Anticoagulant and Lytic Therapy for Arterial Thromboembolism in Extremities



Anticoagulant and Lytic Therapy for Arterial Thromboembolism in Extremities



Lina Vargas and Timur P. Sarac


Acute limb ischemia and thromboembolic events continue to remain a challenge to vascular surgeons. Pharmacologic thrombolysis and, more recently, percutaneous mechanical thrombectomy have proved to hold great potential in this regard. Both techniques can effectively clear peripheral arteries from occluding thrombus in a minimally invasive fashion, restore blood flow to the affected extremity, and facilitate identification of any underlying lesion potentially responsible for the occlusive event. The unmasked culprit lesion can then be addressed in a directed fashion with angioplasty, stenting, or a limited operative procedure performed electively in a medically optimized patient.



Perioperative Management


A complete history and thorough physical examination is the most important aspect of the evaluation of patients with acute limb ischemia. Specific details from the history can suggest the etiology of the process: If a patient has a history of arrhythmias, a central source of embolism should be suspected; on the other hand, if the patient has a history of previous bypass grafting, thrombosis should be suspected. Aggressive fluid resuscitation has been proved to be of paramount importance for long-term survival. Once the initial assessment has been completed and a sense of urgency has been determined, an arteriogram could be performed if it is expected that it will significantly affect the planning of the procedure and that any delays will not adversely affect the outcome of the jeopardized extremity.


Immediate anticoagulation with 100 U/kg of heparin and institution of a heparin drip at 20 U/kg per hour can prevent propagation of the thrombus. Several other anticoagulants are also clinically available in the event antibodies or resistance to heparin is suspected. Bivalirudin has been the most extensively studied and is the easiest to use with regard to therapeutic levels. Laboratory tests have little to offer in terms of preoperative diagnosis, but electrolyte and acid–base abnormalities are common and should be corrected before reperfusion. After finishing the intervention that restores blood flow to an ischemic limb, it is crucial to consider the potential deleterious effects of reperfusion and edema that could potentially create further damage and impair inflow to the affected limb. In this situation, a fasciotomy should be performed without hesitation.



Thrombolysis and Results


In the 1970s Dotter proposed the use of local catheter–directed thrombolytic therapy to avoid systemic effects of these agents and to achieve a stronger and quicker effect. In the 1980s, McNamara developed a protocol of graded intraarterial urokinase administration. Modifications of that protocol set the standard for therapy. The validation of the safety and efficacy of thrombolysis in acute limb ischemia came from the completion of prospective randomized trials comparing it to open surgical intervention. However, to date there is not a drug approved for use in the United States for pharmacologic thrombolysis for acute lower extremity ischemia, and the drugs available are used off-label.




Outcome Studies of Thrombolysis versus Primary Operation


Three multicenter randomized trials were published in the 1990s comparing thrombolysis with open surgery for arterial occlusion (Table 1).



The Rochester Study compared urokinase to immediate operation in patients with acute peripheral arterial occlusion with an endpoint of amputation-free survival. Patients were randomly assigned to thrombolysis with urokinase (n = 57) or to immediate operation (n = 57). At 1 year, the amputation-free survival rates were 75% and 52% respectively, a statistically significant difference. Closer analysis revealed this finding to be the result of a higher rate of cardiopulmonary deaths in the operative group, which supported the suspicion that stressing these critically ill patients with a surgical insult without time to optimize their medical condition more often than not led to the patient’s death. Early thrombolysis improved limb perfusion enough to maintain limb viability while allowing enough time to medically optimize the patient’s overall status.


The STILE (Surgery versus Thrombolysis for Ischemia of the Lower Extremity) study was a large (394 patients) multicenter randomized prospective trial that compared outcomes between patients undergoing immediate surgery versus thrombolysis with one of two thrombolytic agents—recombinant tissue plasminogen activator (rt-PA) or urokinase (UK)—in patients with arterial occlusion of less than 180 days’ duration. The primary endpoint was a composite outcome that included ongoing or recurrent ischemia, death or major amputation, life-threatening hemorrhage, and a variety of perioperative complications. Amputation and mortality were not primary endpoints.


The clinical outcomes among both thrombolysis groups were very similar; therefore, their data were combined for comparison to surgery. Post hoc stratification of patients into two subgroups on the basis of the duration of symptoms before enrollment (>14 days vs. <14 days) revealed that among patients with symptoms of longer duration, the surgical group had lower amputation rates than the thrombolysis group at 6 months (3% vs. 12%, p = .01). In contrast, among patients with symptoms of shorter duration, patients assigned to thrombolysis had lower amputation rates than surgical patients (11% vs. 30%, p = .02). Nevertheless, some pitfalls of STILE were that patients were randomized before attempting to place the infusion catheter into the thrombus, and appropriate thrombus cannulation was not possible in 28% of patients in the thrombolytic group. Also, successful catheter placement was not possible in 39% of patients with bypass graft occlusion.


The Thrombolysis or Peripheral Arterial Surgery trial (TOPAS) was the third study. It was designed based on the analysis of the results obtained from the Rochester trial. In TOPAS, 757 patients with lower extremity occlusion (native artery or bypass graft) of 14 days’ duration or less were randomized to be treated with recombinant urokinase (r-UK) versus primary surgery. Amputation-free survival rates 6 months after randomization (Phase II) were 71.8% in the r-UK and 74.8% in the operative group (p = .43; 95% confidence interval [CI] for the difference between treatments, −10.5–4.5). There was also no significant difference in the rates of amputation-free survival at discharge from the hospital or in the rate of mortality at the time of discharge. At the end of 6 months, open surgical procedures were avoided in 31.5% of the patients undergoing thrombolysis. Intraarterial r-UK thrombolysis achieved a similar rate of amputation-free survival, with a lower requirement for open surgical procedures when compared with primary operation. In patients assigned to thrombolysis, those with occlusions in bypass grafts had better clinical outcomes and rates of clot dissolution, concurrent with lower rates of hemorrhagic complications compared to patients with native artery occlusions. Major hemorrhagic complications occurred in 12.5% in the r-UK group, compared with 5.5% in the surgery group (p = .005). The risk of bleeding was significantly greater when therapeutic heparin was used compared to when it was not (p = .02).

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Aug 25, 2016 | Posted by in CARDIOLOGY | Comments Off on Anticoagulant and Lytic Therapy for Arterial Thromboembolism in Extremities

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