A modern thrombolysis service is superior to primary angioplasty

A modern thrombolysis service is superior to primary angioplasty

Rob Henderson

Consultant Cardiologist

Trent Cardiac Centre

Nottingham

Rob Henderson

Consultant Cardiologist

Trent Cardiac Centre

Nottingham

Thanks…..but NO!Thanks…..but NO!

Responses to a request to defend thrombolysis at BCIS Autumn

meeting

Responses to a request to defend thrombolysis at BCIS Autumn

meeting

Responses to a request to defend thrombolysis at BCIS Autumn meeting

Responses to a request to defend thrombolysis at BCIS Autumn meeting

Yes……but can I take the other side?Yes……but can I take the other side?

Fibrinolytic Therapy Triallists35 Day Outcome in 58 600 patients

Fibrinolytic Therapy Triallists35 Day Outcome in 58 600 patients

9.6%

1.2% 1.1%

11.2%

0.8% 0.4%

Mortality Stroke Major bleed

fibrinolytic

control

9.6%

1.2% 1.1%

11.2%

0.8% 0.4%

Mortality Stroke Major bleed

fibrinolytic

control

Lancet 1994:343;311Lancet 1994:343;31116 per 1000 lives saved16 per 1000 lives saved

Thrombolysis equivalence trials‘ceiling’ of benefit?

Thrombolysis equivalence trials‘ceiling’ of benefit?

6.3%

7.2%6.6%

6.2%

7.3% 7.5%6.8%

6.2%

0%

2%

4%

6%

8%

10%

GUSTO-I GUSTO-III In-TIME Assent-2

acc alteplase streptokinase reteplase

lanoteplase tenecteplase

6.3%

7.2%6.6%

6.2%

7.3% 7.5%6.8%

6.2%

0%

2%

4%

6%

8%

10%

GUSTO-I GUSTO-III In-TIME Assent-2

acc alteplase streptokinase reteplase

lanoteplase tenecteplase

30 d mortality30 d mortality

Thrombosaurus RexThrombosaurus Rex

EXTINCTOPLASE ?

Courtesy Bob Wilcox Courtesy Bob Wilcox

Patency of infarct-related arteryPatency of infarct-related artery

54%

97% 96% 93% 89%73%

27%

0%

20%

40%

60%

80%

100%

Acc tPA PAR PAMI-1 PAMI-2 Stent-PAMI

GUSTO-IIB

TIMI 2

TIMI 3

54%

97% 96% 93% 89%73%

27%

0%

20%

40%

60%

80%

100%

Acc tPA PAR PAMI-1 PAMI-2 Stent-PAMI

GUSTO-IIB

TIMI 2

TIMI 3

NEJM 1993;335:1313NEJM 1993;335:1313

% Patients% Patients

PCIPCI

Citation Year Treated Control

Akhras 1997 0 / 42 4 / 45Andersen 2002 52 / 790 59 / 782Aversano 2002 12 / 225 16 / 226Bonnefoy 2002 20 / 421 16 / 419de Boer 2002 3 / 46 9 / 41De Wood 1990 3 / 46 2 / 44Garcia 1997 3 / 95 10 / 94Gibbons 1993 2 / 47 2 / 56Grines 1993 5 / 195 13 / 200Grines 2002 6 / 71 8 / 66Grinfeld 1996 5 / 54 8 / 58GUSTO IIb 1997 32 / 565 40 / 573Hochman 1999 71 / 152 84 / 150Kastrati 2002 2 / 81 5 / 81Le May 2001 3 / 62 2 / 61Ribichini 1996 1 / 55 3 / 55Ribiero 1993 3 / 50 1 / 50Schomig 2000 3 / 71 5 / 69Vermeer 1999 5 / 75 5 / 75Widimsky 2002 29 / 429 42 / 421Widimsky 2000 7 / 101 14 / 99Zijlstra 1997 1 / 47 1 / 53Zijlstra 1993 2 / 152 11 / 149

Combined (23) 270 / 3872 360 / 3867

0.1 0.2 0.5 1 2 5 10

Favours PPCI Favors Lysis

Primary PCI versus Thrombolysis - meta-analysis of 23 trials

OR 0.70, 95% CI 0.59-083, P<0.0001Keeley et al, 2003

Quantitative review of 23 trials of primary angioplasty versus thrombolysis (n=7739)Quantitative review of 23 trials of primary angioplasty versus thrombolysis (n=7739)

5.0%

3.0%

1.0%0.1%

8.0%7.0% 7.0%

2.0%1.0%

14.0%

0.0%

5.0%

10.0%

15.0%

Death Re-MI Stroke Haemstroke

Any event

Primary PCI

Thrombolysis

5.0%

3.0%

1.0%0.1%

8.0%7.0% 7.0%

2.0%1.0%

14.0%

0.0%

5.0%

10.0%

15.0%

Death Re-MI Stroke Haemstroke

Any event

Primary PCI

Thrombolysis

Keeley, Lancet 2003;361:13Keeley, Lancet 2003;361:13

Short-term clinical outcomesShort-term clinical outcomes

Keeley meta-analysis of 23 trialsSome limitations…

Keeley meta-analysis of 23 trialsSome limitations…

• Suboptimal lytic strategies – symptom onset to drug ≈ 3 hrs

– streptokinase in 8 trials

• Inclusion of SHOCK trial (only 63% lysis)

• End-points not defined, no blinded validation

• Most trials (15) had fewer than 200 patients

• Double counting of fatal stroke

• 2% excess major bleeding in PPCI group

• Suboptimal lytic strategies – symptom onset to drug ≈ 3 hrs

– streptokinase in 8 trials

• Inclusion of SHOCK trial (only 63% lysis)

• End-points not defined, no blinded validation

• Most trials (15) had fewer than 200 patients

• Double counting of fatal stroke

• 2% excess major bleeding in PPCI group

Keeley meta-analysis: proof of concept?

Keeley meta-analysis: proof of concept?

Patient groupPatient group NN Absolute Absolute mortality mortality

differencedifference

OROR

95%CI95%CI

P valueP value

All 23 trialsAll 23 trials 77397739 2.3%2.3%0.700.70

(0.59-0.83)(0.59-0.83)<0.0001<0.0001

PCI vs fibrin-PCI vs fibrin-specific lyticspecific lytic 59025902 1.7%1.7%

0.770.77

(0.63-0.94)(0.63-0.94)0.0090.009

PCI vs acc tPAPCI vs acc tPA 53145314 1.6%1.6%0.780.78

(0.64-0.96)(0.64-0.96)0.0190.019

PCI vs acc tPA, PCI vs acc tPA, excluding SHOCKexcluding SHOCK 50125012 1.2%1.2%

0.810.81

(0.64-1.02)(0.64-1.02)0.070.07

Citation Year Treated Control

Andersen 2002 52 / 790 59 / 782Aversano 2002 12 / 225 16 / 226Bonnefoy 2002 20 / 421 16 / 419Garcia 1997 3 / 95 10 / 94Grines 2002 6 / 71 8 / 66GUSTO IIb 1997 32 / 565 40 / 573Kastrati 2002 2 / 81 5 / 81Le May 2001 3 / 62 2 / 61Ribichini 1996 1 / 55 3 / 55Schomig 2000 3 / 71 5 / 69Vermeer 1999 5 / 75 5 / 75

Fixed Combined (11) 139 / 2511 169 / 2501

0.1 0.2 0.5 1 2 5 10

Favours PPCI Favors Lysis

Primary PCI versus thrombolysis

Accelerated tPA trials, excluding Shock OR 0.81, 95% CI 0.64-1.02, P=0.07

NRMI-2: Primary angioplasty versus thrombolysisReal life registry

NRMI-2: Primary angioplasty versus thrombolysisReal life registry

5.2%

2.5%

0.7%

5.4%

2.9%

1.6%

0.0%

5.0%

10.0%

Death Re-MI Stroke

In-h

ospi

tal e

vent

rat

es

Primary angioplasty (n=4939)

Alteplase (n=24705)

5.2%

2.5%

0.7%

5.4%

2.9%

1.6%

0.0%

5.0%

10.0%

Death Re-MI Stroke

In-h

ospi

tal e

vent

rat

es

Primary angioplasty (n=4939)

Alteplase (n=24705)

Tiefenbrunn, JACC 1998;31:1240Tiefenbrunn, JACC 1998;31:1240Presentation to alteplase 42 minPresentation to balloon 111 minPresentation to alteplase 42 minPresentation to balloon 111 min

P<0.0001P<0.0001

Problem with primary PCI……Problem with primary PCI……

Time is muscleis survival

Time is muscleis survival

Reperfusion therapyReperfusion therapy

Thrombolysis: the ‘golden hour’Thrombolysis: the ‘golden hour’

2020

4040

6060

8080

0033 66 99 1212 1515 1818 2121 2424

Treatment delay (h)Treatment delay (h)

Absolute reduction in 35 day mortality per 1000 patients treatedAbsolute reduction in 35 day mortality per 1000 patients treated

FTT data - closed circlesSmaller trials - open circlesFTT data - closed circlesSmaller trials - open circles

00

Boersma, Lancet 1996;348:771Boersma, Lancet 1996;348:771

Liv

es

save

d p

er 1

000

trea

ted

pat

ien

tsL

ive

s sa

ved

per

10

00 tr

eate

d p

atie

nts

Time delay from symptom onset to primary PCI: every minute counts

Time delay from symptom onset to primary PCI: every minute counts

De Luca, Circulation 2004;109:1223De Luca, Circulation 2004;109:1223

00 6060 120120 180180 240240 300300 36036000

22

44

66

88

1010

1212

Ischaemic time (mins)Ischaemic time (mins)

One

yea

r m

orta

lity

(%)

One

yea

r m

orta

lity

(%)

6 RCTs of primary PCI by the Zwolle group 1994-2001(1791 STEMI patients)

6 RCTs of primary PCI by the Zwolle group 1994-2001(1791 STEMI patients)

RR 1.08 for every 30 min delay95% CI 1.01-1.16, p<0.0001

RR 1.08 for every 30 min delay95% CI 1.01-1.16, p<0.0001

23 trials of PCI versus thrombolysis (n=7419)

23 trials of PCI versus thrombolysis (n=7419)

00

-5-5

55

1010

1515

00 2020 4040 6060 8080 100100PCI-related time delay (mins)PCI-related time delay (mins)

Abs

olut

e be

nefit

of

PC

I in

4-6

wee

k m

orta

lity

(%)

Abs

olut

e be

nefit

of

PC

I in

4-6

wee

k m

orta

lity

(%)

Nallamothu, Am J Cardiol 2003;92:824Nallamothu, Am J Cardiol 2003;92:824Circles reflect trial sample sizeBlue line: weighted meta-regressionCircles reflect trial sample sizeBlue line: weighted meta-regression

Mean delay 39.5 min (SD 22.1)For every 10 min delay there is 0.94% decrease in mortality benefit, p=0.006. No benefit if delay>62mins

Mean delay 39.5 min (SD 22.1)For every 10 min delay there is 0.94% decrease in mortality benefit, p=0.006. No benefit if delay>62mins

Relationship between time of day and time to reperfusion Relationship between time of day and time to reperfusion

33

95

34

116

0

20

40

60

80

100

120

140

Thrombolysis(n=68439)

Primary PCI(n=33647)

Geo

met

ric m

ean

door

to

drug

or

ballo

on t

imes

(m

ins)

Regular hours

Off hours

33

95

34

116

0

20

40

60

80

100

120

140

Thrombolysis(n=68439)

Primary PCI(n=33647)

Geo

met

ric m

ean

door

to

drug

or

ballo

on t

imes

(m

ins)

Regular hours

Off hours

Regular hours = weekdays 7am to 5pm67.9% lysis and 54.2% PPCI were treated off hoursNRMI registry 1999-2002

Regular hours = weekdays 7am to 5pm67.9% lysis and 54.2% PPCI were treated off hoursNRMI registry 1999-2002 Magid, JAMA 2005;294:803Magid, JAMA 2005;294:803

Main cause of delay to

treatment

Main cause of delay to

treatment

Delays to treatment in AMIDelays to treatment in AMI

Needle30 m ins

Balloon90-120 m ins

Door

Contact

Call

Sym ptom s

Needle30 m ins

Balloon90-120 m ins

Door

Contact

Call

Sym ptom s

TIMETIME

Patient educationPatient education

Pre-hospital intervention (lytics, IIbIIIa etc)Pre-hospital intervention (lytics, IIbIIIa etc)

LogisticsInterhospital transferLogisticsInterhospital transfer

Meta-analysis of 6 trials ofpre-hospital thrombolysis (n=6436)

Meta-analysis of 6 trials ofpre-hospital thrombolysis (n=6436)

% mortality in-hospitalthrombolysis

% mortality in-hospitalthrombolysis

% m

orta

lity

pre-

hosp

ital

thr

ombo

lysi

s%

mor

talit

y pr

e-ho

spita

l t

hrom

boly

sis

22 44 66 88 1010 1212 141400

22

00

44

66

88

1010

1212

1414

Morrison, JAMA 2000;283:2686Morrison, JAMA 2000;283:2686

For all cause in-hospital mortalityOR 0.83 95% CI 0.70-0.98

For all cause in-hospital mortalityOR 0.83 95% CI 0.70-0.98

Time from symptoms (SE) tothrombolysis:104 (7) min for pre-hospital162 (16) mins for in-hospital(Urokinase, anistreplase, t-PA)

Time from symptoms (SE) tothrombolysis:104 (7) min for pre-hospital162 (16) mins for in-hospital(Urokinase, anistreplase, t-PA)

Comparison of primary PCI and prehospital thrombolysis in acute MI (CAPTIM n=840)

Comparison of primary PCI and prehospital thrombolysis in acute MI (CAPTIM n=840)

4.8%

6.2%

3.8%

8.2%

0%

2%

4%

6%

8%

10%

Death Death, re-MI, CVA

Primary PCI

Pre-hospital alteplase (rescue PCI 26%)

4.8%

6.2%

3.8%

8.2%

0%

2%

4%

6%

8%

10%

Death Death, re-MI, CVA

Primary PCI

Pre-hospital alteplase (rescue PCI 26%)

Bonnefoy, Lancet 2002;360:825Bonnefoy, Lancet 2002;360:825

Events at 30 daysEvents at 30 days

Planned 1200 patientsSymptoms to lysis 130 minSymptoms to balloon 190 min

Planned 1200 patientsSymptoms to lysis 130 minSymptoms to balloon 190 min

P=0.61 P=0.29

Pre-hospital thrombolysis vs primary PCIFrench Nationwide USIC 2000 registry (n=1922)Pre-hospital thrombolysis vs primary PCI

French Nationwide USIC 2000 registry (n=1922)

Danchin et al, Circulation 2004;110:1909Danchin et al, Circulation 2004;110:1909

Pre-hospital lysis 94%Pre-hospital lysis 94%

In-hospital lysis 89%In-hospital lysis 89%

Primary PCI 89%Primary PCI 89%

No reperfusion 79% No reperfusion 79%

00 180180 360 days360 days

100100

9090

8080

7575

8585

9595

Age-adjusted survival (%)Age-adjusted survival (%)

P<0.0001P<0.0001

%%

Grampion region early anistreplase trial

Grampion region early anistreplase trial

Years

00 11 22 33 44 556060

7070

8080

9090

100100

% S

urvi

val

% S

urvi

val

Prehospital lysis 75%Prehospital lysis 75%

In-hospital lysis 64%In-hospital lysis 64%

Delaying thrombolysis by 1 hour results in 43 additional deaths per 1000 lives over 5 years

Delaying thrombolysis by 1 hour results in 43 additional deaths per 1000 lives over 5 years

Rawles, J Am Coll Cardiol 1997;30:1181

Time from symptom onset to treatment in recent trials

Time from symptom onset to treatment in recent trials

115

130

104

169

160

195

190

162

224

188

277

ASSENT-3 Plus

CAPTIM

Morrison Meta

DANAMI 2 referal

DANAMI 2 tertiary

PRAGUE 2

Primary PCIIn-hospital lysisPrehospital lysis

115

130

104

169

160

195

190

162

224

188

277

ASSENT-3 Plus

CAPTIM

Morrison Meta

DANAMI 2 referal

DANAMI 2 tertiary

PRAGUE 2

Primary PCIIn-hospital lysisPrehospital lysis

Time from symptom onset to treatment (mins)Time from symptom onset to treatment (mins)

Onset of pain to needle timeEast Midlands Ambulance Service

Onset of pain to needle timeEast Midlands Ambulance Service

0

5

10

15

20

25

20 60 100 140 180 220 260 300 340 380

Time (minutes)

0

5

10

15

20

25

20 60 100 140 180 220 260 300 340 380

Time (minutes)

Median symptom onset to needle 93 minutes

N=117

Median symptom onset to needle 93 minutes

N=117

EMAS PHT audit 04/05EMAS PHT audit 04/05

Pre-hospital thrombolysis in the UK(27 of 31 ambulance services participating)

Pre-hospital thrombolysis in the UK(27 of 31 ambulance services participating)

0

1000

2000

3000

Mar

-03

May

-03

Jul-0

3

Sep-0

3

Nov-0

3

Jan-

04

Mar

-04

May

-04

Jul-0

4

Sep-0

4

Nov-0

4

Jan-

05

Mar

-05

May

-05

Jul-0

5

0

1000

2000

3000

Mar

-03

May

-03

Jul-0

3

Sep-0

3

Nov-0

3

Jan-

04

Mar

-04

May

-04

Jul-0

4

Sep-0

4

Nov-0

4

Jan-

05

Mar

-05

May

-05

Jul-0

5

Ambulance Service Association andJoint Royal Colleges Ambulance Liaison committee

http://www.asancep.org.uk/thromb%20update%20August05.doc

Ambulance Service Association andJoint Royal Colleges Ambulance Liaison committee

http://www.asancep.org.uk/thromb%20update%20August05.doc

2877 patients treated 2877 patients treated

Dr Curzen liaises with Hampshire Ambulance Service

Trust

Dr Curzen liaises with Hampshire Ambulance Service

Trust

At July 05 HAST had treated 8 patients with pre-hospital lysisAt July 05 HAST had treated 8 patients with pre-hospital lysis

Primary PCI - providing a UK service?Primary PCI - providing a UK service?

• In 2004 there were 3447 STEMI interventions

• This morning Peter Ludman estimated number of

STEMIs requiring reperfusion at 30000

• Provision of nationwide PPCI service is not

feasible in the short term!

• In 2004 there were 3447 STEMI interventions

• This morning Peter Ludman estimated number of

STEMIs requiring reperfusion at 30000

• Provision of nationwide PPCI service is not

feasible in the short term!

What would you want…?What would you want…?

• You develop central chest pain….• The paramedic arrives and does an ECG….

• The ECG is faxed to the local CCU who confirm evolving anterior myocardial infarction

• You develop central chest pain….• The paramedic arrives and does an ECG….

• The ECG is faxed to the local CCU who confirm evolving anterior myocardial infarction

What would you want…?What would you want…?

• The local DGH is 30 mins away.…and the

door to balloon time is 30 mins

• The local PCI unit is 45 mins away…. and the

door to balloon time is 90 mins

• The paramedic is clutching a syringe of lytic...

• The local DGH is 30 mins away.…and the

door to balloon time is 30 mins

• The local PCI unit is 45 mins away…. and the

door to balloon time is 90 mins

• The paramedic is clutching a syringe of lytic...

The choice is yours!The choice is yours!

ConclusionsConclusions

• For foreseeable future thrombolysis will remain the default reperfusion strategy in most UK hospitals

• Pre-hospital thrombolysis saves lives and is only practical strategy for timely delivery of reperfusion therapy

• The NHS should fully implement a national programme of pre-hospital thrombolysis (with rescue PCI as necessary) targeting symptom-onset to drug times less than 120 minutes

• Primary PCI programmes are costly, potentially delay treatment, and disturb our sleep!

• For foreseeable future thrombolysis will remain the default reperfusion strategy in most UK hospitals

• Pre-hospital thrombolysis saves lives and is only practical strategy for timely delivery of reperfusion therapy

• The NHS should fully implement a national programme of pre-hospital thrombolysis (with rescue PCI as necessary) targeting symptom-onset to drug times less than 120 minutes

• Primary PCI programmes are costly, potentially delay treatment, and disturb our sleep!

My opponent has a

tendency to overestimate

size!(and treatment

effect)

My opponent has a

tendency to overestimate

size!(and treatment

effect)

National Infarct Angioplasty Pilot (NIAP)National Infarct Angioplasty Pilot (NIAP)

• 3 of 6 pilot sites are not running 24/7

• At 1 centre median door to balloon times

were >90 mins for 5 consecutive months

• 3 of 6 pilot sites are not running 24/7

• At 1 centre median door to balloon times

were >90 mins for 5 consecutive months

Introduction of Primary PCIat a NIAP centre

Introduction of Primary PCIat a NIAP centre

9.9% 9.1%7.3%

16.6%

0%

5%

10%

15%

20%

Apr-Oct 03 Sept 04-Mar 05 Mar 05-Jul 05 Mar 05-Jul 05

30 d

mor

talit

y

Lysis

Primary PCI

9.9% 9.1%7.3%

16.6%

0%

5%

10%

15%

20%

Apr-Oct 03 Sept 04-Mar 05 Mar 05-Jul 05 Mar 05-Jul 05

30 d

mor

talit

y

Lysis

Primary PCI

…..careful case selection?…..careful case selection?

Comparison of angioplasty and prehospital thrombolysis in acute MI (CAPTIM n=840)

Comparison of angioplasty and prehospital thrombolysis in acute MI (CAPTIM n=840)

5.7%

3.7%

2.2%

5.9%

0%

2%

4%

6%

8%

10%

Symptoms to Rx <2hrs Symptoms to Rx >2hrs

Primary PCI

Pre-hospital alteplase (rescue PCI 26%)

5.7%

3.7%

2.2%

5.9%

0%

2%

4%

6%

8%

10%

Symptoms to Rx <2hrs Symptoms to Rx >2hrs

Primary PCI

Pre-hospital alteplase (rescue PCI 26%)

Steg, Circulation 2003;108:2851Steg, Circulation 2003;108:2851

Mortality at 30 daysMortality at 30 days

Interaction test HR 4.19, 95%CI 1.03-17.0, p=0.045Interaction test HR 4.19, 95%CI 1.03-17.0, p=0.045

N=460N=460 N=374N=374

Meta-analysis in cardiologyHypothesis-generating or definitive

research?

Meta-analysis in cardiologyHypothesis-generating or definitive

research?

Rx for STEMIRx for STEMI Meta-analysisMeta-analysis Definitive trialDefinitive trial

iv magnesium iv magnesium +ve+ve ISIS-4ISIS-4

iv nitrateiv nitrate +ve+ve ISIS-4ISIS-4

GISSI-3GISSI-3

GIKGIK +ve+ve ??

Primary PCIPrimary PCI +ve+ve ??