Usefulness of Local Delivery of Thrombolytics Before Thrombectomy in Patients With ST-Segment ElevationMyocardial

Infarction Undergoing Primary Percutaneous Coronary Intervention.

(The Delivery of Thrombolytics Before Thrombectomy in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention [DISSOLUTION]

Randomized Trial)

Cesare Greco, MD, Francesco Pelliccia, MD, Gaetano Tanzilli, MD, Maria Denitza Tinti, MD,

Paola Salenzi, MD

Am J Cardiol 2013;112:630e635

Introduction • Thrombus aspiration during percutaneous coronary

intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) is said to reduce PCI-induced distal occlusion.

• In an attempt to enhance its effectiveness, thrombus aspiration is often coupled with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors, although conflicting results with this strategy have been reported.

• GP IIb/IIIa antagonists inhibit the final common pathway that leads to platelet aggregation and leukocyte plugging, which are the main components of fresh thrombi.

• However, they are unable to modify the morphologic characteristics of older thrombi (i.e., lytic changes and organization), which are found in nearly 50% of patients with STEMI.

• Fibrinolytic agents, in contrast, can weaken the structure of older thrombi and therefore have the potential to facilitate manual aspiration

• Accordingly, we designed the DISSOLUTION trial, a prospective, randomized, single-blind trial, to evaluate the hypothesis that intrathrombus delivery of thrombolysis before manual thrombectomy can enhance the efficacy of thrombus aspiration in primary PCI.

Methods

• All consecutive patients within the first 12 hours of STEMI undergoing primary PCI were evaluated for the trial during a 3-year period (from July 2009 to June 2012).

• Inclusion criteria – Age ≥18 years, – had symptoms consistent with STEMI for >30 minutes, – showed 1 mm of ST-segment elevation in 2 contiguous leads

or new left bundle branch block, and – had evidence of totally occlusive thrombosis in the culprit

artery

• Exclusion criteria – unfavorable coronary anatomic patterns (i.e., presence of

tortuous calcified tracts that affect mechanical aspiration); – contraindications to study medications or contrast; – planned surgery necessitating antiplatelet agent

interruption; – a known creatinine clearance of <30 ml/min/1.73 m2;

dialysis; – recent major bleeding; bleeding diathesis or current

warfarin use; – a history of intracranial disease, ischemic stroke, or

transient ischemic attack within 6 months; – platelet count <100,000 or >700,000 cells/mm3; and

hemoglobin level <10 g/dl.

• The DISSOLUTION trial was an open-label, prospective, randomized, single-blind evaluation of intrathrombus thrombolysis before manual aspiration thrombectomy in patients undergoing primary PCI for STEMI.

• The study patients were randomized to 1 of 2 groups: – Group A, intrathrombus administration of urokinase

(200,000 IU in 10 ml within 5 minutes) followed by manual thrombus aspiration, or

– Group B, intrathrombus administration of saline (10 ml within 5 minutes) followed by manual thrombus aspiration.

• Primary PCI of the infarct-related artery was performed through the femoral access route.

• The study drugs were infused directly into the thrombus using a 1.9F infusion microcatheter (Vascoþ10, Balt Extrusion, Montmorency, France), which was embedded in the thrombus using imaging guidance.

• Manual aspiration thrombectomy was performed 5 minutes after urokinase infusion with the Pronto System (Vascular Solutions, Minneapolis, Minnesota).

• The protocol specified active aspiration whenever the lesion was crossed or the catheter was withdrawn, making several passes until no additional thrombus or debris was retrieved.

• The aspirated blood and intracoronary material were collected in the collection bottle provided with a filter with the device.

• After thrombectomy, PCI was performed using standard techniques, with bare metal or drug-eluting stent implantation at the operator’s discretion.

• No distal protection system was used in any patient.

• All patients without contraindications were pretreated with aspirin, 324 mg orally and clopidogrel (loading dose of 600 mg).

• The patients received procedural anticoagulation with weight-adjusted doses (100 U/kg) of unfractionated heparin.

• During PCI, additional doses of unfractionated heparin were given to achieve and maintain an activated clotting time >300 seconds.

• All patients were given aspirin 100 mg/day and clopidogrel 75 mg/day for 12 months after PCI, regardless of whether they had received a bare metal stent or drug-eluting stent at primary PCI.

• The Thrombolysis In Myocardial Infarction (TIMI) flow grades, frame counts, and myocardial blush grades were measured according to the original definitions.

• A patient was considered to have angiographic evidence of total thrombotic occlusion if TIMI thrombus grade 5 was present.

• The baseline and post-PCI electrocardiograms were analyzed ,Single-lead ST-segment resolution was measured by comparing the most prominent ST-segment deviation before coronary angiography and after PCI.

• During the hospital stay, the patients underwent serial assessment of the serum biomarkers and echocardiography on day 3.

• . • Follow-up visits were scheduled at 6 months and

included clinical evaluation and repeat echocardiography.

• Major adverse cardiac and cerebrovascular events included all-cause death, stroke, myocardial infarction, and any repeat revascularization.

• Major adverse cardiac events were defined as death, reinfarction, new-onset severe heart failure, and rehospitalization for heart failure.

Results

• Total of 102 patients with STEMI who were included in the trial (70 men and 30 women, mean age 60 ±17 years),

• 51 were randomized to receive intrathrombus urokinase followed by manual thrombus aspiration (group A) and 51 patients received intrathrombus saline followed by manual thrombus aspiration (group B).

• No difference in the use of drugs was seen between the 2 groups at primary PCI.

• Specifically, 3 patients in group A and 1 in group B had received intracoronary nitroprusside.

• Also, 2 patients in group A and 2 in group B had received intracoronary verapamil.

• After PCI, a significantly greater proportion of group A than group B patients had TIMI grade 3 flow, a TIMI myocardial blush grade of 2 or 3, and complete ST-segment resolution at 60 minutes.

• Also, group A had a lower post-PCI corrected TIMI frame count.

• In contrast, no patient had evidence of coronary dissection. • During the post-PCI hospital stay, neither significant bleeding

complications nor pericardial effusions were detected. • No significant differences in infarct size between the 2 groups

were seen. • Also, the serial assessment of serum biomarkers did not show

any difference between groups A and B in peak creatine kinase-MB (165 ±145 vs 194 ± 166 IU/L, p ¼ 0.318) and peak troponin I (59 ± 44 vs 73 ± 41 umg/L, p ¼ 0.999).

• Also, echocardiography on day 3 showed no difference in the left ventricular ejection fraction (51 ± 12% vs 49 ± 10%, p ¼ 0.363) or wall motion score index (1.81 ± 0.36 vs 1.60 ± 0.49, p ¼ 0.907) between the 2 groups.

• During the 6-month follow-up period, similar proportions of groups A and B received b blockers (84% vs 80%, p ¼ 0.795), angiotensin-converting enzyme inhibitors (61% vs 66%, p ¼ 0.680), angiotensin receptor blockers (33% vs 29%, p ¼ 0.831), and calcium antagonists (22% vs 18%, p ¼ 0.803).

• During the follow-up period, no significant differences in total major adverse cardiac and cerebrovascular events were detected between the 2 randomized groups (Table 3).

• An analysis of individual clinical safety or efficacy end points showed that rehospitalization for heart failure occurred in 6 patients in group B during the 6-month period, for a significant difference in total major adverse cardiac events between the 2 groups.

• Follow-up echocardiography showed that group A tended to have a higher left ventricular ejection fraction (57 ± 13% vs 52 ± 17%, p ¼ 0.098) and lower wall motion score index (1.76 ±0.44 vs 1.91 ± 0.39; p ¼ 0.071) than group B.

• Gross pathologic examination disclosed that the amount of aspirated thrombotic material was greater in group A than in group B (4 ± 3 vs 2 ± 1 mm3, p ¼ 0.049).

• Histologic features of aspirated material – fresh thrombus (<1 day old) were found in 50% of the cases (6 in group A

and 5 in group B).– In 36% of patients (4 in group A and 4 in group B), the thrombus showed

lytic or organized changes compatible with an origin of days before the onset of STEMI symptoms.

– In 1 patient in group A and 2 in group B, the thrombus showed combined features of both fresh and older thrombi.

• Intrathrombus administration of urokinase was associated with the finding of large, regularly shaped, and optically empty, noneneutrophil-associated vacuoles (Figure 1).

• These vacuoles were found in 7 of 11 patients in group A and in no patients in group B (Figure 2); thus, they appeared to be the histologic counterpart of thrombolysis induced enzymatic digestion.

Discussion

• The principal findings from the present prospective, randomized trial of patients presenting with STEMI and undergoing primary PCI was that a strategy of intrathrombus urokinase delivery can enhance the effects of subsequent manual thrombus aspiration, because it improves the postprocedural indexes of myocardial perfusion compared with standard thrombectomy.

• These results should be placed in the context of previous studies comparing different mechanical strategies of reperfusion (thrombus aspiration vs no aspiration), different pharmacologic agents (thrombolytics vs GP IIB/IIIa inhibitors), and different routes of drug administration (local or intrathrombus delivery vs intracoronary infusion).

• Trials of manual aspiration thrombectomy have reported conflicting results and, in contrast to single-center studies, multicenter aspiration trials have largely reported negative results.

• In the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS), a trial that randomized 1,071 patients with STEMI to manual aspiration versus no aspiration before primary PCI, thrombectomy resulted in modest improvements in the TIMI myocardial blush grades and ST-segment resolution and a marked reduction in 1-year mortality.

• In subsequent investigations, such as the recent INFUSE-AMI trial, however, manual thrombus aspiration did not reduce the infarct size, making a substantial clinical benefit unlikely and questioning its routine use in STEMI.

• Similarly, it remains unclear whether the combination of abciximab with subsequent thrombectomy will be associated with improved efficacy.

• The recent INFUSE-AMI trial was designed to maximize the likelihood that a reduction in infarct size could be demonstrated with intracoronary abciximab or aspiration thrombectomy, or both.

• The results of that trial showed that the 30-day infarct size was significantly reduced when intracoronary abciximab preceded manual aspiration thrombectomy.

• Prati et al investigated whether local abciximab delivery to the site of intracoronary thrombus would be more effective than intracoronary bolus infusion in patients with acute coronary syndromes undergoing PCI and demonstrated that a local delivery route using a dedicated perfusion catheter would reduce the thrombus burden with the potential to improve the coronary microcirculation.

• Similar findings have recently been obtained in the INFUSE-AMI trial, indicating that local drug delivery can directly achieve high intraclot concentrations of drugs at the site of coronary artery occlusion compared with the standard intracoronary approach.

• The results of the present pilot trial have shown that intrathrombus delivery of thrombolysis can be an alternative strategy to achieve effective thrombus aspiration during primary PCI.

• The pathophysiologic background of this strategy lies in the histologic demonstration that thrombotic material at the site of a coronary artery occlusion is often characterized by lytic and organized areas rather than only layered patterns of fibrin and intact platelets, erythrocytes, and granulocytes.

• These observations make questionable the utility of GP IIb/IIIa antagonists, whose primary mechanism of action is inhibition of the final common pathway that leads to platelet aggregation and leukocyte plugging.

• A recent study has demonstrated that the occurrence of a distal filling defect with no reflow during thrombus aspiration is caused by embolization of larger thrombi with an erythrocyte-rich component.

• These pathologic substrates might respond to a fibrinolytic agent but not to GP IIb/IIIa inhibitors.

• Pioneering studies in the 1990s demonstrated the efficacy of urokinase therapy administered by local drug delivery catheters with conventional urokinase infusion techniques in dissolving intraluminal clot and intramurally depositing drug at the site of the arterial injury.

• Local delivery of urokinase using catheter-based techniques resulted in more complete lysis of intraluminal thrombus compared with conventional urokinase infusion techniques.

• Mechanical deformation of thrombus, possibly resulting from an increase in the surface area available for thrombolysis and the physical disruption of clot, could be an important component of the mechanism of site-specific thrombolysis.

• Local delivery techniques can also deposit significant amounts of urokinase at balloon angioplasty sites, creating an intramural reservoir of drug that might result in prolonged local thrombolysis.

• These earlier results, along with the present findings, have indicated that the higher concentration of the thrombolytic agent at the thrombus site might weaken the structure of thrombotic material, making mechanical removal of the thrombus more effective and reducing distal embolization.

• Our study had several limitations. • The trial was a single blind study, with the operator

knowing the randomization ssignment. • Although some bias could not be excluded, the

patients and follow-up personnel were unaware of the treatments provided, just as were those who performed the evaluations at the core laboratories and the physicians who recorded the clinical events.

• Another limitation was that the assessment of infarct sizes was determined by the serial assessment of serum biomarkers rather than late gadolinium enhancement on cardiovascular magnetic resonance imaging.

• study included a relatively small number of patients; therefore, our findings should basically be considered hypothesis generating.

• Larger trials are required to determine whether the favorable effects in some clinical outcomes at 6 months achieved with intrathrombus urokinase plus thrombectomy might translate into improved longer term clinical outcomes.

• Similarly, no conclusions about safety can be derived at present. One should consider, however, that urokinase was chosen for our study, because the safety of its intracoronary use has already been proved.

• In contrast, the safety of the newer fibrinolytic agents, reteplase or tenecteplase, remains questionable when coupled with angiographic procedures