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Indian Journal of Pharmacology
Medknow Publications on behalf of Indian Pharmacological Society
ISSN: 0253-7613 EISSN: 1998-3751
Vol. 41, Num. 1, 2009, pp. 4-8
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Indian Journal of Pharmacology, Vol. 41, No. 1, January-February, 2009, pp. 4-8
Review Article
The effect of dyslipidemic drugs on mortality: A meta-analysis
Jain Shuchi, Vaishnavi Vikas, Chakraborty BhaswatS
Research and Development, Cadila Pharmaceuticals, Ahmadabad, Gujarat
Correspondence Address:Research and Development, Cadila Pharmaceuticals, Ahmadabad, Gujarat
drb.chakraborty@cadilapharma.co.in
Date of Submission: 20-May-2008
Date of Decision: 20-Dec-2008
Date of Acceptance: 09-Feb-2009
Code Number: ph09002
Abstract
Most of the previously published meta-analyses include studies exploring the effect of statins, rather than all dyslipidemic drugs, on mortality. We explored the overall effect of all dyslipidemic drugs on coronary artery disease mortality, cardio-vascular disease mortality and all-cause mortality. A meta-analysis of all randomized controlled trials that were published before February 2006 was carried out. Data sources were published articles in bibliographic electronic databases and medical journals. The article selection criteria included all randomized placebo-controlled trials of at least one year duration and those which measured at least one of the following clinical endpoints: coronary artery disease mortality, cardio-vascular mortality or all-cause mortality. Information on sample size, follow up period, drug used, and clinical outcomes was abstracted independently by two authors. Disagreements were resolved by consensus. The meta-analysis (19 trials, 59033 patients) showed a significant relative risk reduction of coronary artery disease mortality of 23% (P<0.00001), cardiovascular disease mortality of 19% (P<0.00001) and all-cause mortality of 14% (P<0.0001), without any significant heterogeneity and inconsistency between the trials. It was concluded from this meta-analyses that dyslipidemic drugs are indeed highly effective medicines and confer benefit to patients, in terms of primary and secondary prevention of coronary artery disease.
Keywords: All-cause mortality, cardio-vascular disease mortality, coronary artery disease mortality, dyslipidemic, meta-analysis
Introduction
Cardio-vascular disease (CVD) is the world′s leading killer, accounting for 16.7 million or 29.2% of the total global deaths in 2003. While deaths from heart attacks have declined more than 50% since the 1960s in many industrialized countries, 80% of the global CVD related deaths now occur in low and middle-income nations, which cover most countries in Asia. In India, in the past five decades, the rate of coronary disease among urban populations has risen from 4 to 11%. [1]
Dyslipidemia (elevated total cholesterol and Low-density Lipoprotein (LDL), and depressed High-density Lipoprotein (HDL) levels are independent risk factors. Statins (HMG-CoA reductase), fibrates and resins are known dyslipidemic drugs, which act by increasing or decreasing lipoprotein (Lp) or its components levels. Many trials have been conducted to show their effectiveness in treating Coronary Artery Diseases (CAD). But very few have shown statistically significant results.
Thus, many meta-analyses have been done to verify the findings of trials involving various dyslipidemic drugs. However, most of these studies include trials of statins only; if the studies included other dyslipidemic drugs also, dietary and other kinds of interventions were also compared, along with the dyslipidemic drugs. Meta-analyses including all the dyslipidemic drug trials only are very few.
The effect of these drugs on all-cause mortality is still unclear. [2],[3],[4] Thus, this meta-analysis was done to evaluate the effectiveness of dyslipidemic drugs on CAD mortality, CVD mortality or all-cause mortality.
Materials and Methods
Eligibility Criteria
Two authors separately reviewed the abstracts produced by the literature search to identify studies that are randomized placebo-controlled trials evaluating the effectiveness of any dyslipidemic drug and reporting one of the following clinical endpoints: CAD mortality, CVD mortality or all-cause mortality. The follow up period should have been greater than or equal to one year.
The most frequent reasons for study exclusion were study duration being less than one year, trial being nonrandomized or non placebo-controlled, two or more drugs being compared to a single placebo in the same study or clinical endpoints not being reported. Studies in which eligibility criteria included a particular lifestyle disease, e.g.: hypertension [5] or diabetes were excluded. Studies published in languages other than English and abstract form only were also excluded.
Study Identification
Strategies to identify studies included an electronic search of bibliographic databases (Clinical Trials, Cochrane Reviews, PubMed and Science Direct), electronic as well as manual search of medical journals (American Journal of Cardiology, Annals of Internal Medicine, Archives of Internal Medicine, British Medical Journal, Circulation, European Heart Journal, Lancet, The Journal of the American Medical Association and The New England Journal of Medicine), consultation with the experts, review of reference lists from eligible trials and use of the "See Related Articles" feature for key publications in PubMed (March 2006).
This search resulted in the identification of 20 eligible studies, which are listed along with their characteristics in [Table - 1]. However, due to increase in heterogeneity (funnel plot), one study (ACAPS) was excluded from the final results, even though it fulfilled the inclusion/exclusion criteria. Thus, the results summarize meta-analysis of 19 studies.
Data Collection
Full articles have been reviewed for eligibility. For articles meeting the inclusion criteria, relevant data was extracted and entered in the evidence table.
Statistical Analysis
Meta-analysis was performed using the Mantel-Haenszel method for fixed effect model and Der-Simonian and the Laird method for random effect model. Graphs of the outcomes for included trials were examined visually and by using the Chi-square test to identify heterogeneity in the outcome variables across different studies. Because the results of our meta-analysis did not vary depending on whether the fixed or random effect model was used, random effect results are presented. The results are displayed as summary odds ratio (OR), relative risk (RR) and 95% confidence interval (CI) of OR and RR for CAD mortality, CVD mortality and all cause mortality. I 2 value is also calculated. An I 2 value represents the percentage of the total variation across trials, which is due to heterogeneity rather than chance, and is considered thus: I 2 value < 25% is low and> 75% is high. All analyses is done using RevMan 4.2.8 (Cochrane Collaboration).
Results [Figure - 1] and [Figure - 2] show the effect of treatment with dyslipidemic drugs on CAD mortality, CVD mortality and all-cause mortality. The point estimate and 95% CI of OR and RR are reported. For all studies, combined patients who received treatment had a statistically significant advantage for all-cause mortality, along with CAD mortality and CVD mortality. Treatment reduced the relative risk of CHD mortality by 23% (summary relative risk is 0.77, 0.71 to 0.82), compared with placebo. For CVD mortality and all-cause mortality, reduction was by 19% (summary relative risk is 0.81, 0.76 to 0.86) and 14% (summary relative risk is 0.86, 0.81 to 0.92) respectively. The corresponding summary OR for CHD was 0.75 (95% CI: 0.70 to 0.81); for CVD the summary OR was 0.79 (95% CI: 0.74 to 0.84) and that for all- cause mortality was 0.84 (95% CI: 0.79 to 0.89) showing a reduction of 25, 21 and 16%, respectively. In each of these analysis, the results of Chi-square test for heterogeneity are not significant ( P >0.10) and the value of I 2 (I 2 < 25%) suggests a fairly low amount of inconsistency across the trials included.
Discussion
This meta-analysis shows that lipid lowering drugs reduce the relative odds of CHD mortality, CVD mortality and all-cause mortality by about 15-25%. The population in these trials includes men, women, elderly people, hypercholesterolemic and patients with normal cholesterol levels.
The conclusions drawn in this meta-analysis are different from that of Pignone et al. , [4] who found that the effect of statins on all-cause mortality is insignificant. The differences are possibly because 1) Pignone et al , limited their analysis to the statin trials only. 2) They included only primary prevention trials. Unlike their study, in this meta-analysis, studies of fibrates and resins have been also included. Apart from this, primary, secondary as well as mixed type trials have been included in this meta-analysis. But these conclusions are similar to that drawn by Ross et al. , [26] who found that statins are effective in reducing CVD mortality, along with all-cause mortality (OR = 0.76, 0.67 to 0.86).
The differences are due to the exclusion of studies in which a second drug was added if the targeted levels of cholesterol were not achieved, in our meta-analysis.
Generalization of these findings to other populations - such as Asians - is difficult, as trials selected for the analysis do not adequately represent this population. Generally, the population that participated was of European or American descent.
The strength of this meta-analysis is that it is based on more than 50,000 randomized patients. However, the short comings of this analysis are: 1) it was not based on individual data but available data from the literature; 2) some of the articles could not be included as they were unavailable; 3) absolute risk was not calculated.
Future research can be done to know the effectiveness of dyslipidemic drugs on people of non European origin. Further research can be done to calculate absolute values to strengthen the findings in this analysis.
References
| 1. | Pandey R. Cardiovascular disease in India and the impact of lifestyle and food habits [online]. 2004 Dec [last accessed on 2006 Apr 21]. Available from: http://www.expresshealthcaremgmt.com/20041215/criticare06.shtml. Back to cited text no. 1 |
| 2. | Hebert PR, Gaziano M, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality an overview of randomized trials. JAMA 1997;278:313-21. Back to cited text no. 2 |
| 3. | LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease a meta-analysis of randomized controlled trials. JAMA 1999;282:2340-6. Back to cited text no. 3 [PUBMED] [FULLTEXT] |
| 4. | Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: Meta-analysis of randomized trials. BMJ 2000;321: 983-6. Back to cited text no. 4 [PUBMED] [FULLTEXT] |
| 5. | Sever PS, Dahlor B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than- average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): A multicentre randomized controlled trial. Lancet 2003;361:1149-58. Back to cited text no. 5 |
| 6. | Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of Coronary heart disease with pravastatin in men with hypercholestrolemia: The West of Scotland Coronary Prevention Study Group (WOSCOPS). N Engl J Med 1995;333:1301-7. Back to cited text no. 6 [PUBMED] [FULLTEXT] |
| 7. | Rubins Hanna B, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of Coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999;341:410-8. Back to cited text no. 7 |
| 8. | LIPID study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57. Back to cited text no. 8 |
| 9. | Sacks FM, Pleffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: The Cholesterol and Recurrent Events Trial (CARE). N Engl J Med 1996;335:1001-9. Back to cited text no. 9 |
| 10. | Downs John R, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA 1998;279:1615-22. Back to cited text no. 10 |
| 11. | Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, et al. Coronary Angiographic Changes with Lovastatin Therapy (MARS). Ann Intern Med 1993;119:969-76. Back to cited text no. 11 |
| 12. | Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomized controlled trial. Lancet 2002;360:1623-30. Back to cited text no. 12 [PUBMED] [FULLTEXT] |
| 13. | Study Group of Physicians of the Newcastle. Trial of Clofibrate in the treatment of Ischemic heart disease. BMJ 1971;4:767-75. Back to cited text no. 13 |
| 14. | Liem AH, van Boven AJ, Veeger NJ, Withagen AJ, Robles de Medina RM, Tijssen JG, et al. Effect of fluvastatin on ischemia following acute myocardial infarction: A randomized trial. Eur Heart J 2002;23:1931-7. Back to cited text no. 14 [PUBMED] [FULLTEXT] |
| 15. | PLAC-I Investigators. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I): Reduction in atherosclerosis progression and clinical events. J A Coll Cardiol 1995;26:1133-9. Back to cited text no. 15 |
| 16. | Crouse JR, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, et al. Pravastatin, Lipids, and Atherosclerosis in the carotid Arteries (PLAC-II). Am J Cardiol 1995;75:455-9. Back to cited text no. 16 |
| 17. | Scandinavian Simvastatin Survival Study Group. Randomised Trial of Cholesterol Lowering In 4444 Patients With Coronary Heart Disease. Lancet 1994;344:1383. Back to cited text no. 17 |
| 18. | MAAS Investigators. Effect of simvastatin on coronary atheroma: The Multicentre Anti-Atheroma Study (MAAS). Lancet 1994;344:633-8. Back to cited text no. 18 |
| 19. | Waters D, Higginson L, Gladstone P, Boccuzzi SJ, Cook T, Lespιrance J. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women: A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy. Circulation 1995;92:2404-10. Back to cited text no. 19 |
| 20. | Furberg CD, Adams HP, Applegate WB, Byington RP, Espeland MA, Hartwell T, et al. Effect of lovastatin on early carotid atherosclerosis and Cardiovascular events: Asymptomatic Carotid Artery Progression Study (ACAPS). Circulation 1994;90:1679-87. Back to cited text no. 20 |
| 21. | Salonen R, Nyyssonen K, Porkkala E, Rummukainen J, Belder R, Park JS, et al. Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;92:1758-64. Back to cited text no. 21 |
| 22. | Jukema JW, Bruschke AG, van Boven JV, Reiber JH, Bal ET, Zwinderman AH, et al. Effect of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels: The Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995;91:2528-40. Back to cited text no. 22 |
| 23. | Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high risk individuals: a randomised placebo controlled trial. Lancet 2002;360:7-22. Back to cited text no. 23 [PUBMED] [FULLTEXT] |
| 24. | Serruys PW, de Feyter P, Macaya C, Kokott N, Puel J, Vrolix M, et al. Fluvastatin for prevention of Cardiac Events following successful first percutaneous coronary intervention: A randomized controlled trial. JAMA 2002;287:3215-22. Back to cited text no. 24 [PUBMED] [FULLTEXT] |
| 25. | Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK, et al. Effects of Therapy with cholestyramine on progression of coronary arteriosclerosis: Results of the NHLBI type II coronary intervention study. Circulation 1984;69:313-24. Back to cited text no. 25 [PUBMED] [FULLTEXT] |
| 26. | Ross SD, Allen IE, Connelly JE, Korenblat BM, Smith ME, Bishop D, et al. Clinical outcomes in statin treatment trials: A meta-analysis. Arch Intern Med 1999;159:1793-802. Back to cited text no. 26 [PUBMED] [FULLTEXT] |
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