Original Research

Comparison of Cardiovascular Outcomes Between Statin Monotherapy and Fish Oil and Statin Combination Therapy in a Veteran Population

A study that compared the use of statin therapies with and without fish oil in a veteran population found an insignificant difference between the 2 arms.

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The Centers for Disease Control and Prevention lists cardiovascular-related diseases as a leading cause of mortality.1 The medication class of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, more commonly known as statins, is first-line therapy to prevent negative cardiovascular outcomes and reduce premature death.2 Additional hyperlipidemia medications, such as fish oil, can be added for potential cardiovascular benefit.

Yokoyama and colleagues demonstrated that fish oil is a promising treatment for the prevention of major coronary events in patients with hypercholesterolemia.3 Furthermore, Macchia and colleagues found reductions in cardiovascular outcomes and all-cause mortality in postmyocardial infarction patients treated with fish oil and statin combination therapy.4 In contrast, the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial found glucose intolerant and patients with diabetes mellitus did not have improved cardiovascular outcomes with fish oil therapy.5 Likewise The Risk and Prevention Study Collaborative Group found fish oil supplementation provided no benefit for primary prevention in patients with multiple cardiovascular risk factors.6 These studies demonstrate fish oil therapy can cause diverse cardiovascular outcomes in different patient populations.

Currently, there are no studies examining the impact of fish oil and statin combination therapy on the US veteran population. The research of Yokoyama, Macchia, and The Risk and Prevention Study Collaborative Group took place in Japanese and Italian populations, which impacts their external validity.3,4,6 Furthermore, these studies had higher rates of female subjects when compared with the US veteran population. For example, 68% of female subjects in the Yokoyama study received fish oil therapy.3 Also, the ORIGIN trial subjects were restricted to patients with diabetes mellitus or who were glucose intolerant, which is not reflective of the entire veteran population.5 These differences can make it difficult to define the role of fish oil and statin combination therapy in treating cardiovascular disease and reducing mortality in the veteran population.

This study aims to help the US Department of Veterans Affairs (VA) primary care providers and clinical pharmacists address the role of fish oil and statin combination therapy in the prevention of cardiovascular disease and all-cause mortality in the veteran population. The addition of fish oil to statin therapy was compared with an established standard of care, statin monotherapy, in veterans at the Fargo Veterans Affairs Health Care System (FVAHCS).


A retrospective chart review was conducted using the FVAHCS Computerized Patient Record System (CPRS). The institution’s review board and VA medical center approved the study. Eligible veterans with prescriptions for fish oil or statin therapy between January 1, 2000 and September 30, 2015 were randomly selected, reviewed, and sorted based on inclusion and exclusion criteria.

These veterans were either placed in the fish oil and statin combination cohort or statin monotherapy cohort. Inclusion criteria required at least 1 year of statin monotherapy for inclusion in the statin cohort or at least 1 year duration of fish oil and statin combination therapy for inclusion in the fish oil and statin combination cohort (Table 1). The exclusion criteria are described in Table 2.

The primary outcome was time to aggregate cardiovascular events, specifically myocardial infarction (MI), stroke, transient ischemic attack, coronary artery bypass graft, and percutaneous intervention. Adverse cardiovascular event data were obtained from the veterans’ International Classification of Disease (ICD) 9 codes. Furthermore, the secondary outcome—time to all-cause mortality—was gathered by death records in CPRS. Time to these events was compared in veterans on fish oil and statin combination therapy or statin monotherapy. The date of the cardiovascular event or death was recorded for each outcome and was obtained by reviewing provider notes that documented the incidence. If a specific day or month of incidence was not documented, July 1 was selected as the default date for the adverse cardiovascular event.

Demographics, medication adherence, diagnoses, lab values within 90 days of initiation of therapy, and primary and secondary outcomes were collected. Demographics that included age, race, and sex all were obtained via chart review. Diagnoses were gathered using ICD 9 codes. Refill history was retrieved to assess adherence. Adherence was calculated by the total days of medication therapy divided by the total days within the study. Total days in the study was calculated by the duration of therapy days between therapy initiation date and a terminating factor. Terminating factors included an adverse cardiovascular event, death, or the study termination date.


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