Statin alternatives or just placebo

Chin Med J 2008;121(16):1588-1594 Review article

Statin alternatives or just placebo: an objective review of omega-3,
red yeast rice and garlic in cardiovascular therapeutics

Hean Teik Ong and Jin Seng Cheah
Keywords: statin; omega-3, red yeast rice; garlic; cardiovascular therapeutics

Objective The aim of this review is to objectively access the trial evidence on the role of omega-3, red yeast rice and
garlic in preventing clinical cardiovascular events. Given the large number of clinical trials favoring statin use in
cardiovascular disease, it is important to see if evidence is available for these supplements and whether they could
replace statin therapy.
Data source A PubMed search was conducted using the keywords ‘trial, omega-3, red yeast rice, xuezhikang, garlic,
cholesterol, cardiovascular, outcomes'; the resulting trials were reviewed together with the references quoted in the
papers obtained.
Study selection The studies selected are prospective, randomized, placebo-controlled studies with predefined clinical
cardiovascular end-points recruiting at least 2000 patients, with a follow-up over 2 years.
Results Modest dose omega-3 fatty acid has been shown in GISSI-P (11 324 patients, follow-up 3.5 years) to produce
a reduction in sudden death of 45%, and in cardiac death of 35%, acting probably via an anti-arrhythmic effect. In JELIS
(18 645 patients, follow-up 4.6 years), high dose omega-3 given to Japanese patients on a high fish diet and already on
statin treatment produced further benefit with a 19% reduction of nonfatal cardiovascular outcomes; fatal cardiac events
are not affected. CCSPS (4870 patients, follow-up 4 years), a secondary prevention trial using xuezhikang, a commercial
red yeast rice preparation, produced a 46% reduction in nonfatal myocardial infarction and coronary death. There has
been no trial to show that garlic reduces clinical cardiovascular outcomes. A rigorous trial with constant assessment of
chemicals in the study material in 192 patients found that over a 6-month follow-up, raw garlic and 2 commercial
preparations do not significantly affect lipid levels.
Conclusions Omega-3 in modest doses reduces cardiac deaths, and in high doses reduces nonfatal cardiovascular
events. Red yeast rice reduces adverse cardiac events to a similar degree as the statins. It is unlikely that garlic is useful
in preventing cardiovascular disease.
Chin Med J 2008;121(16):1588-1594 espite the overwhelming evidence favoring keywords: (1) ‘trial, omega-3, cholesterol, cardiovascular, D prescription drug therapy, the public is keen on outcomes'; (2) "trial, red yeast rice, xuezhikang, herbal and dietary medicine, sales of which in the United cholesterol, cardiovascular, outcomes" and (3) ‘trial, States are estimated at $4 billion annually.1 A telephone garlic, cholesterol, cardiovascular, outcomes'. The results survey in 2002 revealed that 18.8% of 8470 subjects had were supplemented by reviewing references quoted in the used herbal or other natural products in the preceding papers obtained. week.2 Over 20% of adults on prescription medication also use dietary supplements, although most do not report As there have been numerous well conducted large this to their doctors.3 It is thus important that medical clinical statin trials, the studies on supplements should be doctors objectively analyze the evidence on herbal and of equivalent quality in order to be taken seriously. Thus, dietary medicine so that they can confidently guide studies highlighted here are prospective, rigorously patients in its usage. The evidence favoring statin therapy conducted, randomized, placebo-controlled trials with in preventing cardiovascular events is highly convincing, predefined clinical cardiovascular end-points recruiting at with over 200 000 patients randomized in prospective least 2000 patients, with a follow-up over 2 years. It is randomized controlled trials around the world.4,5 To not the intention to perform a meta-analysis by objectively assess the role of dietary products in statistically integrating the trials since to do a post-hoc cardiovascular disease, it is important to seek out similar analysis carries the risk of statistically manufacturing data prospective, randomized, long term trials with clinical when none exist. By objectively reviewing the individual end-points. Omega-3 fatty acids (eicosapentaenoic acid clinical trials with an open mind, this paper seeks to (EPA), docosahexaenoic acid (DHA)), red yeast rice (RYR) and garlic are chosen for this review since they are Consultant Cardiologist, HT Ong Heart Clinic, Penang, Malaysia commercially available as oral supplements and have been promoted for their cardiovascular protective effects. Professor of Medicine, National University of Singapore, Singapore 119074, Singapore (Cheah JS) Correspondence to: Dr. Hean Teik Ong, HT Ong Heart Clinic, A three step PubMed search was conducted using the Penang 10350, Malaysia (Email: htyl@streamyx. com) Chinese Medical Journal 2008; 121(16):1588-1594 derive practical lessons from their results. reduction of the primary end-point of major coronary events (0.81, 0.69–0.95, P=0.011). This study is OMEGA-3 FATTY ACIDS
especially relevant in demonstrating that omega-3 has an additive protective effect even in patients already on stain Epidemiological evidence reveals that communities therapy. Furthermore, it shows that even when fish consuming large amounts of fish have lower cardiac consumption is high, supplementation adds further deaths. The Japanese, who consume an average of one cardiovascular protection. There was no difference in the serving of fish per day, have a cardiac death rate of 2.5 total, low density lipoprotein (LDL) and high density per 1000 person-years, compared to a rate of 17 per 1000 lipoprotein (HDL) cholesterol levels in the two groups, person-years in Italians.6 Within the same community, although triglycerides were significantly lower in the EPA those eating more fish are better off. A 30-year follow-up group compared to control (change from baseline –9% vs in Chicago showed that men who consume 35 g or more –4%, P <0.0001). of fish daily had a 38% lower risk of heart disease mortality.7 Similarly, amongst 85 000 women followed There is some evidence that omega-3 can effect the for 16 years, those taking fish 2 to 4 times a week had a atherosclerotic process. An angiographic study on 233 31% lower risk of death from heart disease compared to patients given omega-3 supplements (6 g/d for 3 months those rarely eating fish.8 and then 3 g/d for 21 months) found treatment to significantly reduce coronary atherosclerosis progression Randomized controlled trials on omega-3 supplements and induce more regression compared to those on with clinical cardiovascular end-points suffer from poor placebo.16 Clinical cardiovascular events occurred in 2 methodology, inadequate follow-up or small numbers patients on omega-3, and 7 in the placebo group, a recruited. Two meta-analyses, each done by the same difference which did not reach statistical significance primary authors and pooling 48 trials with 36 913 patients, (P=0.10). Triglycerides were lower in the omega-3 group, suggested that omega-3 fatty-acids are not useful in although LDL cholesterol was elevated. A meta-analysis reducing clinical cardiovascular outcomes.9,10 However, of different anti-lipidemic agents involving 97 studies, these meta-analyses did not differentiate between dietary with 276 116 patients found that only statins and omega-3 intervention trials from those using oral omega-3 significantly reduced total mortality (statins 0.87, supplements. Significant heterogeneity was noted in the 0.81–0.94; omega-3 0.77, 0.63–0.94) and cardiac study design, background diet and end-point definition of mortality (statins 0.78, 0.72–0.84; omega-3 0.68, the various studies pooled into the meta-analyses. A more 0.52–0.90).17 This occurred despite the fact that total rigorous meta-analysis reviewing only trials lasting over cholesterol was not altered with omega-3 treatment, 1 year found omega-3 to reduce total mortality, unlike the case with statins. Thus, cardiovascular myocardial infarction (MI) and sudden cardiac death for protection from omega-3 is probably not related to its both secondary (11 trials, 19 403 patients) and primary influence on lipid levels. Omega-3 reduces sudden prevention (1 trial, 13 578 patients).11 There appears to be cardiac death in patients with a prior MI, and also in sound logic in the recommendations of healthcare healthy individuals.18,19 As this protection comes on early societies for cardiac patients to consume 1 g DHA and and with low dose supplements, it has been attributed to an anti-arrhythmic effect produced when the ratio of n-3 to n-6 polyunsaturated fatty acid is elevated.20 High doses In the GISSI-Prevenzione trial, 11 324 patients who also appear to reduce cardiac events, but mainly nonfatal recently had a MI were randomized daily to 1 g omega-3, events, raising the possibility of omega-3 having an effect 300 mg vitamin E, both or none and followed up for 3.5 on the atherosclerotic lesion, whether through years.14 The primary end-point was death, non-fatal MI anti-inflammatory or plaque regression consequences.16,21 and non-fatal stroke. In comparing the 2836 patients only on omega-3 with the 2828 controls, treatment The lessons from the two clinical omega-3 trials
significantly reduced the primary end-point (RR 0.85,
Table 1 shows that the reduction in primary end-point in 95%CI 0.74–0.98), total mortality (0.80, 0.67–0.94) and GISSI-P of 15% (P = 0.023) was driven by the reduction cardiovascular death (0.70, 0.56–0.87). Trigyceride levels in cardiac death of 35% (P <0.001) and in sudden death of patients on omega-3 decreased significantly compared of 45% (P <0.001); there was no reduction in nonfatal to controls (–3.4% vs +1.4%, P=0.0001). Vitamin E had cardiovascular events (RR 0.96, 95%CI 0.76–1.21).18 The no significant effect on lipid levels or outcomes. The marked reduction in sudden death and cardiac death Japanese JELIS trial recruited 18 645 hyper- suggests that a daily modest dose of 1 g omega-3 prevents cholesterolemic patients and randomized 9326 to 1.8 g of mortality via an anti-arrhythmic effect. As total and LDL EPA as well as 10–20 mg pravastatin or 5–10 mg cholesterol levels in both the placebo and omega-3 groups simvastatin, with the control group of 9319 receiving just rose during this trial, treatment with omega-3 does not statin treatment.15 After a mean follow-up of 4.6 years, have a significant impact on lipid levels and does not EPA supplement significantly reduced unstable angina exert a statin-like action. (0.76, 0.62–0.95, P=0.014) and non-fatal coronary events (0.81, 0.68–0.96, P=0.015) leading to a significant All patients in JELIS were also on statins and so the Chin Med J 2008;121(16):1588-1594 Table 1. Clinical outcomes in the GISSI-Prevenzione trial: highly
produced a mean reduction in total cholesterol of 0.91 significant reduction in coronary mortality with no reduction of mmol/L, LDL-cholesterol of 0.73 mmol/L, triglyceride of non-fatal MI with low dose omega-3 (1 g) daily 0.41 mmol/L and a mean rise in HDL-cholesterol of 0.15 Primary end point* 0.85 Non-fatal CV events A large, randomized, placebo-controlled trial with clinical end-points involving xuezhikang, a commercial RYR *Primary end point: composite of death, non-fatal MI & non-fatal stroke. CV: preparation, has produced impressive results comparable to the statin studies.29 The China Coronary Secondary Prevention Study (CCSPS) recruited 4870 patients with a protection demonstrated with omega-3 is additive to that prior MI and baseline cholesterol between 4.40–6.47 obtained from statin therapy alone. JELIS used a high mmol/L. They were randomized to xuezhikang 0.6 g dose regime of 1.8 g omega-3, in a Japanese population twice daily or matching placebo and followed for a mean that already has a high baseline serum omega-3 levels of 4 years. The primary end-point of non-fatal MI and from high fish consumption.22 Amongst controls, cardiac fatal coronary events was significantly reduced in the death rate per 1000 person-years was 17 in GISSI-P but treatment group (0.54, 0.44–0.66, only 2.5 in JELIS.6 This lower cardiac death rate in the P <0.0001). Cardio- vascular mortality (0.68, 0.52–0.88, JELIS control is due to the higher fish consumption P=0.0048) and total mortality (0.66, 0.52–0.82, amongst the Japanese, and is compatible with the trial P=0.0003) were also significantly reduced. Changes in plasma lipids were less results of GISSI-P which show omega-3 supplement to impressive, with a reduction in total cholesterol of 10.3%, reduce sudden death. In the JELIS trial, there was a LDL-cholesterol of 14.7% and a rise in HDL-cholesterol lowering of non-fatal cardiac events in patients on the of 4.2%. The calculated number needed to treat (NNT) to high dose omega-3 regime (Table 2). Thus, high dose prevent a primary end-point over the trial duration is 21; omega-3 still provides further additive cardiovascular this is comparable to the NNT in the various secondary protection, against non-fatal outcomes. Although there is prevention statin trials that range from 19 to 56.30 This a fear of mercury contamination from high fish ingestion, marked clinical event reduction with xuezhiang treatment, it has been suggested that the benefit from fish and occurring despite only modest lipid level changes, is in omega-3 intake is more than any potential adverse effect keeping with an analysis of the AFCAPS-TEXCAPS trial arising from contaminants.23 using lovastatin which found on-treatment LDL- cholesterol to be unrelated to risk of clinical Table 2. Equivalent primary end-point reduction in GISSI-P and
cardiovascular outcomes.31 Subsequent sub-group Variables GISSI-P analyses of CCSPS, published in the English medical Number of patients literature, confirm the reduction of cardiovascular Follow-up (years) outcomes amongst diabetics and in the elderly.32,33 Dose of omega-3 (g) Primary end-point ( Trials outside China have also shown the lipid lowering RR (95% CI))* 0.85 and anti-inflammatory properties of xuezhikang.34 It is Non-fatal cardiac events ( tempting to attribute the cardiovascular benefit of RYR to RR (95% CI)) 0.96 lovastatin, since all preparations contain this clinically proven useful statin. Yet only 0.8% of xuezhikang is RR (95% CI)) 0.65 lovastatin.35 Thus in CCSPS, the treated group received GISSI-P: Gruppo Italiano per lo Studio della sopravvivenzanell' Infarto. about 10 mg of lovastatin daily, well below the dose of Miocardico-Prevenzione. JELIS: Japan EPA Lipid Intervention Study. *Primary 20–40 mg used in the AFCAPS-TEXCAPS trial. It may end-point in GISSI-P: death, non-fatal myocardial infarction (MI), non-fatal well be that other manocolins present in xuezhikang also stroke. Primary end-point in JELIS: major coronary event including sudden have cardio-protective effects, in addition to that cardiac deaths, fatal and non-fatal MI, unstable angina, angioplasty, stenting and produced by lovastatin (manocolin K). It has been shown bypass grafting. that the cardioprotective effect of statins in Japanese RED YEAST RICE (RYR)
occurs at lower doses than in Western populations.36-38 Thus it is also possible that the low dose 10 mg lovastatin RYR is the fermented product obtained after red yeast found in xuezhikang is sufficient to produce the reduction (Monascus purpureus) is grown on rice. It had been used of cardiac events amongst Chinese patients studied in the in China for centuries as a food flavoring as well as a medicinal product.24 Recent studies have shown RYR to contain lovastatin, amongst other possibly useful Different commercial preparations of RYR have different compounds, and numerous studies have suggested a concentrations of manocolins, and some even contain a beneficial lipid lowering effect from commercial toxic by-product of yeast fermentation, citrinin.39 Before preparations of this traditional supplement.24-27 In a RYR can be routinely recommended for cardiovascular meta-analysis involving 9625 patients in 93 randomized prevention, strict regulations have to be enforced to trials, 3 different commercial preparation of RYR ensure that available products are standardized and Chinese Medical Journal 2008; 121(16):1588-1594 efficacious. Consumers feel that herbal products are safer evidence of clinical event reduction, means that at present than pharmaceutical drugs, but the reality may be that the garlic treatment can not be recommended for unregulated usage of herbal products, with different hyperlipidemia or for patients at risk of cardiovascular manufacturers producing differing amounts of active and toxic constituents, is a far more risky practice. CONCLUSION
Results from large prospective placebo-controlled clinical Garlic (Allium sativum) use in cardiovascular therapeutics trials must be analyzed seriously when judging the value has an even longer history than RYR, with records dating of any treatment intervention. The two omega-3 trials back over 3000 years to ancient Egypt.40 Numerous have together recruited over 30 000 patients and confirm animal studies have shown garlic to have a cholesterol the value of both modest and high dose supplementation lowering effect, but human studies on the effects of garlic in reducing adverse cardiac events. Thus, it is reasonable have produced inconsistent results.41-44 A meta-analysis of to recommend 1–1.8 g omega-3 daily to reduce clinical 45 randomized trials had suggested that garlic may have a cardiovascular events especially in patients with hypolipidemic effect at 3 months, but not at 6 months of established ischemic heart disease. It is interesting to usage.45 However, the randomization, blinding and postulate that modest dose omega-3 reduces arrhthymic methodology of many of the trials reviewed were poor events, while higher doses may work via an and there was inadequate definition of the specific anti-atherosclerotic process to reduce nonfatal events. biologically active constituent of the various forms of However, more clinical trials or animal experiments are garlic ingested. The active chemical in garlic is allicin, needed to test these hypotheses. which is produced when raw garlic is crushed, allowing the enzyme alliinase to act on the stable precursor alliin. The CCSC trial showed that reduction of cardiovascular Commercial garlic preparations have been found to events in secondary prevention using the RYR produce unexpectedly low amounts of active allicin, and preparation, xuezhikang, is equivalent to that obtained this could account for the absence of a demonstrable lipid from the landmark 4S statin trial (Table 3). It is pertinent lowering effect in some studies.46 to ask whether the benefit of xuezhikang comes from the 10 mg lovastatin it contains especially since recent A recent randomized trial sought to overcome these reports have shown that lower lipid levels reached with problems by including treatment with raw garlic, and higher statin doses produce more reduction in extensively characterizing the chemicals in the garlic cardiovascular outcomes.48-52 However, a review of the supplements used before and throughout the trial.47 This AFCAPS-TEXCAPS trial, which also involved lovastatin, Stanford University study recruited 192 patients with showed no correlation between on treatment LDL-cholesterol between 3.36–4.91 mmol/L and LDL-cholesterol levels with clinical cardiovascular randomized them to 1 of 4 treatment arms using raw outcomes.31 By reducing C-reactive protein and garlic, powdered garlic (garlicin), aged garlic extract inflammation, statin therapy has been reported to reduce (Kyolic) or placebo. After 6 months, there was no clinical cardiovascular events independent of the effect on significant difference in the LDL-cholesterol levels in the lipid levels.53,54 There is also good evidence that statins 4 groups (raw garlic +0.01 mmol/L, powdered garlic reduce endothelial dysfunction and enhance +0.08 mmol/L, aged garlic extract +0.005 mmol/L, vasodilatation.55,56 It could well be that lovastatin placebo –0.10 mmol/L). There was also no difference in (manocolin K) acts more via non-lipid lowering the HDL-cholesterol, triglycerides and total mechanisms, thereby explaining the marked cholesterol-HDL ratio. This trial was well conducted with cardiovascular protection with modest lipid reduction. It patient retention of nearly 90% in all arms, monthly blood may also be possible that the cardiovascular protection of lipid assay, assessment of the chemicals in the study RYR in fact arises from the other manocolins present, and material throughout the trial duration and patient not just from lovastatin. A third possibility is that Asians adherence assessment by weekly logs and tablet count. may indeed respond to lower statin doses than that used Chemical characterization ensured that adequate levels of in the conventional trials with Caucasian patients.36-38 the active allicin were studied in the 3 treatment groups. Further trials are necessary to resolve these issues. In fact, the dosage used in the 2 commercial garlic supplements was several times above that recommended An objective review of the trial evidence confirms the value by the manufacturers. No serious adverse effects were of omega-3 and RYR in reducing clinical cardiovascular noted in the groups using garlic, although bad odor was events. The evidence favoring omega-3 is highly convincing noted in over half those on raw garlic treatment. but RYR could be more confidently recommended if another large randomized clinical trial, preferably in a non-Chinese It is pertinent to note that there has been no clinical population, could reproduce the results of CCSPS. Garlic cardiovascular event trial with garlic therapy, such as is probably does not significantly affect lipid levels and has no available with omega-3 and RYR. The negative result evidence supporting a role in reducing clinical outcomes. from the Stanford study, together with the absence of any The trials have confirmed that supplements are safe, with Chin Med J 2008;121(16):1588-1594 Table 3. The reduction in adverse clinical outcome with
Moore H, Worthington HV, et al. Omega 3 fatty acids for xuezhikang in CCSPS and 4S study prevention and treatment of cardiovascular disease. Cochrane Database Syst Rev 2004; 4: CD003177. Number of patients Follow-up (years) Hooper L, Thompson RL, Harrison RA, Summerbell CD, Ness AR, Moore HJ, et al. Risks and benefits of omega 3 fats for mortality, cardiovascular disease, and cancer: systematic Primary end-point review. BMJ 2006; 332: 752-760. 11. Wang C, Harris WS, Chung M, Lichtenstein AH, Balk EM, Relative risk (95% CI) 0.54 Kupelnick B, et al. N-3 fatty acids from fish or fish oil supplements, but not α-linolenic acid, benefit cardiovascular Change from baseline disease outcomes in primary and secondary prevention Total cholesterol studies: a systematic review. Am J Clin Nutr 2006; 84: 5-17. 12. Kris-Etherton PM, Harris WS, Appel LJ, for the Nutrition Triglycerides – –10% Committee. AHA Scientific Statement. Fish consumption, CCSPS: China Coronary Secondary Prevention Study. 4S: Scandinavian Simvastatin Survival Study. CHD: coronary heart disease. MI: myocardial fish oil, omega-3 fatty acids, and cardiovascular disease. infarction. NNT: number needed to treat. LDL: low density lipoprotein. Circulation 2002; 106: 2747-2757. 13. Deckelbaum RJ, Akabas SR. n-3 fatty acids and an adverse effect profile similar to placebo. Nevertheless cardiovascular disease: navigating toward recommendations. fears of mercury and industrial contamination of fish Am J Clin Nutr 2006; 84: 1-2. stock are increasing.57,58 While proper purification 14. GISSI-Prevenzione Investigators. Dietary supplementation processes may help ensure that prescription preparations with n-3 polyunsaturated fatty acids and vitamin E after are safer, both omega-3 supplements and RYR are widely myocardial infarction: results of the GISSI-Prevensione trial. available in non-prescription forms which may differ in Lancet 1999; 354: 447-455. content and impurities.39,59 The involvement of regulatory 15. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito bodies is needed to ensure that the standardization and Y, Ishikawa Y, et al, for the Japan EPA lipid intervention manufacturing processes of herbal products are as strict study (JELIS) investigators. Effects of eicosapentaenoic acid as those with pharmacological drugs. Only then can these on major coronary events in hypercholesterolaemic patients supplements have a routine role in clinical practice. (JELIS): a randomized open-label, blinded endpoint analysis. Lancet 2007; 369: 1090-1098. 16. von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. The effect of dietary omega-3 fatty acids on coronary Ernst E. Herbal medicines: where is the evidence? BMJ 2000; atherosclerosis: A randomized, double-blind, placebo- controlled trial. Ann Intern Med 1999; 130: 554-562. Kelly JP, Kaufman DW, Kelly K, Rosenberg L, Anderson TE, 17. Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. Mitchell AA. Recent trends in use of herbal and other natural Effect of different antilipidemic agents and diets on mortality. products. Arch Intern Med 2005; 165: 281-286. Arch Intern Med 2005; 165: 725-730. Gardiner P, Graham RE, Legedza ATR, Eisenberg DM, 18. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di Phillips RS. Factors associated with dietary supplement use Mascio R, et al, on behalf of the GISSI-Prevenzione among prescription medication users. Arch Intern Med 2006; Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: Ong HT. Evidence-based prescribing of statins: A developing time-course analysis of the results of the Gruppo Italiano per world perspective. PLoS Med 2006; 3: e50. lo Studio della sopravvivenza nell'Infarto Miocardico Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, (GISSI)-Prevenzione. Circulation 2002; 105: 1897-1903. Pollicino C, et al, for the Cholesterol Treatment Trialists' 19. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, (CTT) Collaborators. Efficacy and safety of cholesterol- Willett WC, et al. Blood levels of long chain n-3 fatty acids lowering treatment: prospective meta-analysis of data from and the risk of sudden death. N Engl J Med 2002; 346: 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-1278. 20. Leaf A. On the reanalysis of the GISSI-Prevenzione. Mozaffarian D. JELIS, fish oil and cardiac events. Lancet Circulation 2002; 105: 1874-1875. 2007; 369: 1062-1063. 21. Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y, et Daviglus ML, Stamler J, Orencia AJ, Dyer AR, Liu K, al, for the JPHC Study Group. Intake of fish and n3 fatty Greenland P, et al. Fish consumption and the 30-year risk of acids and risk of coronary heart disease among Japanese; the fatal myocardial infarction. N Engl J Med 1997; 336: Japanese Public Health Centre-Based (JPHC) Study Cohort I. Circulation 2006; 113: 195-202. Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, 22. Nakamura T, Azuma A, Kuribayashi T, Sugihara H, Okuda S, Albert CM, et al. Fish and omega-3 fatty acid intake and risk Nakagawa M. Serum fatty acid levels, dietary style and of coronary heart disease in women. JAMA 2002; 287: coronary heart disease in three neighboring areas in Japan: the Kumihama study. Br J Nutr 2003; 89: 267-272. Hooper L, Thompson RL, Harrison RA, Summerbell CD, 23. Mozaffarian D, Rimm EB. Fish intake, contaminants and Chinese Medical Journal 2008; 121(16):1588-1594 human health. Evaluating the risks and the benefits. JAMA hypercholesterolemic patients. Circ J 2003; 67: 287-294. 2006; 296: 1885-1899. 37. Koba S, Sasaki J. Treatment of hyperlipidemia from Japanese 24. Wang J, Lu Z, Chi J. Multi-center clinical trial of the serum evidence. J Atheroscler Thromb 2006; 13: 267-280 lipid-lowering effects of a Monascus Purpureus (Red Yeast) 38. Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, rice preparation from traditional Chinese medicine. Curr Ther Toyota T, et al, for the MEGA Study Group. Primary Res 1997; 58: 964-978. prevention of cardiovascular disease with pravastatin in Japan 25. Lin CC, Li TC, Lai MM. Efficacy and safety of Monascus (MEGA Study): a prospective randomized controlled trial. Purpureus Went rice in subjects with hyperlipidemia. Eur J Lancet 2006; 368:1155-1163. Endo 2005; 153; 679-686. 39. Heber D, Lembertas A, Lu QY, Bowerman S, Go VLW. An 26. Zhao SP, Liu L, Cheng YC, Shishehbor MH, Liu MH, Peng analysis of nine proprietary Chinese red yeast rice dietary DQ, et al. Xuezhikang, an extract of Cholestin, protects supplements: implications of variability in chemical profile endothelial function through anti-inflammatory and lipid- and contents. J Alt Comp Med 2001; 7: 133-139. lowering mechanisms in patients with coronary heart disease. 40. Rahman K, Lowe GM. Garlic and cardiovascular disease; a Circulation 2004; 110: 915-920. critical review. J Nutr 2006; 136: 736S-740S. 27. Zhao SP, Liu L, Cheng YC, Li YL. Effect of Xuezhikang, a 41. Warshafsky S, Kamer RS, Sivak SL. Effect of garlic on total Cholestin extract, on reflecting postprandial triglyceridemia serum cholesterol: a meta-analysis. Ann Intern Med 1993; after a high fat meal in patients with coronary heart disease. Atherosclerosis 2003; 168: 375-380. 42. Steiner M, Khan AH, Holbert D, Lin RI. A double-blind 28. Liu JP, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fonnebo V. crossover study in moderately hypercholesterolemic men that Chinese red yeast rice (Monascus Purpureus) for primary compared the effect of aged garlic extract and placebo hyperlipidemia: a meta-analysis of randomized controlled administration on blood lipids. Am J Clin Nutr 1996; 64: trials. Chin Med 2006; 1: 4. 29. China Coronary Secondary Prevention Study Group. China 43. Berthold HK, Sudhop T, von Bergmann K. Effect of a garlic coronary secondary prevention study (CCSPS) – Lipid oil preparation on serum lipoproteins and cholesterol regulating therapy with xuezhikang for secondary prevention metabolism: a randomized controlled trial. JAMA 1998; 279: of coronary heart disease. Chin J Cardiol (Chin) 2005; 33; 44. Gardner CD, Chatterjee LM, Carson JJ. The effect of a garlic 30. Ong HT. The statin studies: from targeting preparation on plasma lipid levels in moderately hypercholesterolemia to targeting the high risk patient. QJM hypercholesterolemic adults. Atherosclerosis 2001; 154: 2005; 98: 599-614. 31. Gotto AM Jr, Whitney E, stein EA, Shapiro DR, Clearfield M, 45. Ackermann RT, Mulrow CD, Ramirez G, Gardner CD, Weis S, et al. Relation between baseline and on treatment Morbidoni L, Lawrence VA. Garlic shows promise for lipid parameters and first acute major coronary events in the improving some cardiovascular risk factors. Arch Intern Med Air Force/Texas Coronary Atherosclerosis Prevention Study 2001; 161: 813-824. (AFCAPS/TexCAPS). Circulation 2000; 101: 477-484. 46. Lawson LD, Wang ZJ. Allicin release from garlic 32. Zhao SP, Lu ZL, Du BM, Chen Z, Wu YF, Yu XH , et al, for supplements: a major problem due to the sensitivities of the China Coronary Secondary prevention Study. Xuezhikang, alliinase activity. J Agric Food Chem 2001; 49: 2592-2599. an extract of cholestin, reduces cardiovascular events in type 47. Gardner CD, Lawson LD, Block E, Chatterjee LM, Kiazand 2 diabetes patients with coronary heart disease: subgroup A, Balise RR , et al. Effect of raw garlic vs commercial garlic analysis of patients with type 2 diabetes from Chian coronary supplements on plasma lipid concentrations in adults with secondary prevention study (CCSPS). J Cardiovasc moderate hypercholesterolemia. Arch Intern Med 2007; 167: Pharmacol 2007; 49: 81-84. 33. Ye P, Lu ZL, Du BM, Chen Z, Wu YF, Yu XH , et al, for the 48. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau CCSPS Investigators. Effects of xuezhikang on cardiovascular JL, Belder R, et al, for the Pravastatin or Atorvastatin events and mortality in elderly patients with a history of Evaluation and Infection Therapy – Throbolysis in myocardial infarction: a subgroup analysis of elderly subjects Myocardial Infarction 22 Investigators. Intensive versus from China coronary secondary prevention study. J Am moderate lipid lowering with statins after acute coronary Geriatr Soc 2007; 55: 1015-1022. syndromes. N Engl J Med 2004; 350: 1495-1540. 34. Heber D, Yip I, Ashley JM, Elashoff DA, Elashoff RM, Go 49. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, VLW. Cholesterol lowering effects of a proprietary Chinese White HD, et al, for the A to Z Investigators. Early intensive red yeast rice dietary supplement. Am J Clin Nutr 1999; 69: vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes. Phase Z of the A to Z trial. 35. Zhang XX, Zhou FR, Shi JM. HPLC Analysis of lovastatin JAMA 2004; 292: 1307-1316. concentration in xuezhikang capsule and other red yeast rice. 50. Nissen SE, Tzucu EM, Schoenhagen P, Brown BG, Ganz P, China J Chin Materia Medica (Chin) 1999; 22: 222-224. Vogel RA, et al, for the REVERSAL Investigators. Effect of 36. Matsuzawa Y, Kita T, Mabuchi H, Matsuzaki M, Nakaya N, intensive compared with moderate lipid-lowering therapy on Oikawa S, et al for the J-LIT Study Group. Sustained progression of coronary atherosclerosis. A randomized reduction of serum cholesterol in low dose 6 year simvastatin controlled trial. JAMA 2004; 291: 1071-1080. treatment with minimum side-effects in 51 321 Japanese 51. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Chin Med J 2008;121(16):1588-1594 Fruchart JC, et al, for the Treating to New Targets (TNT) 55. Dogra GK, Watts GF, Chan DC, Stanton K. Statin therapy Investigators. Intensive lipid lowering with atorvastatin in improves brachial artery vasodilator function in patients with patients with stable coronary disease. N Engl J Med 2005; Type 1 diabetes and microalbuminuria. Diabet Med 2005; 22: 52. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, 56. Strey CH, Young JM, Molyneux SL, George PM, Florkowski Tikkanen MJ, Holme I, et al, for the Incremental Decrease in CM, Scott RS, et al. Endothelium-ameliorating effects of End Points Through Aggressive lipid Lowering (IDEAL) statin therapy and coenzyme Q 10 reductions in chronic heart Study Group. High-dose atorvastatin vs usual-dose failure. Atherosclerosis 2005; 179: 201-206. simvastatin for secondary prevention after myocardial 57. Domingo JL, Bocio A, Falco G, Llobet JM. Benefits and risks infarction. The IDEAL Study: A randomized controlled trial. of fish consumption Part 1. A quantitative analysis of the JAMA 2005; 294: 2437-2445. intake of omega-3 fatty acids and chemical contaminants. 53. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Toxicology 2007; 230: 219-226. Tsai J, et al, for the Reversal of Athrosclerosis with 58. Bays HE. Safety considerations with omega-3 fatty acid Aggressive Lipid Lowering (REVERSAL) Investigators. therapy. Am J Cardiol 2007; 99: 35C-43C. Effects of statin therapy on LDL cholesterol, C-reactive 59. Brunton S, Collins N. Differentiating prescription omega-3 protein, and the progression of coronary artery disease. N acid ethyl esters (P-OM3) from dietary omega-3 fatty acids. Engl J Med 2005; 352: 29-38. Curr Med Res Opin 2007; 23: 1139-1145. 54. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. Clinical relevance of C-reactive protein (Received December 3, 2007) levels after statin therapy. N Engl J Med 2005; 352: 20-28. Edited by WANG Mou-yue and LIU Huan


Jia336221 202.207

Journal of the International Association of Physicians in AIDS Care (JIAPAC) Known to Be Positive But Not in Care: A Pilot Study From Thailand Pratuma Rithpho, Deanna E. Grimes, Richard M. Grimes and Wilawan Senaratana 2009; 8; 202 originally published online May 4, 2009; J Int Assoc Physicians AIDS Care (Chic Ill) DOI: 10.1177/1545109709336221

Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium IMI Work Package 5: Report 2:b:ii Benefit - Risk Wave 2 Case Study Report: Rosiglitazone Benefit-Risk Analysis Lawrence Phillips, Billy Amzal, Alex Asiimwe, Edmond Chan, Chen Chen, Diana Hughes, Juhaeri Juhaeri, Alain Micaleff, Shahrul Mt-Isa, Becky Noel, Susan Shepherd, Nan Wang On behalf of PROTECT Work Package 5 participants

Copyright © 2008-2016 No Medical Care