Reanalysis of Gissi-Prevenzione Demonstrates Antiarrhythmic Effect
When the Grupo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico prevensione (GISSI-Prevensione) trial was first analyzed, it appeared evident that increased intake (1 gram per day) of n-3 polyunsaturated fatty acids (PUFA) reduced overall and cardiovascular mortality without affecting the risk of nonfatal coronary events. In this week’s issue of Circulation (Circulation. 2002;105:1897–1903), researchers involved in the study, led by Roberto Marchioli, MD, reanalyzed the data based on the time-course of the effects of the n-3 PUFA in the large study.
In the study, 11 232 patients were assigned to receive supplements of either n-3 PUFA, vitamin E (300 mg daily), both, or no treatment, in addition to optimal drug treatment and lifestyle advice. The efficacy of the n-3 PUFA treatment for total, cardiovascular, cardiac, coronary and sudden death, nonfatal myocardial infarction, total coronary heart disease, and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month, after randomization up to 12 months.
Marchioli et al found that the survival curves for the n-3 PUFA treatment diverged early after the patients were randomized, and that total mortality was significantly lower after 3 months of treatment. At 4 months, the reduction in the risk of sudden death was specifically relevant and statistically significant. A similar pattern was seen for cardiovascular, cardiac, and coronary deaths.
From this, the researchers surmised that the early effect of the n-3 PUFA treatment on both total mortality and sudden cardiac death meant that the treatment had an antiarrhythmic effect, a result that goes along with the evidence from laboratory experiments on isolated myocytes, animal models, and epidemiological studies.
In an accompanying editorial in this issue of Circulation (Circulation. 2002;105:1874–1875), Alexander Leaf, MD, of the Department of Medicine at Massachusetts General Hospital and Harvard Medical School in Boston, wrote that the new analysis of the study “increases the importance of this large, well conducted clinical trial.”
He points out that the most common sources of n-3 fatty acids are sea fish, but the effect of the acids “stem the ability of single-cell phytoplankton and algae to convert the parent of n-6 fatty acid, linoleic acid, to the parent n-3 fatty acid, α-linoleic acid, which enters the food chain of marine life and is further elongated and desaturated to produce the fish oil fatty acids epicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).” According to Dr Leaf, constant fishing is depleting the ocean and raising the prices of those marine vertebrates that are caught. “One may ask where the dietary n-3 PUFA will come from in the future,” he wrote. A recent discovery by one of his colleagues, Jing X. Kang, MD, PhD, may provide the answer in a finding from the lowly roundworm, C elegans(Proc Natl Acad Sci U S A. 2001;98: 4050–4054).
The cDNA encoding of an n-3 fatty acid desaturase, when transfected into cultured mammalian cardiomyocytes, allowed the cells to change n-6 fatty acids to the corresponding n-3 PUFA. “This discovery raises the potential of transfecting the cells of animals, fowl, and of edible plants with the cDNA of the roundworm n-3 fatty acid desaturase to convert their content of n-6 PUFA to n-3 PUFA,” he wrote. A brave new world, indeed.
Antianginal Drug Might Also Ward Off Cardiovascular Disease
The drug nicorandil, used primarily for its antianginal effects, might also have cardioprotective effects, according to researchers for the Impact of Nicorandil in Angina (IONA) Study Group, in a report in the April 13, 2002, issue of The Lancet (Lancet. 2002;359:1269–1275).
In their study, 5126 patients with a high risk of coronary events were randomly assigned to 20 mg of nicorandil or placebo, in addition to standard antianginal therapy. Patients were monitored for between 1 and 6 years. In the follow-up period, 16% of the patients on nicorandil and 13% on placebo died of coronary heart disease, had a nonfatal myocardial infarction, or were admitted to the hospital for cardiac chest pain. The researchers concluded, “We showed a significant reduction in major coronary events by antianginal therapy with nicorandil in patients with stable angina.” The difference between the groups was statistically significant (P=0.014).
In an accompanying editorial, Edward Lesnefsky, MD, from the Louis Stokes Veterans Affairs Medical Center in Cleveland, Ohio, said, “The results of IONA provide strong evidence that the cellular effectors of ischemic preconditioning will continue to emerge as key therapeutic targets in the development of strategies to manage ischemic heart disease” (Lancet. 2002;359:1262).
PCI Wins Over Thrombolytics
Percutaneous intervention (PCI) was more beneficial than accelerated administration of the thrombolytic tissue plasminogen activator (tPA) when the two treatments were compared in hospitals that lacked cardiac surgery programs, according to a report by researchers involved in the Atlantic Cardiovascular Patient Outcomes Research Team (C-PORT) in the April 17, 2002, issue of the Journal of the American Medical Association (JAMA. 2002;287:1948–1951). The study, performed in 11 community hospitals in Maryland and Massachusetts, randomized 451 thrombolytic-eligible patients with acute myocardial infarction of <12 hours’ duration to either primary PCI or to accelerated treatment with tPA (bolus dose of 15 mg and an infusion of 0.75 mg/kg for 30 minutes, followed by 0.5 mg/kg for 60 minutes).
At 6 weeks after treatment, 10.7% of patients who had received PCI experienced death, recurrent heart attack, or stroke, compared with 17.7% in the thrombolytic group. At 6 months, 12.4% of patients in the PCI group had reached one of the primary end points, compared with 19.9% of those in the thrombolytic group.
The researchers concluded that, “primary PCI is superior to accelerated thrombolytic therapy for treatment of acute MI in the community hospital setting, and that superiority is sustained for at least 6 months after the index MI.” They noted, however, that a formal development program for PCI is crucial to ensuring beneficial outcomes for patients treated in the community institutions.
In an accompanying editorial, Christopher P. Cannon, MD, of the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School in Boston, wrote, “The time is now to reevaluate the optimal approach to treating patients with acute MI, with an interventional approach appearing to be the optimal strategy. The task for cardiologists and other physicians is to make the best possible therapy available to every patient with acute MI” (JAMA. 2002;287:1987–1989).