CS-PUFA-02: PUFAs and Left Ventricular Function in Heart Failure

• Sponsor: Università degli Studi di Brescia (Other)
• Overall Status: Completed
• CT.gov ID: NCT01223703
• Collaborator: (none)
• Enrollment: 133
• Location: 1
• Arms: 2
• Duration (Months): 19
• Patients Per Site Per Month: 7

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Dilated Cardiomyopathy; Heart Failure	Drug: n-3 PUFAs; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 133 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Effects of n-3 Polyunsaturated Fatty Acids (PUFAs) on Left Ventricular Function and Functional Capacity in Patients With Dilated Cardiomyopathy
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: n-3 PUFAs	Drug: 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.; Other Names: OMACOR, Pronova Biopharma, Lysaker, Norway
Placebo Comparator: Placebo	Drug: 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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arrhytmias and Heart failure Unit-Spedali Civili Hospital	Brescia		Italy	25100

Sponsors and Collaborators

• Università degli Studi di Brescia

Investigators

• Principal Investigator: Savina Nodari, MD, Department of Experimental and Applied Medicine-Section of Cardiovascular Diseases
• Study Director: Livio Dei Cas, MD, Department of Experimental and Applied Medicine-Section of Cardiovascular Diseases

Study Documents (Full-Text)

None provided.

More Information

Publications

• 1.Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet2008;372:1223-30. 2.Duda MK, O'Shea KM, Tintinu A, et al. Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction. Cardiovasc Res 2009;81:319-27. 3.Duda MK, O'Shea KM, Lei B, et al. Dietary supplementation with omega-3 PUFA increases adiponectin and attenuates ventricular remodeling and dysfunction with pressure overload. Cardiovasc Res 2007;76:303-10. 4.Vargiu R, Littarru GP, Fraschini M, et al. Enhancement of shortening velocity, power, and acto-myosin crossbridge (CB) kinetics following long-term treatment with propionyl-L-carnitine, coenzyme Q10, and omega-3 fatty acids in BIO TO-2 cardiomyopathic Syrian hamsters papillary muscle. Biofactors 2010;36:229-39. 5.Pepe S, McLennan PL. Cardiac membrane fatty acid composition modulates myocardial oxygen consumption and postischemic recovery of contractile function. Circulation 2002;105:2303-8. 6.Duda MK, O'Shea KM, Stanley WC. omega-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential. Cardiovasc Res 2009;84:33-41.

• Responsible Party: Savina Nodari, Effects of n-3 Polyunsaturated Fatty Acids (PUFAs) on Left Ventricular Function and Functional Capacity in Patients With Dilated Cardiomyopathy, Università degli Studi di Brescia
• ClinicalTrials.gov Identifier: NCT01223703
• Other Study ID Numbers: CS-PUFA-02
• First Posted: Oct 19, 2010
• Last Update Posted: Jan 31, 2012
• Last Verified: Jan 1, 2012

• Keywords provided by Savina Nodari, Effects of n-3 Polyunsaturated Fatty Acids (PUFAs) on Left Ventricular Function and Functional Capacity in Patients With Dilated Cardiomyopathy, Università degli Studi di Brescia: n-3 PUFAs; Heart Failure; Dilated cardiomyopathy; Ejection Fraction; Exercise Capacity
• Additional relevant MeSH terms: Heart Failure; Cardiomyopathies; Cardiomyopathy, Dilated

Study Results

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 Detail	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.

Arm/Group Title	n-3 PUFAs	Placebo
Arm/Group Description	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.	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
Period Title: Overall Study
STARTED	67	66
COMPLETED	67	66
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	n-3 PUFAs	Placebo	Total
Arm/Group Description	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.	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	Total of all reporting groups
Overall Participants	67	66	133
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (11)	64 (9)	62.9 (10.1)
Sex: Female, Male (Count of Participants)
Female	3 4.5%	10 15.2%	13 9.8%
Male	64 95.5%	56 84.8%	120 90.2%

Outcome Measures

1. Primary Outcome

Title	Change in Left Ventricular (LV) Systolic Function Expressed as Left Ventricular Ejection Fraction (LVEF) Between Baseline and 12-month Follow-up
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	n-3 PUFAs	Placebo
Arm/Group Description	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.	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
Measure Participants	67	66
baseline	36 (7)	37 (6)
12th month follow up	39 (6)	35 (6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	n-3 PUFAs, Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.05
	Comments
	Method	t-test, 2 sided
	Comments	The analysis was done following an intention-to-treat approach by means of the unpaired student t test or Wilcoxon rank sum test as appropriated.

2. Secondary Outcome

Title	LV Diastolic Function
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	n-3 PUFAs	Placebo
Arm/Group Description	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.	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
Measure Participants	67	66
E/A baseline	0.89 (0.29)	0.90 (0.37)
E/A 12 month	0.84 (0.19)	0.98 (0.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	n-3 PUFAs, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.05
	Comments
	Method	t-test, 2 sided
	Comments	The analysis was done following an intention-to-treat approach by means of the unpaired student t test or Wilcoxon rank sum test as appropriated.

3. Secondary Outcome

Title	Functional Capacity (Change in Peak Oxygen Uptake, VO2)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	n-3 PUFAs	Placebo
Arm/Group Description	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.	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
Measure Participants	67	66
baseline	19.5 (3.8)	18.3 (4.4)
12th month	20.7 (4.3)	17.4 (4.2)

4. Secondary Outcome

Title	Change in Mean New York Heart Association (NYHA) Functional Class Between Baseline and 12th Month Follow up.
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	n-3 PUFAs	Placebo
Arm/Group Description	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.	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
Measure Participants	67	66
baseline	2.21 (0.51)	2.17 (0.57)
12th month	1.91 (0.54)	2.32 (0.61)

Adverse Events

Arm/Group Title	n-3 PUFAs		Placebo
Arm/Group Description	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.		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
All Cause Mortality
	n-3 PUFAs		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	n-3 PUFAs		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	n-3 PUFAs		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/67 (0%)		0/66 (0%)

Limitations/Caveats

Our investigation was a single-center trial with a small sample size and a limited number of clinical events. Therefore, our results cannot be generalized to HF patients.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.