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

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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

N Engl J Med 2016; 375:2423-­‐34

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

63

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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