
| Sex: Female, Male Male | 64 Participants | 56 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 67 | 0 / 66 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Change in Left Ventricular (LV) Systolic Function Expressed as Left Ventricular Ejection Fraction (LVEF) Between Baseline and 12-month Follow-up
The primary end point of the study was the change in LV systolic function expressed as LVEF between baseline and 12-month follow-up. The following parameters were measured according to the professional standards defined by the American Society of Echocardiography and the European Association of Echocardiography
Time frame: one year
Population: A sample of 65 patients in each group was calculated to have 80% power to detect such 0.5 effect size with p\<0.05 (2-tailed) at the Student t test for unpaired data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| n-3 PUFAs | Change in Left Ventricular (LV) Systolic Function Expressed as Left Ventricular Ejection Fraction (LVEF) Between Baseline and 12-month Follow-up | baseline | 36 ejection fraction (percentage) | Standard Deviation 7 |
| n-3 PUFAs | Change in Left Ventricular (LV) Systolic Function Expressed as Left Ventricular Ejection Fraction (LVEF) Between Baseline and 12-month Follow-up | 12th month follow up | 39 ejection fraction (percentage) | Standard Deviation 6 |
| Placebo | Change in Left Ventricular (LV) Systolic Function Expressed as Left Ventricular Ejection Fraction (LVEF) Between Baseline and 12-month Follow-up | baseline | 37 ejection fraction (percentage) | Standard Deviation 6 |
| Placebo | Change in Left Ventricular (LV) Systolic Function Expressed as Left Ventricular Ejection Fraction (LVEF) Between Baseline and 12-month Follow-up | 12th month follow up | 35 ejection fraction (percentage) | Standard Deviation 6 |
Comparison: null hypothesis is no difference n3 PUFA administration and placebo. To demonstrate an effect size of 0.5 in LVEF, a sample of 65 patients in each group was calculated to have 80% power to detect such 0.5 effect size with alpha=0.05 (2-tailed) at the Student t test.~for unpaired data.p-value: <0.05t-test, 2 sided
Secondary
Change in Mean New York Heart Association (NYHA) Functional Class Between Baseline and 12th Month Follow up.
NYHA class I: No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when walking, climbing stairs, etc... NYHA class II: Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. NYHA class III: Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. walking short distances (20-100 m). Comfortable only at rest NYHA class IV: Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients.
Time frame: one year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| n-3 PUFAs | Change in Mean New York Heart Association (NYHA) Functional Class Between Baseline and 12th Month Follow up. | baseline | 2.21 units on a scale | Standard Deviation 0.51 |
| n-3 PUFAs | Change in Mean New York Heart Association (NYHA) Functional Class Between Baseline and 12th Month Follow up. | 12th month | 1.91 units on a scale | Standard Deviation 0.54 |
| Placebo | Change in Mean New York Heart Association (NYHA) Functional Class Between Baseline and 12th Month Follow up. | 12th month | 2.32 units on a scale | Standard Deviation 0.61 |
| Placebo | Change in Mean New York Heart Association (NYHA) Functional Class Between Baseline and 12th Month Follow up. | baseline | 2.17 units on a scale | Standard Deviation 0.57 |
Secondary
Functional Capacity (Change in Peak Oxygen Uptake, VO2)
Change in functional capacity expressed as a peak oxygen uptake (VO2), that was acquired breath-by-breath by pneumotachograph (with bidirectional differential pressure) during cardiopulmonary exercize testing.
Time frame: one year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| n-3 PUFAs | Functional Capacity (Change in Peak Oxygen Uptake, VO2) | baseline | 19.5 ml/kg/min | Standard Deviation 3.8 |
| n-3 PUFAs | Functional Capacity (Change in Peak Oxygen Uptake, VO2) | 12th month | 20.7 ml/kg/min | Standard Deviation 4.3 |
| Placebo | Functional Capacity (Change in Peak Oxygen Uptake, VO2) | baseline | 18.3 ml/kg/min | Standard Deviation 4.4 |
| Placebo | Functional Capacity (Change in Peak Oxygen Uptake, VO2) | 12th month | 17.4 ml/kg/min | Standard Deviation 4.2 |
Secondary
LV Diastolic Function
Change in LV diastolic function assessed by echocardiography: mitral diastolic inflow velocities (peak velocity of early ventricular filling \[E-wave\], peak velocity of late ventricular filling \[A-wave\], E/A ratio, and E-wave deceleration time), diastolic function score (graded on a scale from 1 to 4) were used.
Time frame: one year
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| n-3 PUFAs | LV Diastolic Function | E/A 12 month | 0.84 E/A ratio | Standard Deviation 0.19 |
| n-3 PUFAs | LV Diastolic Function | E/A baseline | 0.89 E/A ratio | Standard Deviation 0.29 |
| Placebo | LV Diastolic Function | E/A 12 month | 0.98 E/A ratio | Standard Deviation 0.4 |
| Placebo | LV Diastolic Function | E/A baseline | 0.90 E/A ratio | Standard Deviation 0.37 |
p-value: <0.05t-test, 2 sided