Download ppt - Primary Angioplasty – The case is not proven: pre-hospital thrombolysis with mandated PCI may be equally effective Primary Angioplasty – The case is not

Primary Angioplasty –

The case is not proven: pre-hospital thrombolysis with mandated PCI may be

equally effective

Primary Angioplasty –

The case is not proven: pre-hospital thrombolysis with mandated PCI may be

equally effective

Tony Gershlick

University Hospitals of Leicester UK

TCT 2005

Department Academic CardiologyDepartment Academic Cardiology

The debate is not about alternatives –but about resources, identifying real outcome differences between treatments, trying remain un-polarised, doing best for all patients with AMI i.e strategies applicable to different scenarios

Does the data support the proposal ?Does the data support the proposal ?

What do Kevin and I agree on? Where are our differences?

1.1. In the real world what is important for the AMI patient ?In the real world what is important for the AMI patient ?

2.2. How good is the PPCI dataHow good is the PPCI data

3.3. How good is real world PPCI (cf trial data)How good is real world PPCI (cf trial data)

4.4. How robust is the evidence for superiority of PPCI over thrombolysis (?)How robust is the evidence for superiority of PPCI over thrombolysis (?)

5.5. How optimal is thrombolysis ? How optimal is thrombolysis ?

6.6. Are there any trials that can still be done ? Are there any trials that can still be done ?

The debate is not about alternatives –but about resources, identifying real outcome differences between treatments, trying remain un-polarised, doing best for all patients with AMI i.e strategies applicable to different scenarios

Does the data support the proposal ?Does the data support the proposal ?

What do Kevin and I agree on? Where are our differences?

1.1. In the real world what is important for the AMI patient ?In the real world what is important for the AMI patient ?

2.2. How good is the PPCI dataHow good is the PPCI data

3.3. How good is real world PPCI (cf trial data)How good is real world PPCI (cf trial data)

4.4. How robust is the evidence for superiority of PPCI over thrombolysis (?)How robust is the evidence for superiority of PPCI over thrombolysis (?)

5.5. How optimal is thrombolysis ? How optimal is thrombolysis ?

6.6. Are there any trials that can still be done ? Are there any trials that can still be done ?

LYTIC MECHANICAL LYTIC MECHANICAL

V

PPCI PPCI

•“To a man with a hammer,

- all nails look as though they need pounding”

Mark Twain

•“To a man with a hammer,

- all nails look as though they need pounding”

Mark Twain

missionmission

lesionslesions stentingstenting

Relationship of TIMI flow grade to survivalRelationship of TIMI flow grade to survival5 and 12 year follow up5 and 12 year follow up

JACC 1999;34:(1) 62-69

P=0.0455

0

10

20

30

40

50

90

100

TIMI 2 TIMI 1/0

Survival percent

121255

55

60

70

80

12

1212

55

TIMI 3

What do we all agree on ? What do we all agree on ?

10

80

70

6060

50

40

30

20

90

100

0

% T

IMI

Gra

de 3

pat

ency

@ 9

0 m

ins

% T

IMI

Gra

de 3

pat

ency

@ 9

0 m

ins

SK tPA Accel Reteplase TNKPA tPA

SK tPA Accel Reteplase TNKPA tPA

Adjunctive Adjunctive

LYSIS PPCI LYSIS PPCI

TIMI GRADE 3 FLOW

1. In the real world what is important for the AMI patient ? TIMI flow/

2. How good is the PPCI data

3. How good is real world PPCI (cf trial data)

4. How robust is the evidence for superiority of PPCI over thrombolysis

5. How optimal is thrombolysis ?

6. Are there any trials that can still be done ?

1. In the real world what is important for the AMI patient ? TIMI flow/

2. How good is the PPCI data

3. How good is real world PPCI (cf trial data)




Clinical outcomeClinical outcome

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

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

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

Short-term outcomeShort-term outcomeShort-term outcomeShort-term outcome

7.0%

3.0%

1.0%0.1%

8.0%9.0%

7.0%

2.0%1.0%

14.0%

0.0%

5.0%

10.0%

15.0%

Death Re-MI Stroke Haemstroke

Any event

Primary angioplastyThrombolysis

0.0002 < 0.0001

short term death non-fatal AMI death, non fatal MI stroke

C-PORT - Primary Endpoint Through 6 monthsPrimary PCI for AMI

Intention to Treat

JAMA 2002; 287:1943-51

7.1

10.6

4.06.2 5.3

2.2

19.9

12.4

0

5

10

15

20

25p = 0.03

p = NS

p = 0.04

p = NS

Accel. t-PA (n=226) PCI (n=225)

Combined* Death Reinfarction DisablingStroke

*Primary Endpoint: Death, Reinfarction, or Stroke

% o

f P

atie

nts

Median Door to Needle Time = 46 minMedian Door to Balloon Time = 102 min

• 2% absolute difference (p=0.0002)• 1.6% cf fibrin specific (p=0.021)• 1.2% exclude shock (p=0.08)

• Size trials (15 < 200 patients) • Variable definition of end points eg re-infarction • Double counting fatal strokes• No blinded validation

• 2% absolute difference (p=0.0002)• 1.6% cf fibrin specific (p=0.021)• 1.2% exclude shock (p=0.08)

• Size trials (15 < 200 patients) • Variable definition of end points eg re-infarction • Double counting fatal strokes• No blinded validation

Issues related to Keeley’s m-aIssues related to Keeley’s m-a

Mortality

Other issues

And in real life ?And in real life ?

Is this evidence to introduce a new strategy ?

Is this evidence to introduce a new strategy ?

NRMI-2: Primary angioplasty versus thrombolysisNRMI-2: Primary angioplasty versus thrombolysis

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

5.2%

2.5%

0.7%

5.4%

2.9%

1.6%

0.0%

5.0%

10.0%

Death Re-MI Stroke

Primary angioplasty (n=4939)

Alteplase (n=24705)

TRANSFER TRANSFER

DANAMI-2: transfer for primary PCIvs on-site Alteplase (n=1572)

DANAMI-2: transfer for primary PCIvs on-site Alteplase (n=1572)

Anderson 2003;349:733Anderson 2003;349:733

p=0.002

P<0.0016.6%

1.6% 1.1%

8.0%

6.3%

2.0%

13.7%

0.0%

5.0%

10.0%

15.0%

Death Re-MI Stroke Any event

Primary angioplasty

Thrombolysis

P=0.35

P=0.0003

7.8%

TIMI Risk Score N= 1134

Low 0-4 High >5

In-H Lysis 5.6% PPCI 8.0 In-H Lysis 36.2% PPCI 25.3% p=0.02

Transfer for primary PCI vs on-site lyticQuantitative review of 5 trials*

Transfer for primary PCI vs on-site lyticQuantitative review of 5 trials*

Keeley, Lancet 2003;361:13Keeley, Lancet 2003;361:13*LIMI, Prague I & II, Air PAMI, DANAMI-2*LIMI, Prague I & II, Air PAMI, DANAMI-2

P=0.057 P<0.0001

7.0%7.0%

1.8%1.8%1.1%1.1%

8.2%8.2%8.9%8.9%

6.7%6.7%

2.2%2.2%

15.0%15.0%

0.0%0.0%

5.0%5.0%

10.0%10.0%

15.0%15.0%

DeathDeath Re-MIRe-MI StrokeStroke Any eventAny event

Primary PCI (n=1466)Primary PCI (n=1466)

Thrombolysis (n=1443)Thrombolysis (n=1443)

P<0.0001

DANAMI-2 Study

• The reduction in re-infarction occurred where only 2.5% of ‘lysed pts in the referring hospitals subsequently

received PCI compared with 28% in invasive centres

– i.e. Lysed patients were treated conservatively in the referring hospitals

NEJM 2003;349:733

• By 30days, 19% ‘lysed pts had PCI and 9% PCI group

required repeat PCI

– ie Primary PCI reduces the need but a significant number require repeat PCI

Prague-2: Transfer for PCI vson-site thrombolysis in acute MI (n=850)

Widimsky, Eur Heart J 2003;24:94

Mortality at 30 daysMortality at 30 days

Symptoms to balloon 277 minSymptom to lysis 195 minPlanned 1200 patients

Symptoms to balloon 277 minSymptom to lysis 195 minPlanned 1200 patients

6.8% 7.3%6.0%

10.0%

7.4%

15.3%

0%

5%

10%

15%

20%

All patients Rx <3hrs ofsymptoms

Rx >3hrs ofsymptoms

Transfer for PCI

Streptokinase

p=0.12 p=0.02

1. In the real world what is important for the AMI patient ? TIMI flow/CO

2. How good is the PPCI data NOT GREAT !

3. How good is real world PPCI (cf trial data) Can the trial criteria be achieved










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 100100

PCI-related time delay (mins)PCI-related time delay (mins)

Abs

olut

e di

ffer

ence

in 4

-6 w

eek

mor

talit

y (%

)A

bsol

ute

diff

eren

ce in

4-6

wee

k m

orta

lity

(%)

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

Mean time delay 39.5 mins (SD 22.1, range 7-104)0.94% decrease in mortality benefit for every 10 min delay, p=0.006No evidence of benefit if delay >62mins

Mean time delay 39.5 mins (SD 22.1, range 7-104)0.94% decrease in mortality benefit for every 10 min delay, p=0.006No evidence of benefit if delay >62mins

Time to angioplasty in 27080 patients with acute myocardial infarction

Cannon, JAMA 2000;283:2941

Multivariate adjusted odds of in-hospital mortality (95% CI) Multivariate adjusted odds of in-hospital mortality (95% CI)

** **

* p<0.001

Median door to balloon time 116 minsMedian door to balloon time 116 mins

00

0.50.5

11

1.51.5

22

2.52.5

0-600-60 61-9061-90 91-12091-120 121-150121-150 151-180151-180 >180>180

Door to balloon time (min)Door to balloon time (min)

High failure rate with out-of-hours PCI even in high volume centre

In 1702 cases – referral centre for 11 hospitals– 48% presented between 1800hrs and 0800hrs

– PCI failure rate 6.9% vs. 3.8% p<0.01– 30d mortality 4.2% vs. 1.9% p< 0.01

Zwolle Group JACC 2003;41:2138

In 1702 cases – referral centre for 11 hospitals– 48% presented between 1800hrs and 0800hrs

– PCI failure rate 6.9% vs. 3.8% p<0.01– 30d mortality 4.2% vs. 1.9% p< 0.01

Zwolle Group JACC 2003;41:2138

Nallamothu BK, Bates E R, Herrin J, et al. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the US. National Registry of Myocardial Infarction (NRMI)-3/4 Analysis. Circulation 2005; 111:761-767

Thrombolysis (IH) can be given 30-60 mins after presentation - 60 min (lysis-PPCI) = 90-120 mins door> 80% lost incremental benefit

Thrombolysis (IH) can be given 30-60 mins after presentation - 60 min (lysis-PPCI) = 90-120 mins door> 80% lost incremental benefit

4278 transfer patients

MINAP Data UK 2004 -6 month 2005




4.

5.





4.

5.


re AMIre

AMI

Primary PCI in the UK Resource Implications

BCS Working Group on Cardiology Workforce Requirements – 2 to 3 pmp additional interventionists for resident shift system or 1-2 pmp

for non-resident shift system for Primary PCI

– additional 150 interventionists for the UK

– 381 SpR’s in UK

We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts













re AMIre

AMI

Recurrent MI post ThrombolysisRecurrent MI post Thrombolysis

Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour.Boersma E, Maas AC, Deckers JW, Simoons ML. Lancet. 1996 Sep 21;348(9030):771-5.

Difficult to achieve – can lysis be optimised ?Difficult to achieve – can lysis be optimised ?

Pre-hospital thrombolysis:meta-analysis of 6 trials (n=6436)

Pre-hospital thrombolysis:meta-analysis of 6 trials (n=6436)

% mortality in-hospitalthrombolysis

% mortality in-hospitalthrombolysis

% m

orta

lity

pre-

hosp

ital

thro

mbo

lysi

s%

mor

talit

y pr

e-ho

spita

l th

rom

boly

sis

2244 66 88 1010 1212 141400

22

00

44

66

88

1010

1212

1414

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

OR 0.83 95% CI 0.70-0.98OR 0.83 95% CI 0.70-0.98

Time (SE) to thrombolysis:104 (7) min for pre-hospital162 (16) mins for in-hospital

Time (SE) to thrombolysis:104 (7) min for pre-hospital162 (16) mins for in-hospital

50 mins

42 mins arrival to needle 34 mins

11 mins

8 mins

EAST MIDLANDS AMBULANCE SERVICE UK EAST MIDLANDS AMBULANCE SERVICE UK

PAINPAIN CALLCALL NEEDLE NEEDLE

?~ 60 mins

~ ~ 20 mins20 mins ~ ~ 20 mins20 mins

PCI PCI


FMCFMC


DOORDOOR


Door to PCI time to

compete is

Door to PCI time to

compete is

11 mins 50 mins

?~ 60 mins 40 mins

FMCFMCPAINPAIN CALLCALL

~ 80- 90~ 80- 90 minsmins ~ 80- 90~ 80- 90 minsmins

Can we improve the outcome of patients receiving pre-hospital lysis ?

Primary Endpoint:Primary Endpoint:Occluded Artery Occluded Artery (or D/MI thru Angio/HD)(or D/MI thru Angio/HD)

15.0

21.7

0

5

10

15

20

25

Occlu

ded

Art

ery

or

Death

/MI

(%

)

PlaceboPlaceboClopidogrelClopidogrel

P=0.00000036P=0.00000036P=0.00000036P=0.00000036

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

Odds Ratio 0.64Odds Ratio 0.64(95% CI 0.53-0.76)(95% CI 0.53-0.76)

1.00.4 0.6 0.8 1.2 1.6

ClopidogrelClopidogrelbetterbetter

PlaceboPlacebobetterbetter

n=1752 n=1739

36%Odds Reduction

36%Odds Reduction

Hierarchical Analysis at 6 MonthsHierarchical Analysis at 6 Months

Re-Lysis Conservative Rescue -PCI Re-Lysis Conservative Rescue -PCI

The REACT trial in press Gershlick et al

C Death 10.6 9.9 5.6

Re AMI 10.6 8.5 2.1

CVA (ich) 0.7 0.7 2.1

Severe HF 7.0 7.8 4.9

C Death 10.6 9.9 5.6

Re AMI 10.6 8.5 2.1

CVA (ich) 0.7 0.7 2.1

Severe HF 7.0 7.8 4.9

Chest Pain

Paramedic AMI

PH LysisPH Lysis

90 min ECG90 min ECG

MANDATED RESCUE PCI (REACT)

Pre-discharge angio

(GRACIA)

REACT-2 REACT-2

PPCI

600 mg

clopidogrel

600 mg

clopidogrel

300 mg

clopidogrel

300 mg

clopidogrel

Primary PCI in the UK Resource Implications

BCS Working Group on Cardiology Workforce Requirements – 2 to 3 pmp additional interventionists for resident shift system or 1-2 pmp

for non-resident shift system for Primary PCI

– additional 150 interventionists for the UK

– 381 SpR’s in UK

We would need to train and recruit the entire output from the SpR scheme for 2 years to fill these posts

Advantages of Integrated approach

• Combines the best of 2 complementary treatments• From the start treatment can be individualised• Lives and myocardium being saved from the start• Emergency PCI required less often (>50% have

TIMI 3 flow)• PCI done more safely –more stable patients, patent

IRA , better visualisation etc etc

• Combines the best of 2 complementary treatments• From the start treatment can be individualised• Lives and myocardium being saved from the start• Emergency PCI required less often (>50% have

TIMI 3 flow)• PCI done more safely –more stable patients, patent

IRA , better visualisation etc etc

Summary & Conclusions

o Case versus Non PPCI is unproven

o PPCI only approach is blinkered Primary PCI may have some advantages if it can be undertaken extremely quickly and within the time frames of the RCT earlier if to compete with PHL !

PHL with mandated rescue has added advantages of earlier treatment, but must have mandated rescue and pre-hospital discharge assessment built in

ONLY when the appropriate trial has been done can PPCI be considered the optimal treatment of choice considering the changes in logistics required for a whole country – even then there is evidence of failure to meet time lines and serious resource implications

Can we afford to implement a strategy that cannot be delivered and may be no better than a model that suits all PHL + Mandated R-PCI ?

o Case versus Non PPCI is unproven

o PPCI only approach is blinkered Primary PCI may have some advantages if it can be undertaken extremely quickly and within the time frames of the RCT earlier if to compete with PHL !

PHL with mandated rescue has added advantages of earlier treatment, but must have mandated rescue and pre-hospital discharge assessment built in

ONLY when the appropriate trial has been done can PPCI be considered the optimal treatment of choice considering the changes in logistics required for a whole country – even then there is evidence of failure to meet time lines and serious resource implications

Can we afford to implement a strategy that cannot be delivered and may be no better than a model that suits all PHL + Mandated R-PCI ?

The problems with the catch-all unselective approach

The “Kevins” of the world

The “Kevins” of the world

“The clinical scientist”

“The clinical scientist”