mon 09 anderson genest acc-r genest workshop...residual.cardiovascular.risk...
TRANSCRIPT
WorkshopTodd Anderson MD / Jacques Genest MD
Game-Changing Trials 2017• COMPASS• Rivaroxaban + ASA• n=27,395• HR 0.76
FOURIEREvolocumabn=27,564HR 0.80
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Key Secondary Endpoint
Months from Randomization
CV Death, MI, or Stroke
0 6 12 18 24 30 36
Hazard ratio 0.80(95% CI, 0.73-0.88)
P<0.00001
Evolocumab
Placebo 7.9%
9.9%
CANTOSCanakinumabn=10,061HR 0.85
Clinicians are faced with clinical trial data that supports targeting LDL-C, inflammation and thrombosis.
CANTOS: MACE +HR: 0.83 (95%CI: 0.72–0.92) p=0.006*
Years
Cumulative incidence
0 1 2 3 4 5
0.00
0.05
0.10
0.15
0.20
0.25
No. at Risk
Placebo
Canakinumab
3344
2284
3107
2135
2921
2039
2578
1824
1238
892
206
201
Placebo
Canakinumab 150 / 300 mg
FOURIER 14.6 / 3 yrsA 60 yo man with stable ASCVD has a residual risk of 3%/year (CV Death, MI, stroke) and 5% risk of MACE+
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 FemalesCanada 79 83
Newfoundland and Labrador 77 81
Prince Edward Island 78 83Nova Scotia 78 82New Brunswick 78 83Quebec 79 83Ontario 79 84Manitoba 77 82Saskatchewan 77 82Alberta 79 83British Columbia 80 84Source: 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:• LDL-C• Non HDL-C• Apo B• Lp(a)• Glucose• Blood pressure
Inflammation• hsCRP• IL-6• Imaging
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
InflammationIf 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 4th 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 5002;; • 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 5003;; Gliclazide 302;; Bisoprolol 2.5;; Ramipril 2.52;; ASA 80;; Sitagliptin 50;; rosuvastatin 10• LDL-C 2.50 mmol/L• HgA1c 8.5What are the priorities of treatment, do preventive measures matter?
PAD Patients in COMPASSPAD Groups Number of patientsAll Patients 7,470
Symptomatic PAD Limbs 4,129
Carotid Disease 1,919
CAD + Low ABI (<0.90) only 1,422
17-‐07-‐01
Mean Follow-‐up: 21months
Primary outcome & components
Outcome
R + AN=2,492
RN=2,474
AN=2,504
Riva + aspirin vs.aspirin Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95% CI) P
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) -‐
August 11, 2017
Limb outcomes
Outcome
R + AN=2,492
RN=2,474
AN=2,504
Riva + aspirin vs.aspirin Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95% CI) P
HR(95% CI) P
MALE 30(1.2)
35(1.4)
56(2.2)
0.54(0.35-‐0.84) 0.005 0.63
(0.41-‐0.96) 0.03
Major amputation
5(0.2)
8(0.3)
17(0.7)
0.30(0.11-‐0.80) 0.01 0.46
(0.20-‐1.08) 0.07
Aug 11, 2017
Key Composite Outcome
Outcome
R + A N=2,492
R N=2,474
A N=2,504
Riva + aspirin vs. aspirin Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95% CI) P
HR(95% CI) P
MACE, MALEor 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
August 14, 2017
Year
CumulativeHazardRate
0.0
0.05
0.10
0.15
0 1 2 3
Aspirin
Rivaroxaban Rivaroxaban + Aspirin
No. at RiskRiva + ASA 2492 2069 893 124Riva 2474 2023 864 147ASA 2504 2034 911 113
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
MACE or MALE or Major Amputation
Major bleeding
Outcome
R + A N=2,492
R N=2,474
A N=2,504
Riva + aspirin vs. aspirin Riva vs. aspirin
N(%)
N(%)
N(%)
HR(95% CI) P
HR(95% CI) P
Major Bleeding 77(3.1)
79(3.2)
48(1.9)
1.61(1.12-‐2.31) 0.009 1.68
(1.17-‐2.40) 0.004
Fatal 4(0.2)
5(0.2)
3(0.1) -‐ -‐ -‐ -‐
Non-‐Fatal ICH 4(0.2)
3(0.1)
8(0.3) -‐ -‐ -‐ -‐
Non-‐fatal other critical organ* 13
(0.5)18(0.7)
8(0.3)
1.55(0.64-‐3.74) 0.33
2.15(0.94-‐4.96) 0.06
*symptomatic
Net clinical benefit in PAD
Outcome
R + A N=2,492
R N=2,474
A N=2,504
Riva + aspirin vs. aspirin Riva vs. aspirin
N (%) N (%) N (%) HR (95% CI) P
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
August 14, 2017
Ridker PM. Circ Res 2016;118:145-‐156.
From CRP to IL-‐6 to IL-‐1: Moving Upstream to Identify Novel Targets for Atheroprotection
Canakinumab
Ridker ESC 2017
Stable CAD (post MI)On Statin, ACE/ARB, BB, ASA
Persistent Elevationof hsCRP (> 2 mg/L)
Randomized Canakinumab 150 mg
SC q 3 months
Randomized Placebo
SC q 3 months
Randomized Canakinumab 300 mg SC q 3 months*
Randomized Canakinumab 50 mg SC q 3 months
Canakinumab Anti-‐Inflammatory Thrombosis Outcomes Study (CANTOS)
N = 10,06139 Countries
April 2011 - June 20171490 Primary Events
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
Ridker ESC2017
Canakinumab SC q 3 months
Characteristic Placebo (N=3347)
50 mg (N=2170)
150 mg (N=2284)
300 mg (N=2263)
Age (years) 61.1 61.1 61.2 61.1Female (%) 25.9 24.9 25.2 26.8Current smoker (%) 22.9 24.5 23.4 23.7Diabetes (%) 39.9 39.4 41.8 39.2Lipid lowering therapy (%) 93.7 94.0 92.7 93.5Renin-‐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 83.5HDL cholesterol (mg/dL) 44.5 43.7 43.7 44.0Triglycerides (mg/dL) 139 139 139 138hsCRP (mg/L) 4.1 4.1 4.2 4.1
CANTOS -‐ Baseline Clinical Characteristics
Canakinumab SC q 3 months
Placebo (N=3347)
50 mg (N=2170)
150 mg (N=2284)
300 mg (N=2263)
P-‐trend
Primary EndpointIR (per 100 person years)HR 95%CI P
4.51.0
(referent) (referent)
4.10.93
0.80-‐1.070.30
3.90.85
0.74-‐0.980.021*
3.90.86
0.75-‐0.990.031
0.020
Secondary EndpointIR (per 100 person years)HR95%CI P
5.11.00
(referent) (referent)
4.60.90
0.78-‐1.030.11
4.30.83
0.73-‐0.950.005*
4.30.83
0.72-‐0.940.004
0.003
*Statistically significant, adjusted for multiplicity, in accordance with the pre-specified closed-testing procedures
CANTOS: Primary Clinical Outcome Effects on MACE and MACE +
Ridker ESC 2017
CANTOS: Consistency of HRs Across All Cardiovascular EndpointsCanakinumab SC q 3 months
Endpoint Placebo (N=3347)
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
1.00 0.70 0.64 0.58 0.005
Any Coronary Revascularization
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 0.39Ridker ESC 2017
* P-value for combined canakinumab doses vs placeboRidker ESC2017
Canakinumab SC q 3monthsAdverse Event Placebo
(N=3347)50mg(N=2170)
150mg(N=2284)
300mg(N=2263)
P-‐trend
Any SAE 12.0 11.4 11.7 12.3 0.43Leukopenia 0.24 0.30 0.37 0.52 0.002Any 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 0.49AnyMalignancy 1.88 1.85 1.69 1.72 0.31
FatalMalignancy 0.64 0.55 0.50 0.31 0.0007Arthritis 3.32 2.15 2.17 2.47 0.002Osteoarthritis 1.67 1.21 1.12 1.30 0.04Gout 0.80 0.43 0.35 0.37 0.0001ALT > 3x normal 1.4 1.9 1.9 2.0 0.19Bilirubin > 2x normal 0.8 1.0 0.7 0.7 0.34
CANTOS: Additional Outcomes (per 100 person years of exposure)
% LDL-C reduction and events in Jupiter study
Ridker et al.EHJ 2016
17082 subjects randomized to Rosuvastatin 20 mg46% obtained a > 50% reduction in LDL-C
Ongoing Outcome Trials with PCSK9 Inhibitors
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.
Study FOURIER ODYSSEYOUTCOMES 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
PopulationMI 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: 17,000SPIRE-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
FOURIERFurther 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 – 66th Annual Scientific Session
Late-‐Breaking Clinical Trial
March 17, 2017
Trial Design
Evolocumab SC 140 mg Q2W or 420 mg QM
Placebo SCQ2W or QM
LDL-C ≥70 mg/dL ornon-HDL-C ≥100 mg/dL
Follow-up Q 12 weeks
Screening, Lipid Stabilization, and Placebo Run-in
High or moderate intensity statin therapy (± ezetimibe)
27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD)
RANDOMIZEDDOUBLE BLIND
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
Pooled data;; no differences between treatment arms
Median time from most recent event ~3 yrs
Lipid Lowering Therapy& Lipid Levels at Baseline
Characteristic Value
Statin use (%)*
High-‐intensity 69
Moderate-‐intensity 30
Ezetimibe use (%) 5
Median lipid measures (IQR) – mg/dL
LDL-‐C 92 (80-‐109)
Total cholesterol 168 (151-‐189)
HDL-‐C 44 (37-‐53)
Triglycerides 133 (100-‐182)
Pooled data;; no differences between treatment arms
*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.
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
LDL Cholesterol (m
g/dl)
Weeks
LDL Cholesterol
Evolocumab(median 30 mg/dl, IQR 19-46 mg/dl)
Placebo
59% mean reduction (95%CI 58-60), P<0.00001
Absolute reduction: 56 mg/dl (95%CI 55-57)
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
10%
12%
14%
16%
Primary Endpoint
Evolocumab
Placebo
Months from Randomization
CV Death, MI, Stroke,
Hosp for UA, or CorRevasc
0 6 12 18 24 30 36
Hazard ratio 0.85(95% CI, 0.79-0.92)
P<0.0001 12.6%
14.6%
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
10%
Key Secondary Endpoint
Months from Randomization
CV Death, MI, or Stroke
0 6 12 18 24 30 36
Hazard ratio 0.80(95% CI, 0.73-0.88)
P<0.00001
Evolocumab
Placebo 7.9%
9.9%
Types of CV Outcomes
EndpointEvolocumab(N=13,784)
Placebo(N=13,780) HR (95% CI)
3-‐yr Kaplan-‐Meier rate
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)
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
0%
2%
4%
6%
8%
Fatal or Nonfatal MI or Stroke
Evolocumab
Placebo
Months from Randomization
Fatal or Nonfatal MI or Stroke
0 3 9 12 24 30 366 12 18
19% RRR
HR 0.81 (95%CI 0.70-0.93)P=0.003
33% RRR
HR 0.67 (95%CI 0.59-0.77)P<0.00001
Safety
Evolocumab(N=13,769)
Placebo(N=13,756)
Adverse events (%)
Any 77.4 77.4Serious 24.8 24.7
Allergic reaction 3.1 2.9Injection-‐site reaction 2.1 1.6Treatment-‐related and led to d/c of study drug 1.6 1.5Muscle-‐related 5.0 4.8Cataract 1.7 1.8Diabetes (new-‐onset) 8.1 7.7Neurocognitive 1.6 1.5
Laboratory results (%)
Binding Ab 0.3 n/aNeutralizing 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-CPositive 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-CPositive outcomes down to 0.2 mmol/LPrimary 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
enrollmentPitavastatin1mg/day Randomization
Pitavastatin 1mg/day
Pitavastatin 4mg/dayLDL-‐C <120mg/dLJan. 2010
-‐Mar. 2013 Jan.-‐Mar. 2016Run-‐in Period (>1 month) Follow-‐up (36-‐60 months)
Pitavastatin 1mg and 4mg have LDL-‐C lowering effect comparable to atorvastatin 5mg and 20mg, respectively.
・Men and women, 20-‐80years of age・Stable CAD: ・ACS or PCI/CABG >3months・Clinical diagnosis with coronary stenosis ≥50% diameter stenosis・LDL-‐C <120mg/dL on pitavastatin 1mg/day during the run-‐in period
Baseline CharacteristicsVariables Pitavastatin 1 mg
(N=6,214)Pitavastatin 4 mg
(N=6,199)Age — years 68.1±8.3 68.0±8.3Male sex 82.5% 82.7%BMI — kg/m2 24.6±3.4 24.6±3.3Hypertension 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/1.73m2) 36.2% 35.4%Aspirin 92.5% 92.4%DAPT 44.6% 43.9%
Serial Changes in Lipid Parameters and hs-CRPLDL-C
TG
HDL-C
hs-CRP
Baseline 0.5 1 Years
Years
Years
Months
2 36,214
88.1
1mg 6,031
89.4
5,615
91.1
5,252
91.1
4,509
91.0
6,199
87.7
4mg1mg4mg5,890
73.7
5,518
75.5
5,203
76.6
4,405
76.6
6,212
50.7
6,028
50.6
5,596
51.6
5,238
51.6
4,498
51.7
6,198
50.7
5,890
51.0
5,482
52.2
5,174
52.3
4,388
52.3
6,208
125.4
1mg 6,032
125.5
5,606
122.3
5,245
122.4
4,507
121.5
6,195
127.1
4mg1mg4mg5,896
117.5
5,498
115.0
5,183
114.5
4,402
114.5
6,032
0.59
5,734
0.59
5,994
0.57
5,585
0.49
Baseline 0.5 Baseline 61 2 3
Baseline 0.5 1 2 3
Pitavastatin 1mg
Main effect p< 0.001Interaction p< 0.001
Main effect p< 0.001Interaction p= 0.17
Pitavastatin 4mg
No. of Patients No. of Patients
No. of Patients No. of Patients
Main effect p< 0.001Interaction p= 0.77
700 0
7580859095
100
0 0110
115
120
125
130
0.45
0.50
0.55
0.60
0.65
50
51
52
53
54
55LDL-C (mg/dL)
TG (mg/dL)
hs-CRP (mg/L)
HDL-C (mg/dL)
Main effect p< 0.001
Primary Endpoint (CV death/MI/ Ischemic stroke/UA)
1mg4mg
6,2146,199
5,7435,631
5,321Years
5,2564,5014,427
2,7602,730
593616
No. at risk
Cumulative incidence(%)
10
2
4
6
8
0
4.2
5.6
1.4
1.2
3.5
2.3
2.9 4.6
0 1 2 3 4 5
NNT for 5 years=63
log-rank P=0.01
No. of patients with event: 4mg 266 (4.3%), 1mg 334 (5.4%) HR 0.81 (95% CI, 0.69-0.95), Cox P=0.01
Pitavastatin 1mgPitavastatin 4mg
Secondary EndpointPrimary Endpoint plus Coronary Revascularization*
log-rank P=0.0028.0
10.4
2.8
2.5
6.74.7
5.8 8.5
2018161412
8642
10
0
5,6605,556
5,1665,131
4,3274,277
2,6272,617
561588
Cumulative incidence(%)
1mg4mg
No. at risk 0 1 2 3 4 56,2146,199
Years
NNT for 5 years=41No. of patients with event: 4mg 489 (7.9%), 1mg 600 (9.7%)HR 0.83 (95% CI, 0.73-0.93), Cox P=0.002
: Excluding TLR for lesions treated at prior PCI*
Pitavastatin 1mgPitavastatin 4mg
How did we get here?
55
PIONEER AF-‐PCI• Study Design• International, multicenter, randomized, open-‐label trial
56
InclusionMen 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
ExclusionHistory 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
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End Points
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Clinically Significant Bleeding
TIMI Minor Bleeding
TIMI Major Bleeding
Bleeding Requiring Medical Attention
Primary Safety Secondary
• Each component of the primary safety endpointSafety
• Major cardiovascular event composite*• Stent thrombosis Efficacy
• ISTH Major bleeding• GUSTO severe bleedingExploratory
*Death from cardiovascular cause, MI, StrokeEach component of the composite
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Treatment Subgroups
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• NVAF• No Prior
Stroke/TIA• PCI with Stent
Placement
Warfarin (INR 2.0-‐3.0) + DAPT
Rivaroxaban 2.5 mg BID + DAPT
Rivaroxaban 15 mg Daily + Clopidogrel 75 mg
Rivaroxaban 15 mg + ASA 75-‐100 mg
Rivaroxaban 15 mg + ASA 75-‐100 mg
Warfarin + ASA 75-‐100 mg
Warfarin + ASA 75-‐100 mg
≤72 hoursAfter sheath
removalRandomization
12 Months
1 month
1 month
6 months
6 months*Rivaroxaban 10 mg daily if CrCl 30-‐<50 mL/min†Prasugrel 10 mg daily or Ticagrelor 90 mg BID in <15% of patientsN Engl J Med 2016; 375:2423-‐34
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
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Patient Characteristics
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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%
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P<0.001 For both comparisons
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Results
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Group 1 Rivaroxaban 15 mg Daily +
P2Y12 12 Months
Primary Safety 16.8% HR:0.59;CI:0.47-‐0.76; P<0.001
Major Adverse Cardiovascular Event 6.5% HR:1.08;CI:0.69-‐
1.68; P=0.75
Group 2 Rivaroxaban 2.5 mg BID + DAPT 1,6,12 Month(s)
Primary Safety 18.0% HR:0.63;CI:0.5-‐0.8; P<0.001
Major Adverse Cardiovascular Event 5.6% HR:0.93;CI:0.59-‐
1.48; P=0.76
Group 3 Warfarin + DAPT
1,6,12 Month(s)
Primary Safety 26.7%
Major Adverse Cardiovascular Event
6.0%
N Engl J Med 2016; 375:2423-‐34
Results
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Results
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