Workshop. Todd Anderson MD / Jacques Genest MD

Transcription

1 Workshop Todd Anderson MD / Jacques Genest MD

2 Game-Changing Trials 2017 FOURIER Evolocumab n=27,564 HR 0.80 CANTOS Canakinumab n=10,061 HR 0.85 COMPASS Rivaroxaban + ASA n=27,395 HR 0.76 Key Secondary Endpoint CV Death, MI, or Stroke 10% 9% 8% 7% 6% 5% 4% 3% Hazard ratio 0.80 (95% CI, ) P< Placebo Evolocumab 9.9% 7.9% 2% 1% 0% Months from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Clinicians are faced with clinical trial data that supports targeting LDL-C, inflammation and thrombosis.

3 CANTOS: MACE + Cumulative incidence HR: 0.83 (95%CI: ) p=0.006* Placebo A 60 yo man with stable ASCVD has a residual FOURIER 14.6 risk / 3 yrs of 3%/year (CV Death, MI, stroke) and 5% risk of Canakinumab MACE+ 150 / 300 mg No. at Risk Years Placebo Canakinumab

4 Rapsomaniki E 2016

5 Residual Cardiovascular Risk A 62 yo. Man with stable ASCVD (MI one year ago;; PCI to LAD);; preserved LVEF. Non diabetic. BP 125/80 LDL-C 1.80 mmol/l 1. What is the life expectancy?* 2. What is the likelihood of a MACE+ in the next 5-10 years?

6 Life Expectancy Canada 2007 to 2009 Males Females Canada Newfoundland and Labrador Prince Edward Island Nova Scotia New Brunswick Quebec Ontario Manitoba Saskatchewan Alberta British Columbia Source: Statistics Canada, CANSIM, table and Catalogue no XIE.

7 Life Expectancy of a 60 yo Canadian Life expectancy (Female): 24.3 years Life expectancy (Male): 21.3 years Leading cause of death: Cancer

8 Precision-Guided Personalized Medicine Can we reliably identify biomarkers of residual cardiovascular risk that can guide therapy and improve outcomes? Metabolic: Inflammation LDL-C hscrp Non HDL-C IL-6 Apo B Imaging Lp(a) Glucose Blood pressure Thrombosis? Structural PAD LV function EP markers CMR markers

9 Which Medication, for how Long? Can we reliably identify biomarkers of residual cardiovascular risk that can guide duration of therapy and improve outcomes? Lipids: Likely lifelong Inflammation If the storm abates? Thrombosis?

10 Residual Cardiovascular Risk A 62 yo. Man with stable ASCVD (MI one year ago;; PCI to LAD);; preserved LVEF. Non diabetic. BP 130/80 LDL-C 2.50 mmol/l on maximally tolerated statin and ezetimibe

11 Residual Cardiovascular Risk A 62 yo. Man with stable ASCVD (MI 2014;; PCI to LAD);; preserved LVEF. Non diabetic. BP 135/85 LDL-C 1.80 mmol/l on maximally tolerated statin and ezetimibe. Recurrent PCIs since 2014 Would your recommendation be different if he had documented PAD and claudication

12 Residual Cardiovascular Risk A 62 yo. Woman with stable ASCVD (MI one year ago;; PCI to LAD);; preserved LVEF. Diabetic;; HgA1c 8.5., creatinine 124;; BP 130/85 LDL-C 2.50 mmol/l on maximally tolerated statin (rosuva 5 mg/day) and ezetimibe 10 mg per day

13 Residual Cardiovascular Risk A 42 yo. East Indian man with 4 th admission with ACS. Multiple PCI (LAD, Cx;; ISR Cx, PDA x2;; last one 2 years ago). Preserved LVEF. Diabetic;; creatinine 74;; BP 132/78 ASA 80;; Atorva 80;; Metformin ;; LDL-C 1.50 mmol/l HgA1c 5.5 Are there biomarkers that can guide therapy?

14 Residual Cardiovascular Risk A 62 yo. Woman with ischemic CMP (MI 10 years ago;; multiple admission in ACS and revascularization) LVEF 32%;; no viable myocardium (MRI). Diabetic;; creatinine 154;; BP 100/85. NYHA 2 Metformin ;; Gliclazide 30 2 ;; Bisoprolol 2.5;; Ramipril ;; ASA 80;; Sitagliptin 50;; rosuvastatin 10 LDL-C 2.50 mmol/l HgA1c 8.5 What are the priorities of treatment, do preventive measures matter?

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16 PAD Patients in COMPASS PAD Groups Number of patients All Patients 7,470 Symptomatic PAD Limbs 4,129 Carotid Disease 1,919 CAD + Low ABI (<0.90) only 1,422 Mean Follow- up: 21 months

17 August 11, 2017 Primary outcome & components Outcome R + A N=2,492 N (%) R N=2,474 N (%) A N=2,504 N (%) Riva + aspirin vs. aspirin HR (95% CI) P Riva vs. aspirin HR (95% CI) P MACE 126 (5.1) 149 (6.0) 174 (6.9) 0.72 ( ) ( ) 0.19 MI 51 (2.0) 56 (2.3) 67 (2.7) 0.76 ( ) ( ) - Stroke 25 (1.0) 43 (1.7) 47 (1.9) 0.54 ( ) ( ) - CV Death 64 (2.6) 66 (2.7) 78 (3.1) 0.82 ( ) ( ) -

18 Limb outcomes Outcome R + A N=2,492 N (%) R N=2,474 N (%) A N=2,504 N (%) Riva + aspirin vs. aspirin HR (95% CI) P Riva vs. aspirin HR (95% CI) P MALE 30 Major amputation (1.2) 5 (0.2) 35 (1.4) 8 (0.3) 56 (2.2) 17 (0.7) 0.54 ( ) 0.30 ( ) ( ) 0.46 ( ) Aug 11, 2017

19 August 14, 2017 Key Composite Outcome Outcome R + A N=2,492 N (%) R N=2,474 N (%) A N=2,504 N (%) Riva + aspirin vs. aspirin HR (95% CI) P Riva vs. aspirin HR (95% CI) P MACE, MALE or Major amputation 157 (6.3) 188 (7.6) 225 (9.0) 0.69 ( ) ( ) 0.08

20 MACE or MALE or Major Amputation Cumulative Hazard Rate Aspirin Rivaroxaban Rivaroxaban + Aspirin Rivaroxaban + Aspirin vs. Aspirin HR: 0.69 ( ) P= Rivaroxaban vs.aspirin HR: 0.84 ( ) P= No. at Risk Year Riva + ASA Riva ASA

21 Major bleeding Outcome R + A N=2,492 N (%) R N=2,474 N (%) A N=2,504 N (%) Riva + aspirin vs. aspirin HR (95% CI) P Riva vs. aspirin HR (95% CI) P Major Bleeding Fatal Non- Fatal ICH Non- fatal other critical organ* 77 (3.1) 4 (0.2) 4 (0.2) 13 (0.5) 79 (3.2) 5 (0.2) 3 (0.1) 18 (0.7) 48 (1.9) 3 (0.1) 8 (0.3) 8 (0.3) 1.61 ( ) ( ) ( ) ( ) 0.06 * symptomatic

22 August 14, 2017 Net clinical benefit in PAD Outcome R + A N=2,492 R N=2,474 A N=2,504 Riva + aspirin vs. aspirin N (%) N (%) N (%) HR (95% CI) P Riva vs. aspirin HR (95% CI) P Net Clinical Benefit 169 (6.8) 207 (8.4) 234 (9.3) 0.72 ( ) ( ) 0.23

23 From CRP to IL- 6 to IL- 1: Moving Upstream to Identify Novel Targets for Atheroprotection Canakinumab Ridker ESC 2017 Ridker PM. Circ Res 2016;118:

24 Canakinumab Anti- Inflammatory Thrombosis Outcomes Study (CANTOS) Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation of hscrp (> 2 mg/l) N = 10, Countries April June Primary Events Randomized Canakinumab 50 mg SC q 3 months Randomized Canakinumab 150 mg SC q 3 months Randomized Canakinumab 300 mg SC q 3 months* Randomized Placebo SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Critical Non-Cardiovascular Safety Endpoints: Cancer and Cancer Mortality, Infection and Infection Mortality Ridker ESC 2017

25 Characteristic CANTOS - Baseline Clinical Characteristics Placebo (N=3347) Canakinumab SC q 3 months 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) Age (years) Female (%) Current smoker (%) Diabetes (%) Lipid lowering therapy (%) Renin- angiotensin inhibitors (%) Prior Revascularization (%) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) hscrp (mg/l) Ridker ESC 2017

26 CANTOS: Primary Clinical Outcome Effects on MACE and MACE + Canakinumab SC q 3 months Primary Endpoint IR (per 100 person years) HR 95%CI P Secondary Endpoint IR (per 100 person years) HR 95%CI P Placebo (N=3347) (referent) (referent) (referent) (referent) 50 mg (N=2170) mg (N=2284) * * 300 mg (N=2263) P- trend *Statistically significant, adjusted for multiplicity, in accordance with the pre-specified closed-testing procedures Ridker ESC 2017

27 Endpoint CANTOS: Consistency of HRs Across All Cardiovascular Endpoints Placebo (N=3347) Canakinumab SC q 3 months 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P- trend Primary Secondary Myocardial Infarction Urgent Revascularization Any Coronary Revascularization <0.001 Stroke Cardiac Arrest CV Death All Cause Mortality Ridker ESC 2017

28 Adverse Event CANTOS: Additional Outcomes (per 100 person years of exposure) Placebo (N=3347) Canakinumab SC q 3 months 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P- trend Any SAE Leukopenia Any infection Fatal infection /0.02* Injection site reaction Any Malignancy Fatal Malignancy Arthritis Osteoarthritis Gout ALT > 3x normal Bilirubin > 2x normal Ridker ESC 2017 * P-value for combined canakinumab doses vs placebo

29 % LDL-C reduction and events in Jupiter study Ridker et al. EHJ subjects randomized to Rosuvastatin 20 mg 46% obtained a > 50% reduction in LDL-C

30 Ongoing Outcome Trials with PCSK9 Inhibitors Study FOURIER ODYSSEY OUTCOMES SPIRE- 1/ SPIRE- 2 Treatment Evolocumab: 420 mg QM or 140 mg Q2W Background: optimal lipid lowering therapy Alirocumab: 75 mg Q2W (up titrated to 150 mg Q2W if LDL >1.3 mmol/l;; down titrated if LDL <0.65 mmol/l) Background: optimized lipid lowering therapy Bococizumab: 150 mg Q2W Background: lipid lowering therapy Population MI or stroke ( last 4 weeks) OR PAD (plus Risk factors for CVD) Patients hospitalized for ACS (<12 months before randomization) Patients at high risk of a CV event # patients 27,500 18,000 SPIRE-1: 17,000 SPIRE-2: 9,000 LDL-C for eligibility LDL-C 1.8 mmol/l (or non- HDL-C 2.6 mmol/l) after 4 week stabilization with optimal lipid lowering therapy 1.8 mol/l or non-hdl-c 2.6 mmol/l SPIRE-1: LDL-C 1.8 and <2.6 mmol/l SPIRE-2: LDL-C 2.6 mmol/l or non-hdl-c 3.4 mmol/l Estimated study completion 2017 December 2017 SPIRE-1:June 2018 SPIRE-2: March 2018 ACS: acute coronary syndrome; CAD: coronary artery disease; CHD: coronary heart disease; CVD: coronary vascular disease; EZE: ezetimibe; FH:Familial Hypercholesterolemia; HeFH: Heterozygous Familial Hypercholesterolemia; PAD: peripheral- artery disease; T2DM: type 2 diabetes mellitus. clinicaltrials.gov accessed August 25, 2015.

31 FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk MS Sabatine, RP Giugliano, AC Keech, N Honarpour, SM Wasserman, PS Sever, and TR Pedersen, for the FOURIER Steering Committee & Investigators American College of Cardiology 66 th Annual Scientific Session Late- Breaking Clinical Trial March 17, 2017

32 Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks Sabatine MS et al. Am Heart J 2016;;173:94-101

33 Endpoints Efficacy Primary: CV death, MI, stroke, hosp. for UA, or coronary revasc Key secondary: CV death, MI or stroke Safety AEs/SAEs Events of interest incl. muscle- related, new- onset diabetes, neurocognitive Development of anti- evolocumab Ab (binding and neutralizing) TIMI Clinical Events Committee (CEC) Adjudicated all efficacy endpoints & new- onset diabetes Members unaware of treatment assignment & lipid levels Sabatine MS et al. Am Heart J 2016;;173:94-101

34 Baseline Characteristics Characteristic Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non- hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Median time from most recent event ~3 yrs Pooled data;; no differences between treatment arms

35 Lipid Lowering Therapy & Lipid Levels at Baseline Characteristic Statin use (%)* Value High- intensity 69 Moderate- intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL- C Total cholesterol HDL- C Triglycerides *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. 92 (80-109) 168 ( ) 44 (37-53) 133 ( ) Pooled data;; no differences between treatment arms

36 LDL Cholesterol Placebo LDL Cholesterol (mg/dl) % mean reduction (95%CI 58-60), P< Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR mg/dl) Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

37 Primary Endpoint CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 14% 12% 10% 8% 6% 4% 2% Hazard ratio % (95% CI, ) P< Placebo 12.6% Evolocumab 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization

38 Key Secondary Endpoint CV Death, MI, or Stroke 10% 9% 8% 7% 6% 5% 4% 3% Hazard ratio 0.80 (95% CI, ) P< Placebo Evolocumab 9.9% 7.9% 2% 1% 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization

39 Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3- yr Kaplan- Meier rate HR (95% CI) CV death, MI, or stroke ( ) Cardiovascular death ( ) Death due to acute MI ( ) Death due to stroke ( ) Other CV death ( ) MI ( ) Stroke ( )

40 Fatal or Nonfatal MI or Stroke 8% 19% RRR 8% 33% RRR Fatal or Nonfatal MI or Stroke 6% 4% 2% HR 0.81 (95%CI ) P=0.003 Placebo 6% 4% 2% HR 0.67 (95%CI ) P< Evolocumab 0% 0% Months from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

41 Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any Serious Allergic reaction Injection- site reaction Treatment- related and led to d/c of study drug Muscle- related Cataract Diabetes (new- onset) Neurocognitive Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline;; adjudicated by CEC

42 PCSK9 Inhibition and Very low LDL- C Giugliano et al. Lancet Aug 28, ,982 Fourier patients 4 week LDL-C Positive outcomes down to 0.2 mmol/l

43 PCSK9 Inhibition and Very low LDL- C Giugliano et al. Lancet Aug 28, ,982 Fourier patients 4 week LDL-C Positive outcomes down to 0.2 mmol/l Primary EP death, MI, revasc, hospitalization for UA

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50 REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease ) A prospective, multi- center, randomized, open- label, blinded endpoint, physician- initiated trial to determine whether high- dose as compared with low- dose pitavastatin therapy within the approved dose range could reduce CV events in Japanese patients with stable CAD. Eligibility: Consent for enrollment Men and women, years of age Stable CAD: ACS or PCI/CABG >3 months Clinical diagnosis with coronary stenosis 50 % diameter stenosis LDL- C <120 mg/dl on pitavastatin 1 mg/day during the run- in period Pitavastatin 1 mg/day Randomization Pitavastatin 1mg/day Pitavastatin 4mg/day Jan LDL- C <120 mg/dl - Mar Jan.- Mar Run- in Period (>1 month) Follow- up (36-60 months) Pitavastatin 1 mg and 4 mg have LDL- C lowering effect comparable to atorvastatin 5 mg and 20 mg, respectively.

51 Baseline Characteristics Variables Pitavastatin 1 mg (N=6,214) Pitavastatin 4 mg (N=6,199) Age years 68.1± ±8.3 Male sex 82.5% 82.7% BMI kg/m ± ±3.3 Hypertension 75.4% 75.9% Diabetes mellitus 40.0% 40.2% Current smoking 15.9% 16.8% History of ACS 71.9% 71.8% ACS within 1 year before randomization 24.2% 24.1% Coronary revascularization 90.5% 90.4% Revascularization within 1 year before randomization 27.7% 27.7% Ischemic stroke 6.9% 6.8% Peripheral vascular disease 7.4% 6.6% CKD (egfr <60 ml/min/1.73m 2 ) 36.2% 35.4% Aspirin 92.5% 92.4% DAPT 44.6% 43.9%

52 Serial Changes in Lipid Parameters and hs-crp LDL-C (mg/dl) LDL-C 100 Pitavastatin 1 mg 55 Pitavastatin 4 mg Main effect p< Interaction p< Baseline No. of Patients 1mg 6,214 6,031 4mg 6,199 5,890 5,615 5,518 Years 5,252 5,203 4,509 4,405 HDL-C (mg/dl) No. of Patients 1mg 4mg ,212 6, ,028 5, ,596 5,482 HDL-C Years Main effect p< Interaction p= ,238 5, Baseline ,498 4,388 TG (mg/dl) No. of Patients 1mg 6,208 6,032 4mg 6,195 5, ,606 5,498 TG Years ,245 5, ,507 4,402 1mg 4mg hs-crp Main effect p< Interaction p= 0.77 Main effect p< Baseline Baseline 6 hs-crp (mg/l) No. of Patients ,032 5,994 Months ,734 5,585

53 Primary Endpoint Cumulative incidence(%) No. at risk 1mg 4mg 6,214 6,199 (CV death/mi/ischemic stroke/ UA) HR 0.81 (95% CI, ), Cox P=0.01 No. of patients with event: 4mg 266 (4.3%), 1mg 334 (5.4%) NNT for 5 years=63 Pitavastatin 1mg Pitavastatin 4mg log-rank P= Years ,743 5,321 4,501 2,760 5,631 5,256 4,427 2,

54 Secondary Endpoint Primary Endpoint plus Coronary Revascularization* Cumulative incidence(%) HR 0.83 (95% CI, ), Cox P=0.002 No. of patients with event: 4mg 489 (7.9%), 1mg 600 (9.7%) NNT for 5 years=41 Pitavastatin 1mg Pitavastatin 4mg 2.8 log-rank P= No. at risk Years 1mg 6,214 5,660 5,166 4,327 2,627 4mg 6,199 5,556 5,131 4,277 2,617 : Excluding TLR for lesions treated at prior PCI *

55 How did we get here? 55

56 PIONEER AF- PCI Study Design International, multicenter, randomized, open- label trial Inclusion Men and women at least 18 years of age Paroxysmal, persistent, or permanent nonvalvular AF Undergone PCI with stent placement Documented AF that occurred within 1 year before screening Exclusion History of stroke or TIA Clinically significant GI bleeding within 12 months before randomization CrCl<30 ml/min Anemia of an unknown cause with a Hgb <10 g/dl Any other condition known to increase the risk of bleeding N Engl J Med 2016; 375:

57 End Points Primary Safety Secondary TIMI Major Bleeding Safety Each component of the primary safety endpoint TIMI Minor Bleeding Bleeding Requiring Medical Attention Efficacy Major cardiovascular event composite* Stent thrombosis Clinically Significant Bleeding Exploratory ISTH Major bleeding GUSTO severe bleeding *Death from cardiovascular cause, MI, Stroke Each component of the composite N Engl J Med 2016; 375:

58 Treatment Subgroups 12 Months NVAF No Prior Stroke/TIA PCI with Stent Placement 72 hours After sheath removal R a n d o m iz a t i o n 1 month Rivaroxaban 15 mg Daily + Clopidogrel 75 mg 6 months Rivaroxaban 2.5 mg BID + DAPT Rivaroxaban 15 mg + ASA mg Rivaroxaban 15 mg + ASA mg Warfarin (INR ) + DAPT Warfarin + ASA mg 1 month *Rivaroxaban 10 mg daily if CrCl 30- <50 ml/min Prasugrel 10 mg daily or Ticagrelor 90 mg BID in <15% of patients N Engl J Med 2016; 375: months Warfarin + ASA mg 58

59 Statistical Analysis Analysis based on pooled data across all strata of DAPT duration (1, 6, or 12 months) Modified intention- to- treat analysis based on data for all participants who underwent randomized and received at least 1 dose of trial drug Intention- to- treat based on data obtained through follow- up of all participants who underwent randomization Comparisons of group 1 vs group 3 and group 2 vs group 3 were performed simultaneously with no adjustment for type I error at a rate of 0.05 N Engl J Med 2016; 375:

60 Patient Characteristics N Engl J Med 2016; 375:

61 Results Participants who received at least one dose of the trial treatment permanently discontinued the treatment before the scheduled termination date Group 1: 21.0% Group 2: 21.1% Group 3: 29.4% P<0.001 For both comparisons N Engl J Med 2016; 375:

62 N Engl J Med 2016; 375:

63 Results Group 1 Rivaroxaban 15 mg Daily + P2Y12 12 Months Group 2 Rivaroxaban 2.5 mg BID + DAPT 1,6,12 Month(s) Group 3 Warfarin + DAPT 1,6,12 Month(s) Primary Safety 16.8% HR:0.59;CI: ; P<0.001 Primary Safety 18.0% HR:0.63;CI: ; P<0.001 Primary Safety 26.7% Major Adverse Cardiovascular Event 6.5% HR:1.08;CI: ; P=0.75 Major Adverse Cardiovascular Event 5.6% HR:0.93;CI: ; P=0.76 Major Adverse Cardiovascular Event 6.0% N Engl J Med 2016; 375:

64 Results N Engl J Med 2016; 375:

65 Results N Engl J Med 2016; 375: