Cardiology Update

11th Update for the General Anaesthetist, June 2017

1

Daniel Bromage

NIHR Clinical Lecturer & Specialty Trainee in Cardiology

Overview

• Acute coronary syndromes & PCI

• Antiplatelet agents

• Pacemakers and peri-operative management

• Atrial fibrillation and stroke prevention

• OOHCA without ST elevation

• What’s new in heart failure?

2

ACUTE CORONARY SYNDROMES & PCI

3

Unstable angina(UA)

ST-segment elevation myocardial infarction

(STEMI)

Non-ST-segment myocardial infarction

(NSTEMI)

Collectively known as NSTE-ACS

7.5

12.1

14.8

0

5

10

15

20

Mortality for ACS

GRACE study (n = 1143)

Mortality doubles within 1 year of discharge from

hospital

In-hospital 6-months 1-year

Mo

rtality

rate

(%

)

Tang EW, et al. Am Heart J 2007;153(1):29-355

Patterns of healing

6In-stent restenosis Acute stent thrombosis?

Drug eluting stents

7Bromage DI, et al. Heart 2012;98(Suppl1):A24

Platform design

8

First-generation DES Newer-generation DES

Stent struts

Thrombus

C

Images provided by Dr N West, Papworth Hospital, Cambridge9

Stent thrombosis

• Uncommon but high mortality (10-40%)

• Mostly in the first month (60%), but even up to 5 years!

• 1.5-2% at 2 years

• Newer-generation DES have a lower risk of stent thrombosis

10Sarno G, et al. JACC. 2014;64:16-24

Risks for stent thrombosis

Procedural factors

• Under-sizing (OR 13.5)

• Dissection (OR 6)

• Poor TIMI flow post PCI (OR 5)

• Long/narrow stents

• Complex procedure/extensive disease

• Acute coronary syndrome

Patient factors

• LVEF <30% (OR 2.7)

• DM

• Renal disease

• Malignancy

Inadequate anti-platelet treatment

• Premature discontinuation of P2Y12 inhibitors (OR 36.5!)

• Resistance to clopidogrel i.e. CYP2C19 status, ?omeprazole use11

Bioresorbable vascular scaffolds

12Lancet. 2016;388:2479

ANTI-PLATELET AGENTS

13

20091998 20111991 2000’s

PrasugrelClopidogrelAspirin Ticlopidine(not available in the UK)

Dual anti-platelet therapy

1980s

TRITON-TIMI 38: Primary endpoint

Days

% o

f P

atie

nts

0

5

10

15

0 30 60 90 180 270 360 450

HR: 0.81(0.73-0.90)P<.001

Prasugrel (n=6813)

Clopidogrel (n=6795)

12.1%

9.9%

NNT=46

Wiviott SD, et al. N Engl J Med. 2007;357(20):2001-2015

CV Death/MI/Stroke at 15 months

14

TRITON-TIMI 38: Stent thrombosis

2.4

1.1

0

2

4

Prasugrel

(n=6813)

Clopidogrel

(n=6795)

% o

f P

atie

nts

P<.001

Wiviott SD, et al. N Engl J Med. 2007;357(20):2001-201515

TRITON-TIMI 38: Safety

1.8

0.9 0.9

0.1

3.0

2.4

1.41.1

0.4

4.0

0

2

4

6

TIMI MajorBleeds

LifeThreatening

Nonfatal Fatal Transfusion

Clopidogrel (n=6795)

Prasugrel (n=6813)

% E

ven

ts

*Most frequent sites of life-threatening bleeding: Gastrointestinal, intracranial, puncture, and retroperitoneal.

Wiviott SD, et al. N Engl J Med. 2007;357(20):2001-2015

P=.03

P=.01 P=.23

P=.002

P<.001

*

16

P2Y12 characteristics

Characteristics Clopidogrel1,2 Prasugrel1,3 Ticagrelor1,4

Direct acting

Reversible binding to P2Y12

receptor

Rapid onset of action

> 60% IPA (mean steady state)

More consistent response

1. Wallentin L. Eur Heart J 2009;30:1964-1977; 2. Clopidogrel. Summary of product characteristics 2010; 3. Prasugrel. Summary of product characteristics 2009; 4. Ticagrelor.

Summary of product characteristics 2010 17

Ticagrelor

• Direct acting

• Reversibly binds toP2Y12 receptor

Ticagrelor is aCyclo-pentyl-triazolo-pyrimidine (CPTP)

Husted S, et al. Eur Heart J 2006;27:1038-1047 18

Ticagrelor is not a prodrug

No in vivobiotransformation

needed

Prasugrel

Active metabolite

Clopidogrel

Active metabolite

85%

inactive

metabolite1

Prodrug

Hydrolysis

(Esterases)

CYP-dependant

oxidation

CYP-dependant

oxidation

Intermediary metabolite

Intermediary metabolite

Ticagrelor

Figure adapted from: Schomig AS. N Eng J Med 2009;36:1108-1111.

1. Clopidogrel. Summary of product characteristics. 2010 19

Ticagrelor onset and efficacy

0

25

50

75

100

0.5 2 4 8

Ticagrelor Clopidogrel

Time post-loading dose (hours)

In

hib

itio

n o

f p

late

let

ag

gre

ga

tio

n (

%)

Patients with stable CAD, which is not a licensed population for ticagreloruse

* p < 0.0001, ticagrelor vsclopidogrel

*

* **

Adapted from: Gurbel PA, et al. Circulation 2009;120:2577-258520

Ticagrelor reduces MACE

Kaplan-Meier estimate of time to primary endpoint (composite of CV death, MI or stroke)

No. at risk

Ticagrelor 9,333 8,628 8,460 6,743 5,161

Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047

4,1478,219

Days after randomisation

0 60 120 180 240 300 360

12

11

10

9

8

7

6

5

4

3

2

1

0

13

Cu

mu

lati

ve

in

cid

en

ce

(%

)

9.8

11.7

HR 0.84 (95% CI 0.77–0.92), p=0.0003

Clopidogrel

Ticagrelor

RRR = 16%ARR = 1.9%NNT = 54

Wallentin L, et al. N Engl J Med 2009;361:1045-1057

All patients received aspirin (75-100 mg/d)

21

0.3

Major bleeding with ticagrelor

NS13

NS

NS

NS

NS

0

K-M

esti

ma

ted

ra

te (

% p

er

ye

ar)

PLATO major bleeding

1

2

3

4

5

6

7

8

9

10

12

11

TIMI major bleeding

Red cell transfusion

PLATO life-threatening/fatal bleeding

Fatal bleeding

11.611.2

7.9 7.7

8.9 8.9

5.8 5.8

0.3

TicagrelorClopidogrel

Wallentin L, et al. N Engl J Med 2009;361:1045-105722

Ticagrelor

Adenosine

Clopidogrel

Prasugrel

Dipyridamol

23

Dyspnoea with ticagrelor

• Dyspnoea in patients receiving ticagrelor is usually mild or moderate in intensity and often resolves without the need for treatment discontinuation2,3

• Dyspnoea during ticagrelor treatment does not appear to be associated with any differences in efficacy or bleeding-related clinical outcomes compared with clopidogrel2

† Most episodes of dyspnoea lasted less than a week

Dyspnoea† (%) Ticagrelor(n=9,235)

Clopidogrel(n=9,186)

p value

Any 13.8 7.8 < 0.001

With discontinuation of treatment 0.9 0.1 < 0.001

1. Wallentin L, et al. N Engl J Med 2009;361:1045-1057; 2. Storey RF, et al. Poster presented at European Society of Cardiology,

Stockholm, Sweden, 28 August–1 September 2010; 3. Ticagrelor. Summary of product characteristics. 201024

ESC guidelines - STEMI

Steg G et al. European Heart Journal 2012;33:2569-2619 25

ESC guidelines - NSTEMI

Hamm CW et al. European Heart Journal 2011;32:2999-3054 26

ESC guidelines – Stable CAD

Montalescot G et al. European Heart Journal 2013;34:2949-3003 27

Duration of DAPT

• Controversial

• Currently, 1 year after ACS, 6 months after DES, 1 month after BMS

• Several trials have examined this: ARCTIC-Interruption1, SECURITY2, DAPT3.

• Conclusions:– High risk of bleeding, stop sooner

– High risk of ischaemia/thrombus, continue

– ?personalised risk score

281. Collet JP et al. Lancet 2014;384:1577-1585; 2. Colombo A et al. JACC 2014;64:2086-2097; 3. Mauri L et al. NEJM 2014;371:2155-2166

NON-CARDIAC SURGERY POST-PCI

Ris

k o

f B

lee

din

g

Ris

k o

f T

hro

mb

osisHaemostatic

Balance

29

Discontinuation of DAPT

• 14.4% stop 1 or 2 antiplatelets for at least 5 days in the first year post PCI

• Causes of discontinuation of DAPT– Bleeding events/invasive procedures (50%)

– Medical decision (32%)

– Patient decision (18%)

• Predictors of discontinuation– Renal impairment

– Previous haemorrhage

– Peripheral vascular disease

Ferreira-Gonzalez et al. Circulation 2010 30

Eisenberg MJ et al. Circulation 2009;119:1634-1642

Discontinuation of DAPT

31

Stop or continue ...

Continuing Aspirin/DAPT

• Increased bleeding– Aspirin alone: 20%

– DAPT: 50%

• No increased mortality except in intracranial surgery

• Increased transfusion by 30%

• Background risk of MI

Withdrawing Aspirin/DAPT

• ?rebound effect

• Early stent thrombosis in up to 35%, with mortality of 20-40%, i.e. Increased peri-operative cardiac death rate 5-10x

• Poorer outcomes of peri-operative MI

MDT: Anaesthetists + Surgeons + Cardiologists + Patients32

ESC recommendation

Windecker S et al. European Heart Journal 2014;35:2541-2619 33

Timing is important: Ontario study

• N=8116, DES in 33%

• Overall event rate = 2.1% (intermediate risk)

Wijeysundera DN, et al. Circulation 2012;126(11):1355-6234

ESC recommendation

Montalescot G et al. European Heart Journal 2013;34:2949-3003 35

PACEMAKERS AND PERI-OPERATIVE MANAGEMENT

36

Cardiac devices

• What type of device is it: pacemaker or defibrillator?

• ID card?

–Device manufacturer

–Model number

–Serial number

–Implanting hospital

–Follow-up hospital

–Date of implant

–Reason for implant

37

What device is this?

38

CRT trials

TRIAL NYHA LVEF (%) QRS (msec) COMMENTS

COMPANION 1(2004)

III-IV ≤35% ≥120 ~20% reduction in all cause mortality or hospitalization from any cause

CARE-HF 2

(2005)III-IV ≤35% ≥120 RRR of death 37%

MADIT-CRT 3

(2009)I-II ≤30% ≥130 CRT-D: 34% reduction in all-cause

mortality and heart failure events vs. ICD

RAFT 4 (2010) II-III ≤30% ≥120 CRT-D: 25% reduction in all-cause mortality and hopitalisations vs. ICD

ECHO-CRT 5

(2013)III-IV ≤35% <130 +

dyssynchronyCRT does not reduce the rate of death or hospitalization for heart failure and may increase mortality

1. Bristow MR, et al. N Engl J Med 2004;350(21):2140-50; 2. Cleland JGF, et al. N Engl J Med 2005;352:1539-49; 3. Moss AJ, et al. N Engl J Med 2009;361:1329-38; 4. Tang

ASL, et al. N Engl J Med 2010;363(25):2385-95; 5. Ruschitzka F, et al. N Engl J Med 2013;369:1395-140539

Practically...

• Get device checked if possible

–Confirm in working order

–Check if pacing dependent

–Programming of device if necessary

• Monitoring

• Resuscitation/pacing equipment

• Magnet?

40

What’s new in EP?

Leadless pacemaker Subcutaneous ICD

41

What’s new in EP?

Telemonitoring Vagal nerve stimulation

42Hindricks G et al. Lancet 2014;384:583-590

ATRIAL FIBRILLATION AND STROKE PREVENTION

43

AF and stroke

• AF is associated with a 5-fold higher stroke risk overall1

• Without prevention, approximately 1 in 20 patients will have a stroke each year3

• Responsible for nearly a third of all strokes,5 and the leading cause of embolic stroke6

1. Savelieva I et al. Ann Med 2007;39:371–91; 2. ACC/AHA/HRS focused update guidelines: Fuster V et al. Circulation 2011;123:e269–357; 3. Atrial Fibrillation Investigators. Arch Intern

Med 1994;154:1449–57; 4. Carlson M. Medscape Cardiol 2004;8; available at http://www.medscape.org/viewarticle/487849; accessed Feb 2010; 5. Hannon N et al. Cerebrovasc Dis

2010;29:43–9; 6. Emmerich J et al. Eur Heart J 2005;7(Suppl C):C28–3344

Strokes in AF are worse!

• Compared with other causes, stroke in AF:

–Is usually more severe1

–Is more likely to be disabling:2

–Has double the post-stroke mortality rate3

1. Savelieva I et al. Ann Med 2007;39:371–91; 2. Dulli DA et al. Neuroepidemiology 2003;22:118–23; 3. Benjamin EJ et al. Circulation 1998;98:946–52 45

Source of thromboembolism in AF

The left atrial appendage is the source of thromboemboli in ~80% of AF patients with stroke

46

47http://www.nice.org.uk/nicemedia/live/14573/68045/68045.pdf

DAPT vs. warfarin

RR = 1.72 AR ↑= 1.0%

48

Stroke prevention: CHA2DS2-VASc

• CCF 1

• Hypertension 1

• Vascular disease 1

• Diabetes 1

• Stroke or TIA 2

• Female gender 1

• Age ≥ 65 1 or

• Age ≥ 75 2

0: No anticoagulation

≥1 (Men) or ≥2 (Women): Anticoagulate

49Lip GY et al. Chest 2010;137(2):263-72, http://www.nice.org.uk/nicemedia/live/14573/68045/68045.pdf

Bleeding risk

• HAS-BLED• Hypertension 1• Abnormal renal or liver function 2• Stroke 1• Bleeding history 1• Labile INR 1• Age > 65 1• Drugs or alcohol 2

• 3+: High risk for bleeding with warfarin

50Pisters R. Chest. 2010 Nov;138(5):1093-100

Warfarin therapeutic window

Relationship between clinical events and INR intensity

ICH=intracranial hemorrhage

INR=international normalized ratio

1. Hylek EM et al. Ann Intern Med 1994;120:897-902; 2. Hylek EM et al. N Engl J Med 1996;335:540-54651

Time in therapeutic range (TTR)

0 500 1000 1500 2000

Survival to stroke (days)

0.6

0.7

0.8

0.9

1.0

Cu

mu

lati

ve s

urv

ival

71–100%

Warfarin group

61–70%51–60%41–50%31–40%<30%Non warfarin

Morgan CL et al. Thrombosis Research 2009;124:37–41 52

Alternatives to warfarin (NOACs)

Factor Xa inhibitors:ApixabanRivaroxabanEdoxaban

Direct Thrombin inhibitor:Dabigatran

53

NOACs vs. warfarin

SSE* vs. Warfarin(ITT population)

ARR HR

D150 0.60 0.65 (0.52-0.81)

D110 0.17 0.90 (0.74-1.10)

Rivaroxaban 0.30 0.88 (0.75-1.03)

Apixaban 0.33 0.79 (0.66-0.95)

Haemorrhagic stroke vs. Warfarin

ARR HR

D150 0.28 0.26 (0.14-0.49)

D110 0.26 0.31 (0.17-0.56)

Rivaroxaban 0.18 0.59 (0.37-0.93)

Apixaban 0.23 0.51 (0.35-0.75)

Connolly et al, N Eng J Med 2009; 361 and Vol. 363 No.19; Patel et al, N Eng J Med 2011; 365; Granger et al, N Eng J Med 2011; 365

*SSE (Stroke, Systemic Embolism)

NOACs vs. warfarin

IntracranialBleeding

ARR HR

D150 0.44 0.41 (0.28-0.06)

D110 0.53 0.30 (0.19-0.45)

Rivaroxaban 0.20 0.67 (0.47-0.93)

Apixaban 0.47 0.42 (0.30-0.58)

Connolly et al, N Eng J Med 2009; 361 and Vol. 363 No.19

Patel et al, N Eng J Med 2011; 365 Granger et al, N Eng J Med 2011; 365

Major Bleeding ARR HR

D150 0.25 0.93 (0.81-1.07)

D110 0.70 0.80 (0.70-0.93)

Rivaroxaban -0.20 1.04 (0.90-1.20)

Apixaban 0.96 0.69 (0.60-0.80)

NOACs

Pros

• No frequent blood tests

• Beneficial in all bleeding risks

• All reduce ICH

Cons

• Caution in patients with elevated bleeding risk and prior to invasive therapy

• Renal and liver impairment

• Drug interactions

• Can’t monitor

• Cost

• NOT licensed in valvular AF or prosthetic valves

56

Practical issues

• Dabigatran prolongs TT but not aPTT• Rivaroxaban and apixaban prolong aPTT (slightly) but

not TT• PT/INR is not helpful• Need to stop at least 5 doses before major surgery• If major bleeding:

– Maintained diuresis– Supportive treatment with blood/platelet

transfusion– Consider PCC (e.g. FEIBA, Beriplex)– Consider haemodialysis (remove 40-60% in 4 hrs)

57

OOHCA WITHOUT ST ELEVATION

58

Meta-analysis

NO RANDOMISED STUDIES!

Larsen JM and Ravkilde Jl. Resuscitation 2012;83:1427-143359

Consensus document

Noc M, et al. Eurointervention 2014;10:31-3760

Advice…

• VF: ischaemia?

• LBBB: ischaemia?

• ACS treatment

• Echo if unsure

61

WHAT’S NEW IN HEART FAILURE?

62

The headlines: PARADIGM

63McMurray JJV, et al. NEJM 2014;371(11):2993-1004

The headlines: SERVE-HF

64Cowie MR, et al. NEJM 2015;373(12):1095-105

The headlines: CONFIRM-HF

65Ponikowski P, et al. EHJ 2015;36(11):657-68

The headlines: EMPA-REG OUTCOME

66Zinman B, et al. NEJM 2015;373(22):2117-28

2016 ESC Guidelines

• Recommendations on the diagnostic criteria for HF with reduced EF (HFrEF), HF with mid-range EF (HFmrEF) and HF with preserved EF (HFpEF)

• A new algorithm for the diagnosis of HF in the non-acute setting based on the evaluation of HF probability

• Recommendations aimed at prevention or delay of the development of overt HF or the prevention of death before the onset of symptoms

• Indications for the use of the new compound sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitors (ARNIs)

• Modified indications for cardiac resynchronization therapy (CRT)• The concept of an early initiation of appropriate therapy going• A new algorithm for a combined diagnosis and treatment

approach of acute HF

67

Cardioprotection

No ‘Conditioning’

Heart Ischaemia Reperfusion‘Conditioned’

Ischaemic

Postconditioning

2003

< 1min

Ischaemic

Preconditioning

1986

0 to 3 hrs

Remote

Ischaemic

Conditioning

Pharmacological

conditioning

68

ERICCA

69Hausenloy D, et al. NEJM 2015;373(15):1408-17

Thank you

Summary

• Acute coronary syndromes & PCI

• Antiplatelet agents

• Pacemakers and peri-operative management

• Atrial fibrillation and stroke prevention

• OOHCA without ST elevation

• What’s new in heart failure – LCZ696, IV iron, SGLT-2 inhibitors

71

• EMPA-REG

• SERVE-HF

72