Assenburg, C. and Bravo-Vergel, Y. and Palmer, S. and Fenwick, E. and de Belder, M. and Abrams ...

29 Pages·2007·0.16 MB·English

Assenburg, C. and Bravo-Vergel, Y. and Palmer, S. and Fenwick, E. and
de Belder, M. and Abrams, K.R. and Sculpher, M. (2007) Assessing the
effectiveness of primary angioplasty compared with thrombolysis and its
relationship to time delay: a Bayesian evidence synthesis. Heart
93:pp. 1244-1250.

http://eprints.gla.ac.uk/4149/

Deposited on: 8 May 2008

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Assessing the Effectiveness of Primary Angioplasty
Compared to Thrombolysis and its Relationship to
Time Delay: A Bayesian Evidence Synthesis

Christian Asseburg,1 Yolanda Bravo Vergel,1 Stephen Palmer,1 Elisabeth
Fenwick,2 Mark de Belder,3 Keith R Abrams,4 Mark Sculpher1

1 Centre for Health Economics, University of York, UK
2 Public Health & Health Policy, Division of Community Based Sciences,
University of Glasgow, UK
3 The James Cook University Hospital, Middlesbrough, UK
4 Centre for Biostatistics and Genetic Epidemiology, Department of Health
Sciences, University of Leicester, UK

Correspondence: Mark Sculpher PhD, Centre for Health Economics, University
of York, Heslington, York YO10 5DD, UK.
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Abstract

Background: Meta-analyses of trials comparing thrombolysis and primary
angioplasty following an acute myocardial infarction (AMI) have shown benefits
for angioplasty. Choice of therapy needs to consider the relationship between
this benefit and any time delay in initiating angioplasty.

Objective: To extend earlier meta-analyses of these alternative forms of
reperfusion by considering both 1- and 6-month outcome data. To use
Bayesian statistical methods to quantify more fully the uncertainty associated
with the estimated relationships.

Methods: A systematic review and meta-analysis published in 2003 was
updated with recently published trials. Data on key clinical outcomes and the
difference between time-to-balloon and time-to-needle were independently
extracted by two researchers. Bayesian statistical methods were used to
synthesise evidence despite differences between trials in follow-up times and
reported outcomes. Outcomes are presented as absolute probabilities of
specific events and odds ratios (with 95% credible intervals (CrI)) as a function
of the additional time-delay associated with angioplasty.

Results: A total of 22 studies were included in the meta-analysis, with 3,760
and 3,758 patients randomised to primary angioplasty and thrombolysis,
respectively. The mean angioplasty-related time delay (over and above time to
thrombolysis) was 54.3 minutes (S.E. 2.2). For this average delay, the mean
event probabilities are lower for primary angioplasty for all outcomes. Mortality
within 1 month is 4.5% following angioplasty and 6.4% after thrombolysis (odds
ratio of 0.68 (95% CrI 0.46, 1.01)). For non-fatal re-infarction, the odds ratio is
0.32 (95% CrI 0.20, 0.51); and for non-fatal stroke it is 0.24 (95% CrI 0.11,
0.50). For all outcomes, the benefit of angioplasty decreases with longer delay
from initiation.

Conclusions: The benefit of primary angioplasty, over thrombolysis, depends
on the former’s additional time delay. For delays between 30 and 90 minutes,
angioplasty is superior, on average, for 1-month fatal and non-fatal outcomes.
Thrombolysis may be the preferred option in terms of 6-month mortality only for
delays at around 90 minutes and beyond but there is considerable uncertainty
for longer time delays.

Keywords: Acute myocardial infarction, primary coronary angioplasty,
thrombolytics, meta-regression.
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INTRODUCTION
In the UK, at least 87,000 individuals under the age of 75 years suffer an acute
myocardial infarction (AMI) each year.1 The relationship between normal
coronary artery blood flow and mortality after MI is well documented,2 so early
restoration of normal myocardial blood flow is a prime therapeutic goal for the
management of MI. Pharmacological treatment with thrombolytic therapy and
primary angioplasty are two different modes of reperfusion therapy for ST
elevation AMI (STEMI).

Meta-analyses of the various randomised trials comparing thrombolysis and
primary angioplasty have shown substantial benefits from angioplasty in terms
of mortality, non-fatal re-infarction and stroke;2-5 and they have also shown that
angioplasty has lower recurrence rates and less residual stenosis.6,7 Despite
the apparent clinical superiority of primary angioplasty, thrombolytic treatment is
the default treatment option in many countries because of practical limitations
on the use of percutaneous interventions including a shortage of cardiac
catheter facilities and appropriately skilled staff. The choice of appropriate
management also needs to consider the possible time delay in initiating
reperfusion with primary angioplasty compared to thrombolysis. The effect of
this angioplasty-related time delay in reducing the mortality benefit of
angioplasty relative to thrombolysis has been demonstrated using meta-
regression methods.8,9

This work has been influential in clinical guidelines for the management of
AMI.10,11 For example, European guidelines suggest that primary angioplasty is
the “preferred treatment if performed by an experienced team less than 90
minutes after first medical contact”.11 However, there are some limitations in
the analyses informing these guidelines. A key meta-analysis only had
abstracts available for some trials,2 and inaccuracy in data extraction has been
observed.12 The quantification of the relationship between the benefit of
angioplasty and time delay until its initiation did not quantify the uncertainty
around this relationship, and the analysis was restricted to a sub-set of major
clinical events.8

This paper seeks to build on these previous analyses by extending their scope
and statistical rigor. It assesses how the treatment effect of angioplasty on fatal
and non-fatal outcomes (re-infarctions and strokes) relates to the additional
delay involved in initiating angioplasty. It also considers both the 1-month and
the 6-month outcome data reported in randomised clinical trials. Furthermore,
in using Bayesian statistical methods, the paper is able to quantify more fully
the uncertainty associated with the estimated relationships.

3
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METHODS
Search strategy and data extraction
To identify trials comparing intravenous thrombolysis and primary angioplasty in
patients with STEMI, the analysis used an earlier review2 as a starting point. To
update this review, the following databases were searched: Cochrane
Controlled Trials Register, UK National Research Register, Medline, Embase,
Database of Abstracts of Reviews of Effects, UK National Health Service
Economic Evaluation Databases, and Health Technology Assessment
Database. The searches were restricted to English-language studies published
between 2002 and 2004. The inclusion criteria were consistent with those used
previously.2,5 Full details of the search strategy are available in a technical
report {note to the editor: a technical report is submitted with this paper with a
view to web-based publication}.

Two researchers (YB, CA) independently extracted the clinical data. Outcomes
of interest were mortality, non-fatal re-infarctions, fatal and non-fatal strokes,
and hemorrhagic strokes, as well as any data regarding time delay to treatment
initiation. Discrepancies were resolved by consensus, and a third researcher
(SP) was consulted when necessary. Data were also extracted on the
difference between time-to-balloon in angioplasty and time-to-needle in
thrombolytic therapy. This definition emphasises the differences in times to
initiation of treatment between the two reperfusion strategies, thus avoiding the
problem of different timing definitions across studies. Mean times to treatment,
together with their standard deviations, were preferred in the analysis, but
medians and quartiles were used when these were not available. Where the
earlier review2 had used preliminary data from conference abstracts, these were
updated with final trial reports; the earlier data extraction was also checked and
any inaccuracies were corrected.

Statistical methods
The comparison in the meta-analysis was between primary angioplasty and
thrombolysis (regardless of type of drug). Because only a limited number of
trials reported 6-month data on fatal or hemorrhagic strokes, these endpoints
were excluded from the meta-analysis. Thus three outcomes (death, non-fatal
strokes, and non-fatal re-infarctions), for which sufficient data were available,
were analysed using an intention-to-treat principle.

The analysis was undertaken using Bayesian statistical methods.13-15 These
methods were used because they are more suitable for synthesising evidence
when there are differences between trials in, for example, follow-up times and
reported outcomes. An important feature of Bayesian methods is that they use
external evidence (so called ‘prior distributions’) which represent beliefs about
the evidence and its uncertainty external to the data extracted from the trials.
This analysis has used ‘non-informative’ prior distributions so that the data are
dominant in the results presented. A sensitivity analysis was undertaken to
verify that changing the specification of the prior distribution did not alter the
results substantially. Bayesian methods also enable direct probability
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statements to be made about quantities of clinical interest, e.g. the probability
that an intervention is superior to another. 13,14

Full details of the statistical methods are presented in the technical report.
Briefly, the meta-analysis models all outcomes of interest as probabilities on the
log-odds scale, and results are reported in terms of the absolute probability of
specific events and odds ratios (with 95% credible intervals (CrI)). It is
assumed that baseline event rates (i.e. clinical events in the thrombolysis arms)
vary randomly between trials, where the degree of variation is estimated from
the data (a ‘random effect’ assumption). That is, although the patient
populations in different trials are not identical, they are similar to each other. So
the results of the analysis are only valid for patient populations similar to a
hypothetical ‘average’ trial population.

For each outcome measure, the relative treatment effect of primary angioplasty
compared to thrombolytic treatment is modelled as a ‘random effect’; similar but
not identical between trials. This relative treatment effect is estimated as a
function of the time delay related to the initiation of angioplasty. This
relationship is used to establish the extent to which any additional effectiveness
of angioplasty is affected by the additional time it takes to deliver the
intervention compared to thrombolysis, whilst taking into account the uncertainty
surrounding the average delay in each trial. When interpreting the results of
such a ‘meta-regression’, caution is needed in extrapolating the relationship
beyond the data on time delay observed in the trials. Also, it should be
recognised that, at the extremes of the time delay data, uncertainty in the
estimates relationship will be greater than around the mid-point.

A feature of the evidence base is that some trials report outcomes at 1 month
follow-up, some at 6 months follow-up and some at both. In order that all these
data can be used, outcomes at 1 month and 6 months are assumed to differ by
a random effect.16 This reflects the fact that clinical events are more likely to
occur within the first month following AMI and, by allowing a relationship
between outcomes at the two time-points, more of the data can be used in the
analysis. Thus, those studies which do not report at 6 months can ‘borrow
strength’ both from those that do and from their own results at 1 month.

RESULTS
Summary of the trial evidence
A total of 24 studies met the inclusion criteria. Two of the studies were
subsequently excluded from the meta-analysis. One of these was excluded
because it did not report times to treatment and, as such, could not provide data
on the delay to primary angioplasty.17 The SHOCK study18 was also excluded
because the primary comparison was between emergency revascularization
without differentiating results by type of intervention (angioplasty 64%, surgery
36%), and hence this treatment strategy is not directly comparable with primary
angioplasty in the other trials.

Table 1 lists the remaining 22 studies included. In comparison with the earlier
review,2 one additional trial19 was identified which had not been published at the
5
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time. In addition, full trial results were available for three studies that had
previously been reported in abstract form only.20-22

Table 1 lists the data extracted from the 22 trials. In total, these trials included
3,760 and 3,758 patients randomised to primary angioplasty and thrombolysis,
respectively. Eight of the 22 trials used streptokinase as the form of
thrombolysis, and 14 used t-PA. For angioplasty, 13/22 trials used coronary
stents, and 8 studies used glycoprotein IIb/IIIa antagonists. The mean value of
angioplasty-related time delay (over and above time to thrombolysis) was 54.3
minutes (S.E. 2.2). All trials reported outcomes at between 30 days and 6
weeks (both are referred to as ‘1 month’ in the meta-analysis results) after the
initial MI; 10 out of the 22 trials also reported outcomes at 6 months follow-up.

6
Table 1. Overview of trials and key endpoints and time to treatment for primary angioplasty (A) and thrombolysis (T).

Time
1 month (4-6 weeks) 6 months
(minutes)

NF Mea Mea
N Death NF Stroke N Death NF Reinfarction NF Stroke
Reinfarction n n

(A) (T) N O.R. N O.R. N O.R. (A) (T) N O.R. N O.R. N O.R. (A) (A)
Study
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) CrI) ) CrI) ) CrI) ) CrI) ) CrI) ) CrI)
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Reinf. = reinfarction; SD = standard deviation; CrI = credibility interval FCE
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