Pharmacy & Therapeutics - May 2008 - (Page 273) DRUG FORECAST Table 1 Pivotal Studies of Omega-3-Acid Ethyl Esters (Lovaza) For the Treatment of Very High Triglyceride Levels Study 1 (Harris) No. of patients Inclusion criteria Treatment Duration Results Total cholesterol Triglycerides LDL-C HDL-C 42 TG 500–2,000 mg/dL Esters 4 g daily or corn oil placebo 16 weeks Change from baseline results of Esters/placebo Study 2 (Pownall) 40 TG 500–2,000 mg/dL Esters 4 g daily or corn oil placebo 6 weeks Change from baseline results of Esters/placebo significant finding was mostly a result of inclusion of one large study that showed an increase in mortality with omega-3 fatty acid supplementation.37 In the third meta-analysis, Hooper et al. noted a risk ratio of 0.8 (95% CI, 0.7–0.9) for overall mortality.38 Limitations to the trials in these metaanalyses included, but were not limited to, variations in sample size (leading to differences in effect size) and variations in fish oil intake.36–38 In interpreting the findings of these studies, it seems likely that the benefits of fish oil for CHD were multifactorial and were not caused by lowering of TG alone. Several large-scale trials are now ongoing, with thousands of patients in each trial, to evaluate the effect of omega-3 fatty acids on the risk of CVD.39 ↓15% / ↓2% ↓45% / ↑15% ↑31% / ↓5% ↑13% / 0% ↓10% / 0% ↓39% / ↑8% ↑17% / ↓4% ↑6% / ↓6% LDL-C = low-density lipoprotein-cholesterol; HDL-C = high-density lipoproteincholesterol; TG = triglyceride. Data from Harris et al. J Cardiovasc Risk 1997;4:385–391;20 and Pownall HJ, et al. Atherosclerosis 1999;143:285–297.21 WARNINGS AND ADVERSE EFFECTS Patients with a known sensitivity or an allergy to fish should use Lovaza with caution. This product was associated with a low frequency of side effects that led to discontinuation of therapy during trials (3.5% vs. 2.6% with placebo, respectively). Adverse effects that were reported more frequently with Lovaza versus placebo included er uctation (belching, 4.9% vs. 2.2%), infection (4.4% vs. 2.2%), taste perversion (fishy taste, 2.7% vs. 0%), and rash (1.8% vs. 0.4%). Some patients experienced elevated alanine aminotransferase (ALT) levels; therefore, liver enzymes should be monitored periodically.8–10 Unlike niacin and fibric acids, Lovaza has not been found to increase the risk of rhabdomyolysis when combined with a statin.8–10 Studies with larger numbers of participants taking the combination are needed to assess this risk. McKenney et al. found that administering simvastatin and Lovaza together did not appear to affect the pharmacokinetics of simvastatin tablets.40 Some studies have shown a prolonged bleeding time with omega-3 fatty acids but no resulting bleeding episodes of clinical significance. In animal studies, omega-3 fatty acids decreased the level of vitamin K–dependent clotting factors and reduced platelet arachidonic acid and thromboxane A2 levels. Clinical studies have not been conducted to thoroughly examine the effect of combining Lovaza and anticoagulants.8–10 continued on page 280 Vol. 33 No. 5 • May 2008 • Blood Pressure Lovaza was compared with placebo for its effects on blood pressure (BP) in three studies. In a study of 57 patients, Grundt et al. noted that giving omega-3acid ethyl esters resulted in a reduction of 8 mm Hg in systolic BP and a reduction of 4 mm Hg in diastolic BP.28 Lungerhausen et al. included 43 hypertensive patients who were taking diuretics, beta blockers, or both. The study drug decreased systolic BP by 3.1 mm Hg and diastolic BP by 1.8 mm Hg.29 Russo et al. found that the study drug had no effect on lowering BP or heart rate.30 C-reactive Protein Chan et al. compared the effects of Lovaza 4 g daily and atorvastatin (Lipitor, Pfizer) 40 mg daily for six weeks on highsensitivity C-reactive protein (hs-CRP) levels in 48 men.31 Ator vastatin significantly reduced hs-CRP levels, whereas Lovaza had no effect. patients who had had an acute myocardial infarction (AMI) within eight days of study entry.32 The results showed a significant benefit on lipids but no difference in the rate of cardiac events. In a study by Eritsland et al., Lovaza reduced the incidence of vein graft occlusion in patients admitted to the hospital for coronary artery bypass graft.33 Johansen et al. noted that Lovaza did not lower the incidence of restenosis in patients undergoing elective coronary angioplasty.34 GISSI–Prevenzione (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico) was a randomized, open label, placebo-controlled study that included 11,324 patients who had an AMI within three months prior to enrollment in the study. Omega-3 fatty acids 1 g daily for approximately 3.5 years significantly improved survival in post-MI patients.35 Mortality Rates The effect of omega-3 fatty acids on mortality have been assessed in three published meta-analyses. Bucher et al. noted a risk ratio of 0.77 (95% confidence interval [CI], 0.63–0.94) for overall mortality with omega-3 fatty acids.36 Studer et al. found a relative risk of 0.87 (95% CI, 0.73–1.03) for patients randomly assigned to receive omega-3 fatty acids. The authors stated that the non- Other Clinical Endpoints Trials that evaluated the effects of Lovaza on clinical endpoints have also been published. Nilson et al. performed a randomized, double-blind, placebocontrolled trial to determine the effects of the study drug at a dose of 4 g daily on cardiac events and serum lipids in those P&T® 273
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