Intern Emerg Med (2014) 9:225–235 DOI 10.1007/s11739-013-1041-8
CE-HEALTH TECHNOLOGY ASSESSMENT
Bridge with intravenous antiplatelet therapy during temporary withdrawal of oral agents for surgical procedures: a systematic review Nuccia Morici • Lorenzo Moja • Valentina Rosato • Alice Sacco Antonio Mafrici • Silvio Klugmann • Maurizio D’Urbano • Carlo La Vecchia • Stefano De Servi • Stefano Savonitto
•
Received: 23 August 2013 / Accepted: 21 December 2013 / Published online: 14 January 2014 Ó SIMI 2014
Abstract Patients needing surgery within 1 year after drug-eluting cardiac stent implantation are challenging to manage because of an increased thrombotic and bleeding risk. A ‘‘bridge therapy’’ with short-acting antiplatelet agents in the perioperative period is an option. We assessed the outcome and safety of such a bridge therapy in cardiovascular and non-cardiovascular surgery. We performed a comprehensive search of MEDLINE, EMBASE, the Cochrane Library, and ongoing trial registers, irrespective of type of design. Our primary outcome was the success rate of bridge therapy in terms of freedom from cardiac ischaemic adverse events, whereas secondary outcome was freedom from bleeding/transfusion. We also performed combined success rate for each bridge therapy drug (tirofiban, eptifibatide, and cangrelor). We included eight case series and one randomised controlled trial. Among the 420 patients included, the technique was effective 96.2 % of the times [95 % confidence interval (CI) 94.4–98.0 %]. The success rate was 100 % for tirofiban (4 studies), 93.8 % for eptifibatide (4 studies), and 96.2 % for
cangrelor (1 study). Freedom from bleeding/transfusion events was observed in 72.6 % of the times (95 % CI 68.4–76.9 %), and was higher with cangrelor (88.7 %; 95 % CI 82.7–94.7 %) than with other drugs (81.0 % for tirofiban and 58.6 % for eptifibatide). Evidence from case series and one randomised controlled trial suggests that, in patients with recent coronary stenting undergoing major surgery, perioperative bridge therapy with intravenous antiplatelet agents is an effective and safe treatment option to ensure low rate of ischaemic events.
N. Morici (&) A. Sacco S. Klugmann Divisione di Cardiologia 1-Emodinamica, Dipartimento Cardiotoraco-vascolare ‘‘A. De Gasperis’’, Azienda Ospedaliera Ospedale Niguarda Ca` Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy e-mail: [email protected]
A. Mafrici Unita` di Terapia Intensiva Coronarica, Dipartimento Cardiotoraco-vascolare ‘‘A. De Gasperis’’, Azienda Ospedaliera Ospedale Niguarda Ca` Granda, Milan, Italy
L. Moja Dipartimento di Scienze Biomediche per la Salute, Universita` degli Studi di Milano, Milan, Italy L. Moja IRCCS Istituto Ortopedico Galeazzi, Milan, Italy V. Rosato C. La Vecchia Dipartimento di Epidemiologia, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Keywords Platelet aggregation inhibitors Stents Surgical procedures Heart diseases
Introduction Dual antiplatelet therapy (DAT) using aspirin and a P2Y12 receptor inhibitor is commonly used for secondary prevention following an acute coronary syndrome (ACS) or
M. D’Urbano S. De Servi Dipartimento Cardiovascolare, Ospedale Civile, Legnano, Italy C. La Vecchia Dipartimento di Scienze Cliniche e di Comunita`, Universita` degli Studi di Milano, Milan, Italy S. Savonitto Divisione di Cardiologia, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy
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coronary stent implantation. Guidelines recommend continuing DAT for 6 weeks after bare-metal stent (BMS) implantation and for 12 months after drug-eluting stent (DES) implantation or an ACS [1–3]. However, DAT becomes a problem in a patient who is found to have a disorder necessitating urgent or emergency surgery. On the one hand, cessation of the P2Y12 receptor inhibitor is recommended for 5–7 days prior to surgery to allow recovery of platelet function and reduce the risk of perioperative bleeding [4]. On the other hand, premature discontinuation of antiplatelet therapy has been associated with high rates of cardiac ischaemic complications (up to 45 %) [5–8]—and death (up to 7 %) [7]. Despite this, the referral of a patient treated with DAT and at high risk of cardiac ischaemic complications from surgery is relatively common. As many as 4–8 % of the patients within the first 12 months after coronary stenting or an ACS will require some type of surgery [9–14]. A prothrombotic state is well described in the perioperative period, especially in the context of orthopaedics (hip arthroplasty), cardiac and oncology surgery [15, 16]. The coronary stenting adds thrombogenic material to a hypercoagulable milieu [15]. This might be a reason why the perioperative morbidity (i.e. myocardial infarction) and mortality among patients undergoing surgical procedures after stenting has been reported to be consistently elevated, up to 26 % [10–12, 17–23], with a median value of 11.5 %. Data to guide the appropriate management of patients who require surgery during DAT are heterogeneous with regard to type of surgery, inclusion criteria, time windows between stent implantation or ACS and surgery, and antiplatelet strategies during the perioperative period [24]. Given the lack of large randomised studies in this clinical scenario, current guidelines and expert opinion recommend a case-by-case approach, weighing ischaemic versus bleeding risks [15, 25]. A bridge therapy with intravenous antiplatelet drugs has been recommended as a possible therapeutic option to protect these patients during the perioperative period [4, 25]. We sought to assess the outcome and safety of this approach through a review of the most relevant papers available.
Methods Eligibility We included any observational and experimental study describing the use of short-acting, glycoprotein IIb/IIIa inhibitors (GPIs) (eptifibatide and tirofiban) or the intravenous reversible inhibitor of the P2Y12 platelet receptor (cangrelor) in patients scheduled for cardiac or non-cardiac surgery within 12 months after percutaneous coronary
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intervention (PCI) with stent implantation or an ACS. We excluded single case reports. Search strategy Studies were identified by searching electronic databases and scanning reference lists of articles. This search was applied to MEDLINE and adapted for EMBASE and the Cochrane Library [i.e. Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects (DARE)] for studies published between January 2007 and August 2013. Trials evaluating the outcome of bridge therapy started accruing patients in 2007, when the first experimental protocol of bridge therapy with the shortacting GPIIb–IIIa receptor blockers were applied during the perioperative withdrawal of oral antiplatelet therapy, and the first report was published in 2008. The strategy was developed using the following search terms: ‘‘(bridge OR bridging) AND (eptifibatide OR tirofiban)’’; ‘‘(bridge OR bridging) AND cangrelor’’; ‘‘coronary stents’’ AND ‘‘surgery’’ AND ‘‘antiplatelet’’. We screened the titles and abstracts of articles found during the search, and retrieved any that were considered potentially relevant and published in English. We also checked the references of these articles to identify any additional possibly relevant studies. Our comprehensive search strategy is reported in Fig. 1. Data extraction Our primary outcome was the rate of adverse ischaemic events as defined and reported in each study. The secondary outcomes were the rates of bleeding, transfusion, and re-operations to stop bleeding, according to each study definition. The exposure under consideration was intravenous antiplatelet administration in patients scheduled for cardiovascular or non-cardiovascular surgery within 12 months after PCI with stent implantation or an ACS. We developed a data extraction sheet, pilot-tested it on two randomly selected studies, and refined it accordingly. The following data from included studies were extracted and entered in the data extraction form: previous diagnosis of ACS, the time elapsed from PCI to surgery, type of implanted stent, concomitant aspirin discontinuation during the perioperative period, type of surgery, the primary and secondary outcomes. Methodological quality For the randomised controlled trial (RCT), we summarised the risk of bias across outcomes throughout the following specific domains: sequence generation, allocation concealment, and incomplete outcome data. An RCT was
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227
Fig.1 Study selection process according to the review methodology following the recommendations published by PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines
considered of high quality if it satisfied two or more criteria. In order to assess the methodological quality of the case series studies, we used an 18-criteria checklist that has been developed through a modified Delphi technique [26– 28]. The sum of positive items based on reviewers’ consensus was counted for each study. The maximum score for a study was 18 as each criterion was weighted equally. A study with 14 or more yes responses (C70 %) was considered to be of acceptable quality. Statistical analysis We calculated the success rates of bridging therapy in terms of freedom from adverse ischaemic events (primary endpoint) and bleeding/transfusion endpoints (secondary endpoint). Freedom from re-operation due to
bleeding was separately analysed and reported. We calculated combined success rates as the ratio between the sum of patients free from adverse cardiac events or bleeding/transfusion end-points and the sum of total patients in all studies. We calculated 95 % confidence intervals (CI) using Normal approximation to the Binomial. Furthermore, we calculated combined success rate for each of the following subgroups: bridge therapy drug (i.e., tirofiban, eptifibatide, cangrelor), previous diagnosis of ACS, type of stent (DES versus BMS), type of surgery (cardiovascular versus non-cardiovascular surgery), and time delay from PCI to surgery. We compared proportions using Fisher’s exact test to evaluate differences between different bridge therapies (i.e. tirofiban versus eptifibatide, tirofiban versus cangrelor, eptifibatide versus cangrelor); we adjusted the p values of these
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123
Period of inclusion
2006–2010
2008–2011
2008– ongoing
2011
Marcos et al. [31]
Savonitto et al. [30]
NCT00653601
Xia et al. [38]
2005–2010
2007–2009
2008–2010
2008–2010
Ceppa et al. [32]
Ben Morrison et al. [33]
Rassi et al. [34]
Alshawabkeh et al. [37]
Bridging with eptifibatide
2007–2008
D’Urbano et al. [35]
Bridging with tirofiban
Reference
Obs, Retrosp
Obs, Retrosp
Obs, Retrosp
Obs, Retrosp
Obs, Prosp
Obs, Prosp,case– control
Obs, Prosp
Obs, Retrosp
Obs, Prosp
Study type
67
100
19
7e
21
_
60
36
4
No of points
59.7 %
13.1 %
74 %
5.6 %f
100
_
73 %
78 %
50 %
Diagnosis of ACSa (% of overall points)
CS 8.7 months
NCS 13.9 months
Mixed;
Mean days ? SD 156.8 ± 154.1
DES
DES (89 %)
DES
Mixed % unknown
DES
_
DES
DES
DES
Type of implanted stent
Mean days 102.1 (range 9–290)
unknown
median 6 months, range 3–8
_
Median 3 month, range 4 days 12 months
Mean days ? SD 80 ± 66
Mean months ? SD 2.25 ± 0.9
Time from PCI to surgery
71.6 %
62 %
68 %
Not reported
0
100 %
33 %
80 %
0
Concomitant ASA
30-day Bleedingc
NCS (59 %)
NCS (76 %)
CVS (24 %)
NCS (22 %)i
CVS (71 %)
NCS (31 %)
CVS (69 %)
NCS (100 %)
Bleeding (GUSTO)
ST, Death
2. MACEj, Platelet transfusion; Bleedingk
1. Blood transfusion
30-day death, ACS, ST, major bleeding, minor bleeding
Compositeg (inhospital)
Deaths, MI, ST, surgical reexploration because of bleeding at 3 months of discharge.
ST Bleeding
Safety endpointd (inhospital)
NCS (65 %)
_
Composite
CVS (35 %)
3 deaths (1 for bleeding), 3 ST, 4 moderate–severe bleeding
MACE:6 deaths, 1 stroke, 65 transfusions
0 death, 0 ACS, 0 ST, 7 major bleedings, 2 minor bleedings
2 transfusions, no other eventsh
No adverse events
No adverse cardiac events
No adverse cardiac events (0 % onetailed 97.5 % CI 0–6.0 %), 2 major bleeding, 3 minor bleeding, 12 transfusions
MACE:0, 6 bleeding
30-day MACEb
NCS (75 %) CABG (41 %)
Risk estimates
No adverse events or haemorrhagic complications
Outcome
Ischaemic or haemorrhagic complications
CVS (25 %)
Surgery type
Table 1 Study characteristics and success rates of bridging therapy in terms of freedom from adverse ischaemic events and bleeding/transfusion end points
93 % (62/67)
93 % (93/ 100)
100 % (19/ 19)
100 % (7/7)
100 % (21/ 21)
_
100 % (60/ 60)
100 % (36/ 36)
100 % (4/4)
Adverse events
94 % (63/67)
35 % (35/ 100)
53 % (10/19)
71 % (5/7)
100 % (21/ 21)
_
72 % (43/60)
83 % (30/36)
100 % (4/4)
Bleeding/ transfusions
Success rate (n/N)
228 Intern Emerg Med (2014) 9:225–235
Period of inclusion
2009–2011
RCT
Study type
106
No of points
Not reported
Diagnosis of ACSa (% of overall points)
Not reported
Time from PCI to surgery
% unknown
Mixed
Type of implanted stent
99 %
Concomitant ASA
CVS (100 %)
Surgery type
Platelet reactivity, Bleeding, death, MI, stroke, urgent revascularisation
Outcome
1 death, 2 MI, 0 stroke, 1 revascularisation, 12 bleeding [RR 1.1 (0.5–2.5)]
Risk estimates
72.6 % (68.4–76.9 %)
(94.4–98.0 %)
89 % (94/ 106)
Bleeding/ transfusions
96.2 %
96 % (102/ 106)
Adverse events
Success rate (n/N)
Bleeding events were defined as haematuria, gastrointestinal bleeding, blood transfusion without bleeding, decrease in haemoglobin concentration or postoperative bleeding that required re-intervention
MACE was defined as any death, repeat myocardial infarction, target vessel revascularisation, target lesion revascularisation or stent thrombosis
ACS included both ST-elevation and NonST Elevation ACS
Case–control study with greedy matching algorithm: 54 patients on clopidogrel (seven of which bridge with eptifibatide), and 108 without
Composite: mortality, postoperative length of stay, perioperative transfusions, reoperations for bleeding, myocardial infarctions, and strokes
% calculated on clopidogrel treated patients
k
j
i
Secondary bleeding end points included intracranial haemorrhage, intraocular haemorrhage, gastrointestinal bleeding, bleeding requiring return to the operating room, severe epistaxis, surgical wound bleeding or hematoma
MACE was defined as any death, myocardial infarction, urgent revascularisation, and ischaemic stroke
Seven did not undergo surgery
Among the seven points treated with eptifibatide there were no preoperative events related to drug-infusion; two of these patients (28.6 %) received perioperative transfusions, but there were no deaths, reoperations, myocardial infarctions or strokes
h
g
f
e
Defined as the composite of cardiovascular death, MI, the angiographic demonstration of an acute occlusion of the target lesion during index hospitalisation, and the need for surgical re-exploration because of bleeding; number of transfused units of blood constituents and non-operative bleeding were included as safety endpoints
d
c
b
a
ACS acute coronary syndrome, ASA acetylsalicylic acid, CABG coronary artery bypass grafting, CVS cardiovascular surgery, DES drug-eluting stent, GUSTO global utilisation of streptokinase and tissue plasminogen activator for occluded coronary arteries, MACE major adverse cardiac events, MI myocardial infarctions, NCS non-cardiovascular surgery, OBS observational studies, RCT randomised controlled trial, RETROSP retrospective studies, ST stent thrombosis, – % calculated on clopidogrel treated patients
Combined Success Rate (95 % confidence interval)
Angiolillo et al. [36]
Bridging with cangrelor
Reference
Table 1 continued
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Fisher’s exact tests by multiplicity of testing using the Bonferroni method.
Results Search results Database searches yielded 1318 references (Fig. 1). After screening the abstracts, 11 full-text articles were assessed for eligibility. We identified nine studies to be included in the review [29–38]. The results of one phase II study [29] were included in a subsequent expanded case-series [30]; therefore, with regard to this study, we only considered the updated results. An ongoing study [39]—‘‘bridging therapy in patients at high risk for stent thrombosis undergoing surgery’’ (NCT00653601)—evaluating preoperative ‘‘bridging’’ with a glycoprotein IIb/IIIa inhibitor, is reported only in the qualitative synthesis. Characteristics of the studies Five studies were performed in the United States, three in Europe, and one in China, including 420 participants (28 % female), with a mean age and standard deviation of 64 ? 10 years. Two were prospective case series with consecutive enrolment of patients [30, 38], six were retrospective case series with consecutive enrolment of patients [31–35, 37], and one was a randomised controlled trial (RCT) [36]. Death and myocardial infarction (MI) were included in the ischaemic endpoint definition in nine studies, stent thrombosis (ST) in eight studies, target vessel revascularisation in one study, urgent revascularisation in two, and stroke in two studies. Among the safety end-points, re-operation due to bleeding was reported in all the studies included. This outcome may be considered the most objective safety endpoint, because it does not depend on the different criteria adopted for bleeding transfusion. Therefore, we decided to evaluate it separately. Table 1 summarises the study characteristics. Methodological quality Non-RCTs Three case-series included in this review were considered to be of acceptable quality according to the prespecified criteria [30, 37, 38]. Details on the quality assessment checklist are reported in Appendix Table 5. RCT The generation of the randomisation sequence and allocation concealment were likely to be appropriate. The outcome reporting was complete. Therefore, this trial was considered at low risk of bias [40].
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Primary outcome measures Only a RCT was included [36]. Angiolillo et al. randomised 210 patients awaiting cardiac surgery to a bridge therapy with cangrelor or placebo. Ischaemic events were reported in the pre-procedure setting and within 30 days following surgery. Cangrelor is associated with a decreased number of pre-procedure ischaemic events compared with placebo [2.8 % (95 % CI 0.0–6.0 %) versus 4.0 % (95 % CI 0.2–7.8 %)] without differences in the post-operative period up to 30 days. When we combined the results of all the included studies, no perioperative morbid events were recorded in 404 of 420 overall patients (96.2 %; 95 % CI 94.4–98.0 %) (Table 1). The success rate was 100 % for tirofiban (based on four studies), 93.8 % for eptifibatide (based on four studies), and 96.2 % for cangrelor (based on one study) (Table 2). We observed a significant difference in the success rates favouring tirofiban versus eptifibatide (p = 0.008). Secondary outcome measures No perioperative bleeding events were recorded in 305 of 420 overall patients (72.6 %; 95 % CI 68.4–76.9 %) (Table 1). The success rate was 80.9 % for tirofiban (based on four studies), 58.6 % for eptifibatide (based on four studies), and 88.7 % for cangrelor (based on 1 study enrolling only patients who were candidates to cardiac surgery) (Table 2). We observed a significant difference in the success rates favouring tirofiban versus eptifibatide (p \ 0.001). Freedom from re-operation due to bleeding was observed in 406 of 420 overall patients (96.7 %; 95 % CI 95.0–98.4 %) (Appendix Table 6). Subgroups outcome measures With regard to the primary endpoints, the success rate was higher when we combined studies with a high percentage of patients with previous ACS compared with studies with a lower percentage, in patients with DES implantation (Table 3) and in non-cardiovascular surgery compared with cardiovascular surgery (Table 4). Data were insufficient to perform subgroup analysis on the efficacy of the technique in relation to the time delay from PCI to surgery. This time interval was longer for studies using eptifibatibe and shorter with those performing bridge therapy with tirofiban.
Discussion Our review suggests that antiplatelet bridging therapy using short-acting, reversible, intravenous agents in patient
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Table 2 Success rate of bridge therapy based on the type of intravenous antiplatelet administered No. of study (ref.)
No. of total points
Adverse events No.
a
Bleeding/transfusions
Success rate (95 % CIb)
No.a
Success rate (95 % CIb)
Bridging with Tirofiban
4 (D’Urbano et al. [35]; Marcos et al. [31]; Savonitto et al. [30]; Xia et al. [38])
121
121
100 %
98
81.0 % (74.0–88.0 %)
Bridging with Eptifibatide
4 (Ceppa et al. [32]; Ben Morrison et al. [33]; Rassi et al. [34]; Alshawabkeh et al. [37])
193
181
93.8 % (90.4–97.2 %)
113
58.6 % (51.6–65.5 %)
Bridging with Cangrelor
1 (Angiolillo et al. [36])
106
102
96.2 % (92.6–99.9 %)
94
88.7 % (82.7–94.7 %)
a
Number of subjects free from the end-points
b
Confidence interval
Table 3 Success rate of bridge therapy based on type of implanted stent and previous ACS No. of study (ref.)
No. of total pts
Adverse events
Bleeding/transfusions
No.a
Success rate (95 % CIb)
No.a
Success rate (95 % CIb)
Stent type DESc
6 (D’Urbano et al. [35]; Marcos et al. [31]; Savonitto et al. [30]; Ben Morrison et al. [33]; Alshawabkeh et al. [37]; Xia et al. [38])
207
202
97.6 % (95.5–99.7 %)
171
82.6 % (77.5–87.8 %)
DESd
6 (D’Urbano et al. [35]; Marcos et al. [31]; Savonitto et al. [30]; Ben Morrison et al. [33]; Alshawabkeh et al. [37]; Rassi et al. [34])
286
274
95.8 % (93.5–98.1 %)
185
64.7 % (59.2–70.2 %)
Diagnosis of ACSe [% of overall pts (range)]
a
B50 % (13–50 %)
2 (D’Urbano et al. [35]; Rassi et al. [34])
104
97
93.3 % (88.5–98.1 %)
39
37.5 % (28.2–46.8 %)
[50 % (59.7–78 %)
5 (Marcos et al. [31]; Savonitto et al. [30]; Ben Morrison et al. [33]; Alshawabkeh et al. [37]; Xia et al. [38])
203
198
97.5 % (95.4–99.7 %)
167
82.3 % (77.0–87.5 %)
Number of subjects free from the end-points
b
Confidence interval
c
Drug-eluting stent
d
89 % DES
e
Acute coronary syndrome
candidates to cardiac or non-cardiac surgery is feasible, and allows the performance of surgical procedures with a much lower rate of cardiac ischaemic events (as compared with historical data derived from case series with no such strategy), without significantly affecting bleeding. In a recently published retrospective cohort study of 41.989 veterans affairs (VA) and non-VA operations, a total of 1980 major cardiovascular events (MACE) (4.7 %) occurred within 30 days of surgery: 1,170 MIs or repeat revascularisations without death. 141 MIs or repeated revascularisations with death, and 669 deaths alone [41]. This study includes the largest cohort reported to date of patients with coronary stents (both bare metal and drugeluting) undergoing surgery and clearly shows that
continuation of oral antiplatelet agents does not mitigate the incidence of perioperative morbidity. Preoperative administration of a short-acting intravenous agent (such as glycoprotein IIb/IIIa inhibitor or cangrelor) has been proposed as an alternative strategy to manage these patients. However, the questions of outcome and safety of such a treatment have been poorly investigated in high-quality studies [42], mostly because there is no reference standard to compare with. The routine use of heparins is generally not recommended, because such treatment is associated with increased bleeding [43], and it has no antiplatelet effect. In our study, the clinical benefits of intravenous antiplatelet drugs were consistent: no MACE occurred in all of
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Table 4 Success rate of bridge therapy based on the type of surgery Reference
Ischaemic events Cardiovascular surgery
Bleeding/transfusions Non-cardiovascular surgery
Cardiovascular surgery
Non-cardiovascular surgery
D’Urbano et al. [35]
1/1a
3/3
1/1
3/3
Marcos et al. [31]
15/15
21/21
13/15
17/21
Savonitto et al. [30] Ceppa et al. [32]
21/21 –
39/39 7/7
15/21 –
28/39 5/7
Ben Morrison et al. [33]
13/13
6/6
8/13
1/6
Rassi et al. [34]
68/71
18/22
–
–
Angiolillo et al. [36]
102/106
–
94/106
–
Alshawabkeh et al. [37]
12/16
49/51
16/16
47/51
Xia et al. [38]
–
21/21
–
21/21
Combined success rate (95 % confidence interval)
95.5 % (92.9–98.1 %)
96.5 % (93.7–99.2 %)
85.5 % (80.2–90.7 %)
82.4 % (76.3–88.6 %)
a
Number of subjects free from the end-points/number of total subjects
the bridge therapy studies using tirofiban. The benefit was less evident for the only existing RCT: however, it is reassuring that the direction of the effect favours the bridge therapy over placebo and that for laboratory outcomes there is a clear advantage [36]. Different study designs and populations may partly or totally explain the variability in success rates reported in studies. For example, different cardiac and non-cardiac operations have variable bleeding risks, thus partially limiting the ability to adequately compare different bridge strategies. The time elapsed between stent implantation and surgery has been regarded as one of the most relevant predictors of perioperative ischaemic adverse events: the studies included were heterogeneous with regard to this variable, and this might affect the final success rate. A further and relevant source of variability is related to the different time-points chosen to resume post-operative bridging, as this is a critical point where patients are in a hyper-coagulable state, yet intravenous treatment is not reinstituted because of the fear of post-operative bleeding, and oral treatment may be ineffective due to post-operative malabsorption. Different drugs are another important source of heterogeneity, possibly having an impact upon different rates of ischaemic and bleeding events. We included bridging with eptifibatide, tirofiban or cangrelor. Eptifibatide and tirofiban are both competitive inhibitors of the GP IIb/IIIa receptor, with a plasma half-life of 1.5–2 h, and a prevalent excretion by the kidney. Cangrelor is a reversible inhibitor of the P2Y12 platelet receptor with an half-life as short as 3–6 min [44]. Specific dose-finding studies have been performed to test cangrelor as bridge therapy in the setting of cardiac surgery, whereas small molecules GPIs are used at dosing regimens recommended for the treatment of ACS and have been tested as bridge therapy also in patient
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candidates to non-cardiac surgery. Cangrelor is not currently approved by the regulatory agencies anywhere, and it is not yet commercially available in Europe. Doseadjustments have to be made for tirofiban in renal insufficiency, whereas severe renal failure (eGFR \ 30 ml/min) is a contraindication for eptifibatide. Cangrelor has not been tested as bridge therapy in patients with estimated glomerular filtration rate (GFR) \30 ml/min or with endstage renal disease. Overall, currently available data are not able to provide a comparison between GPIs and cangrelor therapy, even if both therapies appear to be an effective and safe strategy in this setting. A major limitation of our study is the fact that most of the data are drawn from retrospective case series. However, the results of the two prospective phase II studies and the single RCT available are consistent with the other findings. Another limitation is the different definitions of ischaemic and bleeding events adopted in each study. Indeed, due to the variety of surgical and endoscopic procedures, both in terms of ischaemic and of bleeding risk, a uniform definition, or standardisation, of the relevant endpoints is difficult. We, therefore, defined success rate in a binary fashion, accepting at face value what was reported by the authors of individual studies. We did not aim at standardised operational definitions: this approach helped us in capturing as many of the different definitions as possible, even if failure to standardise the primary outcome weakens any conclusions made. Despite the above mentioned limitations, we think that our paper may add useful information to the current literature. Due to the high mortality and myocardial infarction rates reported in retrospective studies with no bridge therapy, it is unlikely that a randomised trial of bridge therapy versus pure withdrawal of DAT will be launched.
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Patients facing surgery shortly after stenting are at higher risk of thrombotic events: the equipoise principle (i.e. the true uncertainty about which of the trial arms is most likely to benefit the patient) driving the starting of an RCT might be lost given the likely merits of the bridge therapy. The slow enrolment in the above mentioned ongoing trial [39] may be partially explained by the orientation of clinicians to offer to patients the ‘‘best therapy’’, limiting the proposal to enter in an RCT to the patients in whom the equipoise is maintained. Therefore, our systematic review of all available evidence may serve as an alternative strategy of gathering useful clinical information to guide clinical decision making in such difficult cases. Conflict of interest
None.
Appendix See Appendix Tables 5 and 6.
Table 5 Quality assessment checklist Checklist criteria
Number of studies with yes responses
Number of studies with no responses
1. Is the hypothesis/aim/ objective of the study clearly stated in the abstract, introduction, or methods section?
8
0
2. Are the characteristics of the participants included in the study described?
8
3. Were the cases collected in more than one centre?
1
4. Are the eligibility criteria (inclusion and exclusion criteria) to enter the study explicit and appropriate?
7
5. Were participants recruited consecutively?
5
3
6. Did participants enter the study at a similar point in the disease?
4
4
7. Was the intervention clearly described in the study?
5
8. Were additional interventions (cointerventions) clearly reported in the study?
7
9. Are the outcome measures clearly defined in the introduction or methods section?
7
Table 5 continued Checklist criteria
Number of studies with yes responses
Number of studies with no responses
10. Were relevant outcomes appropriately measured with objective and/or subjective methods?
7
1
11. Were outcomes measured before and after intervention?
3
5
12. Were the statistical tests used to assess the relevant outcomes appropriate?
6
2
13. Was the length of followup reported?
8
0
14. Was the loss to follow-up reported?
8
0
15. Does the study provide estimates of the random variability in the data analysis of relevant outcomes?
3
5
16. Are adverse events reported?
8
0
17. Are the conclusions of the study supported by results?
8
0
18. Are both competing interest and source of support for the study reported?
3
5
Table 6 Number of subjects free from re-operation due to bleeding and combined success rate 0
Reference
Re-operation for bleeding
D’Urbano et al. [35]
4/4a
7
Marcos et al. [31]
35/36
1
Savonitto et al. [30] Ceppa et al. [32]
60/60 7/7
Ben Morrison et al. [33]
18/19
3
Rassi et al. [34]
90/100
Angiolillo et al. [36]
104/106
Alshawabkeh et al. [37]
67/67
Xia et al. [38]
21/21
Combined success rate (95 % confidence interval)
96.7 % (95.0–98.4 %)
a
Number of subjects free from the end-point/number of total subjects
1
References 1
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CE-HEALTH TECHNOLOGY ASSESSMENT
Bridge with intravenous antiplatelet therapy during temporary withdrawal of oral agents for surgical procedures: a systematic review Nuccia Morici • Lorenzo Moja • Valentina Rosato • Alice Sacco Antonio Mafrici • Silvio Klugmann • Maurizio D’Urbano • Carlo La Vecchia • Stefano De Servi • Stefano Savonitto
•
Received: 23 August 2013 / Accepted: 21 December 2013 / Published online: 14 January 2014 Ó SIMI 2014
Abstract Patients needing surgery within 1 year after drug-eluting cardiac stent implantation are challenging to manage because of an increased thrombotic and bleeding risk. A ‘‘bridge therapy’’ with short-acting antiplatelet agents in the perioperative period is an option. We assessed the outcome and safety of such a bridge therapy in cardiovascular and non-cardiovascular surgery. We performed a comprehensive search of MEDLINE, EMBASE, the Cochrane Library, and ongoing trial registers, irrespective of type of design. Our primary outcome was the success rate of bridge therapy in terms of freedom from cardiac ischaemic adverse events, whereas secondary outcome was freedom from bleeding/transfusion. We also performed combined success rate for each bridge therapy drug (tirofiban, eptifibatide, and cangrelor). We included eight case series and one randomised controlled trial. Among the 420 patients included, the technique was effective 96.2 % of the times [95 % confidence interval (CI) 94.4–98.0 %]. The success rate was 100 % for tirofiban (4 studies), 93.8 % for eptifibatide (4 studies), and 96.2 % for
cangrelor (1 study). Freedom from bleeding/transfusion events was observed in 72.6 % of the times (95 % CI 68.4–76.9 %), and was higher with cangrelor (88.7 %; 95 % CI 82.7–94.7 %) than with other drugs (81.0 % for tirofiban and 58.6 % for eptifibatide). Evidence from case series and one randomised controlled trial suggests that, in patients with recent coronary stenting undergoing major surgery, perioperative bridge therapy with intravenous antiplatelet agents is an effective and safe treatment option to ensure low rate of ischaemic events.
N. Morici (&) A. Sacco S. Klugmann Divisione di Cardiologia 1-Emodinamica, Dipartimento Cardiotoraco-vascolare ‘‘A. De Gasperis’’, Azienda Ospedaliera Ospedale Niguarda Ca` Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy e-mail: [email protected]
A. Mafrici Unita` di Terapia Intensiva Coronarica, Dipartimento Cardiotoraco-vascolare ‘‘A. De Gasperis’’, Azienda Ospedaliera Ospedale Niguarda Ca` Granda, Milan, Italy
L. Moja Dipartimento di Scienze Biomediche per la Salute, Universita` degli Studi di Milano, Milan, Italy L. Moja IRCCS Istituto Ortopedico Galeazzi, Milan, Italy V. Rosato C. La Vecchia Dipartimento di Epidemiologia, IRCCS, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
Keywords Platelet aggregation inhibitors Stents Surgical procedures Heart diseases
Introduction Dual antiplatelet therapy (DAT) using aspirin and a P2Y12 receptor inhibitor is commonly used for secondary prevention following an acute coronary syndrome (ACS) or
M. D’Urbano S. De Servi Dipartimento Cardiovascolare, Ospedale Civile, Legnano, Italy C. La Vecchia Dipartimento di Scienze Cliniche e di Comunita`, Universita` degli Studi di Milano, Milan, Italy S. Savonitto Divisione di Cardiologia, IRCCS Arcispedale S. Maria Nuova, Reggio Emilia, Italy
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coronary stent implantation. Guidelines recommend continuing DAT for 6 weeks after bare-metal stent (BMS) implantation and for 12 months after drug-eluting stent (DES) implantation or an ACS [1–3]. However, DAT becomes a problem in a patient who is found to have a disorder necessitating urgent or emergency surgery. On the one hand, cessation of the P2Y12 receptor inhibitor is recommended for 5–7 days prior to surgery to allow recovery of platelet function and reduce the risk of perioperative bleeding [4]. On the other hand, premature discontinuation of antiplatelet therapy has been associated with high rates of cardiac ischaemic complications (up to 45 %) [5–8]—and death (up to 7 %) [7]. Despite this, the referral of a patient treated with DAT and at high risk of cardiac ischaemic complications from surgery is relatively common. As many as 4–8 % of the patients within the first 12 months after coronary stenting or an ACS will require some type of surgery [9–14]. A prothrombotic state is well described in the perioperative period, especially in the context of orthopaedics (hip arthroplasty), cardiac and oncology surgery [15, 16]. The coronary stenting adds thrombogenic material to a hypercoagulable milieu [15]. This might be a reason why the perioperative morbidity (i.e. myocardial infarction) and mortality among patients undergoing surgical procedures after stenting has been reported to be consistently elevated, up to 26 % [10–12, 17–23], with a median value of 11.5 %. Data to guide the appropriate management of patients who require surgery during DAT are heterogeneous with regard to type of surgery, inclusion criteria, time windows between stent implantation or ACS and surgery, and antiplatelet strategies during the perioperative period [24]. Given the lack of large randomised studies in this clinical scenario, current guidelines and expert opinion recommend a case-by-case approach, weighing ischaemic versus bleeding risks [15, 25]. A bridge therapy with intravenous antiplatelet drugs has been recommended as a possible therapeutic option to protect these patients during the perioperative period [4, 25]. We sought to assess the outcome and safety of this approach through a review of the most relevant papers available.
Methods Eligibility We included any observational and experimental study describing the use of short-acting, glycoprotein IIb/IIIa inhibitors (GPIs) (eptifibatide and tirofiban) or the intravenous reversible inhibitor of the P2Y12 platelet receptor (cangrelor) in patients scheduled for cardiac or non-cardiac surgery within 12 months after percutaneous coronary
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intervention (PCI) with stent implantation or an ACS. We excluded single case reports. Search strategy Studies were identified by searching electronic databases and scanning reference lists of articles. This search was applied to MEDLINE and adapted for EMBASE and the Cochrane Library [i.e. Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects (DARE)] for studies published between January 2007 and August 2013. Trials evaluating the outcome of bridge therapy started accruing patients in 2007, when the first experimental protocol of bridge therapy with the shortacting GPIIb–IIIa receptor blockers were applied during the perioperative withdrawal of oral antiplatelet therapy, and the first report was published in 2008. The strategy was developed using the following search terms: ‘‘(bridge OR bridging) AND (eptifibatide OR tirofiban)’’; ‘‘(bridge OR bridging) AND cangrelor’’; ‘‘coronary stents’’ AND ‘‘surgery’’ AND ‘‘antiplatelet’’. We screened the titles and abstracts of articles found during the search, and retrieved any that were considered potentially relevant and published in English. We also checked the references of these articles to identify any additional possibly relevant studies. Our comprehensive search strategy is reported in Fig. 1. Data extraction Our primary outcome was the rate of adverse ischaemic events as defined and reported in each study. The secondary outcomes were the rates of bleeding, transfusion, and re-operations to stop bleeding, according to each study definition. The exposure under consideration was intravenous antiplatelet administration in patients scheduled for cardiovascular or non-cardiovascular surgery within 12 months after PCI with stent implantation or an ACS. We developed a data extraction sheet, pilot-tested it on two randomly selected studies, and refined it accordingly. The following data from included studies were extracted and entered in the data extraction form: previous diagnosis of ACS, the time elapsed from PCI to surgery, type of implanted stent, concomitant aspirin discontinuation during the perioperative period, type of surgery, the primary and secondary outcomes. Methodological quality For the randomised controlled trial (RCT), we summarised the risk of bias across outcomes throughout the following specific domains: sequence generation, allocation concealment, and incomplete outcome data. An RCT was
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227
Fig.1 Study selection process according to the review methodology following the recommendations published by PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines
considered of high quality if it satisfied two or more criteria. In order to assess the methodological quality of the case series studies, we used an 18-criteria checklist that has been developed through a modified Delphi technique [26– 28]. The sum of positive items based on reviewers’ consensus was counted for each study. The maximum score for a study was 18 as each criterion was weighted equally. A study with 14 or more yes responses (C70 %) was considered to be of acceptable quality. Statistical analysis We calculated the success rates of bridging therapy in terms of freedom from adverse ischaemic events (primary endpoint) and bleeding/transfusion endpoints (secondary endpoint). Freedom from re-operation due to
bleeding was separately analysed and reported. We calculated combined success rates as the ratio between the sum of patients free from adverse cardiac events or bleeding/transfusion end-points and the sum of total patients in all studies. We calculated 95 % confidence intervals (CI) using Normal approximation to the Binomial. Furthermore, we calculated combined success rate for each of the following subgroups: bridge therapy drug (i.e., tirofiban, eptifibatide, cangrelor), previous diagnosis of ACS, type of stent (DES versus BMS), type of surgery (cardiovascular versus non-cardiovascular surgery), and time delay from PCI to surgery. We compared proportions using Fisher’s exact test to evaluate differences between different bridge therapies (i.e. tirofiban versus eptifibatide, tirofiban versus cangrelor, eptifibatide versus cangrelor); we adjusted the p values of these
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123
Period of inclusion
2006–2010
2008–2011
2008– ongoing
2011
Marcos et al. [31]
Savonitto et al. [30]
NCT00653601
Xia et al. [38]
2005–2010
2007–2009
2008–2010
2008–2010
Ceppa et al. [32]
Ben Morrison et al. [33]
Rassi et al. [34]
Alshawabkeh et al. [37]
Bridging with eptifibatide
2007–2008
D’Urbano et al. [35]
Bridging with tirofiban
Reference
Obs, Retrosp
Obs, Retrosp
Obs, Retrosp
Obs, Retrosp
Obs, Prosp
Obs, Prosp,case– control
Obs, Prosp
Obs, Retrosp
Obs, Prosp
Study type
67
100
19
7e
21
_
60
36
4
No of points
59.7 %
13.1 %
74 %
5.6 %f
100
_
73 %
78 %
50 %
Diagnosis of ACSa (% of overall points)
CS 8.7 months
NCS 13.9 months
Mixed;
Mean days ? SD 156.8 ± 154.1
DES
DES (89 %)
DES
Mixed % unknown
DES
_
DES
DES
DES
Type of implanted stent
Mean days 102.1 (range 9–290)
unknown
median 6 months, range 3–8
_
Median 3 month, range 4 days 12 months
Mean days ? SD 80 ± 66
Mean months ? SD 2.25 ± 0.9
Time from PCI to surgery
71.6 %
62 %
68 %
Not reported
0
100 %
33 %
80 %
0
Concomitant ASA
30-day Bleedingc
NCS (59 %)
NCS (76 %)
CVS (24 %)
NCS (22 %)i
CVS (71 %)
NCS (31 %)
CVS (69 %)
NCS (100 %)
Bleeding (GUSTO)
ST, Death
2. MACEj, Platelet transfusion; Bleedingk
1. Blood transfusion
30-day death, ACS, ST, major bleeding, minor bleeding
Compositeg (inhospital)
Deaths, MI, ST, surgical reexploration because of bleeding at 3 months of discharge.
ST Bleeding
Safety endpointd (inhospital)
NCS (65 %)
_
Composite
CVS (35 %)
3 deaths (1 for bleeding), 3 ST, 4 moderate–severe bleeding
MACE:6 deaths, 1 stroke, 65 transfusions
0 death, 0 ACS, 0 ST, 7 major bleedings, 2 minor bleedings
2 transfusions, no other eventsh
No adverse events
No adverse cardiac events
No adverse cardiac events (0 % onetailed 97.5 % CI 0–6.0 %), 2 major bleeding, 3 minor bleeding, 12 transfusions
MACE:0, 6 bleeding
30-day MACEb
NCS (75 %) CABG (41 %)
Risk estimates
No adverse events or haemorrhagic complications
Outcome
Ischaemic or haemorrhagic complications
CVS (25 %)
Surgery type
Table 1 Study characteristics and success rates of bridging therapy in terms of freedom from adverse ischaemic events and bleeding/transfusion end points
93 % (62/67)
93 % (93/ 100)
100 % (19/ 19)
100 % (7/7)
100 % (21/ 21)
_
100 % (60/ 60)
100 % (36/ 36)
100 % (4/4)
Adverse events
94 % (63/67)
35 % (35/ 100)
53 % (10/19)
71 % (5/7)
100 % (21/ 21)
_
72 % (43/60)
83 % (30/36)
100 % (4/4)
Bleeding/ transfusions
Success rate (n/N)
228 Intern Emerg Med (2014) 9:225–235
Period of inclusion
2009–2011
RCT
Study type
106
No of points
Not reported
Diagnosis of ACSa (% of overall points)
Not reported
Time from PCI to surgery
% unknown
Mixed
Type of implanted stent
99 %
Concomitant ASA
CVS (100 %)
Surgery type
Platelet reactivity, Bleeding, death, MI, stroke, urgent revascularisation
Outcome
1 death, 2 MI, 0 stroke, 1 revascularisation, 12 bleeding [RR 1.1 (0.5–2.5)]
Risk estimates
72.6 % (68.4–76.9 %)
(94.4–98.0 %)
89 % (94/ 106)
Bleeding/ transfusions
96.2 %
96 % (102/ 106)
Adverse events
Success rate (n/N)
Bleeding events were defined as haematuria, gastrointestinal bleeding, blood transfusion without bleeding, decrease in haemoglobin concentration or postoperative bleeding that required re-intervention
MACE was defined as any death, repeat myocardial infarction, target vessel revascularisation, target lesion revascularisation or stent thrombosis
ACS included both ST-elevation and NonST Elevation ACS
Case–control study with greedy matching algorithm: 54 patients on clopidogrel (seven of which bridge with eptifibatide), and 108 without
Composite: mortality, postoperative length of stay, perioperative transfusions, reoperations for bleeding, myocardial infarctions, and strokes
% calculated on clopidogrel treated patients
k
j
i
Secondary bleeding end points included intracranial haemorrhage, intraocular haemorrhage, gastrointestinal bleeding, bleeding requiring return to the operating room, severe epistaxis, surgical wound bleeding or hematoma
MACE was defined as any death, myocardial infarction, urgent revascularisation, and ischaemic stroke
Seven did not undergo surgery
Among the seven points treated with eptifibatide there were no preoperative events related to drug-infusion; two of these patients (28.6 %) received perioperative transfusions, but there were no deaths, reoperations, myocardial infarctions or strokes
h
g
f
e
Defined as the composite of cardiovascular death, MI, the angiographic demonstration of an acute occlusion of the target lesion during index hospitalisation, and the need for surgical re-exploration because of bleeding; number of transfused units of blood constituents and non-operative bleeding were included as safety endpoints
d
c
b
a
ACS acute coronary syndrome, ASA acetylsalicylic acid, CABG coronary artery bypass grafting, CVS cardiovascular surgery, DES drug-eluting stent, GUSTO global utilisation of streptokinase and tissue plasminogen activator for occluded coronary arteries, MACE major adverse cardiac events, MI myocardial infarctions, NCS non-cardiovascular surgery, OBS observational studies, RCT randomised controlled trial, RETROSP retrospective studies, ST stent thrombosis, – % calculated on clopidogrel treated patients
Combined Success Rate (95 % confidence interval)
Angiolillo et al. [36]
Bridging with cangrelor
Reference
Table 1 continued
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Fisher’s exact tests by multiplicity of testing using the Bonferroni method.
Results Search results Database searches yielded 1318 references (Fig. 1). After screening the abstracts, 11 full-text articles were assessed for eligibility. We identified nine studies to be included in the review [29–38]. The results of one phase II study [29] were included in a subsequent expanded case-series [30]; therefore, with regard to this study, we only considered the updated results. An ongoing study [39]—‘‘bridging therapy in patients at high risk for stent thrombosis undergoing surgery’’ (NCT00653601)—evaluating preoperative ‘‘bridging’’ with a glycoprotein IIb/IIIa inhibitor, is reported only in the qualitative synthesis. Characteristics of the studies Five studies were performed in the United States, three in Europe, and one in China, including 420 participants (28 % female), with a mean age and standard deviation of 64 ? 10 years. Two were prospective case series with consecutive enrolment of patients [30, 38], six were retrospective case series with consecutive enrolment of patients [31–35, 37], and one was a randomised controlled trial (RCT) [36]. Death and myocardial infarction (MI) were included in the ischaemic endpoint definition in nine studies, stent thrombosis (ST) in eight studies, target vessel revascularisation in one study, urgent revascularisation in two, and stroke in two studies. Among the safety end-points, re-operation due to bleeding was reported in all the studies included. This outcome may be considered the most objective safety endpoint, because it does not depend on the different criteria adopted for bleeding transfusion. Therefore, we decided to evaluate it separately. Table 1 summarises the study characteristics. Methodological quality Non-RCTs Three case-series included in this review were considered to be of acceptable quality according to the prespecified criteria [30, 37, 38]. Details on the quality assessment checklist are reported in Appendix Table 5. RCT The generation of the randomisation sequence and allocation concealment were likely to be appropriate. The outcome reporting was complete. Therefore, this trial was considered at low risk of bias [40].
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Primary outcome measures Only a RCT was included [36]. Angiolillo et al. randomised 210 patients awaiting cardiac surgery to a bridge therapy with cangrelor or placebo. Ischaemic events were reported in the pre-procedure setting and within 30 days following surgery. Cangrelor is associated with a decreased number of pre-procedure ischaemic events compared with placebo [2.8 % (95 % CI 0.0–6.0 %) versus 4.0 % (95 % CI 0.2–7.8 %)] without differences in the post-operative period up to 30 days. When we combined the results of all the included studies, no perioperative morbid events were recorded in 404 of 420 overall patients (96.2 %; 95 % CI 94.4–98.0 %) (Table 1). The success rate was 100 % for tirofiban (based on four studies), 93.8 % for eptifibatide (based on four studies), and 96.2 % for cangrelor (based on one study) (Table 2). We observed a significant difference in the success rates favouring tirofiban versus eptifibatide (p = 0.008). Secondary outcome measures No perioperative bleeding events were recorded in 305 of 420 overall patients (72.6 %; 95 % CI 68.4–76.9 %) (Table 1). The success rate was 80.9 % for tirofiban (based on four studies), 58.6 % for eptifibatide (based on four studies), and 88.7 % for cangrelor (based on 1 study enrolling only patients who were candidates to cardiac surgery) (Table 2). We observed a significant difference in the success rates favouring tirofiban versus eptifibatide (p \ 0.001). Freedom from re-operation due to bleeding was observed in 406 of 420 overall patients (96.7 %; 95 % CI 95.0–98.4 %) (Appendix Table 6). Subgroups outcome measures With regard to the primary endpoints, the success rate was higher when we combined studies with a high percentage of patients with previous ACS compared with studies with a lower percentage, in patients with DES implantation (Table 3) and in non-cardiovascular surgery compared with cardiovascular surgery (Table 4). Data were insufficient to perform subgroup analysis on the efficacy of the technique in relation to the time delay from PCI to surgery. This time interval was longer for studies using eptifibatibe and shorter with those performing bridge therapy with tirofiban.
Discussion Our review suggests that antiplatelet bridging therapy using short-acting, reversible, intravenous agents in patient
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Table 2 Success rate of bridge therapy based on the type of intravenous antiplatelet administered No. of study (ref.)
No. of total points
Adverse events No.
a
Bleeding/transfusions
Success rate (95 % CIb)
No.a
Success rate (95 % CIb)
Bridging with Tirofiban
4 (D’Urbano et al. [35]; Marcos et al. [31]; Savonitto et al. [30]; Xia et al. [38])
121
121
100 %
98
81.0 % (74.0–88.0 %)
Bridging with Eptifibatide
4 (Ceppa et al. [32]; Ben Morrison et al. [33]; Rassi et al. [34]; Alshawabkeh et al. [37])
193
181
93.8 % (90.4–97.2 %)
113
58.6 % (51.6–65.5 %)
Bridging with Cangrelor
1 (Angiolillo et al. [36])
106
102
96.2 % (92.6–99.9 %)
94
88.7 % (82.7–94.7 %)
a
Number of subjects free from the end-points
b
Confidence interval
Table 3 Success rate of bridge therapy based on type of implanted stent and previous ACS No. of study (ref.)
No. of total pts
Adverse events
Bleeding/transfusions
No.a
Success rate (95 % CIb)
No.a
Success rate (95 % CIb)
Stent type DESc
6 (D’Urbano et al. [35]; Marcos et al. [31]; Savonitto et al. [30]; Ben Morrison et al. [33]; Alshawabkeh et al. [37]; Xia et al. [38])
207
202
97.6 % (95.5–99.7 %)
171
82.6 % (77.5–87.8 %)
DESd
6 (D’Urbano et al. [35]; Marcos et al. [31]; Savonitto et al. [30]; Ben Morrison et al. [33]; Alshawabkeh et al. [37]; Rassi et al. [34])
286
274
95.8 % (93.5–98.1 %)
185
64.7 % (59.2–70.2 %)
Diagnosis of ACSe [% of overall pts (range)]
a
B50 % (13–50 %)
2 (D’Urbano et al. [35]; Rassi et al. [34])
104
97
93.3 % (88.5–98.1 %)
39
37.5 % (28.2–46.8 %)
[50 % (59.7–78 %)
5 (Marcos et al. [31]; Savonitto et al. [30]; Ben Morrison et al. [33]; Alshawabkeh et al. [37]; Xia et al. [38])
203
198
97.5 % (95.4–99.7 %)
167
82.3 % (77.0–87.5 %)
Number of subjects free from the end-points
b
Confidence interval
c
Drug-eluting stent
d
89 % DES
e
Acute coronary syndrome
candidates to cardiac or non-cardiac surgery is feasible, and allows the performance of surgical procedures with a much lower rate of cardiac ischaemic events (as compared with historical data derived from case series with no such strategy), without significantly affecting bleeding. In a recently published retrospective cohort study of 41.989 veterans affairs (VA) and non-VA operations, a total of 1980 major cardiovascular events (MACE) (4.7 %) occurred within 30 days of surgery: 1,170 MIs or repeat revascularisations without death. 141 MIs or repeated revascularisations with death, and 669 deaths alone [41]. This study includes the largest cohort reported to date of patients with coronary stents (both bare metal and drugeluting) undergoing surgery and clearly shows that
continuation of oral antiplatelet agents does not mitigate the incidence of perioperative morbidity. Preoperative administration of a short-acting intravenous agent (such as glycoprotein IIb/IIIa inhibitor or cangrelor) has been proposed as an alternative strategy to manage these patients. However, the questions of outcome and safety of such a treatment have been poorly investigated in high-quality studies [42], mostly because there is no reference standard to compare with. The routine use of heparins is generally not recommended, because such treatment is associated with increased bleeding [43], and it has no antiplatelet effect. In our study, the clinical benefits of intravenous antiplatelet drugs were consistent: no MACE occurred in all of
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Table 4 Success rate of bridge therapy based on the type of surgery Reference
Ischaemic events Cardiovascular surgery
Bleeding/transfusions Non-cardiovascular surgery
Cardiovascular surgery
Non-cardiovascular surgery
D’Urbano et al. [35]
1/1a
3/3
1/1
3/3
Marcos et al. [31]
15/15
21/21
13/15
17/21
Savonitto et al. [30] Ceppa et al. [32]
21/21 –
39/39 7/7
15/21 –
28/39 5/7
Ben Morrison et al. [33]
13/13
6/6
8/13
1/6
Rassi et al. [34]
68/71
18/22
–
–
Angiolillo et al. [36]
102/106
–
94/106
–
Alshawabkeh et al. [37]
12/16
49/51
16/16
47/51
Xia et al. [38]
–
21/21
–
21/21
Combined success rate (95 % confidence interval)
95.5 % (92.9–98.1 %)
96.5 % (93.7–99.2 %)
85.5 % (80.2–90.7 %)
82.4 % (76.3–88.6 %)
a
Number of subjects free from the end-points/number of total subjects
the bridge therapy studies using tirofiban. The benefit was less evident for the only existing RCT: however, it is reassuring that the direction of the effect favours the bridge therapy over placebo and that for laboratory outcomes there is a clear advantage [36]. Different study designs and populations may partly or totally explain the variability in success rates reported in studies. For example, different cardiac and non-cardiac operations have variable bleeding risks, thus partially limiting the ability to adequately compare different bridge strategies. The time elapsed between stent implantation and surgery has been regarded as one of the most relevant predictors of perioperative ischaemic adverse events: the studies included were heterogeneous with regard to this variable, and this might affect the final success rate. A further and relevant source of variability is related to the different time-points chosen to resume post-operative bridging, as this is a critical point where patients are in a hyper-coagulable state, yet intravenous treatment is not reinstituted because of the fear of post-operative bleeding, and oral treatment may be ineffective due to post-operative malabsorption. Different drugs are another important source of heterogeneity, possibly having an impact upon different rates of ischaemic and bleeding events. We included bridging with eptifibatide, tirofiban or cangrelor. Eptifibatide and tirofiban are both competitive inhibitors of the GP IIb/IIIa receptor, with a plasma half-life of 1.5–2 h, and a prevalent excretion by the kidney. Cangrelor is a reversible inhibitor of the P2Y12 platelet receptor with an half-life as short as 3–6 min [44]. Specific dose-finding studies have been performed to test cangrelor as bridge therapy in the setting of cardiac surgery, whereas small molecules GPIs are used at dosing regimens recommended for the treatment of ACS and have been tested as bridge therapy also in patient
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candidates to non-cardiac surgery. Cangrelor is not currently approved by the regulatory agencies anywhere, and it is not yet commercially available in Europe. Doseadjustments have to be made for tirofiban in renal insufficiency, whereas severe renal failure (eGFR \ 30 ml/min) is a contraindication for eptifibatide. Cangrelor has not been tested as bridge therapy in patients with estimated glomerular filtration rate (GFR) \30 ml/min or with endstage renal disease. Overall, currently available data are not able to provide a comparison between GPIs and cangrelor therapy, even if both therapies appear to be an effective and safe strategy in this setting. A major limitation of our study is the fact that most of the data are drawn from retrospective case series. However, the results of the two prospective phase II studies and the single RCT available are consistent with the other findings. Another limitation is the different definitions of ischaemic and bleeding events adopted in each study. Indeed, due to the variety of surgical and endoscopic procedures, both in terms of ischaemic and of bleeding risk, a uniform definition, or standardisation, of the relevant endpoints is difficult. We, therefore, defined success rate in a binary fashion, accepting at face value what was reported by the authors of individual studies. We did not aim at standardised operational definitions: this approach helped us in capturing as many of the different definitions as possible, even if failure to standardise the primary outcome weakens any conclusions made. Despite the above mentioned limitations, we think that our paper may add useful information to the current literature. Due to the high mortality and myocardial infarction rates reported in retrospective studies with no bridge therapy, it is unlikely that a randomised trial of bridge therapy versus pure withdrawal of DAT will be launched.
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233
Patients facing surgery shortly after stenting are at higher risk of thrombotic events: the equipoise principle (i.e. the true uncertainty about which of the trial arms is most likely to benefit the patient) driving the starting of an RCT might be lost given the likely merits of the bridge therapy. The slow enrolment in the above mentioned ongoing trial [39] may be partially explained by the orientation of clinicians to offer to patients the ‘‘best therapy’’, limiting the proposal to enter in an RCT to the patients in whom the equipoise is maintained. Therefore, our systematic review of all available evidence may serve as an alternative strategy of gathering useful clinical information to guide clinical decision making in such difficult cases. Conflict of interest
None.
Appendix See Appendix Tables 5 and 6.
Table 5 Quality assessment checklist Checklist criteria
Number of studies with yes responses
Number of studies with no responses
1. Is the hypothesis/aim/ objective of the study clearly stated in the abstract, introduction, or methods section?
8
0
2. Are the characteristics of the participants included in the study described?
8
3. Were the cases collected in more than one centre?
1
4. Are the eligibility criteria (inclusion and exclusion criteria) to enter the study explicit and appropriate?
7
5. Were participants recruited consecutively?
5
3
6. Did participants enter the study at a similar point in the disease?
4
4
7. Was the intervention clearly described in the study?
5
8. Were additional interventions (cointerventions) clearly reported in the study?
7
9. Are the outcome measures clearly defined in the introduction or methods section?
7
Table 5 continued Checklist criteria
Number of studies with yes responses
Number of studies with no responses
10. Were relevant outcomes appropriately measured with objective and/or subjective methods?
7
1
11. Were outcomes measured before and after intervention?
3
5
12. Were the statistical tests used to assess the relevant outcomes appropriate?
6
2
13. Was the length of followup reported?
8
0
14. Was the loss to follow-up reported?
8
0
15. Does the study provide estimates of the random variability in the data analysis of relevant outcomes?
3
5
16. Are adverse events reported?
8
0
17. Are the conclusions of the study supported by results?
8
0
18. Are both competing interest and source of support for the study reported?
3
5
Table 6 Number of subjects free from re-operation due to bleeding and combined success rate 0
Reference
Re-operation for bleeding
D’Urbano et al. [35]
4/4a
7
Marcos et al. [31]
35/36
1
Savonitto et al. [30] Ceppa et al. [32]
60/60 7/7
Ben Morrison et al. [33]
18/19
3
Rassi et al. [34]
90/100
Angiolillo et al. [36]
104/106
Alshawabkeh et al. [37]
67/67
Xia et al. [38]
21/21
Combined success rate (95 % confidence interval)
96.7 % (95.0–98.4 %)
a
Number of subjects free from the end-point/number of total subjects
1
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