Sompongse Suwanwalaikorn, MD

Options to achieve low LDL-C targets  Use maximal doses of currently available statins  Consider new mega-statins  Consider combination therapy  Use maximal doses of currently available statins  Consider new mega-statins  Consider combination therapy

Simvastatin Efficacy in Familial Hypercholesterolemia randomized, double blind study, N = 110 pts. LDL 251 mg/dl; Trig 168 mg/dl; HDL 50 mg/dl Clin Drug Invest 1995;10: randomized, double blind, placebo controlled study N = 2221 pts. LDL 188 mg/dl; TG 132 mg/dl; HDL 45 mg/dl 4S Study. Lancet 1994;344: Nutr Metab Cardiov Dis 1998;8: ; randomized, double blind study N = 355 LDL 240 mg/dl; Trigl 159 mg/dl (TG-1); HDL 48.6 Subgroup of pts with triglycerides mg/dl (TG-2, N = 83) Simvastatin 10 mg Simvastatin 40 mg Simvastatin 20 mg Simvastatin 80 mg

IDEAL Trial: Safety & Tolerability Profile in Real World Parameter Simvastatin 20/40mg (n = 4,449) Atorvastatin 40/80mg (n = 4,439) P value Any adverse event resulting in permanent discontinuation of study drug 186 (4.2%)426 (9.6%)<.001 AST ≥ 3 X ULN at 2 consecutive measurements 2 (0.04%)18 (0.41%)<.001 ALT ≥ 3 X ULN at 2 consecutive measurements 5 (0.11%)43 (0.97%)<.001 Down-titration to atorvastatin 40mg (from Atorvastatin 80mg) due to adverse events: 587 (13%) JAMA, Nov 16, 2005-Vol 294, No. 19

Br J Cardiol 2004 Adverse event withdrawal rates of statins

Br J Cardiol 2004 Myopathy in association with statins is dose-related

Options to achieve low LDL-C targets  Use maximal doses of currently available statins  Consider new mega-statins  Consider combination therapy  Use maximal doses of currently available statins  Consider new mega-statins  Consider combination therapy

8 LDL Reduction by Individual Statins 5 mg10 mg20 mg40 mg80 mg Fluvastatin21%24% Lovastatin21%24%30%40% Pravastatin22%32%34% Simvastatin22%30%35%41%47% Atorvastatin39%43%50%60% Rosuvastatin45%52%58%69% In general, doubling dose = additional 6% reduction in LDL Source: Gau G, Mayo Clinic Cardiovascular Review

Atorvastatin (n=78) Simvastatin (n=76) Lovastatin (n=78) Fluvastatin (n=76) First titration % Patients reaching goal Percentage of Patients Reaching Goal with Starting Dose and after First Titration Adapted from Brown AS J Am Coll Cardiol 1998;32:665– % 31% 53% 22% 39% 10% 1% 10% 10 Initial dose

LDL-C reduction across statin dose ranges in the STELLAR study Br J Cardiol 2004

Change in HDL-C across statin dose ranges in the STELLAR study

Options to achieve low LDL-C targets  Use maximal doses of currently available statins  Consider new mega-statins  Consider combination therapy  Use maximal doses of currently available statins  Consider new mega-statins  Consider combination therapy

13 Theoretical Basis for Combination Rx  Multiple pathogenetic pathways of cholesterol in development of CAD  Differential effects of various lipid- lowering agents:  Act on different pathways  Target different lipid particles

Net Cholesterol Balance in Humans

Indications for Combination Rx  Treatment goals not met with single agent  Risk of intolerance, toxicity, or adverse drug  interactions with higher dose of single agent  Perceived benefit from ≥ 2 agents due to complementary: Mechanisms of actionMechanisms of action Effects on different lipidsEffects on different lipids Effects on CHD riskEffects on CHD risk

Agents Commonly Used in Combination with Statins  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe

17 Agents Commonly Used in Combination with Statins  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe

Bile Acid Sequestrants: Favorable Lipid Effects of Colesevelam with Statins % Change vs Statin Alone ColesevelamStatin TCLDL-CHDL-CTG 2300 mg (~4 tablets) Lovastatin 10 mg –7–12 to –10–3 to –1–8 to mg (~4 tablets) Simvastatin 20 mg –6–8– mg (6 tablets) Simvastatin 10 mg –9– mg (6 tablets) Atorvastatin 10 mg –4– Bays H, et al. Expert Opin Pharmacother. 2003;4:

Agents Commonly Used in Combination with Statins  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe

PPAR- Agonists (Fibrates) and Statins  Combination may significantly improve TG, LDL-C, and HDL-C levels  Fibrates plus statins associated with increased risk for myopathy and rhabdomyolysis  Probably not due to cytochrome P450 drug interaction  Gemfibrozil may impair glucuronidation of statins  Fenofibrate may have relatively less potential for impairment of statin metabolism  Combination may significantly improve TG, LDL-C, and HDL-C levels  Fibrates plus statins associated with increased risk for myopathy and rhabdomyolysis  Probably not due to cytochrome P450 drug interaction  Gemfibrozil may impair glucuronidation of statins  Fenofibrate may have relatively less potential for impairment of statin metabolism Ballantyne CM, et al. Arch Intern Med. 2003;163: Bays H. Am J Cardiol. 2002;90:30K-43K. Bays HE, et al. Expert Opin Pharmacother. 2003;4: Bays H. Am J Cardiol. 2002;90:30K-43K. Bays HE, et al. Expert Opin Pharmacother. 2003;4:

Adding Fibrate to Statin Rx Improves Profile of Atherogenic Dyslipidemia in Patients with Metabolic Sydrome Mean mg/dL Mean ratio large/small LDL Vega. Am J Cardiol. 2003;91:956. * P ≤0.05 vs. placebo; † P ≤0.05 vs. simvastatin alone * * † † simvastatin fenofibratesimvastatin+fenofibrate

Percentage of patients reaching ADA lipid targets Diabetes Care 2002;25: LDLTGHDL % of patients reaching ADA goals Atorvastatin 20 mgFenofibrate 200 mgAtorvastatin 20 mg + Fenofibrate 200 mg

Clinical Trials of Fibrates  Statins  FIELD (Fenofibrate Intervention and Event Lowering in Diabetes)  9,000 patients with diabetes  Fenofibrate vs. placebo  No statistically significant difference in the primary composite endpoint of CHD death or nonfatal MI.  A significant reduction in nonfatal MI  ACCORD (Action to Control Cardiovascular Risk in Diabetes)  5800 patients with type 2 diabetes in fibrate substudy  Fenofibrate + statin vs. placebo + statin  Study completion FIELD. Available at: Accessed March 2, ACCORD. Available at: Accessed March 2, 2005.

PPAR- Agonists (TZDs) and Statins  Metabolic effects of TZDs may be complementary to lipid-altering effects of statins:  Increased LDL-C particle size  Reduced TG levels (with pioglitazone)  Increased HDL-C levels (with pioglitazone and rosiglitazone)  Number of LDL particles  Unchanged with pioglitazone  Potentially worsened with rosiglitazone Bays HE. Br J Diabetes Vascular Dis. 2003;3: Ginsberg HN. Am J Cardiol. 2003;91:29E-39E.

Agents Commonly Used in Combination with Statins  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe

Fish Oils and Statins  Marine fish oils rich in omega-3 fatty acids: Lower TG levels Lower TG levels May be alternative to fibrate plus statin May be alternative to fibrate plus statin  Other CV effects complementary to statins: Reduction in malignant ventricular dysrhythmias Reduction in malignant ventricular dysrhythmias Increased heart rate variability Increased heart rate variability Antithrombotic effects Antithrombotic effects Improved endothelial reactivity/relaxation Improved endothelial reactivity/relaxation Anti-inflammatory effects Anti-inflammatory effects Slight lowering of blood pressure Slight lowering of blood pressure  Marine fish oils rich in omega-3 fatty acids: Lower TG levels Lower TG levels May be alternative to fibrate plus statin May be alternative to fibrate plus statin  Other CV effects complementary to statins: Reduction in malignant ventricular dysrhythmias Reduction in malignant ventricular dysrhythmias Increased heart rate variability Increased heart rate variability Antithrombotic effects Antithrombotic effects Improved endothelial reactivity/relaxation Improved endothelial reactivity/relaxation Anti-inflammatory effects Anti-inflammatory effects Slight lowering of blood pressure Slight lowering of blood pressure Bays HE, et al. Expert Opin Pharmacother. 2003;4: Kris-Etherton PM, et al. Circulation. 2002;106:

27 Commercial Fish Oil Preparations  Capsules available containing >1000 mg omega- 3 fatty acids, including:  Eicosapentaenoic acid (EPA)  Docosahexaenoic acid (DHA)  TG benefits usually associated with combined dose of EPA + DHA of 4 g/d to 9 g/d  Side effects include fishy aftertaste and dyspepsia  Inconsistent reports of early, short-lived, potential increase in blood glucose levels in patients with diabetes mellitus Bays HE, et al. Expert Opin Pharmacother. 2003;4: Kris-Etherton PM, et al. Circulation. 2002;106:

Fish Oil and Hematologic Factors  May impair platelet aggregation and increase bleeding time  Potentially reduces risk for thrombosis  Concomitant use with anticoagulants (aspirin or warfarin):  No significant increase in risk of bleeding in clinical trials  May impair platelet aggregation and increase bleeding time  Potentially reduces risk for thrombosis  Concomitant use with anticoagulants (aspirin or warfarin):  No significant increase in risk of bleeding in clinical trials Bays HE, et al. Expert Opin Pharmacother. 2003;4: Kris-Etherton PM, et al. Circulation. 2002;106:

Agents Commonly Used in Combination with Statins  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe

Role of Niacin in Combination Therapy  As monotherapy, niacin effects include:  Increases in HDL-C  Decreases in LDL-C, triglycerides, lipoprotein(a)  Converts small LDL into more buoyant (less atherogenic) particles  Safe and effective in combination with statins or bile acid sequestrants  Consider tolerability profiles of different formulations  May adversely effect glucose, insulin sensitivity  As monotherapy, niacin effects include:  Increases in HDL-C  Decreases in LDL-C, triglycerides, lipoprotein(a)  Converts small LDL into more buoyant (less atherogenic) particles  Safe and effective in combination with statins or bile acid sequestrants  Consider tolerability profiles of different formulations  May adversely effect glucose, insulin sensitivity Miller M. Mayo Clin Proc. 2003;78:735.

31 Niaspan ® Combination Therapy When Response to Statin is Insufficient Addition of Niaspan to Stable Dose of a Statin Wolfe et.al. Am J Cardiol 2001; 87: g NIASPAN (n=66)2g NIASPAN (n=29) Percent Change from baseline TCLDLHDLTG -23% 23% 24% -24% -30% -8% -18%

Niacin in Combination with Statins  Stein et al—17-week randomized trial; N=180  Immediate-release niacin plus simvastatin more effective than either drug alone at raising HLD-C and lowering VLDL-C  Guyton et al—48-week open-label trial; N=269  ER niacin plus statin (lovastatin, pravastatin, simvastatin):  Reduced TC 23%; LDL-C 32%; TG 30%; Lp(a) 19%  Increased HDL-C 26% Stein et al. J Cardiovasc Pharmacol Ther. 1996;1:107. Guyton et al. Am J Cardiol. 1998;82:737.

% Change from Baseline Week 8Week 12 Niacin ER+L (1000/40 mg) Atorvastatin (10 mg) Niacin ER+L (1000/40 mg) Simvastatin (20 mg) LDL-C –38%* –42%*–35% HDL-C +20%* † +3%+19%* † +8% TG –30%* † –20%–36%* † –15% Lp(a) –16%* † +8%–20%* † –1% Enhanced Lipid-lowering with Combination Niacin Extended-release Plus Lovastatin vs Statin Monotherapy Bays H, et al. Am J Cardiol. 2003;91: *P≤ 0.05 vs simvastatin; † P ≤0.05 vs atorvastatin *P≤ 0.05 vs simvastatin; † P ≤ 0.05 vs atorvastatin

Issues of Safety and Tolerability of Niacin and Fibrates  Niacin  Chief complaint is flushing, intolerable in 10% of patients  Also conjunctivitis, nasal stuffiness, loose stools/diarrhea, acanthosis nigricans, ichthyosis, hepatitis  Fibrates  Abdominal discomfort, possible gallstones  Myositis with impaired renal function  Increased risk of rhabdomyolysis with fibrate or niacin + statin Knopp RH. N Engl J Med. 1999;341: ; Jones PH, Davidson MH. Am J Cardiol. 2005;95: ; Bellosta S, et al. Circulation. 2004;109(23 Suppl 1):III50-57 Statin No. of Cases of Rhabdomyolysis Associated With: FibratesNiacin Atorvastatin10 Not reported Fluvastatin4 Lovastatin51 Pravastatin61 Simvastatin332

Agents Commonly Used in Combination with Statins  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe  Bile acid sequestrants  PPAR agonists (fibrates)  Fish oils  Niacin  Ezetimibe

Increased biliary cholesterol secretion in patients with obesity Ref; Mok, von Bergmann,Grundy, Journal of Lipid Research 20, 389, 1979 Non-obeseObese Cholesterol secretion (mg/day) Absorption 1451 mg/day Absorption 666 mg/day Absorption rate 63% 59%

CHD (+)CHD (-) CHD (+)CHD (-) Increased cholesterol absorption in diabetic patients with CHD Cholesterol Absorption p<0.05 NS (%) (mg/kg/d) Gylling H, Miettinen TA: Atherosclerosis 1996; 126: CHD (+) ： n=7, Total chol: 6.01±0.33 (mmol) CHD (-): n=6, Total chol: 6.25±0.27 (mmol) Cholesterol Synthesis

BLOOD Chylomicrons Remnants DIET Micelles Free cholesterol Cholesterol Bile acids Unstirred water layer Synthesis FC biosynthesis ACAT Cholesteryl Ester (CE) FC ENTEROCYTE Brush Border Plaque formation CE Bile acid sequestrants X Sterols/ stanols XX Statins X Cholesterol Absorption Inhibitors (e.g., ezetimibe) X Ezetimibe Blocks Cholesterol Metabolism at a New Site

Ezetimibe: Indications  Hypercholesterolemia  Monotherapy  Combination therapy with statins  Homozygous familial hypercholesterolemia  Homozygous sitosterolemia Note: no data are yet available on effects of ezetimibe (alone or in combination therapy) on CHD morbidity and mortality  Hypercholesterolemia  Monotherapy  Combination therapy with statins  Homozygous familial hypercholesterolemia  Homozygous sitosterolemia Note: no data are yet available on effects of ezetimibe (alone or in combination therapy) on CHD morbidity and mortality Bays H. Expert Opin Investig Drugs. 2002;11:

Ezetimibe: Mechanism of Action  Selective inhibition of intestinal cholesterol absorption  Intestinal delivery of cholesterol to liver  Expression of hepatic LDL receptors  Cholesterol content of atherogenic particles  Enterohepatic circulation of ezetimibe and active glucuronide metabolite Delivers agent back to site of action Limits systemic exposure  Selective inhibition of intestinal cholesterol absorption  Intestinal delivery of cholesterol to liver  Expression of hepatic LDL receptors  Cholesterol content of atherogenic particles  Enterohepatic circulation of ezetimibe and active glucuronide metabolite Delivers agent back to site of action Limits systemic exposure Bays H. Expert Opin Investig Drugs. 2002;11:

Low Systemic Exposure of Ezetimibe May Reduce Potential for Adverse Effects/ Drug Interactions van Heek M, et al. Br J Pharmacol. 2000;129: h post- 3 H ezetimibe IV dosing Intestinal wall PlasmaLiverBile Intestinal lumen 3 H-DPM (x 10 –6 )

Ezetimibe: Dosage and Administration  10 mg once daily  Any time of day, with or without food  May be taken concomitantly with statin  Dosage adjustment not necessary according to  Gender  Mild hepatic or renal insufficiency  Age (ie, elderly)  Ezetimibe not recommended in children <10 years old  10 mg once daily  Any time of day, with or without food  May be taken concomitantly with statin  Dosage adjustment not necessary according to  Gender  Mild hepatic or renal insufficiency  Age (ie, elderly)  Ezetimibe not recommended in children <10 years old Bays H. Expert Opin Investig Drugs. 2002;11:

Ezetimibe: Contraindications  Hypersensitivity to any component of agent  Combination with statins in patients with active liver disease or unexplained persistent elevations in serum transaminases  Pregnancy C category as monotherapy (no adequate studies in pregnant women)  All statins are contraindicated in pregnant and nursing women  Precaution: Moderate or severe hepatic insufficiency  Hypersensitivity to any component of agent  Combination with statins in patients with active liver disease or unexplained persistent elevations in serum transaminases  Pregnancy C category as monotherapy (no adequate studies in pregnant women)  All statins are contraindicated in pregnant and nursing women  Precaution: Moderate or severe hepatic insufficiency Bays H. Expert Opin Investig Drugs. 2002;11:

LDL-C Ezetimibe “Add On” Study: Improved Lipid Profiles Gagné C, et al. Am J Cardiol. 2002;90: *P<0.001; † P<0.05; ‡ P<0.001 –25.1* 1.0 –2.9 –14.0 ‡ HDL-CTG – † % Reduction from Baseline at Week Statin + Placebo (n=390) Statin + Ezetimibe 10 mg (n=379)

LDL-C Reduction across the Dose Range *p<0.001 vs. corresponding dose of simvastatin Adapted from Goldberg AC et al Mayo Clin Proc 2004;79:620–629. VYTORIN ™ (ezetimibe/simvastatin) is a trademark of MSP Singapore Company, LLC. Mean % change from baseline to week 12 0 –20 –30 –40 –50 –10 –70 –60 10/20 mg (n=86) –51%* 20 mg (n=89) –35% 10/40 mg (n=89) –55%* 40 mg (n=90) –42% 10/80 mg (n=91) –61%* 80 mg (n=87) –46% Simvastatin VYTORIN ™ vs. Simvastatin Efficacy Study VYTORIN

Ezetimibe “Add On” Study: Marked Increase in Patients Reaching Treatment Goals Gagné C, et al. Am J Cardiol. 2002;90: % * 19%19% Statin + Placebo (n=390) Statin + Ezetimibe (n=379) Patients at NCEP Goal (%) *P<

47 Ezetimibe + Statin: Effects on LDL-C with Each Statin Tested Lovastatin Mono + ezetimibe (n=220) (n=192) Pravastatin Mono + ezetimibe (n=205) (n=204) Simvastatin Mono + ezetimibe (n=263) (n=274) Atorvastatin Mono + ezetimibe (n=248) (n=255) Lovastatin ezetimibe + Statin Mean % Change in LDL-C From Untreated Baseline All data are pooled across doses; * p < 0.01 for ezetimibe + statin vs statin alone. Simvastatin Pravastatin Atorvastatin –25% –36% –44% –40% * –39% * –51% * –56% * –70% –60% –50% –40% –30% –20% –10% 0% Ballantyne CM et al. Circulation 2003; 107: Melani L et al. Eur Heart J 2003;24: Davidson MH et al. J Am Coll Cardiol 2002;40(12): Kerzner B et al. Am J Cardiol 2003;91(4)

Effect of Ezetimibe on LDL-C in Type 2 Diabetes Subgroup Total Population % Change From Baseline Statin and EZE (n=90) Statin and PBO (n=98) * p<0.001 vs statin + placebo * Simons et al. EASD 2002 Diabetes Subgroup *

Changes in Other Cardiovascular Parameters *Except for CRP, shown as median percent changes **p<0.001 vs. simvastatin 10–80 mg Mean* % change from baseline to week 12 –20 –40 – –29% –42%** –9% –33%** Apo B CRP –34% –49%** Non–HDL-C Eze/Simva 10/10–10/80 mg pooled doses Simvastatin 10–80 mg pooled doses Eze/Simva 10/10–10/80 mg pooled doses Simvastatin 10–80 mg pooled doses (n=340) (n=328) (n=353) (n=345) (n=209) (n=204)

1-STEP COADMINISTRATION 3-STEP TITRATION Statin and Complementary GI-Acting Drugs vs Statin Titration Statin at starting dose 1st1st2nd2nd3rd3rd 18%18% DoublingDoubling + GI-acting drug % Reduction in LDL-C 6%6%6%6% 6%6% Bays H, et al. Expert Opin Pharmacother. 2003;4:

Optional LDL-C Goal to <1.8 mmol/L (<70 mg/dL) in Diabetes Patients: Ezetimibe/Simvastatin Superior to Atorvastatin VYTAL Study Adapted from Goldberg RB, et al. Mayo Clin Proc. 2006;81:1579–1588. Patients With LDL-C <1.8 mmol/L at Week 6, % Ezetimibe/ Simvastatin 10/20 mg (n=238) Usual Starting DosesNext-Higher Doses Atorvastatin 10 mg (n=237) Atorvastatin 20 mg (n=240) Ezetimibe/ Simvastatin 10/40 mg (n=242) Atorvastatin 40 mg (n=241) P< P<

52 Large Clinical Outcomes Program in >21,000 Patients at High-Risk of CV Events Study, NStudy PopulationTreatments Primary Endpoint ENHANCE, ~725 HeFHEzetimibe/ simvastatin 10/80 mg Simvastatin 80 mg CA IMT SHARP, ~9000 Chronic kidney diseaseEzetimibe/ simvastatin 10/20 mg Placebo CV outcomes (MI, stroke, coronary revascularization) SEAS, ~1400 Asymptomatic aortic stenosis with LDL-C <6 mmol/L Ezetimibe/ simvastatin 10/40 mg Placebo CV death, aortic surgery, CV outcomes IMPROVE-IT, ~10,000 ACSEzetimibe/ simvastatin 10/40 mg Simvastatin 40 mg CV death, major coronary events, stroke CA IMT = Carotid artery intima-media thickness Adapted from Kastelein JJP, et al. Am Heart J. 2005;149:234–239; Baigent C, Landry M. Kidney Int. 2003;63(suppl 84):S207–S210; Oxford Clinical Trial Service Unit. The Study of Heart and Renal Protection (SHARP). Available at: ~sharp/. Accessed June 2005; Rossebo A, et al, for the SEAS Steering Committee. Presented at: XIII International Symposium on Atherosclerosis; September 23–October 2, 2003; Kyoto, Japan. Poster 3P-0870; Schering-Plough. IMPROVE-IT: Examining outcomes in subjects with acute coronary syndrome: Vytorin (ezetimibe/simvastatin) vs simvastatin (Study P04103). Available at: Accessed November 2006.

T Killilea et al Am J Managed Care Vol 12, No. 11 Sup. Pps S

54Conclusion:Conclusion:  Different lipid-lowering agents affect different lipid parameters  Combination therapy may further reduce CHD risk vs monotherapy  Consider combination therapy if:  Treatment goals cannot be met with statins alone  Risk for intolerance, toxicity, or adverse drug interactions with higher dose of single lipid- lowering agent

55ConclusionsConclusions  Inhibition of cholesterol absorption and production via coadministration of ezetimibe with a statin or ezetimibe/simvastatin in the single tablet  Is helping to set a new standard  Provides greater efficacy than statin therapy alone to get patients to a lower LDL-C goal  Outcomes studies will determine if the risk of cardiac endpoints decreases as LDL-C levels decrease with ezetimibe/simvastatin

Treatment Paradigm Combination therapy-Statin plus what?  For LDL  Cholesterol absorption inhibitor – Ezetimibe/Ezetrol ®  Bile acid sequestrant  For HDL  Niacin/Niaspan ® /Fibrate  For TG  Fibrate (fenofibrate)/Niacin/Niaspan ®  For LDL  Cholesterol absorption inhibitor – Ezetimibe/Ezetrol ®  Bile acid sequestrant  For HDL  Niacin/Niaspan ® /Fibrate  For TG  Fibrate (fenofibrate)/Niacin/Niaspan ®

Thank you

58 © Continuing Medical Implementation ® …...bridging the care gap Statin Evidence/Cost/Efficacy Grid © Continuing Medical Implementation ®

59 © Continuing Medical Implementation ® …...bridging the care gap Statin Evidence/Cost/Efficacy Grid © Continuing Medical Implementation ®

60 © Continuing Medical Implementation ® …...bridging the care gap Statin/Combination Therapy Cost Efficacy