Supplement: Tables Supplement Table 1. Study Eligibility Criteria Supplement Table 2. Categorization of Statin Intensity Based on Potential Low-Density Lipoprotein Cholesterol Reduction Supplement Table 3. Index of Included Trials by Combination Therapy Agent Supplement Table 4. All Adverse Events Reported in Included Trials by Combination Therapy Agent
Supplement Table 1. Study Eligibility Criteria Population and condition of interest Interventions and approaches Comparisons of interest Outcomes and Timing Adults at high-risk for ASCVD including those with preexisting ASCVD (acute coronary syndromes, or a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin), baseline LDL-c 190 mg/dl (4.91 mmol/l) or trial inclusion criteria LDL-c 190 mg/dl (4.91 mmol/l), preexisting diabetes mellitus. Excluded studies if they included only adults with low or moderate ASCVD risk Excluded studies that included only patients with homozygous familial hypercholesterolemia (FH) Studies must have evaluated a combination regimen of interest Included studies of bile acid sequestrants + statin Included studies of ezetimibe + statin Included studies of fibrates + statin Included studies of niacin + statin Included studies of omega-3 fatty acids + statin Excluded studies of lifestyle modifications Excluded studies of drugs approved only for the treatment of homozygous FH Excluded studies of drugs not approved by the FDA or investigational drugs Excluded studies of prepackaged medications that contained non lipid-lowering medications Included comparisons of higher intensity statin monotherapy Excluded studies if a study statin monotherapy was of the same or lower intensity than combination arm Excluded studies if there was no comparison or only placebo comparison Clinical outcomes including mortality, acute coronary events, cerebrovascular events, revascularization procedures at any time point Surrogate outcomes including LDL-c at any time point Adherence (investigator defined) at any time point Harms outcomes (investigator defined) including serious adverse events, withdrawal due to adverse events at any time point Type of study Included studies from the prior report that met all other criteria Included randomized controlled trials Included non-randomized extension of clinical trial over 24 weeks duration (clinical outcomes, SAE and harms only) Included FDA reports (SAE and harms only) Excluded studies with other observational designs Excluded studies with no original data (e.g., reviews, editorials, comments, letters) Excluded studies published only as abstracts Excluded qualitative studies Excluded crossover trials with fewer than 4 weeks washout and/or lacking paired observation, within person differences, or pre-crossover data Excluded non-english publications Abbreviations: ASCVD atherosclerotic cardiovascular disease; FH familial hypercholesterolemia; FDA Food and Drug Administration; LDL-c low-density lipoprotein cholesterol; RCT randomized controlled trial; SAE serious adverse event.
Supplement Table 2. Categorization of Statin Intensity Based on Potential Low-Density Lipoprotein Cholesterol Reduction Statin Low Intensity (<30% LDL-c reduction) Mid Intensity (30-40% LDL-c reduction) High Intensity (>40% LDL-c reduction) Atorvastatin Fluvastatin Fluvastatin XL 5 20 and/or 40 -- Lovastatin 5 and/or 10 and/or 20 Pitavastatin 1 Pravastatin 10 and/or 20 and/or 40 Rosuvastatin Simvastatin -- 10 10 80 80 40 and/or 80 2 and/or 4 80 2.5 20 20 and/or 40 and/or 80 -- -- -- -- -- 5 and/or 10 and/or 20 and/or 40 Abbreviations: LDL-c low-density lipoprotein cholesterol. *Studies that use simvastatin 80mg in statin naïve patients were excluded. 40 and/or 80*
Supplement Table 3. Index of Included Trials by Combination Therapy Agent Author, Year (Reference) Bile acid sequestrants Ismail, 1990 (30) Barbi, 1992 (31) Johansson, 1995 (28) Knapp, 2001 (29) Pravastatin Multicenter Study Group II, 1993 (32) Schrott, 1995 (33) Ezetimibe Araujo, 2010 (34) McKenney, 2007 (36) Averna, 2010 (19) Bardini, 2010 (38)*** Barrios, 2005 (39) Cho, 2011 (40) Hamdan, 2011 (43) Matsue, 2012 (44) Okada, 2011 (45) Therapeutic Regimen (Intensity) in Eligible Arms M: PRV 80mg (mid) C: Cholestyramine 24g + PRV 40mg (low) C1: Colestipol 5g + SMV 20g (mid) C2: Colestipol 10g + SMV 20mg (mid) M: SMV 20mg (mid) C: Colesevelam 3.8g + SMV 10mg (low) M: PRV 80mg (mid) C: Cholestyramine 24g + PRV 40mg (low) M: LOV 40mg (mid) C1: Colestipol 5g + LOV 20mg (low) C2: Colestipol 10g + LOV 20mg (low) M: SMV 80mg (high) C: Ezetimibe 10mg + SMV 10mg (low) M: RSV 20mg (high) M1: RSV 5mg (high) M2: ATV 20mg (high) C1: Ezetimibe 10mg + RSV 2.5mg (mid) C2: Ezetimibe 10mg + ATV 10mg (mid) Baseline N in Eligible Arms by Population Outcome(s) Reported HLD CVD DM Clinical* LDL-c Adherence Harms 18 X 83 X 73 X X 127 X 70 X X 23 X 145 X X X 112 X X X 87 87 X X X 435 NR** X X 85 X X X 93 X X 243 X 165 X
Ostad, 2009 (20) Pesaro, 2012 (41) Pesaro, 2013 (42) Piorkowski, 2007 (37) Roeters van Lennep, 2007 (21) Yamazaki, 2013 (46) Zieve, 2010 (47) Ben-Yehuda, 2011 (48) Bays, 2013 (49) Constance, 2007 (22) Foody, 2010 (53) Gaudiani, 2005 (56) Goldberg, 2006 (50) Guyton, 2007 (51) Tomassini, 2009 (52) Kawagoe, 2011 (57) Lee, 2013 (54) Rosen, 2013 (23) Jimenez, 2013 (24) Rosen, 2013 (25) Rudofsky, 2012 (35) Torimoto, 2013 (55) M: ATV 80mg (high) M: SMV 80mg (high) M: ATV 40mg (high) M1: ATV 20mg (high) M: RSV 10mg (high) C: Ezetimibe 10mg + RSV 2.5mg (mid) M1: RSV 10 mg (high) M2: ATV 20mg (high) M1: ATV 40mg (high) M2: ATV 20mg (high) C1: Ezetimibe 10mg + SMV 20mg (mid) M1: ATV 40mg (high) M2: ATV 20mg (high) M: FLV 60mg (mid) C: Ezetimibe 10mg + FLV 20mg (low) M1: RSV 10mg (high) M3: ATV 20mg (high) M: SMV 80mg (high) C: Ezetimibe 10mg + SMV 10mg (low) M: RSV 5mg (high) C: Ezetimibe 10mg + RSV 2.5mg (mid) 49 X X X 78 X X 51 X 367 X 46 X 891** 223** X 733** X 439 X X X X NR** X 214 X X 737 X 24 X 132 X X 808 X X X 21 X 75 X Fibrates Athyros, 2002 (58) 654 X X
Shah, 2007 (59) Farnier, 2011 (26) Niacin C1: Gemfibrozil 1200mg + SMV 20mg (mid) C2: Ciprofibrate 100mg + SMV 20mg (mid) C3: Gemfibrozil 1200mg + PRV 20mg (low) C4: Ciprofibrate 100mg + PRV 20mg (low) M1: ATV 20mg (high) C1: Fenofibrate 200mg + ATV 10mg (mid) C2: Fenofibrate 200mg + SMV 20mg (mid) M: SMV 20mg (mid) C: Fenofibrate 160mg + PRV 40mg (low) 102 X X 291 X X X X Bays, 2003 (60) M1: ATV 40mg (high) C1: Niacin-ER 1g + LOV 40mg (mid) C2: Niacin-ER 2g + LOV 40mg (mid) 315 X X X Hunninghake, 2003 (27) M: LOV 40mg (mid) C: Niacin-ER 1g + LOV 20mg (low) 118 X X X M: LOV 40mg (mid) Insull, 2004 (61) C1: Niacin-ER 2.5g + LOV 10mg (low) C2: Niacin-ER 2.5g + LOV 20mg (low) 101 X X X Abbreviations: ATV atorvastatin; C combination therapy; CVD population with preexisting atherosclerotic cardiovascular disease; DM population with diabetes mellitus; FLV fluvastatin; HLD population with LDL-c>= 190 mg/dl; LDL-c low-density lipoprotein cholesterol; LOV lovastatin; M monotherapy; NR not reported; PRV pravastatin; RSV rosuvastatin; SMV simvastatin. *Clinical outcomes include mortality, acute coronary events, cerebrovascular events, and/or revascularization procedures. **Indicates this population was included as part of a subgroup analysis in this trial. ***Inclusion criteria for this trial included CHD and DM.
Supplement Table 4. All Adverse Events Reported in Included Trials by Combination Therapy Agent Author, Year (Reference) Bile acid sequestrants Knapp, 2001 (29) Ezetimibe Averna, 2010 (19) Bardini, 2010 (38) Barrios, 2005 (39) Cho, 2011 (40) Therapeutic Regimen (Intensity) in Eligible Arms M: SMV 20mg (mid) C: Colesevelam 3.8g + SMV 10mg (low) Time Point (Population) (HLD) (CVD, DM) Adverse Event and/or hepatitis Elevation in CPK 10 times ULN and/or hepatitis Elevation in CPK 10 times ULN Elevation in CPK 10 times ULN and/or hepatitis Events Reported (%) C: 1 (3%) M: 1 (2%) M: 1 (2%) M: 13 (22%) C: 13 (22%) C: 1 (2%) M: 2 (4%) C: 1 (3%) M: 10 (20%) C: 5 (12%) M: 2 (1%) C: 5 (2%) M: 8 (4%) C: 5 (2%) M: 51 (24%) C: 44 (20%) C: 1 (<1%) M: 1 (3%) Between Group Difference p=0.47 p=0.45 p=0.40 p=0.45 p=0.41 p=0.35
Constance, 2007 (22) Gaudiani, 2005 (56) Hamdan, 2011 (43) Lee, 2013 (54) McKenney, 2007 (36) Ostad, 2009 (20) Pesaro, 2012 (41) Pesaro, 2013 (42) Rosen, 2013 (23) Jimenez, 2013 (24) M: RSV 20mg (high) M: ATV 80mg (high) M: SMV 80mg (high) M1: RSV 10mg (high) (DM) 24 weeks (DM) 12 weeks 12 weeks (DM) 12 weeks (HLD) 8 weeks (DM) Elevation in CPK 10 times ULN CPK >10 times ULN and/or hepatitis Elevation in AST/ALT >3 times ULN Elevation in CPK>10 times ULN and/or hepatitis M: 5 (2%) C: 1 (<1%) M: 2 (1%) C: 3 (1%) M: 42 (19%) C: 51 (23%) C: 1 (<1%) M: 1 (1%) C: 5 (5%) M: 5 (5%) C: 2 (2%) M: 11 (10%) C: 19 (18%) C: 1 (1%) M: 10 (22%) C: 2 (4%) M: 1 (2%) C: 3 (5%) M: 1 (1%) M: 5 C: 2 M1: 2 (1%) M2/3: 1 (1%) p=0.12 p=0.40 p=0.11 p=0.45 p=0.11 p=0.48 p=0.01 p=0.62 p=0.42 M1 vs c: M2/3 vs C:
Rosen, 2013 (25) Fibrates Athyros, 2002 (58) Farnier, 2011 (26) Shah, 2007 (59) Niacin Bays, 2003 (60) M3: ATV 20mg (high) C1: Gemfibrozil 1200mg + SMV 20mg (mid) C2: Ciprofibrate 100mg + SMV 20mg (mid) C3: Gemfibrozil 1200mg + PRV 20mg (low) C4: Ciprofibrate 100mg + PRV 20mg (low) M: SMV 20mg (mid) C: Fenofibrate 160mg + PRV 40mg (low) M1: ATV 20mg (high) C1: Fenofibrate 200mg + ATV 10mg (mid) C2: Fenofibrate 200mg + SMV 20mg (mid) M1: ATV 40mg (high) 52 weeks (HLD) 12 weeks (DM) 13 weeks 1 (HLD) Elevation in CPK>10 times ULN Elevation in AST and/or ALT > 3 times ULN Elevation in CPK Elevation in CPK > 5 times ULN Change in Cr > 20 mg/ml or CrCl<50 ml/min Elevation in AST or ALT > 3 times ULN C: 2 (1%) M1: 1 (<1%) M2/3: 3 (2%) C: 7 (2%) M1: 28 (9%) M2/3: 13 (9%) C: 33 (10%) M1: 1 (<1%) M2/3: 0 M1: 0 M2/3: 0 C1: 3 (2%) C2: 3 (2%) C3: 1 (1%) C4: 0 C1: 1 (1%) C2: 0 C3: 1 (15) C4: 0 M: 1 (1%) C: 1 (1%) M: 22 (15%) C: 25 (17%) M1: 0 M2: 2 (9%) C1: 0 C2: 0 M1: 0 M2: 0 M1 vs C: p=0.06 M2/3 vs C: M1 vs C: p=0.48 M2/3 vs C: p=0.42 M1 vs c: M2/3 vs C: p=0.84 p=0.29 p=0.73 p=0.89
C1: Niacin-ER 1g + LOV 40mg (mid) C2: Niacin-ER 2g + LOV 40mg (mid) C1: 0 C2: 0 Elevation in CPK > 5 times ULN M1: 0 M2: 0 C1: 0 C2: 0 M: (19%) C: (10%) p=0.06 Elevation in AST or ALT >3 times ULN M: 1 NR Hunninghake, 2003 M: LOV 40mg (mid) 28 weeks Elevation in CPK > 10 times ULN (27) C: Niacin-ER 1g + LOV 20mg (low) (HLD) M: 4 (7%) C: 2 (4%) p=0.68 Elevation in fasting glucose > 1.3 times ULN M: (7%) C (4%) p=0.68 M: 17 (52%) C1: 15 (44%) C2: 21 (62%) p=0.84 Insull, 2004 (61) Elevation in AST or ALT > 3 times ULN C1: 1 (3%) M: LOV 40mg (mid) 20 weeks C2: 1 (3%) C1: Niacin-ER 2.5g + LOV 10mg (low) (HLD) C2: Niacin-ER 2.5g + LOV 20mg (low) Elevation in CPK > 3 times ULN C1: 0 C2: 0 Hyperglycemia C1: 2 (6%) C2: 1 (3%) p=0.77 Abbreviations: AE adverse event; ALT alanine aminotransferase; AST aspartate aminotransferase; ATV atorvastatin; C combination therapy; CVD population with preexisting atherosclerotic cardiovascular disease; CI confidence interval; CPK creatinine phosphokinase; Cr creatinine; CrCl creatinine clearance; DM population with diabetes mellitus; FLV fluvastatin; HLD population with LDL-c >=190 mg/dl; LOV lovastatin; M monotherapy; not applicable; NR not reported and unable to calculate from information provided; NS not significant; PRV pravastatin; RSV rosuvastatin; SMV simvastatin; ULN upper limit of normal.