The Effects of Omega-3 Fatty Acids on Aspirin Resistance

• Sponsor: University of Rochester (Other)
• Overall Status: Completed
• CT.gov ID: NCT00771914
• Collaborator: GlaxoSmithKline (Industry), American College of Clinical Pharmacy (Other), Cornell University (Other)
• Enrollment: 27
• Location: 1
• Arms: 4
• Duration (Months): 2
• Patients Per Site Per Month: 13.5

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if omega-3 fatty acids enhance the antiplatelet effects of aspirin.

Condition or Disease	Intervention/Treatment	Phase
Increased Drug Resistance	Drug: Aspirin; Drug: Lovaza; Drug: Both Aspirin and Lovaza; Other: Placebo	Phase 1/Phase 2

Detailed Description

Although aspirin has been a stalwart treatment in the prevention and treatment of myocardial infarction and stroke, it does not have its expected effects in a significant proportion of the population. This phenomenon has been termed "aspirin resistance". Omega-3 fatty acid supplementation has been associated with a reduced risk of sudden cardiac death and myocardial infarction. The beneficial effects of omega-3s are considered to be partially due to their ability to prevent platelet aggregation. However, the ability of omega-3s to enhance the effects of aspirin in those who suffer from aspirin resistance has not been determined. It is known that aspirin stimulates the production of potent lipid mediators from omega-3 fatty acids and that these mediators have powerful antiinflammatory and tissue-protective effects. Thus, the treatment of individuals at high risk for myocardial infarction and stroke with both aspirin and a pharmaceutical-grade omega-3 fatty acid medication may be a powerful combination in the prevention and treatment of life-threatening cardiovascular disease.

Study Protocol: Non-smoking male and female subjects between the ages of 18 and 50 not taking any medications, vitamin pills, nutritional supplements, or herbal preparations were recruited. Subjects with a history of chronic diseases (e.g. cardiovascular, renal, hepatic, neurodegenerative, neoplastic, metabolic , hypertension; based on screening medical history, a complete blood count, and comprehensive metabolic profile), or allergic reactions to aspirin, fish, fish oils, or non-steroidal anti-inflammatory drugs were excluded. Other exclusions included drinking more than three alcoholic beverages a day, or having any of the following conditions: an ulcer or bleeding in the stomach, liver or kidney disease, bleeding or blood clotting disorder (e.g. hemophilia), congestive heart failure, fluid retention, high blood pressure, gout, asthma, arthritis, or nasal polyps. This was a randomized, placebo-controlled, double-blinded trial with a cross-over design. Each subject served as his/her own control. The study involved four visits four weeks apart, all hosted in the University of Rochester Clinical Research Center. At each separate study visit, each subject received (using a randomized protocol) placebo, 81 mg aspirin, 4 g Lovaza(R)(3.4g of EPA+DHA), or both aspirin and Lovaza(R). Thus, each subject received each of these treatments individually in a random fashion over the four visits. Subjects, Center staff, and investigators were blinded as to which treatment was given at each visit and this ensured by the study pharmacist making the tablets and capsules for each treatment appear identical. Prior to each visit, subjects ate a standard low-fat dinner the prior evening, then fasted for at least 8 hours prior to arrival at the Center. Subjects were required to abstain from taking aspirin or non-steroidal anti-inflammatory drugs for 10 days prior to each visit and omega-3 fatty acids for 30 days prior to the baseline study visit, and all subsequent clinic visits. Visits lasted approximately 6 hours, with subjects at bedrest. A venous catheter was placed in a peripheral vein (saline lock, 18 gauge or larger, in the forearm) with blood drawn, at baseline and 4 hours post-treatment, into citrated tubes at each visit for Platelet Function Analyzer-100 (PFA-100-Siemens, Deerfield, IL) closure time testing. Subjects were provided with a standard low-fat breakfast after the baseline phlebotomy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effects of Omega-3 Fatty Acids on Aspirin Resistance
• Study Start Date: Nov 1, 2008
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: Jan 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo, Lovaza, Aspirin, Both Aspirin and Lovaza First Placebo, then 4 grams of Lovaza, then 81mg of Aspirin, then both 4 grams of Lovaza and 81 mg of Aspirin	Drug: Aspirin; Aspirin 81mg tablet; Drug: Lovaza; Lovaza 4 grams; Other Names: ethyl EPA + DHA; fish oil ; Drug: Both Aspirin and Lovaza; Lovaza 4 grams plus aspirin 81 mg; Other Names: Lovaza and aspirin ; Other: Placebo; Capsule resembling fish oil and a tablet resembling aspirin
Experimental: Aspirin, Lovaza, Both Aspirin and Lovaza, Placebo First 81mg of Aspirin, then 4 grams of Lovaza, then both 81mg of Aspirin and 4 grams of Lovaza, then placebo	Drug: Aspirin; Aspirin 81mg tablet; Drug: Lovaza; Lovaza 4 grams; Other Names: ethyl EPA + DHA; fish oil ; Drug: Both Aspirin and Lovaza; Lovaza 4 grams plus aspirin 81 mg; Other Names: Lovaza and aspirin ; Other: Placebo; Capsule resembling fish oil and a tablet resembling aspirin
Experimental: Lovaza, Both Aspirin and Lovaza, Placebo, Aspirin First 4 grams of Lovaza, then both 81mg of Aspirin and 4 grams of Lovaza, then placebo, then 81mg of Aspirin	Drug: Aspirin; Aspirin 81mg tablet; Drug: Lovaza; Lovaza 4 grams; Other Names: ethyl EPA + DHA; fish oil ; Drug: Both Aspirin and Lovaza; Lovaza 4 grams plus aspirin 81 mg; Other Names: Lovaza and aspirin ; Other: Placebo; Capsule resembling fish oil and a tablet resembling aspirin
Experimental: Both Aspirin and Lovaza, Placebo, Lovaza, Aspirin First both 81mg of Aspirin and 4 grams of Lovaza, then placebo, then 4 grams of Lovaza, then 81mg of Aspirin	Drug: Aspirin; Aspirin 81mg tablet; Drug: Lovaza; Lovaza 4 grams; Other Names: ethyl EPA + DHA; fish oil ; Drug: Both Aspirin and Lovaza; Lovaza 4 grams plus aspirin 81 mg; Other Names: Lovaza and aspirin ; Other: Placebo; Capsule resembling fish oil and a tablet resembling aspirin

Outcome Measures

Primary Outcome Measures

1. the Difference Between the Time to Clot Formation in Seconds at Baseline and After Each Treatment [4 hours]

   The PFA-100 test measures platelet function as the time that it takes for a clot to form in a collagen-lined cartridge.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Willing to participate by providing informed consent and committing to complete the study. This includes adhering to the study diet.

• No chronic disease by history and based on a complete blood count and comprehensive metabolic profile.

• Commitment to not taking aspirin, non-steroidal anti-inflammatory medications, and to limit fish intake to ≤2 meals during the 7 days prior to each CRC study period. They will also need to abstain from taking a list of over-the-counter medications that include aspirin. For the duration of the study, they will also be asked to abstain from taking fish and flax seed oil supplements.

Exclusion Criteria:

• Reports the presence of chronic disease (e.g. cardiovascular, renal, hepatic, neurodegenerative, neoplastic, metabolic , hypertension).

• Reports taking a systemic medication chronically.

• History of serious adverse reaction or allergy to aspirin or fish oil.

• Baseline platelet count <100 000 or >500 000, hematocrit <30%, or white blood cell count >20 000.

• Any abnormality from a screening CBC and complete blood count that suggests acute or chronic disease.

• Nicotine user.

• History of alcohol abuse

• Pregnancy by history or urine/serum pregnancy test

• History of intestinal malabsorption syndrome including gastric bypass surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Rochester School of Medicine and Dentistry	Rochester	New York	United States	14642

Sponsors and Collaborators

• University of Rochester
• GlaxoSmithKline
• American College of Clinical Pharmacy
• Cornell University

Investigators

• Principal Investigator: Robert C Block, MD, MPH, University of Rochester

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Robert Block, Principal Investigator, University of Rochester
• ClinicalTrials.gov Identifier: NCT00771914
• Other Study ID Numbers: Study Protocol 112421
• First Posted: Oct 15, 2008
• Last Update Posted: Nov 6, 2012
• Last Verified: Oct 1, 2012

• Keywords provided by Robert Block, Principal Investigator, University of Rochester: aspirin; omega 3 fatty acids; Lovaza; myocardial infarction; aspirin resistance; cardiovascular disease
• Additional relevant MeSH terms: Aspirin

Study Results

Participant Flow

Arm/Group Title	Placebo, Lovaza, Aspirin, Both Aspirin and Lovaza	Aspirin, Lovaza, Both Aspirin and Lovaza, Placebo	Lovaza, Both Aspirin and Lovaza, Placebo, Aspirin	Both Aspirin and Lovaza, Placebo, Lovaza, Aspirin
Arm/Group Description	First Placebo, then 4 grams of Lovaza, then 81mg of Aspirin, then both 81mg of Aspirin and 4 grams of Lovaza	First 81mg of Aspirin, then both 81mg of Aspirin and 4 grams of Lovaza, then 4 grams of Lovaza, then 81mg of Aspirin	First 4 grams of Lovaza, then both 81mg of Aspirin and 4 grams of Lovaza, then placebo, then 81 mg of Aspirin	First both 81mg of Aspirin and 4 grams of Lovaza, then placebo, then 4 grams of Lovaza, then 81mg of Aspirin
Period Title: Overall Study
STARTED	7	6	6	8
COMPLETED	7	6	6	6
NOT COMPLETED	0	0	0	2

Baseline Characteristics

Arm/Group Title	Placebo, Lovaza, Aspirin, Both Aspirin and Lovaza	Aspirin, Lovaza, Both Aspirin and Lovaza, Placebo	Lovaza, Both Aspirin and Lovaza, Placebo, Aspirin	Both Aspirin and Lovaza, Placebo, Lovaza, Aspirin	Total
Arm/Group Description	First Placebo, then 4 grams of Lovaza, then 81 mg of aspirin, then both 81mg of Aspirin and 4 grams of Lovaza	First 81mg of Aspirin, then 4 grams of Lovaza, then both 81mg of Aspirin and 4 grams of Lovaza, then placebo	First 4 grams of Lovaza, then both 81mg of Aspirin and 4 grams of Lovaza, then Placebo, then 81mg of Aspirin	First both 81mg of Aspirin and 4 grams of Lovaza, then Placebo, then 4 grams of Lovaza, then 81mg of Aspirin	Total of all reporting groups
Overall Participants	7	6	6	8	27
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	6 100%	6 100%	8 100%	27 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.7 (9.7)	32.9 (11.6)	25.9 (3.4)	29.3 (10.2)	29.3 (9.1)
Sex: Female, Male (Count of Participants)
Female	4 57.1%	3 50%	3 50%	4 50%	14 51.9%
Male	3 42.9%	3 50%	3 50%	4 50%	13 48.1%
Region of Enrollment (participants) [Number]
United States	7 100%	6 100%	6 100%	8 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	the Difference Between the Time to Clot Formation in Seconds at Baseline and After Each Treatment
Description	The PFA-100 test measures platelet function as the time that it takes for a clot to form in a collagen-lined cartridge.
Time Frame	4 hours

Outcome Measure Data

Analysis Population Description

Each participant acted as own control since each received the intervention (placebo, aspirin, lovaza, and both aspirin and lovaza) and had these effects compared to baseline (four hour effect of each intervention).

Arm/Group Title	Placebo	Aspirin	Lovaza	Both Aspirin and Lovaza
Arm/Group Description	All participants received Placebo intervention regardless of sequence.	All participants received Aspirin intervention regardless of sequence.	All participants received Lovaza intervention regardless of sequence.	All participants received Aspirin and Lovaza intervention regardless of sequence.
Measure Participants	25	25	25	25
Mean (Standard Deviation) [seconds]	0.0 (30)	10.9 (50.23)	-6.5 (63.6)	30.5 (60.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	The Wilcoxon Signed-Rank Test was used to determine significant differences between the closure time effect (clotting)in seconds from baseline compared to four hours after placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.00
	Comments	The analyses were not adjusted for multiple comparisons.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aspirin
	Comments	The Wilcoxon Signed-Rank Test was used to determine significant differences between the closure time effect (clotting)in seconds from Aspirin compared to Placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments	The analyses were not adjusted for multiple comparisons.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	12
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lovaza
	Comments	The Wilcoxon Signed-Rank Test was used to determine significant differences between the closure time effect (clotting)in seconds from Lovaza compared to Placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments	The analyses were not adjusted for multiple comparisons.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Both Aspirin and Lovaza
	Comments	The Wilcoxon Signed-Rank Test was used to determine significant differences between the closure time effect (clotting)in seconds from both Aspirin and Lovaza compared to Placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments	The analyses were not adjusted for multiple comparisons.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	30
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Placebo, Lovaza, Aspirin, Both Aspirin and Lovaza		Aspirin, Lovaza, Both Aspirin and Lovaza, Placebo		Lovaza, Both Aspirin and Lovaza, Placebo, Aspirin		Both Aspirin and Lovaza, Placebo, Lovaza, Aspirin
Arm/Group Description	First Placebo, then 4 grams of Lovaza, then 81 mg of aspirin, then both 81mg of Aspirin and 4 grams of Lovaza		First 81mg of Aspirin, then 4 grams of Lovaza, then both 81mg of Aspirin and 4 grams of Lovaza, then placebo		First 4 grams of Lovaza, then both 81mg of Aspirin and 4 grams of Lovaza, then Placebo, then 81mg of Aspirin		First both 81mg of Aspirin and 4 grams of Lovaza, then Placebo, then 4 grams of Lovaza, then 81mg of Aspirin
All Cause Mortality
	Placebo, Lovaza, Aspirin, Both Aspirin and Lovaza		Aspirin, Lovaza, Both Aspirin and Lovaza, Placebo		Lovaza, Both Aspirin and Lovaza, Placebo, Aspirin		Both Aspirin and Lovaza, Placebo, Lovaza, Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo, Lovaza, Aspirin, Both Aspirin and Lovaza		Aspirin, Lovaza, Both Aspirin and Lovaza, Placebo		Lovaza, Both Aspirin and Lovaza, Placebo, Aspirin		Both Aspirin and Lovaza, Placebo, Lovaza, Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Placebo, Lovaza, Aspirin, Both Aspirin and Lovaza		Aspirin, Lovaza, Both Aspirin and Lovaza, Placebo		Lovaza, Both Aspirin and Lovaza, Placebo, Aspirin		Both Aspirin and Lovaza, Placebo, Lovaza, Aspirin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)		0/6 (0%)		1/6 (16.7%)
Surgical and medical procedures
Headache, nausea, lightheadness	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

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.