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Diet Still Saves Lives, Even When Risk Well-Managed with Drugs

Michael R

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It's becoming increasingly difficult to prove that new cardiovascular therapies are effective, in part because it's become widely accepted that it isn't ethical to enroll people in clinical trials and deny them access to proven therapies to test an unproven one. So all participants in modern trials have their risk factors "optimally managed" with drugs: those with high cholesterol get statins, and those with high BP get thiazides and other BP meds, most will get daily aspirin, and so on. This has the potential to have the perverse effect, in some cases, of making a drug or other therapy that might, on its own, be very protective against cardiovascular events appear to be inefffective, because risk is already so low and some of the mechanisms by which the new drug might act are already brought to very safe level. This would be fine, except that the potential is that a new drug with fewer side effects or even better long-term effects, or that works better for a small subset of patients, never gets a chance to prove itself. There are several cases where it appears possible that this has occurred.
One such case is omega-3 fatty acids. A clinical trial of omega-3 fatty acids in post-MI patients with multiple CVD risk factors all intended to be optimally managed with drugs found no effect of either EPA+DHA or ALA or both in the study population as a whole(2) — but did appear to show a quite substantial effect in a post hoc analysis of the 9% of patients in the trial who were consistent non-users of statins:

Among the statin users 49 (13% [of all such patients]) and among the statin non-users 62 (15%) developed a major cardiovascular event. In statin users, an additional amount of n-3 fatty acids did not reduce cardiovascular events [hradj 1.02; 95% confidence interval (CI): 0.80, 1.31; P = 0.88]. In statin non-users, however, only 9% of those who received EPA–DHA plus ALA experienced an event compared with 18% in the placebo group (HRadj 0.46; 95% CI: 0.21, 1.01; P = 0.051).(3)

Eating well contributes to some of these redundant pathways. Yet a recent prospective analysis of patiaents enrolled in the same trial, eating well managed to very substantially cut mortality across the board:

Almost all patients received drug treatment: 86% used statins, 90% used antihypertensive medication, and 98% used antithrombotic medication. ... The median time after myocardial infarction at baseline was 3.7 y (IQR: 1.7-6.3 y). During a median of 6.5 y of follow-up (IQR: 5.3-7.6 y) [so, for a total of ≈10 y after their original heart attack], 801 patients died; 342 of those died of CVD. One patient was lost to follow-up. A substantially higher average amount of [ Dutch Healthy Nutrient and Food Score (DHNaFS)] foods (∼1750 g/d) than [Dutch Undesirable Nutrient and Food Score (DUNaFS)] foods (∼650 g/d) was consumed [overall]. ...

Patients in the fifth quintile of the DHNaFS had a 30% (HR: 0.70; 95% CI: 0.55, 0.91) lower CVD risk and a 32% (HR: 0.68; 95% CI: 0.47, 0.99) lower all-cause mortality risk than did patients in the first quintile. The DUNaFS was unrelated to both CVD and all-cause mortality.(1)

1: Sijtsma FP, Soedamah-Muthu SS, de Goede J, Oude Griep LM, Geleijnse JM, Giltay EJ, de Boer MJ, Jacobs DR Jr, Kromhout D. Healthy eating and lower mortality risk in a large cohort of cardiac patients who received state-of-the-art drug treatment. Am J Clin Nutr. 2015 Oct 21. pii: ajcn112276. [Epub ahead of print] PubMed PMID: 26490494.[/size]
2: Risk and Prevention Study Collaborative Group, Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, Marchioli R. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013 May 9;368(19):1800-8. doi: 10.1056/NEJMoa1205409. Erratum in: N Engl J Med. 2013 May 30;368(22):2146. PubMed PMID: 23656645.[/size]
3: Eussen SR, Geleijnse JM, Giltay EJ, Rompelberg CJ, Klungel OH, Kromhout D. Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction. Eur Heart J. 2012 Jul;33(13):1582-8. doi: 10.1093/eurheartj/ehr499. Epub 2012 Feb 1. PubMed PMID: 22301766; PubMed Central PMCID: PMC3388014.[/size]

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Thanks so much. My (non-CR) wife has borderline high cholesterol (genetics...) and I've been debating whether to recommend she take an Omega-3 supplement. I know this is not directly applicable, since it was a secondary prevention trial. Nevertheless the idea you present that other treatments may mask the effective of things like Omega-3's pushes me in the direction of yes (she doesn't take a statin).


Thanks as always,



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