Atherosclerosis 237 (2014) 319e335
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Review
Combination therapy in dyslipidemia: Where are we now? Alberico L. Catapano a, b, *, Michel Farnier c, JoAnne M. Foody d, Peter P. Toth e, f, Joanne E. Tomassini g, Philippe Brudi g, Andrew M. Tershakovec g a
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy IRCSS Multimedia, Milan, Italy c Point M edical, Dijon, France d Division of Cardiovascular Medicine, Department of Internal Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA e CGH Medical Centre, Sterling, IL, USA f Johns Hopkins University School of Medicine, Baltimore, MD, USA g Merck Sharp and Dohme Corp., Whitehouse Station, NJ, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 June 2014 Received in revised form 8 September 2014 Accepted 8 September 2014 Available online 30 September 2014
Lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of cardiovascular disease: each 1.0 mmol/L (38.7 mg/dL) reduction in LDL-C reduces the incidence of major coronary events, coronary revascularizations, and ischemic stroke by approximately 20%. Statins are a well-established treatment option for dyslipidemia, with LDL-C reduction in the range of 27e55%. Several lipid goal-driven guidelines recommend reducing LDL-C to 400 mg/dL [109,115,116]. 5.2.4. Ezetimibe In the SEAS trial, despite a 53% reduction in LDL-C, ezetimibe 10 mg plus simvastatin 40 mg did not reduce the primary composite endpoint of major aortic-valve-related events (AVE) and ischemic cardiovascular events (ICE) significantly more than placebo (35.3% vs 38.2%, respectively; P ¼ 0.59) during 4.4 years of therapy in patients (n ¼ 1873) with mild-to-moderate AS, and without known CHD [33]. For the secondary endpoints, there was no significant difference in AVE (aortic valve replacement, death from cardiovascular causes, hospitalization for heart failure) (P ¼ 0.73); however ICE (cardiovascular death, non-fatal acute myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, hospitalization for unstable angina pectoris, non-hemorrhagic stroke) was significantly reduced (22%; P ¼ 0.02) by ezetimibe plus simvastatin vs placebo. Further analysis showed that the combination reduced ICE risk by 47% and 36%, respectively, in the lower two tertiles of patients with less severe AS, consistent with that expected from the degree of LDL-C lowering achieved in SEAS, and based on the CTT meta-analysis of statin trials [34]. Lack of ICE risk reduction in patients with
more severe AS was possibly due to confounding by AS-related CVD events. In the recent SHARP study, ezetimibe plus simvastatin (20 mg) compared with placebo in CKD patients (n ¼ 3023 on dialysis and n ¼ 6247 not on dialysis [mean glomerular filtration rate 27 mL/ min]), showed a 17% (P ¼ 0.002) proportional reduction in the incidence of major atherosclerotic events ([MAE], nonfatal MI or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure) over 4.9 years [32]. The combination also significantly reduced major vascular events (MAE plus noncoronary cardiac deaths and hemorrhagic stroke) by 15% compared with placebo (P ¼ 0.0012). The reduction of CVD events per 1 mmol/l (38.7 mg/dL) reduction in LDL-C was proportional to the observed degree of LDL-C lowering and consistent with the CTT meta-analysis in patients without CKD [6]. While both SEAS and SHARP showed an overall reduction of cardiovascular ischemic events proportional to the degree of LDL-C lowering, an assessment of the impact of ezetimibe plus statin combination therapy vs statin monotherapy on clinical outcomes is ongoing in the IMPROVE-IT trial [35,96]. The trial is designed to assess the effect of the combination on cardiovascular outcomes in stabilized, high-risk ACS patients (~18,000), and evaluate any incremental clinical benefit of LDL-C lowering in a range lower than previously studied in any clinical trial (i.e. in patients who have already achieved an average LDL-C lowering to
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Review
Combination therapy in dyslipidemia: Where are we now? Alberico L. Catapano a, b, *, Michel Farnier c, JoAnne M. Foody d, Peter P. Toth e, f, Joanne E. Tomassini g, Philippe Brudi g, Andrew M. Tershakovec g a
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy IRCSS Multimedia, Milan, Italy c Point M edical, Dijon, France d Division of Cardiovascular Medicine, Department of Internal Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA e CGH Medical Centre, Sterling, IL, USA f Johns Hopkins University School of Medicine, Baltimore, MD, USA g Merck Sharp and Dohme Corp., Whitehouse Station, NJ, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 23 June 2014 Received in revised form 8 September 2014 Accepted 8 September 2014 Available online 30 September 2014
Lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of cardiovascular disease: each 1.0 mmol/L (38.7 mg/dL) reduction in LDL-C reduces the incidence of major coronary events, coronary revascularizations, and ischemic stroke by approximately 20%. Statins are a well-established treatment option for dyslipidemia, with LDL-C reduction in the range of 27e55%. Several lipid goal-driven guidelines recommend reducing LDL-C to 400 mg/dL [109,115,116]. 5.2.4. Ezetimibe In the SEAS trial, despite a 53% reduction in LDL-C, ezetimibe 10 mg plus simvastatin 40 mg did not reduce the primary composite endpoint of major aortic-valve-related events (AVE) and ischemic cardiovascular events (ICE) significantly more than placebo (35.3% vs 38.2%, respectively; P ¼ 0.59) during 4.4 years of therapy in patients (n ¼ 1873) with mild-to-moderate AS, and without known CHD [33]. For the secondary endpoints, there was no significant difference in AVE (aortic valve replacement, death from cardiovascular causes, hospitalization for heart failure) (P ¼ 0.73); however ICE (cardiovascular death, non-fatal acute myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, hospitalization for unstable angina pectoris, non-hemorrhagic stroke) was significantly reduced (22%; P ¼ 0.02) by ezetimibe plus simvastatin vs placebo. Further analysis showed that the combination reduced ICE risk by 47% and 36%, respectively, in the lower two tertiles of patients with less severe AS, consistent with that expected from the degree of LDL-C lowering achieved in SEAS, and based on the CTT meta-analysis of statin trials [34]. Lack of ICE risk reduction in patients with
more severe AS was possibly due to confounding by AS-related CVD events. In the recent SHARP study, ezetimibe plus simvastatin (20 mg) compared with placebo in CKD patients (n ¼ 3023 on dialysis and n ¼ 6247 not on dialysis [mean glomerular filtration rate 27 mL/ min]), showed a 17% (P ¼ 0.002) proportional reduction in the incidence of major atherosclerotic events ([MAE], nonfatal MI or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure) over 4.9 years [32]. The combination also significantly reduced major vascular events (MAE plus noncoronary cardiac deaths and hemorrhagic stroke) by 15% compared with placebo (P ¼ 0.0012). The reduction of CVD events per 1 mmol/l (38.7 mg/dL) reduction in LDL-C was proportional to the observed degree of LDL-C lowering and consistent with the CTT meta-analysis in patients without CKD [6]. While both SEAS and SHARP showed an overall reduction of cardiovascular ischemic events proportional to the degree of LDL-C lowering, an assessment of the impact of ezetimibe plus statin combination therapy vs statin monotherapy on clinical outcomes is ongoing in the IMPROVE-IT trial [35,96]. The trial is designed to assess the effect of the combination on cardiovascular outcomes in stabilized, high-risk ACS patients (~18,000), and evaluate any incremental clinical benefit of LDL-C lowering in a range lower than previously studied in any clinical trial (i.e. in patients who have already achieved an average LDL-C lowering to
