Background. There is a paucity of data regarding the effectiveness and safety of lipid-lowering treatments among South-Asian patients. Methods. Sixty-four South-Asian Canadians with coronary artery disease or diabetes and persistent hypercholesterolemia on statin therapy, were randomized to ezetimibe 10？mg/day co-administered with statin therapy (EZE + Statin) or doubling their current statin dose (STAT2). Primary outcome was the proportion of patients achieving target LDL-C (<2.0？mmol/L) after 6 weeks. Secondary outcomes included the change in lipid profile and the incidence of treatment-emergent adverse events through 12 weeks. Exploratory markers for vascular inflammation were assessed at baseline and 12 weeks. Results. At 6 weeks, the primary outcome was significantly higher among the EZE + Statin patients (68% versus 36%; ) with an OR (95% CI) of 3.97 (1.19, 13.18) upon accounting for baseline LDL-C and adjusting for age. At 12 weeks, 76% of EZE + Statin patients achieved target LDL-C compared to 48% ( ) of the STAT2 patients (adjusted OR (95% CI) = 3.31 (1.01,10.89)). No significant between-group differences in exploratory markers were observed with the exception of CRP. Conclusions. Patients receiving ezetimibe and statin were more likely to achieve target LDL-C after 6 and 12 weeks compared to patients doubling their statin dose. Ezetimibe/statin combination therapy was well tolerated among this cohort of South-Asian Canadians, without safety concerns. 1. Introduction Despite a steady decline in coronary artery disease (CAD)-related mortality over the past 25 years, CAD remains a leading cause of death among Canadians [1]. The direct association between higher serum concentrations of low-density lipoprotein cholesterol (LDL-C) and increased risk of CAD is well known [2–8]. In patients with primary hypercholesterolemia, the main treatment goal is lowering LDL-C to reduce CAD risk [9]. The 2009 Canadian dyslipidemia guidelines recommend treatment of patients with CAD or CAD risk equivalent conditions with an LDL-C level ≥ 2.0？mmol/L with lipid-lowering agents [9]. With declining LDL treatment targets, multiple therapies may be required to achieve these goals. Hydroxymethylglutaryl-coenzyme-A (HMG-CoA) redu-ctase inhibitors (statins) are considered first-line therapy for hypercholesterolemia [9]. For patients not achieving their target LDL-C levels, increasing the statin dose, switching to another statin, or coadministration of complementary drugs to statins may be tried. The cholesterol absorption inhibitor, ezetimibe, reduces cholesterol
References
[1]
“Statistics Canada: Age-standardized mortality rates by selected causes, by sex,” http://www.statcan.gc.ca/tables-tableaux/sum-som/l01/cst01/health30a-eng.htm.
[2]
J. C. LaRosa, S. M. Grundy, D. D. Waters et al., “Intensive lipid lowering with atorvastatin in patients with stable coronary disease,” The New England Journal of Medicine, vol. 352, no. 14, pp. 1425–1435, 2005.
[3]
T. R. Pedersen, “Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S),” The Lancet, vol. 344, no. 8934, pp. 1383–1389, 1994.
[4]
The Long-Term Intervention with Pravastatin in Ischaemic Disease (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,” The New England Journal of Medicine, vol. 339, pp. 1349–1357, 1998.
[5]
R. Collins, J. Armitage, S. Parish, P. Sleight, and R. Peto, “MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomised placebo-controlled trial,” The Lancet, vol. 360, no. 9326, pp. 7–22, 2002.
[6]
G. G. Schwartz, A. G. Olsson, M. D. Ezekowitz et al., “Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes the MIRACL study: a randomized controlled trial,” Journal of the American Medical Association, vol. 285, no. 13, pp. 1711–1718, 2001.
[7]
C. P. Cannon, E. Braunwald, C. H. McCabe, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators, et al., “Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes,” The New England Journal of Medicine, vol. 350, pp. 1495–1504, 2004.
[8]
J. A. De Lemos, M. A. Blazing, S. D. Wiviott et al., “Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial,” Journal of the American Medical Association, vol. 292, no. 11, pp. 1307–1316, 2004.
[9]
J. Genest, R. McPherson, J. Frohlich et al., “2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations,” Canadian Journal of Cardiology, vol. 25, no. 10, pp. 567–579, 2009.
[10]
E. Bruckert, P. Giral, and P. Tellier, “Perspectives in cholesterol-lowering therapy: the role of ezetimibe, a new selective inhibitor of intestinal cholesterol absorption,” Circulation, vol. 107, no. 25, pp. 3124–3128, 2003.
[11]
M. Gupta, N. Singh, and S. Verma, “South Asians and cardiovascular risk: what clinicians should know,” Circulation, vol. 113, no. 25, pp. e924–e929, 2006.
[12]
M. Gupta and S. Brister, “Is South Asian ethnicity an independent cardiovascular risk factor?” Canadian Journal of Cardiology, vol. 22, no. 3, pp. 193–197, 2006.
[13]
S. A. Pandey, S. Bissonnette, S. Boukas, et al., “Effectiveness and tolerability of ezetimibe co-administered with statins versus statin dose-doubling in high-risk patients with persistent hyperlipidemia: the EZE, (STAT)2 Trial,” Archives of Medical Science, vol. 7, no. 5, pp. 767–775, 2011.
[14]
V. B. Patel, M. A. Robbins, and E. J. Topol, “C-reactive protein: a “golden marker” for inflammation and coronary artery disease,” Cleveland Clinic Journal of Medicine, vol. 68, no. 6, pp. 521–534, 2001.
[15]
S. Volpato, J. M. Guralnik, L. Ferrucci et al., “Cardiovascular disease, interleukin-6, and risk of mortality in older women: the women's health and aging study,” Circulation, vol. 103, no. 7, pp. 947–953, 2001.
S. S. Anand, S. Yusuf, V. Vuksan et al., “Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE),” The Lancet, vol. 356, no. 9226, pp. 279–284, 2000.
[18]
P. C. Deedwania, M. Gupta, M. Stein, J. Y？as, and A. Gold, “Comparison of rosuvastatin versus atorvastatin in south-asian patients at risk of coronary heart disease (from the IRIS Trial),” American Journal of Cardiology, vol. 99, no. 11, pp. 1538–1543, 2007.
[19]
K. C. Ferdinand, L. T. Clark, K. E. Watson et al., “Comparison of efficacy and safety of Rosuvastatin versus Atorvastatin in African-American patients in a six-week trial,” American Journal of Cardiology, vol. 97, no. 2, pp. 229–235, 2006.
[20]
R. Lloret, J. Y？as, M. Stein, and S. Haffner, “Comparison of Rosuvastatin Versus Atorvastatin in Hispanic-Americans With Hypercholesterolemia (from the STARSHIP Trial),” American Journal of Cardiology, vol. 98, no. 6, pp. 768–773, 2006.
[21]
J. K. Liao, “Safety and efficacy of statins in Asians,” American Journal of Cardiology, vol. 99, no. 3, pp. 410–414, 2007.
[22]
R. McPherson, J. Frohlich, G. Fodor, and J. Genest, “Canadian Cardiovascular Society position statement—recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease,” Canadian Journal of Cardiology, vol. 22, no. 12, pp. 913–927, 2006.
[23]
M. Gupta, M. F. B. Braga, H. Teoh, M. Tsigoulis, and S. Verma, “Statin effects on LDL and HDL cholesterol in South Asian and white populations,” Journal of Clinical Pharmacology, vol. 49, no. 7, pp. 831–837, 2009.
[24]
T. A. Pearson, M. A. Denke, P. E. McBride, W. P. Battisti, W. E. Brady, and J. Palmisano, “A community-based, randomized trial of ezetimibe added to statin therapy to attain NCEP ATP III goals for LDL cholesterol in hypercholesterolemic patients: the ezetimibe add-on to statin for effectiveness (EASE) trial,” Mayo Clinic Proceedings, vol. 80, no. 5, pp. 587–595, 2005.
[25]
E. Lindmark, E. Diderholm, L. Wallentin, and A. Siegbahn, “Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy,” Journal of the American Medical Association, vol. 286, no. 17, pp. 2107–2113, 2001.
[26]
E. N. Deliargyris, R. J. Raymond, T. C. Theoharides, W. S. Boucher, D. A. Tate, and G. J. Dehmer, “Sites of interleukin-6 release in patients with acute coronary syndromes and in patients with congestive heart failure,” American Journal of Cardiology, vol. 86, no. 9, pp. 913–918, 2000.
[27]
J. C. Chambers, S. Eda, P. Bassett et al., “C-reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European whites,” Circulation, vol. 104, no. 2, pp. 145–150, 2001.
[28]
S. L. Janson, M. E. Alioto, and H. A. Boushey, “Attrition and retention of ethnically diverse subjects in a multicenter randomized controlled research trial,” Controlled Clinical Trials, vol. 22, supplement 6, pp. 236S–43S, 2001.
[29]
P. A. Areán, J. Alvidrez, R. Nery, C. Estes, and K. Linkins, “Recruitment and retention of older minorities in mental health services research,” Gerontologist, vol. 43, no. 1, pp. 36–44, 2003.
[30]
S. M. Stahl and L. Vasquez, “Approaches to improving recruitment and retention of minority elders participating in research: examples from selected research groups including the National Institute on Aging's Resource Centers for Minority Aging Research,” Journal of Aging and Health, vol. 16, supplement 5, pp. 9S–17S, 2004.
[31]
G. Moreno-John, A. Gachie, C. M. Fleming et al., “Ethnic minority older adults participating in clinical research: developing trust,” Journal of Aging and Health, vol. 16, supplement 5, pp. 93S–123S, 2004.
