Curr Cardiol Rep (2016) 18:30 DOI 10.1007/s11886-016-0707-z
INTERVENTIONAL CARDIOLOGY (S RAO, SECTION EDITOR)
The Role of Manual Aspiration Thrombectomy in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI Aiman Alak 1,2 & Sanjit S. Jolly 1,3
# Springer Science+Business Media New York 2016
Abstract In STEMI, primary PCI restores macrovascular coronary blood flow effectively but microvascular perfusion remains a challenge. Thrombus has the potential to embolize to the microvasculature limiting effective coronary blood flow. Thrombus burden is associated with a higher mortality and manual aspiration thrombectomy has the potential to reduce thrombus burden. The first large trial of routine aspiration thrombectomy (TAPAS, N = 1071) showed an improvement in myocardial blush and an unexpected reduction in mortality. Reinforcing the enthusiasm for this finding metaanalysis of small trials also showed a reduction in mortality, which led to routine manual thrombectomy becoming a class IIa recommendation in the American and European Guidelines for STEMI. Subsequently; however, large trials such as TOTAL (N = 10,732) and TASTE (N = 7244) and meta-analysis showed an increase in the risk of stroke with routine manual thrombectomy but no improvement in mortality, myocardial infarction, stent thrombosis, or severe heart failure. As such, manual thrombectomy should not be routinely used instead saving it as a bailout procedure as indicated.
This article is part of the Topical Collection on Interventional Cardiology * Sanjit S. Jolly [email protected] Aiman Alak [email protected]
Keywords Thrombectomy . STEMI . ST-segment elevation myocardial infarction . Percutaneous coronary intervention . Outcomes
Introduction STEMI is commonly associated with plaque rapture and occlusion of the infarct-related artery with thrombus. Rapid reperfusion of infarct artery has transformed care in patients STEMI and improved outcomes. Primary PCI has been shown to be superior to fibrinolysis and so is the preferred method of reperfusion when available [1, 2]. The goal of acute intervention in STEMI is to restore normal epicardial coronary blood flow (macrovascular perfusion) and microvascular perfusion. Primary PCI restores macrovascular coronary blood flow usually reported as Thrombolysis in Myocardial Infarction (TIMI) 3 flow effectively in more than 90 % of patients. However, one of the major limitations of primary PCI is that thrombus can embolize downstream and obstruct the microvasculature [3, 4]. Distal embolization can occur in 10–15 % of patients undergoing PCI for STEMI and is associated with a marked increase in long-term mortality (44 vs 9 %, p < 0.001). Despite TIMI-3 flow being achieved in more than 94 % of patients undergoing primary PCI, impaired microvascular flow (myocardial blush grades 0–1) occurs in about a third of patients. Myocardial blush was strongly predictive of 1year mortality: 18.3 % in patients with absent myocardial blush (grade 0 or 1) compared to 6.8 % of patients with normal myocardial blush (grade 3, p = 0.004) [3].
1
The Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
2
Room 8 N-01 North Wing, Hamilton General Hospital, 237 Barton St East, Hamilton L8L 2X2, Ontario, Canada
High Thrombus Burden and Outcome
3
Rm. C3-118 DBCSVRI Building, Hamilton General, Hospital, 237 Barton St. East, Hamilton L8L 2X2, Ontario, Canada
Thrombus burden in the infarct artery can be graded angiographically with the TIMI thrombus grading system (Table 1)
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[5, 6]. Thrombus burden can be reclassified after wire crossing because a significant proportion of patients go from an occluded vessel to lower grades of thrombus after wire crossing [7]. Patients with a higher thrombus burden during primary PCI had a higher mortality at 1 year (12.9 vs 7.8 %, p = 0.025) and higher rate of stent thrombosis (8.2 vs 1.3 %, p < 0.001) [8]. Therefore, specific therapies (device or pharmacologic) are needed in this population. Angiographic assessment of thrombus may be relatively insensitive. Optical coherence tomography is more sensitive to assess thrombus burden due to its high resolution and can be used as a tool to assess thrombus burden [9].
Curr Cardiol Rep (2016) 18:30
Box 1: Optimal technique of manual aspiration thrombectomy [13] •Aspiration should be started prior to crossing the lesion to reduce distal embolization of thrombus during crossing the lesion. •If aspiration stops suddenly and does not restart with a new syringe, the aspiration catheter should be removed and flushed outside body as thrombus may be obstructing the lumen. •After thrombectomy, the guide catheter should be aspirated to remove air or thrombus. The guide should be well engaged before withdrawing the thrombectomy catheter to avoid embolizing the thrombus to infarct- or non-infarct-related arteries or to the cerebrovascular vessels.
Rationale for Thrombectomy
Review of the Evidence
Aspiration thrombectomy (manual or mechanical techniques) could potentially decrease the thrombus burden at the target lesion; thus reducing distal embolization, improving final myocardial blush grade thereby improving outcomes. Other advantages of thrombectomy in that the lesion and artery are better visualized aiding in the sizing of the stent. Potential disadvantages of aspiration thrombectomy include embolization of thrombus during removal of thrombectomy catheter to other vascular territories. Other potential risks are coronary artery dissection including the left main artery [10]. One limitation of aspiration thrombectomy is that the aspiration catheter cannot reach or cross the occlusion in approximately 10 % of cases [11]. Predictors of inability to reach or cross the lesion were calcified lesions, a bifurcation lesion, and marked proximal tortuosity. When thrombus catheters were successful in crossing the lesion, no aspirate material could be obtained in approximately a quarter of the cases [11, 12]. Technique is important during manual thrombectomy and tips for optimal technique are outlined in Box 1.
Early Trials of Thrombus Aspiration
Table 1
TIMI thrombus grading system
Thrombus Definition grade G0 G1
No angiographic evidence of thrombus Possible thrombus: reduced contrast density, haziness, irregular lesion contour, or a smooth convex meniscus at site of total occlusion suggestive but not diagnostic of thrombus
G2
Definite thrombus but with largest dimension equal or less than ½ vessel diameter Definite thrombus with largest linear dimension greater than ½ but less than twice vessel diameter Definite thrombus with largest dimension greater or equal to twice vessel diameter Total vessel occlusion: unable to assess thrombus burden
G3 G4 G5
The first large trial of routine aspiration thrombectomy was the TAPAS, (N = 1071, Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study) trial, which was a single center trial [14]. The incidence of the primary outcome of impaired myocardial blush (grade of 0 or 1) was improved with thrombectomy: 17.1 % in the aspiration thrombectomy arm compared to 26.3 % in the standard arm (RR 0.65, 95 % CI 0.51–0.83, p < 0.001). Unexpectedly, mortality at 1 year was reduced by nearly half: 4.7 % (25/535) in the aspiration thrombectomy arm compared to 7.6 % (41/536) in the conventional PCI arm (HR 1.67, 95 % CI 1.02–2.75, p = 0.042) [12]. Subsequent meta-analyses of small randomized trials, which were driven by TAPAS, showed a mortality benefit for thrombectomy but a trend for increased stroke [15]. The TAPAS trial results led to routine manual thrombectomy becoming a class IIa recommendation in both the American and European guidelines [16, 17]. It is important to note that the early trials of thrombectomy in STEMI focused on surrogate outcomes. In a meta-analysis of these early randomized trials, manual thrombectomy showed improvements in the surrogate outcomes of myocardial blush grade, distal embolization, and ST segment resolution [18•]. The INFUSE-AMI (Intralesional Abciximab and Thrombus Aspiration in Patients With Large Anterior Myocardial Infarction) was a multicenter 2 × 2 factorial trial of intracoronary abciximab and manual aspiration thrombectomy in patients with primary PCI for anterior STEMI (N = 452) [19, 20]. As assessed by cardiac magnetic resonance imaging, there was no significant differences in the infarct size in the aspiration thrombectomy group (median 17.0 %; IQR 9.0–22.8 %, n = 174) versus the no aspiration group (median 17.3 %; IQR 7.1–25.5 %, n = 179, p = 0.51). Similarly, there were no differences in the absolute infarct mass or abnormal wall motion score. At 1 year of follow-up,
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there was a reduction in hospitalization for heart failure with thrombus aspiration (0.9 vs 5.4 % p = 0.008) but no significant difference in mortality. Large Multicenter Trials Powered for Clinical Outcomes The TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) trial was a registrybased study randomizing patients to thrombus aspiration and PCI or PCI alone (N = 7244) [21••, 22••]. The primary outcome of all-cause mortality at 30 days was not different (2.8 % thrombectomy vs 3.0 % PCI alone; HR 0.94, 95 % CI 0.72– 1.22, p = 0.63). At 1-year follow-up, there was no difference in all-cause mortality with a rate of 5.3 % in the aspiration thrombectomy arm compared to 5.6 % in the PCI only arm (p = 0.94). At 30 days, there was a trend toward reduction of rehospitalization due to reinfarction (HR 0.61, 95 % CI 0.34– 1.07, p = 0.09) and stent thrombosis (HR 0.47, 95 % CI 0.20– 1.02, p = 0.06) at 30 days. However, at 1 year there was no significant difference in reinfarction and stent thrombosis. The Fig. 1 a Meta-analysis for mortality outcome. b Metaanalysis for stroke outcome. (With permission for both figures from: Jolly SS, Cairns JA, Yusuf S, et al., Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction, Eur Heart J, June 2015, by permission of Oxford University Press) [27••]
a
b
rate of stroke or neurologic complication during index hospitalization was 0.5 % in both arms (HR 1.06, 95 % CI 0.55– 2.02, p = 0.87). The TOTAL trial (N = 10,732) was an international, multicenter, randomized, event-driven trial and included important sub-studies using OCT and angiography [23••, 24]. The TOTAL trial randomized patients to routine manual thrombectomy versus PCI alone with bailout thrombectomy. Bailout thrombectomy was allowed if there was a failure of initial PCI alone strategy defined as occluded vessel (TIMI 0 or 1) after balloon dilatation or if there was a persistent large thrombus after stent deployment. Bailout thrombectomy occurred in 7.0 % in the PCI alone group. The primary outcome a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days occurred at 6.9 % in the aspiration thrombectomy group compared to 7.0 % in the PCI alone group (HR 0.99, 95 % CI 0.85–1.15, p = 0.86). The rate of recurrent myocardial infarction was similar (3.1 vs 3.5 %, p = 0.62). Likewise, there was
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no difference in the rate of stent thrombosis (1.5 vs 1.7 %, p = 0.42). The incidence of cardiovascular death at 180 days was 3.1 % in the aspiration thrombectomy arm compared to 3.5 % in the PCI alone arm (HR 0.90, 95 % CI 0.73–1.12, p = 0.34). The TOTAL trial angiographic sub-study showed no difference in myocardial blush grade but improvements in both distal embolization and ST segment resolution [25]. Of interest, TOTAL showed in a multivariable analysis that distal embolization was independent predictor of outcome but not blush grade. In a TOTAL OCT sub-study (N = 214), OCT was performed immediately after thrombectomy or PCI alone then it was repeated after stent deployment [26••]. A core lab performed blinded assessment of OCT data. The primary outcome of mean pre-stent thrombus burden as a percentage of segment analyzed was not different between routine aspiration thrombectomy and standard PCI (2.36 vs 2.88 %, p = 0.373). The mean absolute thrombus volume was also not different between groups (2.99 vs 3.74 mm3, p = 0.329). Likewise, the mean quadrants of thrombus were 26.88 in the thrombectomy group compared with 29.69 in the PCI-alone group (p = 0.488). Post-stent atherothrombotic burden and post-stent atherothrombotic volume were also not different between both groups. Stroke In the TOTAL trial, the primary safety outcome of stroke was adjudicated by neurologists blinded to group assignment. The incidence of stroke was 0.7 % (33/5033) in the aspiration thrombectomy arm compared to 0.3 % (16/5030) in the PCI alone group (HR 2.06, 95 % CI 1.13–3.75, p = 0.02) [27••]. Differences in stroke were present within 48 h and included differences in strokes with major disability or fatality. Stroke after primary PCI is associated with a poor prognosis with a mortality of 31 % compared to 3 % in those patients without a stroke.
recommend against the use of routine thrombus aspiration and recommend its use for selected cases to improve TIMI 3 flow or to prevent stent thrombosis [17]. These guideline recommendations predate the publication of the largest thrombectomy trial to date, the TOTAL trial. Meta-analysis of Randomized Trials After TASTE and TOTAL In an updated meta-analysis of randomized trials (N = 21,173), there was a borderline reduction in mortality associated with aspiration thrombectomy (OR 0.87, 95 % CI 0.76–1.00, p = 0.05, I2 = 0 %, Fig. 1a) [27••]. However, this result did not maintain statistical significance when a random-effect model was used (OR 0.88, 95 % CI 0.77–1.01, p = 0.07). Stroke occurred more frequently in the aspiration thrombectomy arm (0.8 %) compared to 0.5 % in the PCI alone arm (OR 1.59, 95 % CI 1.11–2.27, p = 0.01, I2 = 0 %, Fig. 1b). The rate of myocardial infarction occurred in 2.1 % in the aspiration thrombectomy group and 2.3 % in PCI alone group (OR 0.94, 95 % CI 0.78–1.13, p = 0.51, I2 = 0 %).
Conclusion and Recommendation Routine manual thrombectomy is not recommended based on the findings of increase in stroke. However, clinical judgment is still needed and aspiration thrombectomy should be used a bailout procedure as clinically indicated. Compliance with Ethical standards Conflict of Interest Aiman Alak declares that he has no conflict of interest. Sanjit S. Jolly reports grants from Medtronic. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
High Thrombus Burden Subgroup There was a clear hypothesis that patients higher thrombus burden may have a greater benefit from thrombus aspiration. Thrombus burden was assessed after wire crossing in TASTE and prior to wire crossing in TOTAL. Both the TASTE and TOTAL trials did not show a benefit for the primary outcome in patients with high thrombus burden [21••, 22••, 23••]. Current Guideline Recommendations The current American College of Cardiology/American Heart Association 2013 guidelines states that routine manual aspiration thrombectomy is considered reasonable to perform (class IIa, level of evidence B) [16] The European 2014 guidelines
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Huynh T, Perron S, O’Loughlin J, et al. Comparison of primary percutaneous coronary intervention and fibrinolytic therapy in STsegment-elevation myocardial infarction Bayesian hierarchical meta-analyses of randomized controlled trials and observational studies. Circulation. 2009;119(24):3101–9.
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Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: quantitative review of randomised trials. Lancet. 2006;367(9510):579–88. Stone GW, Peterson MA, Lansky AJ, et al. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol. 2002;39(4):591–7. Henriques JPS, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J. 2002;23(14):1112–7. TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985;312(14):932–6. Gibson CM, de Lemos JA, Murphy SA, et al. Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction A TIMI 14 substudy. Circulation. 2001;103(21):2550–4. Sianos G, Papafaklis MI, Serruys PW. Angiographic thrombus burden classification in patients with ST-segment elevation myocardial infarction treated with percutaneous coronary intervention. J Invasive Cardiol. 2010;22(10 Suppl B):6B–14B. Sianos G, Papafaklis MI, Daemen J, et al. Angiographic stent thrombosis after routine use of drug-eluting stents in ST-segment elevation myocardial infarction: the importance of thrombus burden. J Am Coll Cardiol. 2007;50(7):573–83. Kajander OA, Koistinen LS, Eskola M, et al. Feasibility and repeatability of optical coherence tomography measurements of pre-stent thrombus burden in patients with STEMI treated with primary PCI. Eur Heart J Cardiovasc Imaging. 2015;16(1):96–107. Alazzoni A, Velianou J, Jolly SS. Left main thrombus as a complication of thrombectomy during primary percutaneous coronary intervention. J Invasive Cardiol. 2011;23(2):E9–E11. Vink MA, Kramer MC, Li X, et al. Clinical and angiographic predictors and prognostic value of failed thrombus aspiration in primary percutaneous coronary intervention. JACC Cardiovasc Interv. 2011;4(6):634–42. Vlaar PJ, Svilaas T, van der Horst IC, et al. 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(9628): 1915–20. Jolly SS, Niemela K. Aspiration thrombectomy in ST-elevation myocardial infarction. Eurointervention. 2014;10(Suppl T):T35–8. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med. 2008;358(6):557–67. Bavry AA, Kumbhani DJ, Bhatt DL. Role of adjunctive thrombectomy and embolic protection devices in acute myocardial infarction: a comprehensive meta-analysis of randomized trials. Eur Heart J. 2008;29(24):2989–3001. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78–e140. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS Guidelines on myocardial revascularization: the Task Force on Myocardial Revascularization of the European Society of
Page 5 of 5 30 Cardiology (ESC) and the European Association for CardioThoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J. 2014;35(37):2541–619. 18.• Kumbhani DJ, Bavry AA, Desai MY, Bangalore S, Bhatt DL. Role of aspiration and mechanical thrombectomy in patients with acute myocardial infarction undergoing primary angioplasty: an updated meta-analysis of randomized trials. J Am Coll Cardiol. 2013;62(16):1409–18. A meta-analysis of randomized trials including surrogate and clinical outcomes prior to the publication of two large multicenter studies. 19. Stone GW, Maehara A, Witzenbichler B, et al. Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA. 2012;307(17):1817–26. 20. Stone GW, Witzenbichler B, Godlewski J, et al. Intralesional abciximab and thrombus aspiration in patients with large anterior myocardial infarction one-year results from the INFUSE-AMI trial. Circ Cardiovasc Interv. 2013;6(5):527–34. 21.•• Fröbert O, Lagerqvist B, Olivecrona GK, et al. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med. 2013;369(17):1587–97. One-month outcomes for the first large randomized trial with manual aspiration thrombectomy (TASTE). 22.•• Lagerqvist B, Fröbert O, Olivecrona GK, et al. Outcomes 1 year after thrombus aspiration for myocardial infarction. N Engl J Med. 2014;371(12):1111–20. One-year outcomes for the first large randomized trial with manual aspiration thrombectomy (TASTE). 23.•• Jolly SS, Cairns JA, Yusuf S, et al. Randomized trial of primary PCI with or without routine manual thrombectomy. N Engl J Med. 2015;372(15):1389–98. 180-day outcomes for the largest randomized trial with manual aspiration thrombectomy (TOTAL). 24. Jolly SS, Cairns J, Yusuf S, et al. Design and rationale of the TOTAL trial: a randomized trial of routine aspiration Thrombectomy with percutaneous coronary intervention (PCI) versus PCI alone in patients with ST-elevation myocardial infarction undergoing primary PCI. Am Heart J. 2014;167(3):315–21. 25. Overgaard C, Sharma, V, Chan W, et al. Myocardial blush and microvascular reperfusion following manual thrombectomy during PCI for STEMI: insights from the TOTAL trial. Eurointervention. Abstracts EuroPCR 2015 (May 2015):Euro15A-OP006. 26.•• Bhindi R, Kajander OA, Jolly SS, et al. 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. 36(29): 1892-900. Optical coherence tomography sub-study of the TOTAL trial showing no differences in thrombus burden with manual aspiration thromebectomy versus no aspiration. 27.•• Jolly SS, Cairns JA, Yusuf S, et al. Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction. Eur Heart J. June 2015. doi:10.1093/eurheartj/ehv296. Analysis of the stroke outcomes for the largest randomized trial with manual aspiration thrombectomy (TOTAL) including an updated meta-analysis of randomized trials for stroke and mortality.
INTERVENTIONAL CARDIOLOGY (S RAO, SECTION EDITOR)
The Role of Manual Aspiration Thrombectomy in Patients Undergoing Primary Percutaneous Coronary Intervention for STEMI Aiman Alak 1,2 & Sanjit S. Jolly 1,3
# Springer Science+Business Media New York 2016
Abstract In STEMI, primary PCI restores macrovascular coronary blood flow effectively but microvascular perfusion remains a challenge. Thrombus has the potential to embolize to the microvasculature limiting effective coronary blood flow. Thrombus burden is associated with a higher mortality and manual aspiration thrombectomy has the potential to reduce thrombus burden. The first large trial of routine aspiration thrombectomy (TAPAS, N = 1071) showed an improvement in myocardial blush and an unexpected reduction in mortality. Reinforcing the enthusiasm for this finding metaanalysis of small trials also showed a reduction in mortality, which led to routine manual thrombectomy becoming a class IIa recommendation in the American and European Guidelines for STEMI. Subsequently; however, large trials such as TOTAL (N = 10,732) and TASTE (N = 7244) and meta-analysis showed an increase in the risk of stroke with routine manual thrombectomy but no improvement in mortality, myocardial infarction, stent thrombosis, or severe heart failure. As such, manual thrombectomy should not be routinely used instead saving it as a bailout procedure as indicated.
This article is part of the Topical Collection on Interventional Cardiology * Sanjit S. Jolly [email protected] Aiman Alak [email protected]
Keywords Thrombectomy . STEMI . ST-segment elevation myocardial infarction . Percutaneous coronary intervention . Outcomes
Introduction STEMI is commonly associated with plaque rapture and occlusion of the infarct-related artery with thrombus. Rapid reperfusion of infarct artery has transformed care in patients STEMI and improved outcomes. Primary PCI has been shown to be superior to fibrinolysis and so is the preferred method of reperfusion when available [1, 2]. The goal of acute intervention in STEMI is to restore normal epicardial coronary blood flow (macrovascular perfusion) and microvascular perfusion. Primary PCI restores macrovascular coronary blood flow usually reported as Thrombolysis in Myocardial Infarction (TIMI) 3 flow effectively in more than 90 % of patients. However, one of the major limitations of primary PCI is that thrombus can embolize downstream and obstruct the microvasculature [3, 4]. Distal embolization can occur in 10–15 % of patients undergoing PCI for STEMI and is associated with a marked increase in long-term mortality (44 vs 9 %, p < 0.001). Despite TIMI-3 flow being achieved in more than 94 % of patients undergoing primary PCI, impaired microvascular flow (myocardial blush grades 0–1) occurs in about a third of patients. Myocardial blush was strongly predictive of 1year mortality: 18.3 % in patients with absent myocardial blush (grade 0 or 1) compared to 6.8 % of patients with normal myocardial blush (grade 3, p = 0.004) [3].
1
The Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
2
Room 8 N-01 North Wing, Hamilton General Hospital, 237 Barton St East, Hamilton L8L 2X2, Ontario, Canada
High Thrombus Burden and Outcome
3
Rm. C3-118 DBCSVRI Building, Hamilton General, Hospital, 237 Barton St. East, Hamilton L8L 2X2, Ontario, Canada
Thrombus burden in the infarct artery can be graded angiographically with the TIMI thrombus grading system (Table 1)
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[5, 6]. Thrombus burden can be reclassified after wire crossing because a significant proportion of patients go from an occluded vessel to lower grades of thrombus after wire crossing [7]. Patients with a higher thrombus burden during primary PCI had a higher mortality at 1 year (12.9 vs 7.8 %, p = 0.025) and higher rate of stent thrombosis (8.2 vs 1.3 %, p < 0.001) [8]. Therefore, specific therapies (device or pharmacologic) are needed in this population. Angiographic assessment of thrombus may be relatively insensitive. Optical coherence tomography is more sensitive to assess thrombus burden due to its high resolution and can be used as a tool to assess thrombus burden [9].
Curr Cardiol Rep (2016) 18:30
Box 1: Optimal technique of manual aspiration thrombectomy [13] •Aspiration should be started prior to crossing the lesion to reduce distal embolization of thrombus during crossing the lesion. •If aspiration stops suddenly and does not restart with a new syringe, the aspiration catheter should be removed and flushed outside body as thrombus may be obstructing the lumen. •After thrombectomy, the guide catheter should be aspirated to remove air or thrombus. The guide should be well engaged before withdrawing the thrombectomy catheter to avoid embolizing the thrombus to infarct- or non-infarct-related arteries or to the cerebrovascular vessels.
Rationale for Thrombectomy
Review of the Evidence
Aspiration thrombectomy (manual or mechanical techniques) could potentially decrease the thrombus burden at the target lesion; thus reducing distal embolization, improving final myocardial blush grade thereby improving outcomes. Other advantages of thrombectomy in that the lesion and artery are better visualized aiding in the sizing of the stent. Potential disadvantages of aspiration thrombectomy include embolization of thrombus during removal of thrombectomy catheter to other vascular territories. Other potential risks are coronary artery dissection including the left main artery [10]. One limitation of aspiration thrombectomy is that the aspiration catheter cannot reach or cross the occlusion in approximately 10 % of cases [11]. Predictors of inability to reach or cross the lesion were calcified lesions, a bifurcation lesion, and marked proximal tortuosity. When thrombus catheters were successful in crossing the lesion, no aspirate material could be obtained in approximately a quarter of the cases [11, 12]. Technique is important during manual thrombectomy and tips for optimal technique are outlined in Box 1.
Early Trials of Thrombus Aspiration
Table 1
TIMI thrombus grading system
Thrombus Definition grade G0 G1
No angiographic evidence of thrombus Possible thrombus: reduced contrast density, haziness, irregular lesion contour, or a smooth convex meniscus at site of total occlusion suggestive but not diagnostic of thrombus
G2
Definite thrombus but with largest dimension equal or less than ½ vessel diameter Definite thrombus with largest linear dimension greater than ½ but less than twice vessel diameter Definite thrombus with largest dimension greater or equal to twice vessel diameter Total vessel occlusion: unable to assess thrombus burden
G3 G4 G5
The first large trial of routine aspiration thrombectomy was the TAPAS, (N = 1071, Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study) trial, which was a single center trial [14]. The incidence of the primary outcome of impaired myocardial blush (grade of 0 or 1) was improved with thrombectomy: 17.1 % in the aspiration thrombectomy arm compared to 26.3 % in the standard arm (RR 0.65, 95 % CI 0.51–0.83, p < 0.001). Unexpectedly, mortality at 1 year was reduced by nearly half: 4.7 % (25/535) in the aspiration thrombectomy arm compared to 7.6 % (41/536) in the conventional PCI arm (HR 1.67, 95 % CI 1.02–2.75, p = 0.042) [12]. Subsequent meta-analyses of small randomized trials, which were driven by TAPAS, showed a mortality benefit for thrombectomy but a trend for increased stroke [15]. The TAPAS trial results led to routine manual thrombectomy becoming a class IIa recommendation in both the American and European guidelines [16, 17]. It is important to note that the early trials of thrombectomy in STEMI focused on surrogate outcomes. In a meta-analysis of these early randomized trials, manual thrombectomy showed improvements in the surrogate outcomes of myocardial blush grade, distal embolization, and ST segment resolution [18•]. The INFUSE-AMI (Intralesional Abciximab and Thrombus Aspiration in Patients With Large Anterior Myocardial Infarction) was a multicenter 2 × 2 factorial trial of intracoronary abciximab and manual aspiration thrombectomy in patients with primary PCI for anterior STEMI (N = 452) [19, 20]. As assessed by cardiac magnetic resonance imaging, there was no significant differences in the infarct size in the aspiration thrombectomy group (median 17.0 %; IQR 9.0–22.8 %, n = 174) versus the no aspiration group (median 17.3 %; IQR 7.1–25.5 %, n = 179, p = 0.51). Similarly, there were no differences in the absolute infarct mass or abnormal wall motion score. At 1 year of follow-up,
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there was a reduction in hospitalization for heart failure with thrombus aspiration (0.9 vs 5.4 % p = 0.008) but no significant difference in mortality. Large Multicenter Trials Powered for Clinical Outcomes The TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) trial was a registrybased study randomizing patients to thrombus aspiration and PCI or PCI alone (N = 7244) [21••, 22••]. The primary outcome of all-cause mortality at 30 days was not different (2.8 % thrombectomy vs 3.0 % PCI alone; HR 0.94, 95 % CI 0.72– 1.22, p = 0.63). At 1-year follow-up, there was no difference in all-cause mortality with a rate of 5.3 % in the aspiration thrombectomy arm compared to 5.6 % in the PCI only arm (p = 0.94). At 30 days, there was a trend toward reduction of rehospitalization due to reinfarction (HR 0.61, 95 % CI 0.34– 1.07, p = 0.09) and stent thrombosis (HR 0.47, 95 % CI 0.20– 1.02, p = 0.06) at 30 days. However, at 1 year there was no significant difference in reinfarction and stent thrombosis. The Fig. 1 a Meta-analysis for mortality outcome. b Metaanalysis for stroke outcome. (With permission for both figures from: Jolly SS, Cairns JA, Yusuf S, et al., Stroke in the TOTAL trial: a randomized trial of routine thrombectomy vs. percutaneous coronary intervention alone in ST elevation myocardial infarction, Eur Heart J, June 2015, by permission of Oxford University Press) [27••]
a
b
rate of stroke or neurologic complication during index hospitalization was 0.5 % in both arms (HR 1.06, 95 % CI 0.55– 2.02, p = 0.87). The TOTAL trial (N = 10,732) was an international, multicenter, randomized, event-driven trial and included important sub-studies using OCT and angiography [23••, 24]. The TOTAL trial randomized patients to routine manual thrombectomy versus PCI alone with bailout thrombectomy. Bailout thrombectomy was allowed if there was a failure of initial PCI alone strategy defined as occluded vessel (TIMI 0 or 1) after balloon dilatation or if there was a persistent large thrombus after stent deployment. Bailout thrombectomy occurred in 7.0 % in the PCI alone group. The primary outcome a composite of death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or NYHA class IV heart failure within 180 days occurred at 6.9 % in the aspiration thrombectomy group compared to 7.0 % in the PCI alone group (HR 0.99, 95 % CI 0.85–1.15, p = 0.86). The rate of recurrent myocardial infarction was similar (3.1 vs 3.5 %, p = 0.62). Likewise, there was
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no difference in the rate of stent thrombosis (1.5 vs 1.7 %, p = 0.42). The incidence of cardiovascular death at 180 days was 3.1 % in the aspiration thrombectomy arm compared to 3.5 % in the PCI alone arm (HR 0.90, 95 % CI 0.73–1.12, p = 0.34). The TOTAL trial angiographic sub-study showed no difference in myocardial blush grade but improvements in both distal embolization and ST segment resolution [25]. Of interest, TOTAL showed in a multivariable analysis that distal embolization was independent predictor of outcome but not blush grade. In a TOTAL OCT sub-study (N = 214), OCT was performed immediately after thrombectomy or PCI alone then it was repeated after stent deployment [26••]. A core lab performed blinded assessment of OCT data. The primary outcome of mean pre-stent thrombus burden as a percentage of segment analyzed was not different between routine aspiration thrombectomy and standard PCI (2.36 vs 2.88 %, p = 0.373). The mean absolute thrombus volume was also not different between groups (2.99 vs 3.74 mm3, p = 0.329). Likewise, the mean quadrants of thrombus were 26.88 in the thrombectomy group compared with 29.69 in the PCI-alone group (p = 0.488). Post-stent atherothrombotic burden and post-stent atherothrombotic volume were also not different between both groups. Stroke In the TOTAL trial, the primary safety outcome of stroke was adjudicated by neurologists blinded to group assignment. The incidence of stroke was 0.7 % (33/5033) in the aspiration thrombectomy arm compared to 0.3 % (16/5030) in the PCI alone group (HR 2.06, 95 % CI 1.13–3.75, p = 0.02) [27••]. Differences in stroke were present within 48 h and included differences in strokes with major disability or fatality. Stroke after primary PCI is associated with a poor prognosis with a mortality of 31 % compared to 3 % in those patients without a stroke.
recommend against the use of routine thrombus aspiration and recommend its use for selected cases to improve TIMI 3 flow or to prevent stent thrombosis [17]. These guideline recommendations predate the publication of the largest thrombectomy trial to date, the TOTAL trial. Meta-analysis of Randomized Trials After TASTE and TOTAL In an updated meta-analysis of randomized trials (N = 21,173), there was a borderline reduction in mortality associated with aspiration thrombectomy (OR 0.87, 95 % CI 0.76–1.00, p = 0.05, I2 = 0 %, Fig. 1a) [27••]. However, this result did not maintain statistical significance when a random-effect model was used (OR 0.88, 95 % CI 0.77–1.01, p = 0.07). Stroke occurred more frequently in the aspiration thrombectomy arm (0.8 %) compared to 0.5 % in the PCI alone arm (OR 1.59, 95 % CI 1.11–2.27, p = 0.01, I2 = 0 %, Fig. 1b). The rate of myocardial infarction occurred in 2.1 % in the aspiration thrombectomy group and 2.3 % in PCI alone group (OR 0.94, 95 % CI 0.78–1.13, p = 0.51, I2 = 0 %).
Conclusion and Recommendation Routine manual thrombectomy is not recommended based on the findings of increase in stroke. However, clinical judgment is still needed and aspiration thrombectomy should be used a bailout procedure as clinically indicated. Compliance with Ethical standards Conflict of Interest Aiman Alak declares that he has no conflict of interest. Sanjit S. Jolly reports grants from Medtronic. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
High Thrombus Burden Subgroup There was a clear hypothesis that patients higher thrombus burden may have a greater benefit from thrombus aspiration. Thrombus burden was assessed after wire crossing in TASTE and prior to wire crossing in TOTAL. Both the TASTE and TOTAL trials did not show a benefit for the primary outcome in patients with high thrombus burden [21••, 22••, 23••]. Current Guideline Recommendations The current American College of Cardiology/American Heart Association 2013 guidelines states that routine manual aspiration thrombectomy is considered reasonable to perform (class IIa, level of evidence B) [16] The European 2014 guidelines
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