To Transfer or Not to Transfer?To Transfer or Not to Transfer?The debate between transfer for PCI The debate between transfer for PCI

versus local thrombolysis.versus local thrombolysis.

Todd Ring, BSc., MD, CCFP

March 11, 2004

University of Calgary

Emergency Medicine Grand Rounds

An Area of Controversy…An Area of Controversy…

OverviewOverview

• Is PCI better than thrombolysis?

• Evidence behind transfer for PCI

• Is transfer safe?

• Is timing everything?

• Issues closer to home

RationaleRationale

• Minority of patients with AMI present directly to PCI center– Reality most present to EMS or local hospital (non PCI

center)

• Results from prior trials comparing PCI to local thrombolysis difficult to extrapolate to non PCI center– Treatment bias– Center and operator experience– Effect of treatment delay unknown

Is PCI Better?Is PCI Better?

Primary Angioplasty Versus Intravenous Primary Angioplasty Versus Intravenous Thrombolytic Therapy for AMI: A Quantitative Thrombolytic Therapy for AMI: A Quantitative

Review of 23 Randomized Trials.Review of 23 Randomized Trials. The Lancet 36. 2003The Lancet 36. 2003

• Meta-analysis of 23 RCT

• 7739 TL eligible patients– 3872 PCI– 3867 TL (67% TPA)

• Short (4 – 6 week) and long term (6 – 18 month) outcomes

p = .003 (excluding SHOCK)

p < .0001

Similar results short and long termfavouring PCI

Major bleed only sig. negative resultfor PCI

Problems with Evidence Problems with Evidence Favoring PCIFavoring PCI

• If SHOCK data is excluded and look at subgroup receiving aTPA– Mortality: 5.5 PCI vs 6.7 TL p = .08

• Definition of re-infarction– Majority of cases of re-infarction in TL group occurs in 1st

hour– At this time patients many patients still in cath lab

demonstrating low flow, spasm, dissection, distal embolization

• Only 2 large trials >1000 pts; 15 trials < 200 pts• No weighting of outcome data

Conclusions Regarding PCIConclusions Regarding PCI

• Evidence favours PCI over all forms of thrombolysis

• ? Evidence is not as convincing at it may appear– Bias from pro-lytic and pro-interventionalists

• TL has higher complications of stroke and re-infarction and PCI higher bleeding risks

• Both groups agree that even despite the large number of trials confirmation in a large trial comparing mortality for PCI vs. modern quick infusion TL is needed

What is the Evidence What is the Evidence Supporting Transfer for PCI?Supporting Transfer for PCI?

PRAGUE:PRAGUE: Multicenter RCT comparing PCI vs. TL vs. Multicenter RCT comparing PCI vs. TL vs. combined strategy for patients with AMI combined strategy for patients with AMI

presenting to a community hospital.presenting to a community hospital. EHJ 21. 2000EHJ 21. 2000

• 1st randomized study to compare transfer for PCI vs. thrombolysis; June ’97 – March ’99

• 17 community referral centers; 4 PCI centers• Patients randomized into one of three groups

– Group A: TL at local hospital; remained at local hospital

– Group B: TL en route; angiographyangioplasty if necessary

– Group C: transfer for PCI

PRAGUEPRAGUE

• 1588 pts with STEMI/new LBBB; 300 randomized

• Within 6h Sx onset

• Endpoints: combined end point (CEP); death/re-infarction/stroke

• Transport distance 5 – 75 km

Re-infarction rate only sig. result

PRAGUE: PRAGUE: Discussion/LimitationsDiscussion/Limitations

• Trial only enrolled 300/1588 eligible patients

• < 6h from Sx onset• Transport time <60min; distance <75km• CEP; largely driven by re-infarct• Support data regarding experienced

labs/operators• No evidence to support facilitated PCI

PRAGUE-2: PRAGUE-2: Long distance transport for PCI vs. immediate Long distance transport for PCI vs. immediate

thrombolysis for AMI. thrombolysis for AMI. EHJ 24. 2003EHJ 24. 2003

• Based on results of PRAGUE and LIMI (Vermeer); larger, nationwide, 30 d mortality as primary endpoint

• Sept ’99 – Jan ’02• 41 community hospitals and 7 PCI centers• 4853 patients with MI; 850 randomized (target

sample 1200)• 2 groups

– TL: streptokinase (remain in first hospital)– PCI: transport to tertiary center; PCI

PRAGUE-2PRAGUE-2

• Based on safety concerns regarding treatment delay subgroup analysis – < 3 h and 3 – 12 h after Sx onset

• Transport distance 5 – 120 km

• Study prematurely stopped– 2.5 fold excess mortality in TL group treated

>3h

Trend p .12

No difference

p < .02

PRAGUE 2:PRAGUE 2:Discussion/LimitationsDiscussion/Limitations

• No difference in < 3 h group• Distance < 120 km• Streptokinase TL agent• TL patients remained at local hospital• Physician at local hospital could elect to

send patients directly for PCI– One reason trial stopped early– ? Source of bias

DANAMI:DANAMI:

A comparison of coronary angioplasty with A comparison of coronary angioplasty with fibrinolytic therapy in AMI. fibrinolytic therapy in AMI. NEJM 349 (8). 2003NEJM 349 (8). 2003

• Danish trial; Dec’97 – Oct ‘01• 24 referral centers; 5 PCI centers

– 62% Danish population

• 2 groups– TL: remained at local hospital– PCI

• CEP (death, re-infarct, stroke) at 30 days• Distance 3 – 150 km (mean 50 km)

DANAMIDANAMI

• 2 concurrent study groups– Referral hospital– Invasive

• 1527 pts1129 from 24 referral hospitals

443 from 5 invasive centers

NNT = 17 NNT = 18

CEP driven by 75 % reduction in re-infarction, BUT30 day mortality 24 % (re-infarct) vs. 6.5 %

DANAMI: DANAMI: Repeat RevascularizationRepeat Revascularization

• 26 of 782 patients (3.3 %) in TL group underwent repeat TL within 12 h; 15 (1.9%) rescue angioplasty

• Over 30 days of follow up 148 (18.9%) of patients in TL vs. 72 (9.1%) of PCI underwent mechanical revascularization (p<.001)

DANAMI: DANAMI: Discussion/LimitationsDiscussion/Limitations

• Primary endpoint CEP• Excluded high risk patients

– ? Benefit most

• Short transport distance• Only 2/5 PCI centers performed PCI prior

to study– ? Greater benefit than reported

• Sickest patients not transported

CAPTIM: CAPTIM: Primary angioplasty vs. prehospital fibrinolysis in Primary angioplasty vs. prehospital fibrinolysis in

AMI: a randomised study. AMI: a randomised study. The Lancet 360. 2002The Lancet 360. 2002

• Randomized, multi-center trial based in France; June ’97 – Sept ’01

• 840 patients (1200 planned—lack of funding) • 27 hospitals and associated EMS• Presented within 6 h• Two groups

– Pre-hospital fibrinolysis (419); alteplase– PCI (421)

• Primary endpoint: CEP (death, re-infarct, stroke) at 30 d

Mortality benefitfavouring TL group(trend)

CEP favouringPCI group (trend)

Mortality rates significantly lower than other trials

Trend (p = .61)

Trend (p = .29)

CAPTIM: DiscussionCAPTIM: Discussion

• Low mortality rate in TL group– Early TL, transfer to invasive center, liberal rescue

angioplasty (25% patients rescue angioplasties), low risk patients

• Benefit of early TL– Mortality reduction if treated < 2 h (57%)– 2.2 TL vs. 5.7 % PCI (p.04)

• Well equipped ambulance– ACLS crew/physician on board

Limitations to Limitations to Generalizations…Generalizations…

• 26 % of patients need rescue angioplasty

• Only 4% of ambulance calls for CP are STEMI eligible for TL

• ½ of patients with STEMI drive themselves to hospital

• Physician in ambulance

Transfer for Primary Angioplasty Versus Transfer for Primary Angioplasty Versus Immediate Thrombolysis in Acute Myocardial Immediate Thrombolysis in Acute Myocardial Infarction: A Meta-Analysis. Infarction: A Meta-Analysis. Circulation 108. 2003Circulation 108. 2003

• 6 RCT’s identified from Jan ’85 – Sept ’02

• 3 significantly favour transfer for PCI and 3 non-significant or no trend

• 2 limited by sample size, 1 a feasibility study, 1 hampered by recruitment

• Primary endpoint: CEP

• Excluded trials or arms of facilitated PCI

NNT = 30 NS (with CAPTIM)

RR = .76 p=.03 (Exclude CAPTIM)

NNT = 33 NNT = 86

Conclusion: Effectiveness of Conclusion: Effectiveness of Transport for PCITransport for PCI

• Overall PCI probably the best option– BUT not always achievable

• TL effective in early MI; > 6h largely ineffective; ? Very early TL as effective as PCI

• With TL significant number of patients will need to go on to further angiography/plasty

• Need to consider other issues surrounding transport– Safety– Timing/Distance– Availability

Safety and Quality of Safety and Quality of TransportTransport

  # of Patients Transported

Failed to be Transported

Deaths en Route

Deaths within 1 h

Adverse Events

Maastricht 146 4 0 n/a 2 VF, 2 brady-

arrhythmias

Prague 201 n/a 0 n/a 2 VF; 2 worsening

CHF

Prague-2 425 4 (3 deaths, 1 worsening

CHF)

2 n/a 3 VF arrest (resuscitated)

Danami 559 8 0 1 8 VF; 13 advanced AV

block

Air-PANAMI

71 0 0 n/a 0

Total 1402 16 (1.1%) 2 (0.1%) 1 (0.07%) 32 (2.3%)

          3.6 %

Quality of PCIQuality of PCI• Impact of Routine Duty Hours vs. Off Hours JACC 41(12).

2003

– 1,702 consecutive patients at one center– Failure rate: 3.8% (routine) vs. 6.9 % (off) p <.01– Mortality rate (30d): 1.9 % vs. 4.2 % p <.01

• Relationship between volume and mortality JAMA 284(24). 2000

– NRMI database– Mortality rate PCI vs. TL: high volume 3.4 vs 5.4 %

p<.001; intermediate 4.5 vs. 5.9 p <.001; low volume 6.2 vs. 5.9 %

– More experienced operators; shorter door-balloon times

Conclusions Regarding Conclusions Regarding Safety/QualitySafety/Quality

• Transport appears to be safe• Quick and dirty vs. slow and clean

– Quick and dirty: fast but only basic equipment– Slow and clean: fully equiped; slow deployment times

• All studies to date some form of slow and clean• No studies look at safety of long transports

– PRAGUE2 longest transports but highest death and adverse events

• Impact of off hours and cath lab volumes likely to affect quality

Is Timing Everything?Is Timing Everything?

Relationship of Symptom Onset to Balloon Time Relationship of Symptom Onset to Balloon Time and Door to Balloon Time with Mortality in and Door to Balloon Time with Mortality in Patients Undergoing Angioplasty for AMI.Patients Undergoing Angioplasty for AMI.

JAMA 83(22). 2000JAMA 83(22). 2000

• Prospective observational study of data collected in the Second National Registry of MI

• 27,080 consecutive patients with STEMI/ new LBBB

• Only 2230 (8% of patients) underwent PCI within 60 min of presentation– In-hospital mortality rate 4.2 %

– > 3 h mortality rate 8.5 % mortality

Relationship of Symptom Onset to Balloon Time Relationship of Symptom Onset to Balloon Time and Door to Balloon Time with Mortality in and Door to Balloon Time with Mortality in Patients Undergoing Angioplasty for AMI.Patients Undergoing Angioplasty for AMI.

JAMA 83(22). 2000JAMA 83(22). 2000

• Performed logistic regression to adjust for baseline differences– Door to balloon time greater than 2h 41 – 62 % increased

risk of death

• Confounding was serious concern in door to balloon times in this study– Shorter time: men, younger, non-DM– Propensity analysis: door to balloon time longer than 2h

still increased risk of death (28 % vs. 41 – 62 %)

• Did not find an increased mortality associated with prolonged Sx onset to balloon time

Percutaneous Coronary InterventionVersus Percutaneous Coronary InterventionVersus Fibrinolytic Therapy in AMI: Is Timing (Almost) Fibrinolytic Therapy in AMI: Is Timing (Almost)

Everything?Everything? AJC 92. 2003AJC 92. 2003

• Meta-regression analysis of the Grines meta-analysis comparing PCI and TL– Assess the impact of time delay– Endpoints were 4-6 week incidence of death and CEP

of death, re-infarction and stroke

• As PCI related time delay increased, mortality reduction favouring PCI decreased– .94% reduction for every 10 minute delay– 2 strategies equal after PCI delay of 62 min

• CEP equivalence occurred at 93 min

Prague Prague 2 DANAMIRandomization to Treatment (time)

PCI 95 82 90

TL 22 12 20

Difference 73 70 70Symptom Onset to Treatment (time)

PCI 215 277 224

TL 132 185 169

Difference 83 92 55

Clinical Characteristics and Outcome of Patients Clinical Characteristics and Outcome of Patients with Early, Intermediate and Late Presentation with Early, Intermediate and Late Presentation

Treated by PCI and TL for AMITreated by PCI and TL for AMI.. EHJ 23. 2002EHJ 23. 2002

• 2635 patients in 10 RCT’s

• Presentation delay associated with older age, female, DM, increased HR

• CEP (death, re-infarction, stroke) at 30d for PCI vs. TL– Early (<2h) group: 5.8 vs. 12.5 %

– Int. (2-4h) group: 8.6 vs. 14.2 %

– Late (>4h) group: 7.7 vs. 19.4 %

• With increase in time to presentation adverse events increase in TL group (p <.04) but not in the PCI group (p >.4)

Conclusions Regarding TimingConclusions Regarding Timing

• PCI superior at all time points• AHA goal TL door-needle time < 30 min; > 6h

ineffective• AHA goal PCI door-balloon time 90 min +/- 30 min• Evidence from transport trials supports feasibility

with respect to timing• With increasing delay (60 – 90 min) for transport

for PCI mortality benefit may be lost• ? Most beneficial group late presenters (>3 – 6h)

Issues Closer to Home…Issues Closer to Home…

• Limited availability of tertiary care centers in Canada (< 10 % of all hospitals)

• Large geographic area• Substantial disparities in the quality of

ambulance and pre-hospital services• Tertiary care center variability• Cost Effectiveness

– $ 10,711 PCI vs. $13,664 TL

Questions to Ask?Questions to Ask?

1. What is the time from Sx onset to medical contact?

2. What is the risk associated with this MI?

3. What are the risks of TL?

4. What are the risks of transport?

5. What is the time to PCI?

ConclusionsConclusions

• Regardless of strategy early reperfusion paramount– In early presenters TL should not be delayed for PCI

especially in those patients at low risk for TL complications

• Each center must decide which strategy is best• Transport appears safe but adverse events during

transport can occur and need to be considered• Time delays need to be minimized

– Door to needle < 30min; door to balloon < 90min