Optimizing CV Risk in Hospitalized Patients

•  Managing Atrial Fibrillation and ACS

•  Using Biomarkers to Assess and Modify Risk •  Antiplatelet Therapy in Patients >75

Jessica L. Mega, MD, MPH Brigham and Women’s Hospital – Harvard Medical School

Boston, Massachusetts

A patient had an NSTEMI with a BMS placed in the left circumflex 1 week prior. She is now hospitalized for AF and hypotension. What antithrombotic therapies would you use for the first month? First year? After the first year, would you be comfortable having this patient on a VKA only?

AF=atrial fibrillation; BMS=bare metal stent; NSTEMI=Non-ST-Elevation Myocardial Infarction; VKA=vitamin k antagonist.

•  AF is a common condition, with a prevalence of approximately 1% and a lifetime risk of approximately 25% after the age of 40.

•  Of those who undergo PCI, 5-7% have a preexisting indication for chronic oral anticoagulation.

Layering Antithrombotics

PCI=percutaneous coronary intervention.

Death relative effect

(95% CI) Nonfatal stroke relative Effect

(95% CI) Nonfatal major

extracranial bleeds relative effect

(95% CI) Warfarin

versus no Tx 0.72 (0.55-0.94) 0.34 (0.23-0.49) 2.58 (1.12-5.97)

ASA versus no Tx

0.89 (0.75-1.05) 0.79 (0.65-0.96) 1.60 (1.40-1.80)

Warfarin versus ASA

0.97 (0.85-1.12) 0.48 (0.33-0.70) 1.42 (0.89-2.29)

Warfarin versus ASA +

clopidogrel 0.98 (0.79-1.22) 0.56 (0.39-0.82) 0.91 (0.67-1.23)

ASA + clopidogrel versus ASA alone

0.98 (0.90-1.07) 0.72 (0.61-0.85) 1.50 (1.18-1.89)

Efficacy and Safety of Antithrombotic Agents in AF

You JJ, et al. Chest. 2012:141(2Suppl):e531S-575S. ASA=aspirin; CI=confidence interval.

0

2

4

6

8

1 0

1 2

Dual Antiplatelet Rx for PCI

8.6

2.7

11

6.2

1.6

5.7

0.5

5.8

0

2

4

6

8

10

12 OAC + ASATiclopidine + ASA

ISAR FANTASTIC STARS MATTIS CLASSICS

% M

AC

E

0.9 1.5 1.2

MACE=major adverse clinical events; OAC=oral anticoagulant. Bertrand ME, et al. Circulation. 2000;102:624-629.

Warfarin, Aspirin or Both after MI

ASPECT-2. Lancet. 2002:360:109-113.

Death Death, MI or stroke

MI=myocardial infarction.

WARIS-2. N Engl J Med. 2002;347:969-974.

Warfarin, Aspirin or Both after MI

n = 3,630

0 24

Rivaroxaban 2.5 mg BID

All Cause Death

0 24

Cardiovascular Death

Months

CV Death / MI / Stroke

Est

imat

ed C

umul

ativ

e in

cide

nce

(%)

HR 0.84

mITT p=0.020

ITT p=0.007

HR 0.66

mITT p=0.002

ITT p=0.005

10.7%

9.1%

0 24

Placebo

Months Months

4.5%

2.9%

4.1%

2.7%

Rivaroxaban 2.5 mg BID

Rivaroxaban 2.5 mg BID

Placebo HR 0.68

mITT p=0.002

ITT p=0.004

NNT = 63

Placebo

NNT = 71 NNT = 63 12 12 12

12% 5% 5%

Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, N Engl J Med. 2012;366:9-19.

Very Low Dose

Rivaroxaban 2.5 mg BID after ACS in addition to antiplatelet therapies

ACS=acute coronary syndrome; BID=twice-daily; CV=cardiovascular.

Definite/Probable

HR (95% CI)

0.65 (0.46 - 0.93) mITT p=0.017 ITT p=0.012

Favors Placebo Favors Rivaroxaban HR 0.5 1.0 2.0

Stent Thrombosis

Definite/Probable/Possible

2 yr KM rates

Riva Placebo

0.69 (0.51 - 0.93) mITT p=0.016 ITT p=0.008

1.5% 1.9%

2.3% 2.9%

Gibson CM, TCT 2012

Full Dose Triple Therapy

Full Dose “Triple Therapy (TT)” = “DAPT” +

Full Dose Anticoagulation

What is the ideal antithrombotic therapy for patients who require DAPT

and full dose OAC?

DAPT=dual antiplatelet therapy.

Verheugt FWA.

Circulation. 2013 in press

European Recommendation

AHA/ACC Recommendation

Layering Antithrombotics: New Directions

•  Improve Time-in-therapeutic Range (TTR) with Vitamin K Antagonists

•  Further explore SAPT with Standard and Novel Anticoagulants

•  Understand TT with Novel Anticoagulants and Consider Dosing

Wallentin L, et al. Lancet. 2010;376:975-983.

US 66%

Time in Therapeutic Range (TTR)

Sweden 77%

•  Open-label, multicenter, randomized, controlled trial in Belgium & the Netherlands

•  Adults receiving oral anticoagulants and undergoing PCI were assigned clopidogrel alone (double therapy) or clopidogrel plus aspirin (triple therapy)

Any Bleeding Death, MI, Stroke, Target-Vessel Revascularization, and Stent Thrombosis

Triple Therapy

DoubleTherapy Triple Therapy

DoubleTherapy

WOEST Trial

Dewilde WJM, et al. Lancet. 2013;381:1107-1115.

Dabigatran (PO)

INITIATION (“Extrinsic”) (Tissue Factor, FVIIa, Ca2+)

X à Xa

Extrinsic Tenase

+ V

Prothrombinase

+

VIII VIIIa Thrombin

V Va Thrombin

AMPLIFICATION (“Intrinsic”) (FXII, FXI, platelet membrane)

Intrinsic Tenase IX IXa Tissue Factor

Rivaroxaban (PO) Apixaban (PO) Edoxaban (PO)

Platelet Activation

Fibrin Formation Prothrombin Thrombin

“Common Pathway”

Warfarin

Coagulation Cascade & Anticoagulants

Novel Anticoagulants: •  Rapid onset, offset •  No monitoring

Novel Anticoagulants in AF

Rivaroxaban Apixaban Edoxaban Dabigatran

Novel Anticoagulants

FIIa Inhibitor Fxa Inhibitor

ONGOING •  More favorable bleeding profile than warfarin. •  At least as efficacious. •  ~10% mortality benefit.

5

10

15

00 30 60 90

Days after start of treatment120 150 180

Clin

ical

ly s

igni

fican

t ble

edin

g (%

) Ptrend< 0.0001

Mega JL, et al. Lancet. 2009;374:29-38.

KMrates (%) HR

20 mg 15.3 5.06(3.45 – 7.42)

15 mg 12.7 3.60(2.32 – 5.58)

10 mg 10.9 3.35(2.31 – 4.87)

5 mg 6.1 2.21(1.25 – 3.91)

Placebo 3.3 Reference

Rivaroxaban:Total Daily Dose

ATLAS ACS – TIMI 46 •     Dose-dependent increased risk in bleeding with antiocoagulation on a background of aspirin and clopdiogrel. •  However, it is unknown how other anticoagulants (eg warfarin) would have performed.

Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM, Lancet. 2009;374:29-38.

PIONEER  AF-­‐PCI  

INR=interna,onal  normalized.  

A 65-year-old woman presents with chest pain. Her ECG demonstrates 2 mm of ST depression in the inferior leads, along with an elevated troponin. She is diagnosed with a NSTEMI. What prognostic information is provided by the troponin? Would you evaluate any other biomarkers?

ECG=electrocardiography.    

GENOME

~2×104

genes

~107 SNPs

~105

proteins

TRANSCRIPTOME PHENOTYPE

~106

modified proteins

>105

transcripts

post-translation modification transcription translation

PROTEOME

ENVIRONMENT

Biomarkers as Surrogates

Recurrent Cardiac Events

Biomarkers – 2013

Cytokines IL-6 MCP-1 TNF-α

Acute Phase Reactants CRP Serum Amyloid A

Endothelial Cell Activation vWF sICAM-1 sVCAM-1 sE-selectin

Oxidative Stress MPO Ox-LDL PLA2

Growth Factors VEGF PIGF HGF

Metaloproteinases MMP-1, 2, 9 PAPP-A

Platelet Activation sCD40L sP-selectin

Ventricular Stress ANP BNP NT-proBNP

Myocardial necrosis /ischemia cTnI / cTnT IMA Myoglobin FABP

Early detection of sub-clinical disease

Diagnosis of acute or chronic syndrome

Risk stratification Selection of therapy

Monitoring disease progression or response to therapy

Improved Patient Care

Morrow DA, de Lemos JA. Circulation. 2007;115:949-952.

Risk Stratification in ACS

CLASS I 1.  Early risk stratification based on symptoms, physical exam findings,

ECG findings, and biomarkers (Level of Evidence: C). 2.  A cardiac troponin is the preferred marker for risk stratification. 3.  For most patients, blood should be obtained for testing at hospital

presentation and at 6–9 h (Level of Evidence: B). CLASS IIa 1.  hs-CRP may be useful, in addition to a cardiac troponin, for risk

assessment in patients with a clinical syndrome consistent with ACS. The benefits of therapy based on this strategy remain uncertain. (Level of Evidence: A).

2. Natriuretic peptides may be useful, in addition to a cardiac troponin, for

risk assessment. The benefits of therapy based on this strategy remain uncertain. (Level of Evidence: A).

NACB Guidelines 2007

Cardiac Troponins

Actin Tropomyosin

cTnI

cTnT

TnC •  Subunits of Tn complex on thin filament of striated muscle

•  TnI & TnT isoforms unique to cardiac m.

•  High tissue specificity provides superior signal/noise

2.5

8.3 7.97.0

0

2

4

6

8

10

12

< 0.1 0.1 - < 0.4 0.4 - < 1.5 >=1.5

(%)

Risk of D/MI by cTnI Strata

REF p < 0.001 p < 0.001 p = 0.001

Bonferroni: p < 0.017 indicates significance

N= 734 181 213

693

Morrow DA, et al. JAMA. 2001;286:2405-2412.

TIMI 11B

cTnI SUBSTUDY Results Morrow DA, et al. J Am Coll Cardiol. 2000;36:1812-1817.

cTnI & Outcomes in CKMB Neg Patients

P < 0.004

1.1 2.26.5 8.67.1

11.6

20

31.6

0

5

10

15

20

25

30

35

40

Death MI UR D/MI/UR

Clin

ical

eve

nts

at 4

3 da

ys (%

) cTnI < 0.1 ng/ml cTnI >= 0.1 ng/ml

Troponin and Benefit of Anti-thrombin and Anti-platelet Rx

5

13

64

0

2

4

6

8

10

12

14

16

TnI Neg TnI Pos

PlaceboTirofiban

6

40

9

21

0

5

10

15

20

25

30

35

40

45

50

TnI Neg TnI Pos

UFHEnox

Heeschen C, et al. Lancet. 1999;354:1757-1762.

TIMI 11B: Enoxaparin D/MI/UR (%)

PRISM: Tirofiban D/MI (%)

Morrow DA, et al. J Am Coll Cardiol. 2000;36:1812-1817.

Troponin I: Death/MI at 30 Days

1.9

10.7

3.0

5.0

0

2

4

6

8

10

12

cTnI - cTnI +

(%)

CONS INV

cTnI cut point = 0.1 ng/ml (60% of Pts cTnI +)

OR=0.44 (0.28, 0.71) *p< 0.001

Interaction

P=0.02

p=NS

*

N= 372 362 532 555

Morrow DA, et al. JAMA. 2001;286:2405-2412.

Background B-type Natriuretic Peptides

Pre-Pro-BNP1-134

26-aa signalsequence

N-terminalPro-BNP1-76

BNP77-108

Pro-BNP1-108

t1/2 = 18 min↑ WALLSTRESS

Natriuresis Vasodilatation↑ lusitropy ↓ RAAS

t1/2 = 1-2 hr

Time (days) 0 50 100 150 200 250 300

0

2

4

6

8

10

Mor

talit

y (%

)

Quartile 4

Quartile 2

Quartile 3

Quartile 1

B-type Natriuretic Peptide (BNP) and Mortality

deLemos JA, et al. N Engl J Med. 2001;345:1014-1021.

Independent of age, Killip class, HR, BP, DM, anterior MI P < 0.001

Days since enrollment

6 months 16.3% vs. 3.6% p < 0.0001

BNP > 80 pg/ml

BNP ≤ 80 pg/ml

Prob

abili

ty o

f Dea

th o

r CH

F (%

)

0 30 150 180 0

10

20

60 120 90

5

15

Results Baseline BNP & Clinical Outcomes Morrow DA, et al. J Am Coll Cardiol. 2003;41:1264-1272.

Multimarkers in ACS Necrosis/Ischemia

cTn IMA

Ventricular Stress BNP/ NT-proBNP

ANP

Inflammation CRP

CD40L MMP MPO

Neopterin

Renal Function CrCl

Cystatin C

Accelerated Athero Glucose HgbA1C Lp-PLA2

Thrombosis Fibrinogen

vWF Hgb

Plt count Plt resistance ACS

Adapted from Morrow, Braunwald Circulation

Multimarkers and Targeted Theprapy

Necrosis/Ischemia cTn IMA

Ventricular Stress BNP/ NT-proBNP

ANP

Inflammation CRP

CD40L MMP MPO

Neopterin

Renal Function CrCl

Cystatin C

Accelerated Athero Glucose HgbA1C Lp-PLA2

Thrombosis Fibrinogen

vWF Hgb

Plt count Plt resistance ACS

Adapted from Morrow, Braunwald Circulation

• LMWH • Early invasive • Myoprotective agents • Anti-anginal

• RAAS inhibition • Diuretics

• ASA • Statins • PPAR • ImmunoRx

• Theinopyridine • GP IIb/IIIa inhib • Long term α-coag

A 82-year-old man with no known history presents with a STEMI about 30 minutes after onset of symptoms; primary PCI is going to be performed. He has received aspirin. What additional antiplatelet strategy would you use?

(A)  Clopidogrel

(B)  Ticagrelor

(C)  Prasugrel (D)  None

ACUTE CORONARY SYNDROMES

NQWMI UA QwMI

Tn

CK-MB

ST elevation ACS Non-ST elevation ACS

UA NSTEMI STEMI

Factors Influencing Platelet Reactivity

Gurbel P, et al. Eur Heart J. 2012;33:1187-1189.

  ↑ Risk of Thrombosis   Increased platelet activation and reactivity   Elevated levels of coagulation factors and

plasminogen activator inhibitor type-1   Decreased bleeding

  ↑ Risk of Bleeding   Medical co-therapies   Drug metabolism   Vascular fragility

Antiplatelet Therapy in Older Patients

CURE

CV Death / MI / CVA

CURE Investigators N Engl J Med. 2001.

CVD=Cardiovascular death; HR=Hazard Ratio; MI=Myocardial Infarction; NSTEMI=Non–ST-Elevation Myocardial Infarction; UA=Unstable Angina

HR Prasugrel Better Clopidogrel Better

OVERALL

≥75 65-74

<65

Female Male

STEMI UA/NSTEMI

Age

18

21 12

25 14 6

19

21

Reduction in Risk (%)

Number of Patients

10,074

10,085 3,523

8,322 3,477 1,809

13,608

3,534

0.5 1.0 2.0

Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015

TRITON-TIMI 38: Primary Endpoint (CVD/MI/Stroke) Analysis of Major Subgroups

Ticagrelor better Clopidogrel better

Ti. Cl. Total

Patients

KM % at Month 12

HR (95% CI) Hazard Ratio

(95% CI)

Yes

Yes

Revascularization History of CABG

Sex

Weight Group

≥65 Years

Characteristic

0.5 1.0 2.0

17256 9.5 11.2 0.86 (0.78, 0.94) <80 kg

1312 13.1 17.3 0.75 (0.60, 0.99) ≥60 kg

5288 11.2 13.2 0.83 (0.71, 0.97)

<60 kg

13336 9.2 11.1 0.85 (0.76, 0.95) Female

2878 16.8 18.3 0.94 (0.78, 1.12)

Male

15744 8.6 10.4 0.82 (0.74, 0.91) ≥75 Years

7979 13.2 16.0 0.83 (0.74, 0.94) <75 Years

10643 7.2 8.5 0.85 (0.74, 0.97) <65 Years

1152 19.0 20.8 0.87 (0.66, 1.13) Age Group

17462 9.2 11.1 0.84 (0.76, 0.93) No

1106 19.5 21.7 0.88 (0.67, 1.15) Previous TIA/Non-hemorrhagic Stroke

17518 9.2 11.0 0.84 (0.77, 0.93) No

Yes

Central/South America

≥80 kg

North America

1237 15.2 17.9 0.86 (0.65, 1.13) Europe/Middle East/Africa

1714 11.4 14.8 0.80 (0.61, 1.04) Asia/Australia

4662 14.1 16.2 0.88 (0.76, 1.03) Region

13962 8.4 10.2 0.83 (0.74, 0.92) No

9513 8.3 10.5 0.79 (0.69, 0.90) Medical History of DM

9055 11.4 12.8 0.90 (0.79, 1.01)

0.2

p- value (Interaction)

0.76

0.84

0.86

0.22

0.82

0.36

0.17

0.05

1814 11.9 9.6 1.25 (0.93, 1.67) 13859 8.8 11.0 0.80 (0.72, 0.90)

0.49

Primary endpoint in pre-defined subgroups (cont’d)

AGE and GENDER in GPI for NSTE-ACS: meta-analysis (n = 31,402)

Boersma E. Lancet. 2002;359:189-198.

Strategies to Reduce Bleeding

•  Limit the duration of triple therapy (eg BMS) •  Radial access during catheterization •  Study the role of novel anticoagulants with

triple therapy •  Use low dose aspirin •  Consider the risks:benefits with the newer

antiplatelet agents especially with >75 data.