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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