AIM HIGH for SATURN and stay SHARP; COURAGE (v1.5)

AIM HIGH for SATURN and stay SHARP; COURAGE (v1.5) Jacques Genest MD Cardiovascular Research Laboratory McGill University Health Center

Disclosure J. Genest MD 2012 Advisory Board, Speaker s Bureau, Consultant, Grants AstraZeneca Merck * Pfizer Novartis AMGEN * Roche * Biotech: Danone; Acasti ; Nutrasource Stock ownership: none; Off label use: none * Scientific Advisory Relevant disclosure: JUPITER, IMPROVE-IT, CANTOS, REVEAL steering Committees.

AIM-HIGH: Study Design

AIM-HIGH: Lipid Changes At 2 years of follow-up, among patients assigned to niacin: LDL-C decreased by an additional 12.0% (62 mg/dl) HDL-C increased by 25.0% (42 mg/dl)

Pourcentage cumulé de patients avec des résultats primaires Étude AIM-HIGH : Résultats 50 40 30 20 10 P=0.79 by log-rank best Niacine plus statine Placebo plus statine 0 0 1 2 3 4 Années No. à risque Placebo plus statine 1695 1581 1381 910 436 Niacin plus statine 1718 1606 1366 903 428

AIM-HIGH: Comment "I do not agree with the decision to stop this trial. It was completely inappropriate. The NIH sponsors saw a weak signal of stroke and panicked, and when all the data have come in, this doesn't appear to be an issue. Now we have lost the opportunity to properly answer the very important question of whether niacin adds any benefit in this population with low LDL levels." Dr Steven Nissen

SATURN Study N Engl J Med 2011; 365:2078-2087

SATURN Study: Patients

SATURN Study: Results

SATURN Study: Results

SATURN Study: Conclusions Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower level of LDL cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of percent atheroma volume was observed in the two treatment groups.

The results of the SHARP trial

SHARP: Eligibility History of chronic kidney disease not on dialysis: elevated creatinine on 2 occasions Men: 1.7 mg/dl (150 µmol/l) Women: 1.5 mg/dl (130 µmol/l) on dialysis: haemodialysis or peritoneal dialysis Age 40 years No history of myocardial infarction or coronary revascularisation Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated

SHARP: Randomisation structure Randomised (9438) Simva/Eze (4193) Simvastatin (1054) Placebo (4191) Not re-randomised (168) Simv/Eze (4650) Randomised (886) Median follow-up 4.9 years Lost to mortality follow-up 1.5% Placebo (4620)

Simv/Eze produces additional reductions in LDL (mmol/l) and apo B (mg/dl) at 1 year Biochemical parameter Simv vs Placebo Simv/Eze vs Simv Simv/Eze vs Placebo Total cholesterol -0.97-0.43-1.39 LDL cholesterol -0.75-0.34-1.09 HDL cholesterol 0.05-0.03 0.02 Non-HDL cholesterol -1.01-0.40-1.41 Triglycerides -0.64 0.07-0.57 Apolipoprotein B -21-7 -28 Apolipoprotein A 1 4.1-1.0 3.2

Proportion suffering event (%) SHARP: Major Atherosclerotic Events 25 20 15 10 Risk ratio 0.83 (0.74-0.94) Logrank 2P=0.0021 Placebo Simv/Eze 5 0 0 1 2 3 4 5 Years of follow-up

Integrating the Data CTT Analysis The benefits of LDL-C reduction Baigent et al. Oxford UK

Proportional effects on MAJOR VASCULAR EVENTS per mmol/l reduction in LDL cholesterol No. of events (% pa) Statin/ Contr ol/ More statin Less statin Relative risk (CI) Nonfatal MI CHD death Any major coronary event 3485 (1.0) 1887 (0.5) 5105 (1.4) 4593 (1.3) 2281 (0.6) 6512 (1.9) 0.73 (0.69-0.78) 0.80 (0.74-0.87) 0.76 (0.73-0.78) CABG PTCA Unspecified Any coronary revascularisation 1453 (0.4) 1767 (0.5) 2133 (0.6) 5353 (1.5) 1857 (0.5) 2283 (0.7) 2667 (0.8) 6807 (2.0) 0.75 (0.69-0.82) 0.72 (0.65-0.80) 0.76 (0.70-0.82) 0.75 (0.72-0.78) Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke 1427 (0.4) 257 (0.1) 618 (0.2) 2302 (0.6) 1751 (0.5) 220 (0.1) 709 (0.2) 2680 (0.8) 0.79 (0.72-0.87) 1.12 (0.88-1.43) 0.88 (0.76-1.01) 0.84 (0.79-0.89) Any major vascular event 10973 (3.2) 13350 (4.0) 0.78 (0.76-0.80) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin/more statin better Control/less statin better

More vs less trials: Proportional effects on MAJOR VASCULAR EVENTS, by baseline LDL cholesterol unweighted for LDL-C differences No. of events (% pa) More statin Less statin Relative risk (CI) < 2 2,<2.5 2.5,<3.0 3,<3.5 3.5 704 (4.6) 1189 (4.2) 1065 (4.5) 517 (4.5) 303 (5.7) 795 (5.2) 1317 (4.8) 1203 (5.0) 633 (5.8) 398 (7.8) 0.88 (0.77-1.00) 0.87 (0.79-0.97) 0.90 (0.80-1.00) 0.77 (0.66-0.90) 0.74 (0.61-0.90) Total 3837 (4.5) 4416 (5.3) 0.85 (0.82-0.89) 99% or 95% CI 0.5 0.75 1 1.25 1.5 More statin better Less statin better

Proportional effects on CAUSE-SPECIFIC MORTALITY per mmol/l LDL-C reduction Cause of death Events (% p.a.) Statin/more Contr ol/less RR (CI) per 1 mmol/l reduction in LDL-C Vascular causes CHD 1887 (0.5) 2281 (0.6) 0.80 (0.74-0.87) Other cardiac 1446 (0.4) 1603 (0.4) 0.89 (0.81-0.98) All car diac 3333 (0.9) 3884 (1.1) 0.84 (0.80-0.88) Ischaemic stroke Haemorrhagic stroke 153 (0.0) 102 (0.0) 139 (0.0) 89 (0.0) 1.04 (0.77-1.41) 1.12 (0.77-1.62) Unknown stoke 228 (0.1) 273 (0.1) 0.85 (0.66-1.08) Stroke 483 (0.1) 501 (0.1) 0.96 (0.84-1.09) Other vascular 404 (0.1) 409 (0.1) 0.98 (0.81-1.18) Any vascular 4220 (1.2) 4794 (1.3) 0.86 (0.82-0.90) Any non-vascular cause 2943 (0.8) 2994 (0.8) 0.97 (0.92-1.03) Unknown cause 479 (0.1) 539 (0.1) 0.87 (0.73-1.03) Any death 7642 (2.1) 8327 (2.3) 0.90 (0.87-0.93) 99% or 95% CI 0.5 0.75 1 1.25 Statin/more better Control/less better

Proportional effects on CANCER INCIDENCE per mmol/l LDL-C reduction More vs less statin PROVE-IT A to Z TNT IDEAL SEARCH Statin vs control No. of events (% pa) Statin/ Control/ More statin Less statin 70 (1.7) 35 (0.9) 359 (1.5) 373 (1.9) 629 (1.6) 64 (1.6) 35 (0.9) 325 (1.4) 375 (1.9) 673 (1.7) 0.5 0.75 1 1.25 1.5 Statin/more statin better Control/less statin better Relative risk (CI) Subtotal (5 trials) 1466 (1.6) 1472 (1.6) 1.02 (0.89-1.18) First cycle (14 trials) 2810 (1.4) 2804 (1.4) 1.00 (0.95-1.04) ALLIANCE 78 (1.5) 71 (1.4) 4D 43 (2.5) 51 (3.0) ASPEN 71 (1.7) 56 (1.3) MEGA 130 (0.6) 130 (0.6) JUPITER 253 (1.3) 274 (1.4) GISSI-HF 117 (1.5) 128 (1.6) AURORA 92 (2.0) 78 (1.7) Subtotal (21 trials) 3594 (1.4) 3592 (1.4) 1.00 (0.95-1.04) Total (26 trials) 5060 (1.4) 5064 (1.4) 1.00 (0.96-1.04) 99% or 95% CI Difference between more vs less and statin vs control: 2 c 1 = 0.1, p=0.73

Five year risk of a major vascular event, % Absolute effect of statin therapy on MAJOR VASCULAR EVENTS 0 5 10 15 20 More statin Statin Control 21% relative risk reduction per mmol/l 15% relative risk reduction per 0.5 mmol/l Combined evidence: ~33% relative risk reduction per 1.5 mmol/l (0.79 x 0.85 = 0.67) 0 1 2 3 4 5 LDL cholesterol, mmol/l

Risk of Incident Diabetes The benefits pitfalls of LDL-C reduction Rajpathak S N et al. Dia Care 2009;32:1924-1929 Preiss, D. et al. JAMA 2011;305:2556-2564

Meta-analysis of clinical trials evaluating the effects of statins on diabetes risk. Rajpathak S N et al. Dia Care 2009;32:1924-1929 Copyright 2011 American Diabetes Association, Inc.

Meta-analysis of New-Onset Diabetes and First Major Cardiovascular Events in 5 Large Trials Comparing Intensive-Dose to Moderate-Dose Statin Therapy CONCLUSION: In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy. Copyright restrictions may apply. Preiss, D. et al. JAMA 2011;305:2556-2564

Courage, Gentlemen PCI for Stable CAD

PCI for Stable CAD Initial Coronary Stent Implantation With Medical Therapy vs Medical Therapy Alone for Stable Coronary Artery Disease Conclusion: Initial stent implantation for stable CAD shows no evidence of benefit compared with initial medical therapy for prevention of death, nonfatal MI, unplanned revascularization, or angina. Stergiopoulos K. Arch Intern Med. 2012;172(4):312-319

Conclusions To date, the HDL Hypothesis remains unproven LDL-C reduction should remain the aim of preventive therapies Intravascular ultrasound studies are really stup Chronic, stable CAD should be initially treated medically