Efficacy and safety of alfimeprase in patients with acute peripheral arterial occlusion (PAO).
OBJECTIVE
To investigate the safety and effectiveness of a novel thrombolytic, alfimeprase, in catheter-directed thrombolysis (CDT) of acute peripheral arterial occlusions (PAO).


METHODS
Between April 2005 and March 2007, patients with acute PAO (Rutherford class I or IIa) of a lower extremity and onset of symptoms within 14 days prior to randomization were included. Studies HA004 and HA007 enrolled respectively 300 and 102 patients. Both studies HA004 and HA007 were placebo-controlled. HA004 had two placebo arms, intrathrombus and perithrombus, while HA007 had intrathrombus placebo arm. HA004 was partially double-blind (perithrombus group was not blinded) and HA007 was double-blind. Patients were randomized to intrathrombus alfimeprase (0.3 mg/kg), intrathrombus (IT) placebo, or perithrombus (PT) placebo (HA004 only) in two divided weight-based infusions 2 hours apart. Depending on arteriographic results after treatment, patients received no further intervention or underwent endovascular therapy or open vascular surgery. The primary endpoint of both studies was efficacy of alfimeprase compared with placebo as measured by avoidance of an open vascular surgery procedure at 30 days.


RESULTS
The avoidance of open vascular surgery at 30 days was seen in 52 (34.9%), 42 (37.2%), and 7 patients (18.4%) with alfimeprase, IT placebo, and PT placebo in HA004 and 15 (29.4%) and 9 patients (17.6%) with alfimeprase and IT placebo in HA007; differences between alfimeprase and IT placebo were not statistically significant. Results were similar for secondary endpoints, including arterial flow restoration in 4 hours, 30-day ankle-brachial index, index limb pain severity, and hospital stay duration. The overall rate of adverse events was higher with alfimeprase than placebo. Hemorrhagic and peripheral embolic event rates with alfimeprase were 23% (34 patients) and 10.1% (15 patients) in HA004 and 9.4% (5 patients) and 9.8% (5 patients) in HA007; rates with IT placebo were 11% (12 patients, P = .107) and 5% (5 patients, P = .148) in HA004 and 10% (5 patients, P = .982) and 0% in HA007 (P = .07). No deaths were related to study drug administration.


CONCLUSIONS
CDT for acute PAO with alfimeprase was as safe as placebo. However, alfimeprase was no more effective than placebo in increasing 30-day surgery-free survival. The surprising effectiveness of placebo alone demonstrates that the inclusion of a placebo arm is essential to the design of future lytic trials.
Han
Sukgu M
SM
Division of Vascular Surgery and Endovascular Therapy, CardioVascular Thoracic Institute, University of Southern California, Los Angeles, CA 90033, USA.
Weaver
Fred A
FA
Comerota
Anthony J
AJ
Perler
Bruce A
BA
Joing
Mark
M
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000842:Ankle / Q000098:blood supply; D001157:Arterial Occlusive Diseases / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D001794:Blood Pressure; D001916:Brachial Artery / Q000503:physiopathology; D002406:Catheterization, Peripheral; D004311:Double-Blind Method; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D006083:Graft Occlusion, Vascular / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D006801:Humans; D007261:Infusions, Intra-Arterial; D007383:Intermittent Claudication / Q000209:etiology; D007902:Length of Stay; D008297:Male; D008666:Metalloendopeptidases / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D016017:Odds Ratio; D010147:Pain Measurement; D015990:Placebo Effect; D020551:Pulse Therapy, Drug; D011859:Radiography; D012039:Regional Blood Flow; D018570:Risk Assessment; D015912:Thrombolytic Therapy / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014656:Vascular Surgical Procedures; D055815:Young Adult
D005343:Fibrinolytic Agents; D008666:Metalloendopeptidases; C436755:alfimeprase