Workshop Todd Anderson MD / Jacques Genest MD
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, 0.73-0.88) P<0.00001 Placebo Evolocumab 9.9% 7.9% 2% 1% 0% 0 6 12 18 24 30 36 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.
CANTOS: MACE + Cumulative incidence 0.00 0.05 0.10 0.15 0.20 0.25 HR: 0.83 (95%CI: 0.72 0.92) 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 0 1 2 3 4 5 Years Placebo 3344 3107 2921 2578 1238 206 Canakinumab 2284 2135 2039 1824 892 201
Rapsomaniki E 2016
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?
Life Expectancy Canada 2007 to 2009 Males Females Canada 79 83 Newfoundland and Labrador 77 81 Prince Edward Island 78 83 Nova Scotia 78 82 New Brunswick 78 83 Quebec 79 83 Ontario 79 84 Manitoba 77 82 Saskatchewan 77 82 Alberta 79 83 British Columbia 80 84 Source: Statistics Canada, CANSIM, table 102-0512 and Catalogue no. 84-537-XIE.
Life Expectancy of a 60 yo Canadian Life expectancy (Female): 24.3 years Life expectancy (Male): 21.3 years Leading cause of death: Cancer
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
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?
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
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
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
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 500 2 ;; LDL-C 1.50 mmol/l HgA1c 5.5 Are there biomarkers that can guide therapy?
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 500 3 ;; Gliclazide 30 2 ;; Bisoprolol 2.5;; Ramipril 2.5 2 ;; 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?
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 17-07- 01
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 (0.57-0.90) 0.005 0.86 (0.69-1.08) 0.19 MI 51 (2.0) 56 (2.3) 67 (2.7) 0.76 (0.53-1.09) - 0.84 (0.59-1.20) - Stroke 25 (1.0) 43 (1.7) 47 (1.9) 0.54 (0.33-0.87) - 0.93 (0.61-1.40) - CV Death 64 (2.6) 66 (2.7) 78 (3.1) 0.82 (0.59-1.14) - 0.86 (0.62-1.19) -
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 (0.35-0.84) 0.30 (0.11-0.80) 0.005 0.01 0.63 (0.41-0.96) 0.46 (0.20-1.08) 0.03 0.07 Aug 11, 2017
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 (0.56-0.85) 0.0003 0.84 (0.69-1.02) 0.08
MACE or MALE or Major Amputation Cumulative Hazard Rate 0.0 0.05 0.10 0.15 Aspirin Rivaroxaban Rivaroxaban + Aspirin Rivaroxaban + Aspirin vs. Aspirin HR: 0.69 (0.56-0.85) P=0.0003 Rivaroxaban vs.aspirin HR: 0.84 (0.69-1.02) P=0.08 0 1 2 3 No. at Risk Year Riva + ASA 2492 2069 893 124 Riva 2474 2023 864 147 ASA 2504 2034 911 113
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 (1.12-2.31) 0.009 1.68 (1.17-2.40) 0.004 - - - - - - - - 1.55 (0.64-3.74) 0.33 2.15 (0.94-4.96) 0.06 * symptomatic
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 (0.59-0.87) 0.0008 0.89 (0.74-1.07) 0.23
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;118:145-156.
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 = 10,061 39 Countries April 2011 - June 2017 1490 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
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) 61.1 61.1 61.2 61.1 Female (%) 25.9 24.9 25.2 26.8 Current smoker (%) 22.9 24.5 23.4 23.7 Diabetes (%) 39.9 39.4 41.8 39.2 Lipid lowering therapy (%) 93.7 94.0 92.7 93.5 Renin- angiotensin inhibitors (%) 79.8 79.3 79.8 79.6 Prior Revascularization (%) 79.6 80.9 82.2 80.7 LDL cholesterol (mg/dl) 82.8 81.2 82.4 83.5 HDL cholesterol (mg/dl) 44.5 43.7 43.7 44.0 Triglycerides (mg/dl) 139 139 139 138 hscrp (mg/l) 4.1 4.1 4.2 4.1 Ridker ESC 2017
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) 4.5 1.0 (referent) (referent) 5.1 1.00 (referent) (referent) 50 mg (N=2170) 4.1 0.93 0.80-1.07 0.30 4.6 0.90 0.78-1.03 0.11 150 mg (N=2284) 3.9 0.85 0.74-0.98 0.021* 4.3 0.83 0.73-0.95 0.005* 300 mg (N=2263) 3.9 0.86 0.75-0.99 0.031 4.3 0.83 0.72-0.94 0.004 P- trend 0.020 0.003 *Statistically significant, adjusted for multiplicity, in accordance with the pre-specified closed-testing procedures Ridker ESC 2017
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 1.00 0.93 0.85 0.86 0.020 Secondary 1.00 0.90 0.83 0.83 0.002 Myocardial Infarction 1.00 0.94 0.76 0.84 0.028 Urgent Revascularization Any Coronary Revascularization 1.00 0.70 0.64 0.58 0.005 1.00 0.72 0.68 0.70 <0.001 Stroke 1.00 1.01 0.98 0.80 0.17 Cardiac Arrest 1.00 0.72 0.63 0.46 0.035 CV Death 1.00 0.89 0.90 0.94 0.62 All Cause Mortality 1.00 0.94 0.92 0.94 0.39 Ridker ESC 2017
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 12.0 11.4 11.7 12.3 0.43 Leukopenia 0.24 0.30 0.37 0.52 0.002 Any infection 2.86 3.03 3.13 3.25 0.12 Fatal infection 0.18 0.31 0.28 0.34 0.09/0.02* Injection site reaction 0.23 0.27 0.28 0.30 0.49 Any Malignancy 1.88 1.85 1.69 1.72 0.31 Fatal Malignancy 0.64 0.55 0.50 0.31 0.0007 Arthritis 3.32 2.15 2.17 2.47 0.002 Osteoarthritis 1.67 1.21 1.12 1.30 0.04 Gout 0.80 0.43 0.35 0.37 0.0001 ALT > 3x normal 1.4 1.9 1.9 2.0 0.19 Bilirubin > 2x normal 0.8 1.0 0.7 0.7 0.34 Ridker ESC 2017 * P-value for combined canakinumab doses vs placebo
% LDL-C reduction and events in Jupiter study Ridker et al. EHJ 2016 17082 subjects randomized to Rosuvastatin 20 mg 46% obtained a > 50% reduction in LDL-C
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.
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
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
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
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
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 (151-189) 44 (37-53) 133 (100-182) Pooled data;; no differences between treatment arms
LDL Cholesterol 100 90 Placebo LDL Cholesterol (mg/dl) 80 70 60 50 40 30 20 10 59% mean reduction (95%CI 58-60), P<0.00001 Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School
Primary Endpoint CV Death, MI, Stroke, Hosp for UA, or Cor Revasc 16% 14% 12% 10% 8% 6% 4% 2% Hazard ratio 0.85 14.6% (95% CI, 0.79-0.92) P<0.0001 Placebo 12.6% Evolocumab 0% 0 6 12 18 24 30 36 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization
Key Secondary Endpoint CV Death, MI, or Stroke 10% 9% 8% 7% 6% 5% 4% 3% Hazard ratio 0.80 (95% CI, 0.73-0.88) P<0.00001 Placebo Evolocumab 9.9% 7.9% 2% 1% 0% 0 6 12 18 24 30 36 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Months from Randomization
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 7.9 9.9 0.80 (0.73-0.88) Cardiovascular death 2.5 2.4 1.05 (0.88-1.25) Death due to acute MI 0.26 0.32 0.84 (0.49-1.42) Death due to stroke 0.29 0.30 0.94 (0.58-1.54) Other CV death 1.9 1.8 1.10 (0.90-1.35) MI 4.4 6.3 0.73 (0.65-0.82) Stroke 2.2 2.6 0.79 (0.66-0.95)
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 0.70-0.93) P=0.003 Placebo 6% 4% 2% HR 0.67 (95%CI 0.59-0.77) P<0.00001 Evolocumab 0% 0% 0 3 6 9 12 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School
Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any 77.4 77.4 Serious 24.8 24.7 Allergic reaction 3.1 2.9 Injection- site reaction 2.1 1.6 Treatment- related and led to d/c of study drug 1.6 1.5 Muscle- related 5.0 4.8 Cataract 1.7 1.8 Diabetes (new- onset) 8.1 7.7 Neurocognitive 1.6 1.5 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
PCSK9 Inhibition and Very low LDL- C Giugliano et al. Lancet Aug 28, 2017 25,982 Fourier patients 4 week LDL-C Positive outcomes down to 0.2 mmol/l
PCSK9 Inhibition and Very low LDL- C Giugliano et al. Lancet Aug 28, 2017 25,982 Fourier patients 4 week LDL-C Positive outcomes down to 0.2 mmol/l Primary EP death, MI, revasc, hospitalization for UA
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, 20-80 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. 2010 LDL- C <120 mg/dl - Mar. 2013 Jan.- Mar. 2016 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.
Baseline Characteristics Variables Pitavastatin 1 mg (N=6,214) Pitavastatin 4 mg (N=6,199) Age years 68.1±8.3 68.0±8.3 Male sex 82.5% 82.7% BMI kg/m 2 24.6±3.4 24.6±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%
Serial Changes in Lipid Parameters and hs-crp LDL-C (mg/dl) LDL-C 100 Pitavastatin 1 mg 55 Pitavastatin 4 mg 95 89.4 91.1 91.1 91.0 54 90 88.1 53 85 87.7 52 80 76.6 75 51 75.5 76.6 73.7 70 Main effect p< 0.001 50 Interaction p< 0.001 0 0 Baseline 0.5 1 2 3 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 50.7 50.7 6,212 6,198 51.0 50.6 6,028 5,890 52.2 51.6 5,596 5,482 HDL-C Years 52.3 51.7 51.6 Main effect p< 0.001 Interaction p= 0.17 5,238 5,174 52.3 Baseline 0.5 1 2 3 4,498 4,388 TG (mg/dl) 130 125 120 127.1 125.4 125.5 No. of Patients 1mg 6,208 6,032 4mg 6,195 5,896 122.3 5,606 5,498 TG Years 122.4 5,245 5,183 121.5 4,507 4,402 1mg 4mg hs-crp 115 117.5 0.50 114.5 115.0 114.5 0.49 110 Main effect p< 0.001 0.45 Interaction p= 0.77 Main effect p< 0.001 0 0 Baseline 0.5 1 2 3 Baseline 6 hs-crp (mg/l) 0.65 0.60 0.55 No. of Patients 0.59 0.57 6,032 5,994 Months 0.59 5,734 5,585
Primary Endpoint Cumulative incidence(%) 10 8 6 4 2 0 No. at risk 1mg 4mg 6,214 6,199 (CV death/mi/ischemic stroke/ UA) HR 0.81 (95% CI, 0.69-0.95), 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 1.4 1.2 2.9 2.3 log-rank P=0.01 0 1 2 Years 3 4 5 5,743 5,321 4,501 2,760 5,631 5,256 4,427 2,730 4.2 3.5 5.6 4.6 593 616
Secondary Endpoint Primary Endpoint plus Coronary Revascularization* Cumulative incidence(%) 20 18 16 14 12 10 8 6 4 2 HR 0.83 (95% CI, 0.73-0.93), 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=0.002 8.0 10.4 5.8 8.5 6.7 4.7 2.5 0 No. at risk 0 1 2 3 4 5 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 * 561 588
How did we get here? 55
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; 375:2423-34 56
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; 375:2423-34 57
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 75-100 mg Rivaroxaban 15 mg + ASA 75-100 mg Warfarin (INR 2.0-3.0) + DAPT Warfarin + ASA 75-100 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; 375:2423-34 6 months Warfarin + ASA 75-100 mg 58
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; 375:2423-34 59
Patient Characteristics N Engl J Med 2016; 375:2423-34 60
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; 375:2423-34 61
N Engl J Med 2016; 375:2423-34 62
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:0.47-0.76; P<0.001 Primary Safety 18.0% HR:0.63;CI:0.5-0.8; P<0.001 Primary Safety 26.7% Major Adverse Cardiovascular Event 6.5% HR:1.08;CI:0.69-1.68; P=0.75 Major Adverse Cardiovascular Event 5.6% HR:0.93;CI:0.59-1.48; P=0.76 Major Adverse Cardiovascular Event 6.0% N Engl J Med 2016; 375:2423-34 63
Results N Engl J Med 2016; 375:2423-34 64
Results N Engl J Med 2016; 375:2423-34 65