Development of treatment in acute and chronic coronary artery disease

Lars Wallentin, Senior Professor Cardiology, Department of Medicine and Uppsala Clinical Research Center Uppsala University, Uppsala, Sweden

Jönköping, Sep 20, 2018

Uppsala University

Uppsala Science for life laboratories

UAS Uppsala University Hospital

Our mission To develop and improve health care by performing research and supporting clinical trials, quality registries and quality enhancement in Sweden and internationally.

Quality registries – peer review

Clinical reality

Scientific evidence – Guidelines

Quality enhancement

New treatment / Clinical Trials

Diagnostic methods

Thromboembolism cause of acute coronary syndromes

• 25.000 AMI/year in Sweden (most common heart disease)

• CAD risk increase with age and risk factors

Risk of Myocardial infarction (MI) • 5-fold increase with diagnosis of CAD

• 15% 1-year mortality after acute MI

• Risk factors for adverse outcomes

• Age

• Previous MI or other vascular disease

• Congestive heart failure

• Diabetes

• Smoking, Hypertension. High cholesterol

Bleeding risk with antithrombotic treatment • Risk factors for bleeding

• Age

• Prior bleeding event

• Anemia

• Renal dysfunction

Treatments aim to balance risk of MI vs the risk of bleeding

Coronary artery disease (CAD)

STEMI

EKG 1960-talet

Behandling av kammarflimmer. • 1947 strömstöt mot hjärtat vid thoraxkirurgi (Beck).

• 1956 strömstöt elektroder utanpå bröstkorgen (Zoll).

• 1953 svensk intern defibrillator (Holmdahl , Uppsala)

• 1953 organisationen för HLR i Uppsala.

• 1969 HLR genom yttre kompression

2.a upplagan 1964

Hjärtinfarkt Behandlingen omfattar följande moment: 1. Sträng immobilisering (fåtöljläge i säng)

a. Ingen avföring första veckan b. Saft-Karell kost 800 Kal

2. Morfin 3. Nor-adrenalin 4. AP 5. Syrgas 6. Strofantin

AP för att nedsätta risken för trombos i nedre

extremiteterna och lungemboli. Man skall icke

föreställa sig att man i nämnvärd grad påverkar

själva tillståndet i hjärtat.

Nylins trappa

Gustav Nylin

Svenska Cardiologföreningens

Första ordförande 1947 – 1949

”Hjärtat är mitt organ”

Hjärtinfarktvård 1960-talet

Och

1980 -talet

Hjärtinsivvård. • 1962 första HIA i England (Julian). • 1966 Borås (Sven-Åke Forsberg).

• 1967 Serafimerlasarettet i Stockholm (Torbjörn Lundman, Lars Mogensen, Erik Orinius). • 1968 Malmö (Bengt W Johansson), Sahlgrenska (Stig Holmberg), Uddevalla

1981

Selective coronary angiography 1958 - 1964

Cykelstudien 1981 - 1985

Myocardial infarction in relation to ECG at rest after unstable CAD

No STT- change

T-inv only ST- elevation

ST- depression

ST-elev & ST-dep

0

5

10

15

20

25

30

Dea

th o

r m

yoca

rdia

l inf

arct

ion

duri

ng 1

2 m

onth

s

237 287 93 216 78

RISC, J Intern Med 1993

RISC 1985-1989

Myocardial infarction in relation to painful and silent ischemia at predischarge e.t.after an episode of unstable CAD.

360 300 240 180 120 60 0 0

10

20

Days

% ST - dep & Pain (n=230)

ST - dep , no pain (n=144)

No ST - dep , Pain (n=145)

No ST - dep , no pain (n=221)

RISC AHJ 1992

RISC 1985-1989

Diagnosis of severe CAD by noninvasive tests after unstable CAD

Ext. SPECT defect or ST - dep e.t.

Extensive SPECT defect

ST - dep and/or low Wmax at e.t.

ST - dep at exercise test

ST - dep in ECG at rest

Previous MI

0 0,1 0,2 0,3 0,4 0,5 0,6 0,7 0,8 0,9 1

Specificity Sensitivity

151 21

28

143

83

88

91 80

83

88

100

71

TRIC 1993

TRIC 1989-1990

Coronary lesions in relation to noninvasive tests after unstable CAD

0 v.d. 1 v.d.

2 v.d. 2 v.d.

LADpx 3 v.d.

Low risk e.t. or no th.defect

High risk e.t. + moderate th.defect

High risk e.t. + extensive th.defect 0

5

10

15

20

25

30

35

num

ber

of p

atie

nts

TRIC 1993

TRIC 1989-1990

n Atherothrombotic inflammatory disease

n Ulcerated thrombotic coronary lesions

n Microembolisation

n Severe coronary stenosis

n Transient recurring symptoms & events

n Myocardial ischemia - injury - infarction

Characteristics of non-ST-elevation ACS

Erling Falk 1982 – 1986

A fixed stenosis alone has to be considerably

greater than 75 % to explain angina pectoris

at rest. Plaque rupture with a variable degree

of haemorrhage into the plaque through the

ruptured surface and/or recurrent mural

thrombus causing rapid progression

characterizes unstable angina pectoris

especially in case of r apid progression to

acute myocardial infarction.

Wallentin L et al. Lancet 1990; JACC 1991;18:1587-93.

0.00

0.05

0.10

0.15

0.20

0.25

0 0 3 3 6 6 9 9 12 12 Months Months

Prob

abili

ty

Prob

abili

ty

of D

eath

or M

I of

Dea

th o

r MI

Placebo Placebo

Aspirin 75 mg Aspirin 75 mg

Risk ratio 0.52 Risk ratio 0.52

95% CL 0.37-0.72 95% CL 0.37-0.72

The RISC trial Low dose aspirin 75 mg o.d. in non-STE ACS

Erik Jorpes 1894 – 1973 Insulin Heparin

The RISC trial

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30

% myocardial infarction and death

<0.01

<0.05

Placebo + Placebo

Heparin + Placebo

Placebo + ASA

Heparin + ASA

Wallentin L et al. Lancet 1990.

Lmw heparin vs. Placebo in addition to aspirin in NSTE-ACS

%

p=0.001

Placebo (n=759)

Dalteparin (n=743)days

76543210

5

4

3

2

1

0Prob

abili

ty of

dea

th, M

I.

FRISC I. Lancet, 1995

AT Xa Wallentin L et al. Lancet 1995

Fondaparinux vs lmw heparin

Days

Cum

ulat

ive

Haza

rd

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44-0.61 p<0.001

Enoxaparin

Fondaparinux

Days

Cum

ulat

ive

Haza

rd

0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR: 0.52 95% CI: 0.44-0.61 p<0.001

Enoxaparin

Fondaparinux

Yusuf S et al NEJM 2006

DaysCu

mul

ativ

e Ha

zard

0.0

0.01

0.02

0.03

0 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97p=0.02

Enoxaparin

Fondaparinux

DaysCu

mul

ativ

e Ha

zard

0.0

0.01

0.02

0.03

0 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97p=0.02

Enoxaparin

Fondaparinux

Bleeding Reduced by 50% Deaths Reduced by 17%

The spectrum of acute coronary syndromes

Non-ST-elevation ACS ST-elevation MI

Coronary by-pass graft surgery (CABG)

1967

PTCA 1977 Andreas Gruntzig, Zurich

Coronary stent 1986 Ulrich Sigwart och Jacques Puel 1986

PCI

STEMI

Stenestrand U, Lindbäck J, Wallentin L JAMA 2006

Primary PCI vs prehospital in inhospital trombolysis over 5 years – adjusted cumulative 1 year mortality

Reperfusion < 2h

Time (days)

Cum

ulat

ive

mor

talit

y

In-hosp Tlys Prehosp Tlys Primary PCI

0 100 200 300 400

0.00

0.

05

0.10

3993 3571 3530 3490 1155 1077 1066 1060 979 936 928 916

Reperfusion > 2h

Time (days) C

umul

ativ

e m

orta

lity

In-hosp Tlys Prehosp Tlys Primary PCI

0 100 200 300 400

0.00

0.

05

0.10

8892 7675 7519 7417 1135 1020 1004 997 3592 3375 3344 3318

Uppsala Clinical Research Centre 2014

Reperfusion treatment in STEMI in Sweden 1995-2013

Primary PCI SK

tPA

TNK

The spectrum of acute coronary syndromes

Non-ST-elevation ACS ST-elevation MI

FRISC II: First revascularisation after randomization

360 330 300 270 240 210 180 150 120 90 60 30 0

Prob

abili

ty o

f rev

ascu

lari

satio

in

.80

.70

.60

.50

.40

.30

.20

.10

.00

days

Noninvasive (n=1235)

Invasive (n=1222)

Wallentin L, Lagerqvist B et al for the FRISC2 study group Lancet 1999 & 2000

720 630 540 450 360 270 180 90 0

Prob

abili

ty o

f dea

th o

r M

I

.18

.16

.14

.12

.10

.08

.06

.04

.02

0.0

Invasive Noninv. RR (95 % CI) p 12.1 % 16.3 % 0.74 (0.61 --0.90) 0.003

Noninvasive (n=1235)

Invasive (n=1222)

720 630 540 450 360 270 180 90 0 Pr

obab

ility

of d

eath

.06

.05

.04

.03

.02

.01

0.0

Invasive Noninv. RR (95 % CI) p 3.7 % 5.4 % 0.68 (0.47 - 0.98) 0.038

Noninvasive (n=1235)

Invasive (n=1222)

Death or MI during follow-up

FRISC2

Mortality during follow-up

Wallentin L, Lagerqvist B et al for the FRISC2 study group Lancet 1999 & 2000

Invasive vs Noninvasive strategy in NSTE-ACS

Storey RF, Parker WAE Circulation 2016; 134: 793

CURE

Months of Follow-up

Cu

mu

lati

ve

Ha

za

rd R

ate

s

0.0

0.0

20

.04

0.0

60

.08

0.1

00

.12

0.1

4

0 3 6 9 12

Cumulative Hazard Rates for CV Death/MI/Stroke

P < 0.001

Clopidogrel

Placebo

Cum

ulat

ive H

azar

d Ra

tes

Months of Follow-up0 3 6 9 12

6303

6259

5780

58664664

4779

3600

3644

2388

2418

Plac

Clop

No of Pts

P < 0.001

Clopidogrel

Placebo

Cum

ulat

ive H

azar

d Ra

tes

Months of Follow-up0 3 6 9 12

6303

6259

5780

58664664

4779

3600

3644

2388

2418

Plac

Clop

No of Pts

Yusuf S et al NEJM 2001

S N O

Cl

OCH 3

HR 0.84

(0.77–0.92) p=0.0003

NNT = 54

Days after randomization

0 60 120 180

12

11

10

9

8

7

6

5

4

3

2

1

0

Cum

ulat

ive

inci

denc

e (%

)

9.8

11.7 Clopidogrel

Ticagrelor

Wallentin L, et al. N Engl J Med. 2009;361:1045-57.

Primary Endpoint (CV death, MI, Stroke)

CV death Clopidogrel

Ticagrelor 4.0

5.1

HR 0.79 (0.69–0.91)

p=0.001

NNT = 90

N=18,624

240 300 180

Ticagrelor vs Clopidogrel in ACS

hjärtinfarkt med ST-höjning, utskrivna levande, alla åldrar, 1995-2008.Figur 22b. Utveckling av användningen av blodproppshämmande behandling vid

ASA ASA+(Plavix eller Ticlid)Plavix eller Ticlid WaranWaran+(Plavix eller Ticlid) Waran+ASAWaran+ASA+(Plavix eller Ticlid) Övrigt

Andel B

lodpro

ppsh

äm

mande (

%)

0

10

20

30

40

50

60

70

80

90

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

ASA & P2Y12 inhibition in STEMI 1995--2013

Uppsala Clinical Research Centre 2014

Ticagrelor

Prasugrel

Clopidogrel

Clopidogrel + ASA

ASA

ASA & P2Y12 inhibition in STEMI 1995--2013

Primary efficacy endpoint

C, no revasc 2571 2413 2362 2084 1829 1326 1104 C, revasc 2676 2590 2547 2299 2075 1528 1291 T, no revasc 2618 2461 2394 2142 1911 1398 1160 T, revasc 2738 2665 2626 2340 2116 1553 1312

No. at risk

0

2

4

6

8

10

12

14

0 60 120 180 240 300

CV

dea

th, M

I (ex

clud

ing

sile

nt),

or

stro

ke (%

)

Days from day 10 post-randomization

Ticagrelor, no revascTicagrelor, revascClopidogrel, no revascClopidogrel, revasc

HR 0.85 (95% CI 0.72–1.01)

Interaction p = 0.93

HR 0.86 (95% CI 0.68–1.09)

Ticagrelor vs Clopidogrel in non-STE-ACS stratified by revascularization

Lindholm D et al Eur Heart J 2014.

Clopidogrel + ASA

ASA

Plt inhibition in NSTE-ACS in Sweden 1995-2013

Uppsala Clinical Research Centre 2013

By hospital 2013

Ticagrelor

Prasugrel

Clopidogrel

Uppsala Clinical Research Centre 2014 Uppsala Clinical Research Centre 2014

ASA & P2Y12 inhibition in Non-STE-ACS 1995--2013