Koreny M, Riedmüller E, Nikfardjam M, Siostrzonek P, Müllner M. Arterial Puncture Closing Devices Compared With Standard Manual Compression After Cardiac CatheterizationSystematic Review and Meta-analysis. JAMA. 2004;291(3):350-357. doi:10.1001/jama.291.3.350
Author Affiliations: Departments of Emergency Medicine (Drs Koreny, Riedmüller, and Müllner) and Internal Medicine 2, Division of Cardiology (Dr Nikfardjam), University of Vienna, Vienna General Hospital, Vienna, Austria; and Department of Internal Medicine, K. H. Barmherzige Schwestern, Linz, Austria (Dr Siostrzonek).
Context Arterial puncture closing devices (APCDs) were developed to replace
standard compression at the puncture site and to shorten bed rest following
percutaneous coronary intervention.
Objective To assess the safety and efficacy of APCDs (Angioseal, Vasoseal, Duett,
Perclose, Techstar, Prostar) compared with standard manual compression in
patients undergoing coronary angiography or percutaneous vascular interventions.
Data Sources A systematic literature search of MEDLINE (1966-January 2003), EMBASE
(1989-January 2003), PASCAL (1996-January 2003), BIOSIS (1990-January 2003),
and CINHAL (1982-January 2003) databases and the Cochrane Central Register
of Controlled Trials for relevant articles in any language.
Study Selection Included randomized controlled trials reporting vascular complications
at the puncture site (hematoma, bleeding, arteriovenous fistula, pseudoaneurysm)
and efficacy (time to hemostasis, time to ambulation, time to discharge from
Data Extraction Two reviewers abstracted the data independently and in duplicate. Disagreements
were resolved by discussion among at least 3 reviewers. The most important
criteria were adequacy of allocation concealment, whether the analysis was
according to the intention-to-treat principle, and if person assessing the
outcome was blinded to intervention group. Random-effects models were used
to pool the data.
Data Synthesis Thirty trials met the selection criteria and included up to 4000 patients.
When comparing any APCD with standard compression, the relative risk (RR)
of groin hematoma was 1.14 (95% confidence interval [CI], 0.86-1.51; P = .35); bleeding, 1.48 (95% CI, 0.88-2.48; P = .14); developing an arteriovenous fistula, 0.83 (95% CI, 0.23-2.94; P = .77); and developing a pseudoaneurysm at the puncture
site, 1.19 (95% CI, 0.75-1.88; P = .46). Time to
hemostasis was shorter in the group with APCD compared with standard compression
(mean difference, 17 minutes; range, 14-19 minutes), but there was a high
degree of heterogeneity among studies. Only 2 studies explicitly reported
allocation concealment, blinded outcome assessment, and intention-to-treat
analysis. When limiting analyses to only trials that used explicit intention-to-treat
approaches, APCDs were associated with a higher risk of hematoma (RR, 1.89;
95% CI, 1.13-3.15) and a higher risk of pseudoaneurysm (RR, 5.40; 95% CI,
Conclusions Based on this meta-analysis of 30 randomized trials, many of poor methodological
quality, there is only marginal evidence that APCDs are effective and there
is reason for concern that these devices may increase the risk of hematoma
The number of annual coronary interventions exceeds 500 000 in
the United States1,2 and is estimated
to exceed 1 million worldwide.1,3 Along
with major complications, such as coronary artery dissection, thrombus formation,
and coronary artery spasm leading to acute occlusion of a coronary vessel,
there are additional complications related to the site of peripheral arterial
access, including hematoma, bleeding, arteriovenous fistula, and pseudoaneurysm.
The reported overall vascular complication rates range from 1.5% to 9%,4- 8 and
20% to 40% of patients who experience such complications require surgical
After removal of the catheter sheath, hemostasis is usually achieved
by manual compression at the vascular access site with or without the use
of adjunctive mechanical compression devices. Thereafter, prolonged bed rest
is often recommended. Bed rest and compression are associated with discomfort
to the patient and may have cost implications. Arterial puncture closing devices
(APCDs) have been developed to avoid manual compression and shorten bed rest.
Various techniques to replace manual compression have been designed:
collagen plugs with or without an anchor from inside the artery (Angioseal,9- 20 Vasoseal21- 30);
balloon-positioning catheters combined with bovine microfibrillar collagen
and thrombin (Duett31,32); a suturelike
stitch placed around the femoral artery (Perclose15,33- 38 [including
Techstar and Prostar]). We estimate that APCDs are now being used in 50% of
patients undergoing a percutaneous coronary intervention.
We performed a systematic review of the literature to assess the safety
and efficacy of APCDs compared with manual compression in patients after coronary
angiography or percutaneous vascular interventions.
We searched MEDLINE (1966-January 2003), EMBASE (1989-January 2003),
PASCAL (1996-January 2003), BIOSIS (1990-January 2003), and CINHAL (1982-January
2003) databases, and the Cochrane Central Register of Controlled Trials. We
searched for terms describing the intervention with and without a filter to
identify randomized controlled trials. The detailed search terms can be provided
by the authors on request. We also contacted companies distributing such devices
(Euromed, Intramed, St Jude, and Crosstec; all located in Vienna, Austria)
and asked whether they were aware of any published or unpublished trials on
APCDs. We also sent the results of our search to specialists in the field
and asked if they were aware of any published or unpublished trials not identified
by our search. We also searched references of all included articles for potentially
relevant trials. We did not apply language restrictions.
We included randomized trials that compared APCDs with exclusive manual
compression or standard manual compression of the femoral artery. Standard manual compression was defined as compression with the facultative
use of adjunctive mechanical compression devices. Mechanical devices use a
stand with a compression disk (eg, C-clamp) or a compression arch with a pneumatic
dome (Femostop). For reasons of simplicity, we will refer to both manual compression
and standard manual compression as standard compression.
We included all articles irrespective of publication length; that is
we did not exclude articles published as abstracts or short reports, even
though critical appraisal of such publications is limited.
Primarily we were interested in safety data. Before extracting data,
we prospectively defined the incidence of the following vascular complications:
hematoma at the puncture site; bleeding at the puncture site; formation of
an arteriovenous fistula at the puncture site; and formation of a pseudoaneurysm
at the puncture site. Further, we extracted other end points as reported by
the authors (such as surgical intervention at the puncture site, receiving
a blood transfusion, leg ischemia). For each end point, we used the definition
given by the study authors.
Efficacy data (time to hemostasis, time to ambulation [ie, duration
of bed rest], and time to discharge from the hospital) were also defined in
Two reviewers abstracted the data independently and in duplicate to
a predefined form. The results were compared and disagreements were resolved
by discussion among at least 3 reviewers. We recorded whether the trial was
reported according to the CONSORT criteria.39 We
considered the most important criteria to be adequacy of allocation concealment
(yes vs unclear or no), whether the analysis was according to the intention-to-treat
principle (explicitly reported vs not), and if the person assessing the outcome
was blinded to the intervention group.40 We
calculated a simple score, ranging from zero (none of the 3 quality items
fulfilled) to 3 (all items fulfilled). This score provides an assessment of
study quality but was not used for sensitivity analysis.
The safety end points were binary and we calculated risk ratios and
95% confidence intervals (CIs) for each trial. When no outcomes occurred in
1 or both groups, 0.5 was added to each cell of the respective contingency
table. When trials reported ordinal categories (eg, increasing hematoma size),
we collapsed the categories to avoid overdispersion. The efficacy end points
were continuous. We excluded trials with continuous end points from the analysis
when the SD, SE, or 95% CIs were not reported, or when the point estimate
was reported as a median only. We used random-effects models to combine the
risk ratios and continuous outcomes. The effect was combined over all devices.
We used STATA statistical software (Release 8, STATA Corp, College Station,
Tex) for all analyses.
We used random-effects meta-regression models to assess whether predefined
clinical variables influence effect size. The following variables were selected:
manual compression control group vs standard manual compression control group;
type of device; and diagnostic angiography vs percutaneous coronary intervention.
Furthermore, we assessed the impact of study quality on the effect size: allocation
concealment (reported vs not reported); blinded outcome assessment (reported
vs not reported); and intention-to-treat analysis (reported vs not reported).
We computed the Cochrane Q by summing the squared
deviations of each study's estimate from the overall meta-analytic estimate,
weighting each study's contribution in the same manner as in the meta-analysis.
We used the Q together with the resulting degrees
of freedom (df) to calculate the proportion of variation
due to heterogeneity (I2)[ = (Q − df)/Q].41 I2 quantifies the degree of heterogeneity. The advantage is that it may
be calculated and compared across meta-analyses of different sizes, different
types of study, and using different types of outcome data. Funnel plots were
drawn to assess visually whether there was evidence of publication bias. We
also used a regression method to quantify publication bias or heterogeneity.42
The electronic search resulted in 1797 hits. We considered 117 articles
to be potentially eligible and retrieved the full-text versions (Figure 1). We contacted specialists in the
field and manufacturers of the APCDs and found another 8 articles. Seven potentially
eligible articles were identified by screening the references of the articles
selected. Our search was intended to be highly sensitive at the cost of specificity.
We scrutinized these articles (n = 132) more closely and excluded another
102 for the following reasons: duplicates (n = 23), different study aim (n
= 8), not containing original data (n = 1), not a randomized controlled trial
(n = 52), and not comparing APCDs with standard compression (n = 18). We finally
included 30 studies in which APCDs were compared with standard compression.
Several were primarily published as abstracts and later as full articles in
peer-reviewed journals; in these cases we used the full article version. Some
authors published several studies on the same topic. If an overlap of data
was suspected, authors were contacted and asked for clarification. When authors
did not reply, the most recent and most detailed publication was included.
After excluding duplicates (n = 20), 56 articles were potentially eligible
for analysis. We finally included 30 studies in which APCDs were compared
with standard compression (Table 1 and Figure 1).
Generally, trial quality was fair (Table 1). Six studies12,16,26,31,33,35 reported
allocation concealment. Four studies14,26,29,31 explicitly
reported an intention-to-treat analysis (in another 15 studies such an analysis
was possible). Three studies23,26,31 explicitly
reported blinded outcome assessment. There were only 2 studies26,31 in
which allocation concealment, intention-to-treat analysis, and blinded outcome
assessment were reported.
Hematoma. Nineteen publications9,11- 14,16,22- 26,28,29,33- 38 with
21 comparison groups assessed the risk of hematoma at the puncture site. The
definition of hematoma varied between studies: some authors simply mention
the presence or absence of hematoma, others use various sizes for grading.
If authors reported 2 or more categories of increasing hematoma size, the
groups were collapsed. When comparing any APCD with standard compression,
the relative risk (RR) of groin hematoma was 1.14 (95% CI, 0.86-1.51) (P = . 35) (Figure 2).
The proportion of variation due to heterogeneity (I2) was moderately
large (33%). The funnel plot showed no evidence of overt publication bias
or heterogeneity (mean bias, 0.01; 95% CI, −1.07 to 1.09).
Local Bleeding. The RR of groin bleeding was
1.48 (95% CI, 0.88-2.48) in the group with APCDs compared with standard compression
(P = .14) (Figure
2).10- 14,16,18,24,27,29- 31 The
proportion of variation due to heterogeneity was 38%. In the funnel plot there
was no overt evidence of publication bias but rather heterogeneity (mean bias,
1.24; 95% CI, 0.02-2.46). This was caused by a single trial in which bleeding
was assessed in a meticulous way.16
Arteriovenous Fistula. The RR of arteriovenous
fistula formation at the puncture site was 0.83 (95% CI, 0.23-2.94) in the
group with APCDs compared with standard compression (Figure 3) (P = .77).24,26,27,33- 35 The
proportion of variation due to heterogeneity was 0%. The mean bias was −0.14
(95% CI, −1.34 to 1.06).
Pseudoaneurysm. The RR of developing a pseudoaneurysm
at the puncture site was 1.19 (95% CI, 0.75-1.88) in the group with APCDs
compared with standard compression (Figure
3) (P = .46).9,11,12,14,23- 27,29,30,33- 36,38 The
proportion of variation due to heterogeneity was zero. There was no evidence
of overt publication bias or heterogeneity (mean bias, 0.21; 95% CI, −0.59
Other End Points. We assessed several other
end points that were reported by authors, but that we did not define a priori.
The RR of a surgical intervention at the puncture site was 1.61 (95% CI, 0.83-3.14)
in the group with APCDs (15 comparisons, 1991 patients) compared with standard
compression (1675 patients).13,14,18,26- 31,33- 35,38 The
RR of receiving a blood transfusion was 1.21 (95% CI, 0.57-2.55) in the group
with APCDs (14 comparisons, 1737 patients) compared with standard compression
(1424 patients).13,14,26- 29,31,33,35,37,38 The
RR of arterial leg ischemia was 2.10 (95% CI, 0.97-4.58) in the group with
APCDs (7 comparisons, 1036 patients) compared with standard compression (1060
Time to hemostasis was shorter in the group with APCDs compared with
standard compression (mean difference, 17 minutes; range, 14-19 minutes).10,12,13,16,18,21,24,25,28- 30,33- 37 There
was a high degree of statistical heterogeneity (I2= 96%), which
may partly be explained by clinical heterogeneity; time points of assessment
were often driven by protocol. Selective nonreporting of smaller differences
(that is, not strongly favoring APCDs) may be possible (mean bias, −7.56;
95% CI, −10.87 to −4.26) (Figure
Duration of bed rest was also shorter in the group with APCDs (1283
patients) compared with standard compression (14 comparisons, 1142 patients)
(mean difference, 10.8 hours; 95% CI, 8.5-13.1 hours).10,12,18,21,28,29,33- 36 There
was strong evidence of statistical heterogeneity (I2 = 98%) or
publication bias in favor of APCDs (mean bias, −6.08; 95% CI, −11.44
to −0.72). However, the data are difficult to interpret because this
end point was mainly driven by protocol and not necessarily a result of the
Duration of hospital stay was shorter in the group with APCDs (4 comparisons,
447 patients) compared with standard compression (368 patients) (mean difference,
0.6 days; 95% CI, 0.1-1.1 days).12,25,32,35 There
was some evidence of statistical heterogeneity (I2 = 58%) and publication
bias (0.69; 95% CI, −6.23 to 7.61). This end point was mainly driven
The association between the intervention and the outcomes was not influenced
when looking at an exclusive manual compression control group vs a standard
manual compression control group (P>.13 for all 4
outcomes). It was also not influenced by type of APCD (Vasoseal, Angioseal,
Duett, Perclose; P>.20 for all 4 devices and all
outcomes) and whether a diagnostic angiography or a coronary intervention
was performed (P>.40 for all outcomes).
When the analysis was not explicitly reported to be intention-to-treat,
trials found a harmful effect less often for APCDs for hematoma (RR, 0.59;
95% CI, 0.29-1.06; P = .08) and pseudoaneurysm (RR,
0.19; 95% CI, 0.04-0.91; P = .04). When allocation
was not concealed, trials were less likely to find a harmful effect of APCDs
in terms of bleeding compared with trials with reported concealment (RR, 0.42;
95% CI, 0.18-0.99; P = .05).
Other main outcomes were not influenced by study quality (all P values >.10). We repeated the analysis including only
trials with explicit intention-to-treat analyses. The RR of hematoma was higher
in the APCD group (1.89; 95% CI, 1.13-3.15) (4 comparisons, 414 patients in
APCD group, 259 patients in control group); the RR of developing a pseudoaneurysm
was also higher in the APCD group (5.40; 95% CI, 1.21-24.5) (same 4 comparisons
as above). When analyzing only trials in which allocation concealment was
explicitly reported, the RR of bleeding was comparable between the groups
(0.97; 95% CI, 0.33-2.83) (3 comparisons, 730 patients in APCD group vs 575
patients in control group).
We are aware of 2 systematic reviews on the topic of hemostatic APCDs.
The first is an economic evaluation that used a systematic review of MEDLINE
to determine a decision analysis.43 Search
strategy, inclusion criteria, and exclusion criteria of this review are not
clear. The authors did not look at methodological quality, except whether
the trials were randomized or not. The authors included 4 randomized controlled
trials and 16 nonrandomized studies. It is not clear how the data were quantitatively
summarized. This review found no significant difference in the incidence of
hematoma, blood transfusion, pseudoaneurysm, or arteriovenous fistula formation
between intervention (APCD) and control groups.
A second review presented data from a MEDLINE review and from abstracts
presented at selected scientific meetings.44 Search
strategy, inclusion criteria, and exclusion criteria are not clear. Methodological
quality of the trials was not assessed and not all were randomized trials.
The author of that review looked at hemostasis success rates and minor and
major complication rates. The qualitative description of the end points is
comprehensive and the author points out a great deal of heterogeneity involving
the definition of end points. Major complications occurred more often when
particular devices (collagen plugs without an anchor) were compared with standard
compression (3.8% vs 1.7%).
In an observational study, Dangas et al45 assessed
the incidence of vascular complications comparing APCDs with manual compression
after percutaneous coronary interventions. The use of an APCD was associated
with a significantly higher rate of hematoma (9.3% vs 5.1%; P<.001), greater decrease in hematocrit (5.2% vs 2.5%; P<.001), and increased need for surgical repair (2.5% vs 1.5%; P = .003). In another observational study, Applegate et
al5 evaluated the outcome of 4525 patients
after percutaneous coronary intervention with concomitant glycoprotein IIb/IIIa
inhibitor therapy and different types of closure methods. Compared with manual
compression, the RR for developing a major complication (vascular death, vascular
repair, major bleeding, vessel occlusion, loss of pulse) was 1.06 (95% CI,
0.45-2.48) for Angioseal and 0.76 (95% CI, 0.42-1.38) for Perclose.
The patients studied in the trials in our systematic review were generally
comparable with patients who undergo cardiac catheterization. A broad range
of clinical, hospital, and geographic settings increase external validity.
Unfortunately, the internal validity of many trials is not clear because most
did not report according to a minimum of required standards.40
It appears that low trial quality biased the results in favor of APCDs.
Even when ignoring trial quality, the precision for some estimates is not
satisfactory. For instance, based on our 95% CIs, local surgery may be less
often necessary by a factor of 0.83, but it also might be required 3.41 times
more often when APCDs are used. Unless prospectively defined, the ideal width
for a 95% CI to assume equivalence is difficult to determine, but we can give
some estimates to guide the reader. The incidence of hematoma in the manual
compression group ranged from zero in some studies and reached up to 35% in
others.23 Accordingly an RR of 1.51 (the upper
95% confidence limit of our meta-analysis) translates to a number needed to
harm of about 6 (Table 2). Based
on our results, it is possible that for every 43 patients treated with an
APCD, 1 patient will need vascular surgery. According to the literature, groin
hematoma is expected in 5% to 23% of patients after manual compression, pseudoaneurysm
in 0.5% to 9%, and arteriovenous fistula in 0.2% to 2%.4 These
are worst-case scenarios, but are within the statistical precision based on
the available evidence.
Although, we tried to identify all relevant trials, it is possible that
some unpublished studies might have been missed. The funnel plot, for example,
was not ideally shaped for trials reporting time to hemostasis. It is possible
that trials reporting small differences in hemostasis time between the intervention
and control groups were selectively not published (Figure 4). More likely, this is a marker of clinical heterogeneity.
The time points of assessment are defined by protocol and are not necessarily
the result of the intervention. One might argue that presenting summary estimates
in the presence of such a high degree of heterogeneity is questionable.
It should also be taken into consideration that many trials used the
earliest version of such devices. Furthermore, a learning curve for the interventionalist
using such devices can be assumed. Safety may have improved because the devices
have been improved and interventionalists have gained experience. However,
we do not know if this translates into a clinically appreciable effect.
Some may argue that it is inappropriate to combine results for all APCDs
because they are very different. In meta-regression analysis the effect was
not influenced by type of device. It also was not influenced by the choice
of control group (exclusively manual compression vs standard manual compression,
in which mechanical devices were also used). The statistical power of such
analyses is low. However, when looking at 95% CIs or P values,
we do not have the impression that a large difference between groups is likely.
Finally, varying definitions for the same outcome parameters were applied.44 For example, bleeding has not been further characterized
in some studies, but has been defined in others as bleeding causing local
compression,27 as subcutaneous bleeding,11 or as any bleeding regardless of severity.14 We assume that the meticulous definition and assessment
of bleeding16 led to heterogeneity. Ideally,
vascular complications should be recorded in a standardized way. Guidelines
from the American College of Cardiology and the American Heart Association
on percutaneous coronary intervention provide useful definitions.1
In this systematic review, APCDs appear to be effective in terms of
reducing time to hemostasis. Currently, there is not enough evidence to assess
whether this translates into a clinically relevant benefit, such as reduced
hospital stay. Most of the studies were of low methodological reporting quality.
When looking only at studies with a higher methodological quality, complications
such as hematoma and pseudoaneurysm formation occurred more often when APCDs
Although APCDs are used widely in clinical practice, the safety of their
use must be pursued further. It appears that manufacturers of such devices
have an obligation to demonstrate efficacy and safety based on large-scale,
high-quality randomized trials. Additional strategies may be found by conducting
individual patient data meta-analysis, and also by tracking device use and
safety data by pooling resources using registries or other relevant platforms.46,47