Christopher Paul Mckneely2014 Doctor of Pharmacy Candidate

Preceptor: Dr. Ali Rahimi

n-3 Fatty Acids in Patients with Multiple Cardiovascular Risk

Factors

Background

n-3 derived fatty acid from fish (EPA/DHA) reduce the risk of cardiovascular disease by means of positive events on arrhythmic, atherosclerotic, inflammatory, and thrombotic processes.Reduction in cardiovascular morbidity and

mortality has been well documented in post-MI patients and heart failure patients.2

This study looked into patients who had NO history of MI

MethodologyRisk and Prevention study

ongoing large-scale, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted in the setting of Italian general practice1

860 General Practitioners

Steering Committee2

Planning and coordinatingAnalyzing and interpretingPrepared the manuscript – submitted for publication

Baseline Characteristics of the patientsX2 for categorical variablesT-test or nonparametric test for continuous dataANOVA used for comparison of multiple groups

BP, glucose, lipids, etc.

Methodology continuedStudy participants2

Men and women who met the inclusion criteriaMultiple cardiovascular risk factorsClinical evidence of atherosclerotic vascular

diseaseExclusion criteria

Previous MI, hypersensitivity to treatment, pregnancy, clinical conditions with poor short term prognosis or they can not give informed consent

11,200 participantsPower of 90%Alpha level of 0.05Would give 1383 events based off of primary

end point – continued until all prescribers could recruit

Methodology continued2

Study ProcedureAssigned to receive 1g of the fatty acids daily (content

not <85%) or placebo (olive oil)12,513 patients total

6239 in treatment group 6266 in control or olive oil placebo group

Essential elements collected at baseline and at the patients yearly follow-upAnthropometric, vitals, lifestyle habits, any new

cardiovascular diagnosis, compliance and if the patient stopped the treatment for any reason

End pointsPrimary (expected to be 2%/year)

Rate of death, non-fatal MI/stroke After one year (due to event rate lower than expected)

Composite of time to death from cardiovascular causes or hospitalizations due to cardiovascular causes

Secondary Original primary end point

Statistics2

Intent to treat population for primary end point1478 patients experienced the primary end point

733 in treatment group (fatty acids)745 in placebo (olive oil)Hazard ratio of 0.97, CI 95%, odds ratio 0.88-1.08,

P=0.58Relative Risk Reduction of 15% stated (assumed)

Calculated (first relative risk) RR = (a/(a+b))/(c/(c+d)) 0.98 RRR = 1-RR or 1-.9837 .016

ARRPrimary end point was met in 11.7% of pts on fatty acids

and 11.9% who received placebo 733 of 6239 in treatment had primary end point 745 of 6266 in the placebo group had the primary end point

Calculated CER- EER or 11.9%-11.7% -- 0.2%

NNT/NNH1/ARR = 500 NNT

Statistics2

Per protocolProtocol was for those who did

NOT stop the treatment regimen 1115 pts stopped treatment in

the fatty acid arm 1218 pts stopped treatment in

the placebo arm 10,172 remained were treated as

per protocol 527 in treatment group

experienced primary end point (10.3%)

510 in placebo group experienced primary end point (10.1%)

Hazard ratio 1.01, Ci 95%, odds ratio 0.89-1.14, P=0.89

Missing data for 22 patients was noted

Statistics2

Cox proportional-hazard models used to analyze the treatment effect study end points2

The Take Home Point2

Discussion

Randomized trial of n-3 fatty acids in a large population of patients with multiple cardiovascular risk factors

Patients had NO history of myocardial infarction

On the basis of the results…Conclude that there was no significant

benefit of n-3 fatty acids in reducing risk of death from cardiovascular causes or hospital admissions for cardiovascular causes

Recommendation3

Dietary recommendation for a specific amount of n-3 fatty acids is not being made

In the view of the ATP III panel, more definitive clinical trials are required before relatively high intakes of n-3 fatty acids (1–2 g/day) can be strongly recommended for either primary or secondary prevention.

References1. Rischio and Prevenzione Investigators. Efficacy of n-3

polyunsaturated fatty acids and feasibility of optimizing preventive strategies in patients at high cardiovascular risk: rationale, design and baseline characteristics of the Rischio and Prevenzione study, a large randomised trial in general practice. Trials. 2010; 11:68. doi: 10.1186/1745-6215-11-68. Accessed May 23, 2013.

2. The Risk and Prevention Study Collaborative Group. n-3 Fatty acids in Patients with Multiple Cardiovascular Risk Factors. NEJM. 2013;368:1800-1808.

3. National Cholesterol Education Program Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143–421.