Thrombus Aspiration in ST-Segment–Elevation Myocardial Infarction: An Individual Patient Meta-Analysis: Thrombectomy Trialists Collaboration
Abstract
Background:
Thrombus aspiration during percutaneous coronary intervention (PCI) for the treatment of ST-segment–elevation myocardial infarction (STEMI) has been widely used; however, recent trials have questioned its value and safety. In this meta-analysis, we, the trial investigators, aimed to pool the individual patient data from these trials to determine the benefits and risks of thrombus aspiration during PCI in patients with ST-segment–elevation myocardial infarction.
Methods:
Included were large (n≥1000), randomized, controlled trials comparing manual thrombectomy and PCI alone in patients with ST-segment–elevation myocardial infarction. Individual patient data were provided by the leadership of each trial. The prespecified primary efficacy outcome was cardiovascular mortality within 30 days, and the primary safety outcome was stroke or transient ischemic attack within 30 days.
Results:
The 3 eligible randomized trials (TAPAS [Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction], TASTE [Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia], and TOTAL [Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI]) enrolled 19 047 patients, of whom 18 306 underwent PCI and were included in the primary analysis. Cardiovascular death at 30 days occurred in 221 of 9155 patients (2.4%) randomized to thrombus aspiration and 262 of 9151 (2.9%) randomized to PCI alone (hazard ratio, 0.84; 95% confidence interval, 0.70–1.01; P=0.06). Stroke or transient ischemic attack occurred in 66 (0.8%) randomized to thrombus aspiration and 46 (0.5%) randomized to PCI alone (odds ratio, 1.43; 95% confidence interval, 0.98–2.10; P=0.06). There were no significant differences in recurrent myocardial infarction, stent thrombosis, heart failure, or target vessel revascularization. In the subgroup with high thrombus burden (TIMI [Thrombolysis in Myocardial Infarction] thrombus grade ≥3), thrombus aspiration was associated with fewer cardiovascular deaths (170 [2.5%] versus 205 [3.1%]; hazard ratio, 0.80; 95% confidence interval, 0.65–0.98; P=0.03) and with more strokes or transient ischemic attacks (55 [0.9%] versus 34 [0.5%]; odds ratio, 1.56; 95% confidence interval, 1.02–2.42, P=0.04). However, the interaction P values were 0.32 and 0.34, respectively.
Conclusions:
Routine thrombus aspiration during PCI for ST-segment–elevation myocardial infarction did not improve clinical outcomes. In the high thrombus burden group, the trends toward reduced cardiovascular death and increased stroke or transient ischemic attack provide a rationale for future trials of improved thrombus aspiration technologies in this high-risk subgroup.
Clinical Trial Registration:
URLs: http://www.ClinicalTrials.gov http://www.crd.york.ac.uk/prospero/. Unique identifiers: NCT02552407 and CRD42015025936.
Introduction
The optimal treatment for ST-segment–elevation myocardial infarction (STEMI) is rapid reperfusion with timely primary percutaneous coronary intervention (PCI) if available.1 However, one of the limitations of primary PCI is embolization of thrombus distally and microvascular occlusion, associated with markedly increased mortality.2 Thrombus aspiration was thought to be a simple method to remove thrombus before stent deployment, thereby reducing distal embolization and improving outcomes.
Thrombus aspiration became part of routine practice on the basis of the promising results of an early trial.3,4 However, the results of recent, larger, multicenter trials have created uncertainty about the benefit of thrombus aspiration and suggested possible harm from increased stroke risk.5–9 None of the individual trials were powered to detect a modest (eg, 20%) reduction in mortality or low-frequency events such as stroke. Accordingly, we undertook an individual patient–level meta-analysis to determine the effect of thrombus aspiration on 30-day cardiovascular mortality and stroke or transient ischemic attack (TIA).
Methods
The meta-analysis was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines for individual patient data meta-analyses.10 The protocol was finalized and registered with PROSPERO (international register of systematic reviews, CRD42015025936) and ClinicalTrials.gov (NCT02552407) before unblinding or any data analysis. Large, randomized trials (recruiting ≥1000 patients) that compared manual thrombus aspiration plus PCI and PCI alone in patients with STEMI were eligible. Only large, randomized trials were included because small trials are more susceptible to publication bias and tend to be lower quality. A comprehensive search strategy was used for Medline, EMBASE, and Cochrane Central Register of Controlled Trials on September 2, 2016, with no language restriction (online-only Data Supplement).
Authors of eligible trials collaboratively shared individual patient–level data. The databases from the individual trials were merged into a dedicated SAS file set up for the present study. Data sets were rigorously reviewed for completeness and consistency to ensure that no errors had occurred in reformatting of the data and to ensure agreement with the original publications. Any differences were resolved by queries within the collaborative group. Variables were not defined according to identical criteria in the studies, but common definitions were defined by consensus within the author group whenever possible. The online-only Data Supplement provides details on outcomes variables. The TAPAS trial [Thrombus Aspiration During Percutaneous Coronary Intervention in Acute Myocardial Infarction] did not prospectively collect stroke or TIA data and was not included for this outcome. Outcomes were not adjudicated in TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) and were obtained from discharge diagnoses in administrative databases and the death registry. The risk of bias was assessed with the Cochrane Collaboration tool (Figure I in the online-only Data Supplement).
The 3 individual trials (TASTE, TAPAS, and TOTAL [Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI) were each approved by an institutional review committee, and participants provided informed consent.
Study Organization
All data were merged at the Uppsala Clinical Research Center (Uppsala, Sweden), and analyses were performed with R version 3.2 (R Foundation for Statistical Computing, Vienna, Austria). Kaplan-Meier curves and forest plot figures were created at the Population Health Research Institute (Hamilton, ON, Canada) with S-PLUS (TIBCO Software Inc, Palo Alto, CA).
Statistical Analysis
For baseline characteristics, the Wilcoxon rank-sum test was used for continuous variables and the Pearson χ2 test for categorical variables. The prespecified primary efficacy outcome was cardiovascular death at 30 days. The prespecified primary safety outcome was stroke or TIA at 30 days. The prespecified primary analysis was a modified intention-to-treat analysis that included all randomized patients who had undergone emergency PCI for STEMI, with all analyses conducted according to the originally allocated study group. Patients who did not undergo PCI for STEMI (ie, normal coronary arteries) were not included in the primary analysis. A fixed-effect model was used. Study level was used as a covariate in analyses, and study-level interaction P values were reported.
A value of P<0.05 was considered statistically significant. Hazard ratios and their 95% confidence intervals (CIs) were estimated with a Cox proportional hazards regression model with treatment group as the predictor variable, and P values from Cox regression were used. For the outcome of stroke or TIA, the exact time of event was not available during initial hospitalization in the TASTE trial, so logistic regression was used for significance testing and to calculate odds ratios and 95% CIs with treatment group as the predictor variable.
Subgroup Analyses
We hypothesized that thrombus aspiration might be more effective in patients with higher thrombus burden. Accordingly, prespecified subgroup analyses were performed comparing TIMI (Thrombolysis in Myocardial Infarction) thrombus grade <3 with ≥3 and grade <4 with ≥4. Additional prespecified subgroup analyses were based on time from symptom onset (<6 versus 6–12 versus >12 hours), initial TIMI flow (grade 0–1 versus 2–3), lesion location (proximal versus nonproximal vessel), tertiles of site primary PCI volume, and use of a glycoprotein IIb/IIIa inhibitor. Statistical interactions were evaluated at a significance level of 0.05 with no adjustment made for multiple comparisons.
Results
Of the 19 047 patients enrolled in the 3 randomized trials, 18 306 underwent PCI and were included in the primary analysis (Figure 1). The individual trials (Table I and Figures II and III in the online-only Data Supplement) included were the TAPAS (n=1071),4 TASTE (n=7244),11 and TOTAL (n=10 732).7 These 3 large trials accounted for 19 047 patients of 22 057 patients enrolled in manual thrombus aspiration trials.
Baseline characteristics were well balanced except that the proportion of smokers was smaller in the thrombus aspiration group (39.9% versus 42.4%; P<0.001; Table 1) and the interval from symptom onset to hospital arrival was longer in the thrombus aspiration group (190 versus 185.5 minutes; P=0.025; Table 1). The majority of patients had TIMI grade 0 or 1 flow in the infarct artery at baseline.
Thrombus Aspiration (n=9155) | PCI Alone (n=9151) | |
---|---|---|
Demographics | ||
Age (mean±SD), y | 63.3 (12.0) | 63.1 (12.1) |
Age >75 y, n (%) | 1620 (17.7) | 1521 (16.6) |
Male, n (%) | 6930 (75.7) | 7002 (76.5) |
Killip class IV, n (%) | 72 (0.8) | 71 (0.8) |
History, n (%) | ||
Current smoker* | 3535 (39.9) | 3740 (42.4) |
Hypertension | 4239 (46.6) | 4228 (46.5) |
Diabetes mellitus | 1419 (15.5) | 1449 (15.9) |
Prior myocardial infarction | 907 (10.0) | 940 (10.3) |
Prior PCI | 788 (8.6) | 821 (9.0) |
Initial PCI procedure | ||
Time from symptom onset to PCI start, min† | 190.0 (128–311) | 185.5 (125–300) |
Radial access, n (%) | 5828 (67.4) | 5843 (67.6) |
Bivalirudin, n (%) | 3846 (42) | 3735 (40.8) |
Enoxaparin, n (%) | 572 (6.2) | 572 (6.3) |
Unfractionated intravenous heparin, n (%) | 7693 (84) | 7761 (84.8) |
Glycoprotein IIb/IIIa inhibitor, n (%)‡ | 2957 (32.3) | 3209(35.1) |
Contrast volume (SD), mL§ | 171 (98) | 168 (100.3) |
Fluoroscopy time (SD), min¶ | 13.2 (19.2) | 12.3 (25.4) |
TIMI thrombus grade, n (%)‖ | ||
0, No thrombus present | 728 (8.0) | 803 (8.8) |
1, Possible thrombus present | 999 (11.0) | 1112 (12.2) |
2, Definite thrombus present, <0.5 vessel diameter | 497 (5.5) | 496 (5.5) |
3, Definite thrombus present, 0.5–2.0 vessel diameters | 1516 (16.6) | 1321 (14.5) |
4, Definite thrombus present, >2.0 vessel diameters | 1658 (18.2) | 1623 (17.8) |
5, Total occlusion | 3718 (40.8) | 3740 (41.1) |
Pre-PCI TIMI grade 0/1 flow, n (%) | 6808 (74.9) | 6870 (75.5) |
Direct stenting, n (%)** | 3594 (39.5) | 1916 (21.1) |
Bare-metal stent, n (%) | 4783 (52.2) | 4806 (52.5) |
≥1 Drug-eluting stent, n (%) | 4059 (44.3) | 4038 (44.1) |
No. of stents, mean (SD) | 1.4 (0.7) | 1.4 (0.7) |
Total stent length, mean (SD), mm | 28 (15.5) | 28.1 (15.4) |
Stent diameter, mean (SD), mm | 3.2 (0.5) | 3.1(0.5) |
Vessel treated at index PCI, n (%) | ||
Left main coronary artery | 79 (0.9) | 86 (0.9) |
Left anterior descending coronary artery | 3945 (43.1) | 4039 (44.1) |
Left circumflex coronary artery | 1404 (15.3) | 1408 (15.4) |
Right coronary artery | 4129 (45.1) | 4069 (44.5) |
Coronary bypass graft | 38 (0.4) | 36 (0.4) |
Medications at hospital discharge, n (%)# | ||
Aspirin | 8238 (97.4) | 8217 (97.3) |
Ticagrelor | 2043 (24) | 2040 (24) |
Prasugrel | 966 (11.4) | 961 (11.3) |
Clopidogrel | 5124 (60.3) | 5085 (59.9) |
Statin | 8097 (95.3) | 8086 (95.3) |
Angiotensin-converting enzyme inhibitor or receptor blocker | 6188 (72.8) | 6251 (73.7) |
β-Blocker | 7161 (84.3) | 7198 (84.9) |
Oral anticoagulant | 493 (5.8) | 497 (5.9%) |
PCI indicates percutaneous coronary intervention; and TIMI, Thrombolysis in Myocardial infarction.
*
Current smoker, P<0.001.
†
Time from symptom onset to PCI, P=0.025.
‡
Glycoprotein IIb/IIIa inhibitor, P<0.001.
§
Contrast volume, P<0.001.
¶
Fluoroscopy time, P<0.001 (TASTE [Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia] and TOTAL [Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI] only).
‖
TIMI thrombus grade, P<0.001.
#
Medications at discharge available only for TASTE and TOTAL.
**
Direct stenting, P<0.001.
In the thrombus aspiration group, direct stenting was more frequent (39.5% versus 21.1%; P<0.001) and glycoprotein IIb/IIa use was slightly lower (32.3% versus 35.1%; P<0.001). The rate of crossover from assigned thrombus aspiration to PCI alone was 5.5% and from PCI alone to thrombus aspiration was 6.8%. Fluoroscopy time was slightly longer with thrombus aspiration (13.2 versus 12.3 minutes; P<0.001; Table 1). Stent length, stent diameter, and number of stents were not different between the groups.
Efficacy and Safety
The primary efficacy outcome of cardiovascular death within 30 days in patients who had undergone PCI for STEMI was 2.4% in the thrombus aspiration group compared with 2.9% in the PCI alone group (hazard ratio, 0.84; 95% CI, 0.70–1.01; P=0.06; study-level interaction P=0.05; Figure 2 and Table 2). The primary safety outcome of stroke or TIA at 30 days was 0.8% in the thrombus aspiration group compared with 0.5% in the PCI alone group (odds ratio, 1.43; 95% CI, 0.98–2.10; P=0.06) but with a significant study-level interaction (P=0.02). There were no statistically significant differences in recurrent myocardial infarction, stent thrombosis, or target vessel revascularization (Table 2). At 1 year, the rate of cardiovascular death was 3.7% in the thrombus aspiration group compared with 4.2% in the PCI alone group (hazard ratio, 0.90; 95% CI, 0.78–1.04; P=0.15; Figure 2).
Outcome | Thrombus Aspiration (n=9155), n (%) | PCI Alone (n=9151), n (%) | HR | 95% CI | P Value |
---|---|---|---|---|---|
Primary outcome | |||||
Cardiovascular death at 30 d | 221 (2.4) | 262 (2.9) | 0.84 | 0.70–1.01 | 0.06 |
Key safety outcome | |||||
Stroke or TIA at 30 d* | 66/8518 (0.8) | 46/8476 (0.5) | 1.43 | 0.98–2.1 | 0.06 |
Other outcomes at 30 d | |||||
All-cause death | 232 (2.5) | 273 (3.0) | 0.85 | 0.71–1.01 | 0.06 |
MI | 96 (1.0) | 104 (1.1) | 0.92 | 0.70–1.21 | 0.55 |
Congestive heart failure† | 141/8653 (1.6) | 128/8648 (1.5) | 1.10 | 0.87–1.40 | 0.44 |
Target vessel revascularization | 215 (2.3) | 239 (2.6) | 0.90 | 0.74–1.08 | 0.24 |
Cardiovascular death, MI, cardiogenic shock, congestive heart failure, stent thrombosis, or target vessel revascularization† | 604/8653 (7.0) | 654/8648 (7.6) | 0.92 | 0.82–1.03 | 0.14 |
Outcomes at 1 y | |||||
Cardiovascular death | 343 (3.7) | 380 (4.2) | 0.90 | 0.78–1.04 | 0.15 |
All-cause death | 426 (4.7) | 464 (5.1) | 0.91 | 0.80–1.04 | 0.18 |
Myocardial infarction | 233 (2.5) | 239 (2.6) | 0.97 | 0.81–1.16 | 0.73 |
Congestive heart failure† | 268/8653 (3.1) | 258/8648 (3.0) | 1.04 | 0.87–1.23 | 0.68 |
Target vessel revascularization | 495 (5.4) | 504 (5.5) | 0.97 | 0.86–1.10 | 0.68 |
Stroke or TIA* | 128/8055 (1.6) | 103/7990 (1.3) | 1.24 | 0.95–1.61 | 0.11 |
CI indicates confidence interval; HR, hazard ratio; MI, myocardial infarction; PCI indicates percutaneous coronary intervention; and TIA, transient ischemic attack.
*
Data available only from TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) and TOTAL (Trial of Routine Aspiration Thrombectomy With PCI Versus PCI Alone in Patients With STEMI), and odds ratios, not HRs, were reported.
†
Data only available from TASTE and TOTAL trials.
Subgroup Findings
In those with high thrombus burden (TIMI thrombus grade ≥3), thrombus aspiration was associated with reduced cardiovascular death (2.5% versus 3.1%; hazard ratio, 0.80; 95% CI, 0.65–0.98; P=0.03) with no significant heterogeneity across studies (study-level interaction P=0.22). However, this subgroup had an excess in stroke or TIA (0.9% versus 0.5%; odds ratio, 1.56; 95% CI, 1.02–2.42; P=0.04; Table 3) with no significant heterogeneity across studies (study-level interaction P=0.09). In the low thrombus burden subgroup (TIMI thrombus grade <3), there were no differences in cardiovascular death (2.2% versus 2.2%; hazard ratio, 1.00; 95% CI, 0.68–1.47) or in stroke or TIA (0.5% versus 0.5%; odds ratio, 0.99; 95% CI, 0.43–2.26). Interaction P values for differences in cardiovascular death and for stroke or TIA according to the cut point of TIMI thrombus grade ≥3 were not statistically significant (P=0.32 and 0.34, respectively; Table 3).
Outcome | Thrombus Aspiration, n (%) | PCI Alone, n (%) | HR | 95% CI | P Value | Interaction P |
---|---|---|---|---|---|---|
Cardiovascular death at 30 d | ||||||
TIMI thrombus grade ≥3 | 170 (2.5) | 205 (3.1) | 0.80 | 0.65–0.98 | 0.03 | 0.32 |
TIMI thrombus grade <3 | 49 (2.2) | 53 (2.2) | 1.00 | 0.68–1.47 | 0.99 | |
TIMI thrombus grade ≥4 | 144 (2.7) | 174 (3.2) | 0.82 | 0.66–1.02 | 0.08 | 0.67 |
TIMI thrombus grade <4 | 75 (2.0) | 84 (2.3) | 0.89 | 0.65–1.22 | 0.48 | |
Stroke or TIA at 30 d* | ||||||
TIMI thrombus grade ≥3 | 55 (0.9) | 34 (0.5) | 1.56 | 1.02–2.42 | 0.04 | 0.34 |
TIMI thrombus grade <3 | 11 (0.5) | 12 (0.5) | 0.99 | 0.43–2.26 | 0.98 | |
TIMI thrombus grade ≥4 | 51 (1.0) | 27 (0.6) | 1.87 | 1.18–3.02 | 0.009 | 0.04 |
TIMI thrombus grade <4 | 15 (0.4) | 19 (0.5) | 0.80 | 0.40–1.57 | 0.512 | |
Other outcomes at 30 d | ||||||
All-cause death | ||||||
TIMI thrombus grade ≥3 | 176 (2.6) | 210 (3.1) | 0.81 | 0.66–0.99 | 0.04 | 0.31 |
TIMI thrombus grade <3 | 54 (2.4) | 58 (2.4) | 1.00 | 0.69–1.45 | 0.99 | |
TIMI thrombus grade ≥4 | 150 (2.8) | 179 (3.3) | 0.83 | 0.67–1.03 | 0.10 | 0.68 |
TIMI thrombus grade <4 | 80 (2.1) | 89 (2.4) | 0.90 | 0.66–1.22 | 0.49 | |
Myocardial infarction | ||||||
TIMI thrombus grade ≥3 | 78 (1.1) | 84 (1.3) | 0.90 | 0.66–1.23 | 0.52 | 0.95 |
TIMI thrombus grade <3 | 17 (0.76) | 20 (0.83) | 0.93 | 0.49–1.77 | 0.82 | |
TIMI thrombus grade ≥4 | 65 (1.2) | 68 (1.3) | 0.96 | 0.68–1.35 | 0.80 | 0.61 |
TIMI thrombus grade <4 | 30 (0.8) | 36 (0.96) | 0.82 | 0.51–1.33 | 0.43 | |
Outcomes at 1 y | ||||||
Cardiovascular death | ||||||
TIMI thrombus grade ≥3 | 261 (3.8) | 298 (4.5) | 0.84 | 0.72–1.0 | 0.05 | 0.17 |
TIMI thrombus grade <3 | 78 (3.5) | 78 (3.2) | 1.08 | 0.79–1.47 | 0.64 | |
TIMI thrombus grade ≥4 | 219 (4.1) | 249 (4.6) | 0.87 | 0.73–1.04 | 0.14 | 0.61 |
TIMI thrombus grade <4 | 120 (3.2) | 127 (3.4) | 0.94 | 0.73–1.21 | 0.64 | |
All-cause death | ||||||
TIMI thrombus grade ≥3 | 318 (4.6) | 353 (5.3) | 0.87 | 0.75–1.01 | 0.07 | 0.20 |
TIMI thrombus grade <3 | 104 (4.7) | 106 (4.4) | 1.06 | 0.81–1.39 | 0.69 | |
TIMI thrombus grade ≥4 | 262 (4.9) | 289 (5.4) | 0.90 | 0.76–1.06 | 0.20 | 0.74 |
TIMI thrombus grade <4 | 160 (4.3) | 170 (4.6) | 0.94 | 0.76–1.16 | 0.56 | |
Stroke or TIA* | ||||||
TIMI thrombus grade ≥3 | 98 (1.6) | 76 (1.3) | 1.24 | 0.92–1.68 | 0.17 | 0.94 |
TIMI thrombus grade <3 | 30 (1.6) | 27 (1.3) | 1.20 | 0.71–2.05 | 0.49 | |
TIMI thrombus grade ≥4 | 81 (1.7) | 54 (1.2) | 1.48 | 1.05–2.10 | 0.03 | 0.11 |
TIMI thrombus grade <4 | 47 (1.4) | 49 (1.5) | 0.96 | 0.64–1.44 | 0.85 |
CI indicates confidence interval; HR, hazard ratio; PCI, percutaneous coronary intervention; TIA, transient ischemic attack; and TIMI, Thrombolysis in Myocardial infarction.
*
Stroke or TIA outcomes have odds ratio reported instead of HR.
When a cut point of TIMI thrombus grade ≥4 rather than ≥3 was chosen, there were similar patterns for cardiovascular death (2.7% versus 3.2%; hazard ratio, 0.82; 95% CI, 0.66–1.02; P=0.08; subgroup interaction P=0.67; study-level interaction P=0.43) and stroke or TIA (1.0% versus 0.6%; odds ratio, 1.87; 95% CI, 1.18–3.02; P=0.009; subgroup interaction P=0.04; study-level interaction P=0.41; Table 3) within 30 days.
There appeared to be a greater benefit for thrombus aspiration in patients receiving a glycoprotein IIb/IIIa inhibitor for cardiovascular death within 30 days (interaction P=0.048), but there was also increased risk of stroke or TIA (interaction P=0.04; Figure 3A and 3B). There appeared to be a potential benefit in patients presenting within 6 hours for cardiovascular death but also harm in terms of stroke (Figure 3A and 3B).
Discussion
In contrast to traditional meta-analyses summarizing group data, the present meta-analysis used individual patient data that provided considerably greater power to examine important but low-frequency events such as cardiovascular death and stroke and allowed the evaluation of specific subgroups such as the one with a high thrombus burden. The protocol was finalized and registered before the analysis was started as per the PRISMA guidelines for individual patient data meta-analyses.10
At 30 days, there were no statistically significant differences for cardiovascular mortality and all-cause mortality between a strategy of routine manual thrombus aspiration and PCI alone overall.
Although there were no statistically significant subgroup interactions, in the subgroup of patients with high thrombus burden, there was a nominal reduction in cardiovascular mortality and all-cause mortality but an increase in stroke or TIA at 30 days. It is biologically plausible that thrombus aspiration is beneficial only in patients with moderate to high thrombus burden. On the other hand, if the mechanism of stroke is embolization of thrombus from the coronary artery to systemic circulation, it is logical that the risk would be higher in patients with high thrombus burden. Finally, in patients with high thrombus burden, the increase in stroke could counterbalance an early benefit such that the effect on all-cause mortality at 1 year was neutral.
For stroke or TIA, there was a significant study-level interaction. One potential reason is that the TASTE trial randomized patients after angiography, whereas TOTAL and TAPAS randomized patients before angiography, so it is possible that angiographic anatomy varied between the studies. Thrombus burden has been linked to stroke risk, and one hypothesis is that TOTAL had a higher stroke risk with thrombus aspiration as a result of the inclusion of patients with a higher thrombus burden.8 To support this hypothesis, in the subgroup of patients with high thrombus burden, we found consistency at the study level for the effect of thrombus aspiration on both cardiovascular death and stroke or TIA. However, these results should be interpreted cautiously, given that this is a post hoc analysis. Furthermore, other important limitations are that TAPAS did not collect data on stroke or TIA and neurological events were not adjudicated in TASTE.
Limitations of current manual thrombus aspiration technology include thrombus embolization downstream as a result of wire crossing (before aspiration); limited ability to deal with large, organized thrombi; and embolization of thrombus to other vascular territories during removal of the aspiration catheter. These limitations are consistent with the TOTAL optical coherence tomography substudy, which showed a similar residual thrombus volume after routine thrombus aspiration and after balloon angioplasty.12
Innovations in device technology should focus on reducing the risk of systemic embolization of thrombus during thrombus aspiration, in addition to improving efficacy. It is conceivable that improved forms of thrombus aspiration that mitigate stroke risk could reduce cardiovascular mortality in patients with high thrombus burden. The effects on cardiovascular mortality and stroke or TIA observed in this meta-analysis in the high thrombus burden subgroup should be considered exploratory, given that the subgroup interactions were not statistically significant and that there was no adjustment for multiple testing. These findings could serve as a basis for much larger trials with new devices that reduce the risk of systemic embolization. Such trials would need to enroll 26 000 patients with a high thrombus burden to be powered for a 20% reduction in cardiovascular mortality on the basis of the event rates observed in this data set. The feasibility of such a trial may be questioned; however, the large fibrinolytic trials enrolled similar numbers of patients.
The finding that thrombus aspiration may reduce cardiovascular mortality but increase stroke or TIA in those treated with glycoprotein IIb/IIIa inhibitors should be interpreted cautiously. First, glycoprotein IIb/IIIa inhibitor use is likely highly correlated to thrombus burden. Second, these were open-label trials, and glycoprotein IIb/IIIa use is a postrandomization variable that may be affected by knowledge of treatment assignment and procedural complications such as no reflow.
This individual-patient meta-analysis is novel because it used cause-specific mortality (cardiovascular mortality) compared with all-cause mortality presented in the original TASTE and TAPAS publications.3,11 This is important because cause-specific mortality is more likely to be responsive to the intervention than all-cause mortality and thus increases study power. Furthermore, we prespecified our primary outcome at 30 days instead of 180 days (primary outcome of TOTAL) because we hypothesized that the greatest benefit may be early for a one-time intervention compared with an ongoing therapy. Finally, we had detailed baseline data and were able to examine the effect of thrombus aspiration on important subgroups on the basis of thrombus burden and time of symptom onset, both factors that may predict benefit of thrombus aspiration.
Limitations of this analysis are related to limitations of the data sets of the individual trials. TAPAS did not prospectively collect the outcome of nonfatal stroke and was not included in the stroke analyses.3 Direct stenting was recommended in TAPAS but not in the other trials. TASTE collected the composite outcome of stroke or TIA but not stroke alone, necessitating the composite of stroke or TIA as a safety outcome in our meta-analysis.11 The time of stroke or TIA during the initial hospitalization was not collected in TASTE, so a time-to-event analysis was not possible for this outcome. Outcomes in the TASTE trial were from administrative databases, clinical registries, and death certificates and were not adjudicated. Another limitation is that thrombus grade was assessed before wire crossing in both TAPAS and TOTAL and after wire crossing in TASTE. There was no adjustment for multiple comparisons, so all secondary analyses should be considered hypothesis generating. Another limitation is that no adjustment for clustering was performed. Finally, despite nearly 20 000 patients randomized, this analysis still was relatively underpowered to detect a modest but clinically important 20% relative risk reduction in cardiovascular mortality within 30 days.
Conclusions
Routine manual thrombus aspiration during PCI for STEMI did not improve clinical outcomes overall. Whether improved methods for thrombus aspiration could reduce the risk of stroke and enhance overall benefit is not known and warrants testing in future trials of patients with high thrombus burden.
Clinical Perspective
•
This is an individual patient meta-analysis of >18 000 patients with ST-segment–elevation myocardial infarction randomized to thrombus aspiration versus percutaneous coronary intervention alone.
•
As a routine strategy, thrombus aspiration did not reduce cardiovascular mortality for patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention.
•
An exploratory analysis of patients with high thrombus burden suggests that thrombus aspiration may improve cardiovascular mortality but at the price of an increased risk of stroke or transient ischemic attack.
•
Thrombus aspiration should not be used as a routine strategy in patients with ST-segment–elevation myocardial infarction.
•
Further larger, randomized trials are needed to determine whether improved forms of thrombus aspiration can reduce cardiovascular mortality and to determine its safety with regard to stroke.
Supplemental Material
File (025371r2_supplemental_material.pdf)
- Download
- 128.55 KB
References
1.
Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13–20. doi: 10.1016/S0140-6736(03)12113-7.
2.
Henriques JP, Zijlstra F, Ottervanger JP, de Boer MJ, van ‘t Hof AW, Hoorntje JC, Suryapranata H. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J. 2002;23:1112–1117. doi: 10.1053/euhj.2001.3035.
3.
Svilaas T, Vlaar PJ, van der Horst IC, Diercks GF, de Smet BJ, van den Heuvel AF, Anthonio RL, Jessurun GA, Tan ES, Suurmeijer AJ, Zijlstra F. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med. 2008;358:557–567. doi: 10.1056/NEJMoa0706416.
4.
Vlaar PJ, Svilaas T, van der Horst IC, Diercks GF, Fokkema ML, de Smet BJ, van den Heuvel AF, Anthonio RL, Jessurun GA, Tan ES, Suurmeijer AJ, Zijlstra F. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet. 2008;371:1915–1920. doi: 10.1016/S0140-6736(08)60833-8.
5.
Fröbert O, Lagerqvist B, Gudnason T, Thuesen L, Svensson R, Olivecrona GK, James SK. Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE trial): a multicenter, prospective, randomized, controlled clinical registry trial based on the Swedish angiography and angioplasty registry (SCAAR) platform: study design and rationale. Am Heart J. 2010;160:1042–1048. doi: 10.1016/j.ahj.2010.08.040.
6.
Lagerqvist B, Fröbert O, Olivecrona GK, Gudnason T, Maeng M, Alström P, Andersson J, Calais F, Carlsson J, Collste O, Götberg M, Hårdhammar P, Ioanes D, Kallryd A, Linder R, Lundin A, Odenstedt J, Omerovic E, Puskar V, Tödt T, Zelleroth E, Östlund O, James SK. Outcomes 1 year after thrombus aspiration for myocardial infarction. N Engl J Med. 2014;371:1111–1120. doi: 10.1056/NEJMoa1405707.
7.
Jolly SS, Cairns JA, Yusuf S, Meeks B, Pogue J, Rokoss MJ, Kedev S, Thabane L, Stankovic G, Moreno R, Gershlick A, Chowdhary S, Lavi S, Niemelä K, Steg PG, Bernat I, Xu Y, Cantor WJ, Overgaard CB, Naber CK, Cheema AN, Welsh RC, Bertrand OF, Avezum A, Bhindi R, Pancholy S, Rao SV, Natarajan MK, ten Berg JM, Shestakovska O, Gao P, Widimsky P, Džavík V; TOTAL Investigators. Randomized trial of primary PCI with or without routine manual thrombectomy. N Engl J Med. 2015;372:1389–1398. doi: 10.1056/NEJMoa1415098.
8.
Jolly SS, Cairns JA, Yusuf S, Meeks B, Gao P, Hart RG, Kedev S, Stankovic G, Moreno R, Horak D, Kassam S, Rokoss MJ, Leung RC, El-Omar M, Romppanen HO, Alazzoni A, Alak A, Fung A, Alexopoulos D, Schwalm JD, Valettas N, Džavík V; TOTAL Investigators. Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction. Eur Heart J. 2015;36:2364–2372. doi: 10.1093/eurheartj/ehv296.
9.
Jolly SS, Cairns JA, Yusuf S, Rokoss MJ, Gao P, Meeks B, Kedev S, Stankovic G, Moreno R, Gershlick A, Chowdhary S, Lavi S, Niemela K, Bernat I, Cantor WJ, Cheema AN, Steg PG, Welsh RC, Sheth T, Bertrand OF, Avezum A, Bhindi R, Natarajan MK, Horak D, Leung RC, Kassam S, Rao SV, El-Omar M, Mehta SR, Velianou JL, Pancholy S, Džavík V; TOTAL Investigators. Outcomes after thrombus aspiration for ST elevation myocardial infarction: 1-year follow-up of the prospective randomised TOTAL trial. Lancet. 2016;387:127–135. doi: 10.1016/S0140-6736(15)00448-1.
10.
Stewart LA, Clarke M, Rovers M, Riley RD, Simmonds M, Stewart G, Tierney JF; PRISMA-IPD Development Group. Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data: the PRISMA-IPD Statement. JAMA. 2015;313:1657–1665. doi: 10.1001/jama.2015.3656.
11.
Fröbert O, Lagerqvist B, Olivecrona GK, Omerovic E, Gudnason T, Maeng M, Aasa M, Angerås O, Calais F, Danielewicz M, Erlinge D, Hellsten L, Jensen U, Johansson AC, Kåregren A, Nilsson J, Robertson L, Sandhall L, Sjögren I, Ostlund O, Harnek J, James SK; TASTE Trial. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med. 2013;369:1587–1597. doi: 10.1056/NEJMoa1308789.
12.
Bhindi R, Kajander OA, Jolly SS, Kassam S, Lavi S, Niemelä K, Fung A, Cheema AN, Meeks B, Alexopoulos D, Kočka V, Cantor WJ, Kaivosoja TP, Shestakovska O, Gao P, Stankovic G, Džavík V, Sheth T. Culprit lesion thrombus burden after manual thrombectomy or percutaneous coronary intervention-alone in ST-segment elevation myocardial infarction: the optical coherence tomography sub-study of the TOTAL (ThrOmbecTomy versus PCI ALone) trial. Eur Heart J. 2015;36:1892–1900. doi: 10.1093/eurheartj/ehv176.
Information & Authors
Information
Published In
Copyright
© 2016 American Heart Association, Inc.
Versions
You are viewing the most recent version of this article.
History
Received: 7 September 2016
Accepted: 28 October 2016
Published online: 9 December 2016
Published in print: 10 January 2017
Keywords
Subjects
Authors
Disclosures
During the conduct of the TOTAL trial, Dr Jolly received an institutional research grant from Medtronic. During the conduct of the TASTE trial, Dr James received institutional research grants from Medtronic, Vascular Solutions, and Terumo Inc. Since then, he has received institutional research grants from Boston Scientific, Abbot Vascular, AstraZeneca, and The Medicines Company. He has received honoraria from AstraZeneca, The Medicines Company, Bayer, and Boston Scientific. The other authors report no conflicts.
Sources of Funding
None.
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
- Intracoronary thrombolysis combined with drug balloon angioplasty in a young ST-segment elevation myocardial infarction patient: A case report, World Journal of Cardiology, 16, 9, (531-541), (2024).https://doi.org/10.4330/wjc.v16.i9.531
- Five-year follow-up of OCT-guided percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction, EuroIntervention, 20, 15, (e937-e947), (2024).https://doi.org/10.4244/EIJ-D-24-00249
- Management of high thrombus burden during primary percutaneous coronary intervention, Journal of Current Cardiology, 2, 2, (85-97), (2024).https://doi.org/10.4103/JCC.JCC_16_24
- The role of intracoronary thrombolysis in thrombus-laden coronary artery: a case report, Intervenční a akutní kardiologie, 23, 1, (43-49), (2024).https://doi.org/10.36290/kar.2024.002
- The Use of Thrombectomy during Primary Percutaneous Coronary Intervention: Resurrecting an Old Concept in Contemporary Practice, Journal of Clinical Medicine, 13, 8, (2291), (2024).https://doi.org/10.3390/jcm13082291
- Determinants and Prognoses of Visual-Functional Mismatches After Mechanical Reperfusion in ST-Elevation Myocardial Infarction, International Journal of General Medicine, Volume 17, (693-704), (2024).https://doi.org/10.2147/IJGM.S444933
- Outcomes, risk factors, and procedural management of acute myocardial infarction caused by stent thrombosis, Vessel Plus, (2024).https://doi.org/10.20517/2574-1209.2024.13
- Angiographic Outcomes in STEMI Patients: Evaluating Pre-dilatation and Thrombus Aspiration Effects, F1000Research, 13, (1138), (2024).https://doi.org/10.12688/f1000research.156104.1
- Coronary Embolism in ST‐Segment–Elevation Myocardial Infarction and Atrial Fibrillation: Not One Size Fits All, Journal of the American Heart Association, 13, 10, (2024)./doi/10.1161/JAHA.124.035372
- Trend and outcomes of aspiration thrombectomy use in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: an analysis of the National Inpatient Sample, Coronary Artery Disease, (2024).https://doi.org/10.1097/MCA.0000000000001429
- See more
Loading...
View Options
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to access the full text.
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.