- Christopher E Ramsden, clinical investigator12,
- Daisy Zamora, epidemiologist2,
- Boonseng Leelarthaepin, retired, original study investigator3,
- Sharon F Majchrzak-Hong, research chemist1,
- Keturah R Faurot, epidemiology doctoral candidate2,
- Chirayath M Suchindran, senior biostatistician4,
- Amit Ringel, guest researcher1,
- John M Davis, professor5,
- Joseph R Hibbeln, senior clinical investigator1
- 1Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
- 2Department of Physical Medicine and Rehabilitation, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- 3University of New South Wales, Sydney, Australia
- 4Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA
- 5Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
- Correspondence to: C E Ramsden
- Accepted 14 December 2012
Objective To evaluate the effectiveness of replacing dietary saturated fat with omega 6 linoleic acid, for the secondary prevention of coronary heart disease and death.
Design Evaluation of recovered data from the Sydney Diet Heart Study, a single blinded, parallel group, randomized controlled trial conducted in 1966-73; and an updated meta-analysis including these previously missing data.
Setting Ambulatory, coronary care clinic in Sydney, Australia.
Participants 458 men aged 30-59 years with a recent coronary event.
Interventions Replacement of dietary saturated fats (from animal fats, common margarines, and shortenings) with omega 6 linoleic acid (from safflower oil and safflower oil polyunsaturated margarine). Controls received no specific dietary instruction or study foods. All non-dietary aspects were designed to be equivalent in both groups.
Outcome measures All cause mortality (primary outcome), cardiovascular mortality, and mortality from coronary heart disease (secondary outcomes). We used an intention to treat, survival analysis approach to compare mortality outcomes by group.
Results The intervention group (n=221) had higher rates of death than controls (n=237) (all cause 17.6% v 11.8%, hazard ratio 1.62 (95% confidence interval 1.00 to 2.64), P=0.05; cardiovascular disease 17.2% v 11.0%, 1.70 (1.03 to 2.80), P=0.04; coronary heart disease 16.3% v 10.1%, 1.74 (1.04 to 2.92), P=0.04). Inclusion of these recovered data in an updated meta-analysis of linoleic acid intervention trials showed non-significant trends toward increased risks of death from coronary heart disease (hazard ratio 1.33 (0.99 to 1.79); P=0.06) and cardiovascular disease (1.27 (0.98 to 1.65); P=0.07).
Conclusions Advice to substitute polyunsaturated fats for saturated fats is a key component of worldwide dietary guidelines for coronary heart disease risk reduction. However, clinical benefits of the most abundant polyunsaturated fatty acid, omega 6 linoleic acid, have not been established. In this cohort, substituting dietary linoleic acid in place of saturated fats increased the rates of death from all causes, coronary heart disease, and cardiovascular disease. An updated meta-analysis of linoleic acid intervention trials showed no evidence of cardiovascular benefit. These findings could have important implications for worldwide dietary advice to substitute omega 6 linoleic acid, or polyunsaturated fats in general, for saturated fats.
Trial registration Clinical trials NCT01621087.
We thank the original SDHS team of researchers for their contributions: Ralph Blacket (principal investigator), Joan Woodhill (coprincipal investigator, lead dietitian), Jean Palmer (coinvestigator), Charles McGilchrist (statistician), Lear Bernstein (senior dietitian), and Janet Aitken (lipid laboratory); the physicians affiliated with the University of New South Wales teaching hospitals for their contributions and referral of participants; all the patients who participated in the study; John Svee (Data Conversion Resource, Westminster, CO, USA), and Steve Morgan and John Glauvitz (Data Recovery Systems, Morgan Hill, CA, USA) for providing technical expertise in data recovery and conversion; Toni Calzone for advice regarding recovery of magnetic tape data; Paul Blacket for efforts searching for study data; and Natalie Kress, Michael Donovan, Jie Qu, and Katherine Ness for proofreading the manuscript.
Contributors: CER designed and directed the project; located, managed, and validated the recovered data; developed the proposed mechanistic model; and was the main writer of the manuscript. BL was an investigator in the original trial, provided the nine track magnetic tape, verified the study methodology and ethical considerations, confirmed validity of recovered data, and revised the manuscript. SFMH performed the literature review, managed and validated recovered data, and assisted in writing and revising the manuscript. John Svee of the Data Conversion Resource completed the data recovery and conversion to modern spreadsheet format, in collaboration with CER and SFMH. DZ conducted the statistical analyses of the main trial, and KRF conducted the meta-analyses, in collaboration with SFMH, CER, JMD, and CMS. JMD, DZ, KRF, and CMS revised the manuscript. AR prepared the illustration of the proposed model and revised the manuscript. JRH directed the project and critically revised the manuscript. All authors contributed to analyses or interpretation of results and to the intellectual content of the manuscript. CER is the guarantor.
Funding: The Life Insurance Medical Research Fund of Australia and New Zealand provided a grant in support of this the SDHS. The Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, supported data recovery and evaluation. The funding source had no role in study design, data collection, analysis, interpretation, or writing of the report.
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: support from the Life Insurance Medical Research Fund of Australia and New Zealand and the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: The SDHS study protocol and patient consent forms were approved by the Dean of the Faculty of Medicine, University of New South Wales, Sydney, Australia. Medical research and clinical practice procedures were carried out according to the June 1964 World Medical Association Declaration of Helsinki and the Australian National Health and Medical Research Council guidelines, which provided the most current ethical principles for medical research involving humans. Patients provided consent to participate without coercion, and were free to refuse participation or withdraw at any time. The Office of Human Research Protection for the National Institutes of Health reviewed these conditions and determined that these de-identified data were suitable for the current analyses (exemption no 5744).
Data sharing: The dataset is available from the corresponding author at. Data sharing consent was not obtained, but the presented data are anonymised and risk of identification is low.
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