Allerg Immunol (Paris). 2000 Sep;32(7):272-8.

Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol).

  Cardiovascular Risks of Nonsteroidal Antiinflammatory Drugs in Patients After Hospitalization for Serious Coronary Heart Disease Circulation: Cardiovascular Quality and Outcomes. 2009;2:155-163

Wayne A. Ray, PhD; Cristina Varas-Lorenzo, MD, MSc, PhD; Cecilia P. Chung, MD, MPH; Jordi Castellsague, MD, MPH; Katherine T. Murray, MD; C. Michael Stein, MB, ChB; James R. Daugherty, MS; Patrick G. Arbogast, PhD and Luis A. García-Rodríguez, MD, MSc
There is growing evidence that the relationship between nonaspirin NSAIDs and cardiovascular disease is more complex than initially thought. Some of the early studies analyzed the NSAIDs as a single group,³⁵ tacitly assuming that a class effect was an important factor in determining their cardiovascular safety. This perspective changed with the introduction of the coxibs. However, even within groups of NSAIDs defined by relative COX2 selectivity, studies of both mechanisms³⁶ and clinical outcomes^5–7 are inconsistent with a uniform class effect. Both individual drug and dose are likely to be important factors in defining cardiovascular safety.

The question of which NSAID has the best cardiovascular safety profile is particularly important for patients with existing cardiovascular disease, for whom data from lower risk populations cannot necessarily be extrapolated. First, these patients have a greater baseline absolute risk and thus small differences in relative risk may be important. Second, approximately 90% of such patients take low dose aspirin,^37,38 which may interact with the NSAID. Third, either recent episodes of acute disease (eg, myocardial infarction) or disease treatment (eg, percutaneous interventions) may alter the cardiac safety of NSAIDs.

We thus studied the cardiovascular safety of individual NSAIDs in nearly 50000 patients with a recent hospitalization for serious coronary heart disease. Cardiovascular safety was best for naproxen. Relative to nonusers of any NSAIDs, current users of naproxen had IRRs of 0.88 (0.66 to 1.17) for serious coronary heart disease and 0.91 (0.78 to 1.06) for the composite end point of myocardial infarction, stroke, or death from any cause. There was no evidence of increased risk for naproxen in higher doses (1000 mg/d), with use of short duration, after the exclusion of prevalent users or among patients in the upper tertile for baseline cardiovascular risk.

In contrast, there was evidence that cardiovascular risk was increased for users of the other study NSAIDs. Relative to naproxen users, those of diclofenac VOLTAREN, which is widely used outside of the United States and has been the reference drug in several coxib outcome trials,^39,40 had 50% increased risk of the composite end point of myocardial infarction, stroke, or death from any cause. The increased risk was present for low/moderate doses (<150 mg/d). Ibuprofen users had 25% increased risk for this end point. When compared to high-dose naproxen use, users of higher doses of celecoxib (>200 mg/d) and rofecoxib (>25 mg/d) had increased risk of serious coronary heart disease.

Current users of diclofenac, ibuprofen, celecoxib and rofecoxib with less than 90 days cumulative duration had increased rates of serious coronary heart disease. This is in contrast to a widely publicized posthoc analysis of the APPROVe trial data, interpreted by some as suggesting no risk for use of less than 18 months duration.^  However, observational studies of rofecoxib have reported increased risk within the first month of therapy,⁷ and in the VICTOR trial rofecoxib patients had increased risk after a mean duration of 7.4 months. Thus, our findings add to the evidence that at least one of the mechanisms for increased cardiovascular risk is acute.

These findings are generally consistent with previous studies, most of which were not restricted to patients with serious coronary heart disease. Placebo-controlled clinical trials have demonstrated increased risk of serious cardiovascular disease for rofecoxib^1,7 and celecoxib in daily doses 400 mg or greater.^2,41 Meta-analyses of both clinical trials⁵ and observational studies^6,7 suggest that naproxen does not increase cardiovascular risk, whereas diclofenac is consistently associated with increased risk in the observational studies. Ibuprofen has been associated with a trend of increased risk in the meta-analyses at doses above 1800 mg daily^5–7 and with increased risk of death in recently hospitalized cardiovascular patients taking low-dose aspirin.⁴² In a case-crossover analysis of patients recently discharged with myocardial infarction, Gislason et al reported increased risk of reinfarction or death for diclofenac, rofecoxib, celecoxib, and ibuprofen in doses >1200 mg/d.⁴³

A key study limitation was that follow-up began 45 days after the qualifying hospitalization admission for coronary heart disease. This was done because study databases identified medication use from filled outpatient prescriptions and lacked information on medications given in the hospital. For this reason, medication information was likely to be incomplete until patients filled/refilled prescriptions after hospital discharge (up to 34 days for the study sites). Thus, our findings cannot be generalized to the early postdischarge period, during which NSAID use may be particularly hazardous.³

Another study limitation was potentially incomplete information for several relevant variables. Although an extensive set of prognostic factors was identified from records of medical care encounters in the study databases, some important covariates (eg, left ventricular ejection fraction) were not directly available (eg, available were diagnosed/treated heart failure). NSAID exposure would be misclassified for patients who self-paid for prescriptions not authorized by their health plan as well as for those with over-the-counter use. This type of misclassification would affect cohort members classified as nonusers of NSAIDs (which would include persons with self-pay/OTC NSAID use) and could thus bias to the null. For similar reasons, misclassification of low-dose aspirin use also is likely for the North American sites, although the practical effect of such misclassification should be limited given that an estimated 90% of the cohort will be using low-dose aspirin.^37,38 Hence, the comparisons with naproxen are important, as these misclassification effects should be reduced for between-NSAID comparisons.

Despite the use of data from 3 large health plans in 3 countries, sample size was limited for several comparisons. Thus, there was insufficient data for robust analysis of the less frequently used NSAIDs and power was reduced for subgroup analyses. There was substantial variation among the study sites in the patterns of use of individual NSAIDs. Naproxen and ibuprofen use came predominantly from a US low-income population and diclofenac use from Canada and the United Kingdom. Although there was no statistical evidence of effect heterogeneity across the sites (with the exception of rofecoxib), study of other populations, including more representative U.S. populations, is needed.

In conclusion, our study provides information on the cardiovascular safety of individual NSAIDs in patients recently hospitalized for serious coronary heart disease. The data suggest that in this population naproxen had better cardiovascular safety than diclofenac, ibuprofen, rofecoxib in doses >25 mg/d, and celecoxib in doses >200 mg/d.

  LYPRINOL

Allerg Immunol (Paris). 2000 Sep;32(7):272-8.

Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol).

Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol).

Halpern GM.

University of California, USA.

A lipid-rich extract, prepared by supercritical fluid (CO2) extraction of freeze-dried stabilized NZ green-lipped mussel powder (Lyprinol) has shown significant anti-inflammatory (AI) activity when given to animals and humans. When treated p.o. with Lyprinol, Wistar and Dark Agouti rats developed neither adjuvant-induced polyarthritis or collagen(II)-induced auto-allergic arthritis. This was achieved with doses < NSAIDs, and 200 times < of other seed or fish oils. Lyprinol subfractions inhibited LTB4 biosynthesis by PMN in vitro, and PGE2 production by activated macrophages. Much of this AI activity was associated with omega-3 PUFAs and natural antioxidants [e.g. carotenoids]. In contrast to NSAIDs, Lyprinol is non-gastro toxic in disease-stressed rats at 300 mg/kg p.o., and does not affect platelet aggregation [human, rat]. Clinical studies, either controlled or randomized, have demonstrated very significant AI activity in patients with osteoarthritis (OA), rheumatoid arthritis (RA), asthma, and other inflammatory conditions. Lyprinol is a reproducible, stable source of bioactive lipids with much greater potency than plant/marine oils currently used as nutritional supplements to ameliorate signs of inflammation.