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). The patients were included in the study if they were ≥18 years, had 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 either on the baseline coronary angiogram or after wiring. The exclusion criteria were 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 m ² ; 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/mm ³ ; and hemoglobin level <10 g/dl. The study was conducted in accordance with the Declaration of Helsinki and was approved by our institutional board review committee. All eligible patients provided written informed consent. The DISSOLUTION trial was registered at ClinicalTrials.gov (identifier no. NCT01568931 ).

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. The enrolling research coordinator (C.G.) and investigators performing the index procedures (F.P., G.T., M.S.) were aware of the study assignments. The patients and all other study personnel, including the cardiac pathologists and core laboratory technicians, were unaware of the randomized treatment.

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 (Vasco+10, 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 or 250 to 500 mg intravenously, 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. As a part of our hospital protocol, 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. Other medications were given as appropriate.

Quantitative analysis of the coronary angiograms obtained before and after PCI was independently performed by the core laboratory (Ricerche Orientate alla Malattia Aterosclerotica, Rome, Italy). The operators who performed the evaluation were unaware of the study protocol, patient characteristics, and the treatments used. 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 by an investigator (M.S.) who was unaware of all other patient and investigational data. 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.

Pathologic examination of the aspirated thrombotic material was performed in the first 25 consecutive patients. The retrieved material was fixed in formalin immediately after thrombus aspiration and brought to the cardiovascular pathology department. After fixation for 24 hours, the material was embedded in paraffin and processed for histologic examination. Serial 5-mm sections were cut and stained with hematoxylin and eosin and elastic von Gieson. The cardiovascular pathologist (P.G.) who performed the histopathologic analyses was unaware of all clinical and angiographic data. The aspirated material allowed definition of the thrombus characteristics and age. The thrombi were classified as fresh or old, as previously reported. Fresh thrombi are characterized by a layered pattern of granulocytes, platelets, and erythrocytes amid fibrin. Older thrombi, in contrast, show lytic areas (i.e., areas of colliquation necrosis and karyorrhexis of granulocytes) and/or organized areas (i.e., areas characterized by ingrowth of smooth muscle cells, with or without depositions of connective tissue).

The data are presented as the mean ± SD for continuous variables or frequency percentages for categorical variables. The chi-square test or Fisher exact test, when appropriate, was used to compare the differences between the categorical variables. All analyses were performed using the S-Plus Statistical Package (Mathsoft, Seattle, Washington). A 2-sided p value <0.05 was considered statistically significant.

Results

Of a 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). The baseline characteristics of the 2 randomized groups were well matched, with no significant differences in the prevalence of risk factors, clinical presentation, or angiographic findings at arrival ( Table 1 ). No study patient had angiographic evidence of bypass graft occlusion. The procedural data were similar in the 2 groups, with no differences in infarct-related artery stenosis characteristics, stents implanted, and occurrence of no-reflow with TIMI grade flow 0 to 1 ( Table 2 ). 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 = 0.318) and peak troponin I (59 ± 44 vs 73 ± 41 μg/L, p = 0.999). Also, echocardiography on day 3 showed no difference in the left ventricular ejection fraction (51 ± 12% vs 49 ± 10%, p = 0.363) or wall motion score index (1.81 ± 0.36 vs 1.60 ± 0.49, p = 0.907) between the 2 groups.

During the 6-month follow-up period, similar proportions of groups A and B received β blockers (84% vs 80%, p = 0.795), angiotensin-converting enzyme inhibitors (61% vs 66%, p = 0.680), angiotensin receptor blockers (33% vs 29%, p = 0.831), and calcium antagonists (22% vs 18%, p = 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 = 0.098) and lower wall motion score index (1.76 ± 0.44 vs 1.91 ± 0.39; p = 0.071) than group B.

Table 3

Clinical end points at 6 months for randomized groups

Variable	Thrombolysis and Aspiration (n = 51)	Aspiration Only (n = 51)	p Value
Major adverse cardiac and cerebrovascular events	4 (8)	4 (8)	0.713
Major adverse cardiac events	3 (6)	11 (21)	0.044
Death	1 (2)	2 (4)	0.999
Myocardial infarction	1 (2)	1 (2)	0.475
New-onset severe heart failure	1 (2)	2 (4)	0.999
Rehospitalization for heart failure	0	6 (12)	0.035
Stroke	1 (2)	0	1.000
Clinically driven target vessel revascularization	1 (2)	1 (2)	0.475
Stent thrombosis, definite or probable	1 (2)	0	1.000

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