Managing the late consequences of CHD: What is the evidence for lipid management Prof Philip Barter The Heart Research Institute Sydney, Australia Slides prepared and presented by

Serum Cholesterol and CHD in 361,662 US Men: MRFIT 6-Year CHD Death Rate per 1000 Men Serum Cholesterol (mg/dl)

Lipoprotein classes and atherosclerosis Chylomicrons, VLDL, and their catabolic remnants LDL HDL Pro-atherogenicAnti-atherogenic

Adhesion Molecule Molecule Monocyte Intima Vessel Lumen Endothelium LDL LDL MCP-1 Macrophage Cytokines Foam Cell MODIFIED LDL ROLE OF LDL IN CAUSING ATHEROSCLEROSIS

CARE-Pra LIPID-Pra 4S-Sim CARE-Plac LIPID-Plac 4S-Plac Statin Trials: LDL-C Levels vs Events Secondary Prevention LDL-C (mg/dL) % with CHD event 70 TNT-Ator10 TNT-Ator80 HPS-Plac HPS-Sim IDEAL-Sim IDEAL-Ator

Median LDL-C (mg/dL) Rand 30 days 4 months 8 months 16 months Final Pravastatin 40 mg (Median LDL-C 95 mg/dL) Atorvastatin 80 mg (Median LDL-C 62 mg/dL) 49%  21%  P<0.001 Cannon CP, et al. N Engl J Med. 2004;350: PROVE-IT: Changes From Baseline LDL-C

PROVE-IT: All-cause Mortality or Major CV Events in All Randomized Subjects Months of follow-up Pravastatin 40 mg (26.3%) Atorvastatin 80 mg (22.4%) 16% RRR P= % patients with event Cannon CP, et al. N Engl J Med. 2004;350:

Patient population: CHD CHD LDL-C: mg/dL ( mmol/L) LDL-C: mg/dL ( mmol/L) Triglycerides  600 mg/dL (  6.8 mmol/L) Triglycerides  600 mg/dL (  6.8 mmol/L) Primary efficacy outcome measure: Time to occurrence of a major CV event: Time to occurrence of a major CV event: –CHD death –Nonfatal, non-procedure-related MI –Resuscitated cardiac arrest –Fatal or nonfatal stroke Atorvastatin 10 mg Open-label run-in n=15,464 8 weeks 1-8 weeks Screening and wash-out n=18,469 Atorvastatin 10 mg LDL-C target: 100 mg/dL (2.6 mmol/L) Median follow-up = 4.9 years Atorvastatin 80 mg LDL-C target: 75 mg/dL (1.9 mmol/L) Double-blind period n=10,001 LDL-C <130 mg/dL (<3.4 mmol/L) n=4995 n=5006 Baseline TNT-Study Design

FinalScreen P<0.001 Baseline Mean LDL-C (mmol/L) Mean LDL-C level = 101 mg/dL (2.6 mmol/L) Mean LDL-C level = 77 mg/dL (2.0 mmol/L) Study visit (months) Mean LDL-C (mg/dL) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) LaRosa JC, et al. N Eng J Med. 2005;352 TNT-Changes in LDL-C By Treatment Group

HR = 0.78 (95% CI 0.69, 0.89) P= Proportion of patients experiencing major cardiovascular event Atorvastatin 10 mg Atorvastatin 80 mg Time (years) Relative risk reduction = 22% LaRosa JC, et al. N Eng J Med. 2005;352 TNT-Primary Efficacy Outcome Measure: Major Cardiovascular Events

Proportion of patients experiencing fatal or nonfatal stroke HR = 0.75 (95%CI 0.59, 0.96) P=0.02 Relative risk reduction = 25% Atorvastatin 10 mg Atorvastatin 80 mg Time (years) LaRosa JC, et al. N Eng J Med. 2005;352 TNT-Stroke (Fatal or nonfatal)

TNT-Primary Endpoint P-value 117 (2.3) 25 (0.5) 243 (4.9) 101 (2.0) 434 (8.7) Atorvastatin 80 mg 155 (3.1) 26 (0.5) 308 (6.2) 127 (2.5) 548 (10.9) Atorvastatin 10 mg No. of patients (%) Nonfatal MI Stroke Resuscitated cardiac arrest CHD death End point 0.78 HR Major CV event LaRosa JC, et al. N Eng J Med. 2005;352

TNT-Safety 2 (0.04)3 (0.06)Rhabdomyolysis* 60 (1.2)9 (0.2)AST/ALT elevation >3  ULN 406 (8.1) 241 (4.8) 289 (5.8) 234 (4.7) Treatment-related AEs Treatment-related myalgia No. of patients (%) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) *No cases were considered by the investigator with direct responsibility for the patient to be causally related to atorvastatin, and none met ACC/AHA/NHLBI criteria 2 for rhabdomyolysis 2. Pasternak RC et al. Circulation. 2002;106: LaRosa JC, et al. N Eng J Med. 2005;352

TNT-Major CVE by on-treatment LDL Quintiles Major CVE (%) < > 2.7 LDL-C quintile (mmol/L)

TNT-Major CVE by on-treatment LDL Quintiles Major CVE (%) < > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:

All-cause mortality (%) TNT-All-cause mortality by on-treatment LDL Quintiles < > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:

Non-CV deaths (%) TNT-Non-CV mortality by on-treatment LDL Quintiles < > 2.7 LDL-C quintile (mmol/L) La Rosa et al. Am J Cardiol 2007; 100:

S (S40) 4S (P) CARE (P40) CARE (P) LIPID (P40) LIPID (P) HPS (S40) HPS (P) Mortality (%) TNT (A10) TNT (A80) Cardiovascular Mortality in Secondary Prevention Studies

Mortality (%) 4S(S40)4S(P)CARE (P40) CARE (P) LIPID (P40) LIPID(P)HPS (S40) HPS(P)TNT (A10) TNT (A80) Non-cardiovascular Mortality in Secondary Prevention Studies

Diabetic Subgroup in TNT Atorva 10 mg N=753 Atorva 80mg N=748 CHD death31 (4.1 %)23 (3.1%) Nonfatal non PR MI61 (8.1%)49 (6.6%) Resuscitated Cardiac Arrest0 (0.0%)3 (0.4%) Stroke43 (5.7%)28 (3.7%) Total135 (17.9%)103 (13.8%) Log-rank p HR (95% CI) (0.58, 0.97) Shepherd et al, Diabetes Care 2006;29:1220.

Metabolic Syndrome Subgroup in TNT Atorva 10 mg N=1771 Atorva 80mg N=1706 CHD death47 (2.7%)32 (1.9%) Nonfatal non PR MI145 (8.2%)98 (5.7%) Resuscitated Cardiac Arrest 3 (0.2%)6 (0.4%) Total195 (11%)136 (8%) Log-rank p HR (95% CI) (0.57, 0.89) Deedwania et al. Lancet 2006

4.8-year follow-up 8888 patients Patient population  Enrolled at 190 sites throughout Scandinavia and the Netherlands  Diagnosed with CHD  Previous hospitalization with MI, and eligible for statin therapy Open-label period with blinded end point evaluations Atorvastatin 80 mg/day Simvastatin 20 mg/day (titrated to 40 mg if required) IDEAL - Protocol Pedersen et al. Am J Cardiol. 2004;94: ; Pedersen et al. JAMA. 2005;294: Secondary  Cardiovascular/coronary events  Cerebrovascular events  PAD  Hospitalization with primary diagnosis of CHF  All-cause mortality Primary  Time to occurrence of a major coronary event −CHD death −Nonfatal MI −Resuscitated cardiac arrest

Mean LDL-C = 104 mg/dL (2.7 mmol/L) Pedersen et al. JAMA. 2005;294: Baseline Week 12 Year 1 Year 2 Year 3 Year 4 Year 5 LDL-C (mg/dL) Atorvastatin Simvastatin LDL-C (mmol/L) Mean LDL-C = 81 mg/dL (2.1 mmol/L) IDEAL: Effect of Treatment On LDL-C

IDEAL: Composite End Points Cumulative Hazard (%) Simvastatin Atorvastatin HR=0.89, P=.07 Cumulative Hazard (%) HR=0.87, P=.02 Years Since Randomization Cumulative Hazard (%) HR=0.84, P<.001 Cumulative Hazard (%) HR=0.84, P<.001 Any CHD Major Coronary Event Any Cardiovascular Disease Major Cardiovascular Disease Years Since Randomization Pedersen et al. JAMA. 2005;294:

MIRACL Study Design 4 months 3073 patients Atorvastatin 80 mg Non-Q-wave infarction or unstable angina Non-Q-wave infarction or unstable angina Randomised 24–96 hours from admission Randomised 24–96 hours from admission Exclusions: Exclusions: Planned CABG/PTCA Planned CABG/PTCA Prior Q-wave <28 days Prior Q-wave <28 days CABG <3 months, PTCA <6 months CABG <3 months, PTCA <6 months IIIb/IV CHF IIIb/IV CHF TC >3.1 mmol/L (270mg/dL) TC >3.1 mmol/L (270mg/dL) Patient population Primary end point: Time to ischaemic events (CHD death, non- fatal MI, cardiac arrest, documented angina requiring hospitalisation) Time to ischaemic events (CHD death, non- fatal MI, cardiac arrest, documented angina requiring hospitalisation) Usual care + double-blind placebo Schwartz et al; JAMA. 2001;285:

MIRACL Results Effects on LDL-C: Placebo group124 mg/dl Atorvastatin group 74 mg/dl Schwartz et al; JAMA. 2001;285:

MIRACL Results Effects on primary endpoint (death, non-fatal MI, cardiac arrest, recurrent ischemia requiring hospitalisation) Placebo group17.4% Atorvastatin group 14.8% 16% reduction (p< 0.05) Schwartz et al; JAMA. 2001;285:

MIRACL Results Effects on stroke (secondary endpoint) Placebo group24 Atorvastatin group 12 (p< 0.05) Schwartz et al; JAMA. 2001;285:

MIRACL Conclusion MIRACL provides convincing evidence of the benefits of commencing aggressive LDL lowering very early in patients with acute coronary syndromes Schwartz et al; JAMA. 2001;285:

ARMYDA trial: Study design 153 patients Stable Angina Positive stress test Indication to PCI No previous statin treatmentAtorvastatin 40 mg/day N=76 PlaceboN=77 PCI Randomization ClinicalFollow-up 7 days 1° Blood sample before PCI 2°-3° Blood samples 8 and 24 h post-PCI 30 days CK MB, Tn-I, Myoglobin CK MB, Tn-I, Myoglobin Pasceri et al, 2004; Circulation 110:

Primary end point Primary end point Incidence of MI, defined as post-PCI increase of CK-MB > 2 times UNL Pasceri et al, 2004; Circulation 110:

Post-PCI incidence of myocardial infarction (CK-MB> 2 times UNL) P=0.025 ARMYDA trial: Primary end point AtorvastatinPlacebo CK-MB (%) 18 5 Pasceri et al, 2004; Circulation 110:

 The ARMYDA randomized trial demonstrates that a short pretreatment with atorvastatin decreases the incidence of myocardial injury during coronary intervention compared with placebo, thereby improving clinical outcome  These results have the potential to influence practice patterns concerning pharmacological therapy prior to percutaneous coronary revascularization ARMYDA trial: Conclusions Pasceri et al, 2004; Circulation 110:

End point Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Any major vascular event ( ) Any major coronary event ( ) Any stroke ( ) All statin clinical outcome trials Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) CTT Collaborators. Lancet. 2010; 376: Number of Events Any coronary revascularisation ( )

Any stroke ( ) End point Aggressive(n=19829) Moderate (n=19783) Relative risk (95% CI) Any major vascular event ( ) Any major coronary event ( ) Effects of aggressive vs moderate therapy with statins Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; subjects; 8,253 events) Number of Events Any coronary revascularisation ( ) CTT Collaborators. Lancet. 2010; 376:

SubgroupTreatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Type 1 diabetes ( ) Type 2 diabetes ( ) All statin clinical outcome trials: effects in diabetes Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events No diabetes ( ) CTT Collaborators. Lancet. 2010; 376:

Relative risk (95% CI) Type 1 diabetes ( ) Type 2 diabetes ( ) Number of Events No diabetes ( ) Aggressive vs moderate statin therapy: effects in diabetes Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; subjects; 8,253 events) Aggressive(n=19829) Moderate (n=19783) Subgroup CTT Collaborators. Lancet. 2010; 376:

Baseline LDL-C Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) < 2 mmol/L ( ) mmol/L ( ) All statin clinical outcome trials: effects of baseline LDL-C Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events mmol/L ( ) mmol/L ( ) > 3.5 mmol/L ( ) Heterogeneity trend test: p=0.3 CTT Collaborators. Lancet. 2010; 376:

Baseline LDL-C Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) < 2 mmol/L ( ) mmol/L ( ) Aggressive vs moderate therapy: effects of baseline LDL-C Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (5 Trials; subjects; 8,253 events) Number of Events mmol/L ( ) mmol/L ( ) > 3.5 mmol/L ( ) Heterogeneity trend test: p=0.2 CTT Collaborators. Lancet. 2010; 376:

Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Male ( ) Female ( ) All statin clinical outcome trials: effects of gender Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Subgroup Heterogeneity trend test: p=0.04 CTT Collaborators. Lancet. 2010; 376:

Duration (years) Treatment-arm(n=84573) Control-arm (n=84565) Relative risk (95% CI) Year ( ) Year ( ) All clinical outcome trials: effects of duration of treatment Relative risk reduction in major vascular events per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol (26 Trials; 169,138 subjects; 24,323 events) Number of Events Year ( ) Year ( ) Year ( ) Year ( ) CTT Collaborators. Lancet. 2010; 376:

Effects of other subgroups on the ability of statins to reduce major vascular events No effect of: Prior vascular disease Prior vascular disease Age Age Blood pressure Blood pressure BMI BMI Smoking Smoking Estimated GFR Estimated GFR CTT Collaborators. Lancet. 2010; 376:

Comparison Treatment-armControl-arm Relative risk (95% CI) More vs less statin 5 trials (n=39,612) ( ) Statin vs Control 21 Trials (n=129, ( ) All statin clinical outcome trials: effects on Cancer Relative risk of cancer per 1.0 mmol/L (40 mg/dL) reduction in LDL-cholesterol Cancer incidence All 26 trials (n=169,138) ( ) CTT Collaborators. Lancet. 2010; 376: