To Transfer or Not to Transfer?
The debate between transfer for PCI
versus local thrombolysis.
Todd Ring, BSc., MD, CCFP
March 11, 2004
University of Calgary
Emergency Medicine Grand
Rounds
An Area of Controversy…
Overview
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Is PCI better than thrombolysis?
Evidence behind transfer for PCI
Is transfer safe?
Is timing everything?
Issues closer to home
Rationale
• 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?
Primary Angioplasty Versus Intravenous
Thrombolytic Therapy for AMI: A Quantitative
Review of 23 Randomized Trials. The 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 < .0001
p = .003 (excluding SHOCK)
Major bleed only
sig. negative result
for PCI
Similar results short and long term
favouring PCI
Problems with Evidence
Favoring 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 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 reinfarction 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
Supporting Transfer for PCI?
PRAGUE:
Multicenter RCT comparing PCI vs. TL vs.
combined strategy for patients with AMI
presenting to a community hospital. EHJ 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; angiographyangioplasty if
necessary
– Group C: transfer for PCI
PRAGUE
• 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:
Discussion/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:
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Long distance transport for PCI vs. immediate
thrombolysis for AMI. EHJ 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-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
p < .02
Trend p .12
No difference
PRAGUE 2:
Discussion/Limitations
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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:
A comparison of coronary angioplasty with
fibrinolytic therapy in AMI. NEJM 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)
DANAMI
• 2 concurrent study groups
– Referral hospital
– Invasive
• 1527 pts1129 from 24 referral hospitals
 443 from 5 invasive centers
CEP driven by 75 % reduction in re-infarction, BUT
30 day mortality 24 % (re-infarct) vs. 6.5 %
NNT = 17
NNT = 18
DANAMI:
Repeat 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:
Discussion/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:
Primary angioplasty vs. prehospital fibrinolysis in
AMI: a randomised study. The 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 benefit
favouring TL group
(trend)
CEP favouring
PCI group (trend)
Trend (p = .29)
Mortality rates significantly
lower than other trials
Trend (p = .61)
CAPTIM: 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
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
Immediate Thrombolysis in Acute Myocardial
Infarction: A Meta-Analysis. Circulation 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
Transport 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
Transport
# of Patients
Transported
Failed to be
Transported
Deaths en
Route
Deaths
within 1 h
Adverse Events
146
4
0
n/a
2 VF, 2
bradyarrhythmias
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
71
0
0
n/a
0
1402
16 (1.1%)
2 (0.1%)
1 (0.07%)
32 (2.3%)
Maastricht
AirPANAMI
Total
3.6 %
Quality 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
Safety/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?
Relationship of Symptom Onset to Balloon Time
and Door to Balloon Time with Mortality in
Patients Undergoing Angioplasty for AMI.
JAMA 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
and Door to Balloon Time with Mortality in
Patients Undergoing Angioplasty for AMI.
JAMA 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
Fibrinolytic Therapy in AMI: Is Timing (Almost)
Everything? AJC 92. 2003
• Meta-regression analysis of the Grines metaanalysis 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
DANAMI
PCI
95
82
90
TL
22
12
20
Difference
73
70
70
PCI
215
277
224
TL
132
185
169
Difference
83
92
55
Randomization to
Treatment (time)
Symptom Onset to
Treatment (time)
Clinical Characteristics and Outcome of Patients
with Early, Intermediate and Late Presentation
Treated by PCI and TL for AMI. EHJ 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 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…
• 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?
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?
Conclusions
• 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