Thrombolytics and Acute Limb Ischemia
Intra-arterial infusion of lytic agents provides an effective way to restore vessel patency.
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The acute occlusion of a peripheral artery is a medical emergency that first must be recognized and then treated accordingly. Acute limb ischemia is defined as any sudden decrease or worsening in limb perfusion that causes a threat to extremity mobility.1 Prompt diagnosis and rapid initiation of therapy are critical, as acute limb ischemia is not only a limb-threatening, but also a potentially life-threatening event.
For years, the gold standard treatment for patients presenting with acute limb ischemia was surgical revascularization. Because of the various comorbidities (typically cardiopulmonary disease) found in this patient group, however, in-hospital mortality following surgery had been found to exceed 20% in some series.2,3 These high mortality rates have prompted the investigation and subsequent widespread use of catheter-directed thrombolysis as an alternative form of therapy for patients presenting with acute limb ischemia.
Acute occlusion of a peripheral artery can be due to a multitude of causes. In situ thrombosis of a native artery or bypass graft is the most common cause, although emboli from either a cardiac source or a more central lesion or aneurysm are also common. Trauma, entrapment syndromes, and vasculitis are more rare causes. Regardless of the etiology, the typical presentation of a patient who has suffered an acute occlusion include the so-called ?5 P’s,? which are pain, pulselessness, pallor, paresthesias, and paralysis.
During the initial clinical assessment of a patient suspected of having acute limb ischemia, it is important not only to confirm the diagnosis, but also to attempt to determine the etiology. Frequently, but not always, patients with an in situ thrombosis will have noticed a progressive increase in their claudication symptoms prior to the acute event. Patients presenting with atrial fibrillation will likely have an embolic source for their symptoms.
Following physical examination, it is important to classify the severity of the ischemia. Patients with viable ischemia have limbs that are not immediately threatened. Their presentation is characterized by no sensory or motor deficits with audible Doppler arterial pulses. Patients with threatened limbs are further subclassified as having marginally or immediately threatened limbs. Although both categories of patients have usually lost arterial Doppler signals, it is the extent of the sensory and motor losses that distinguishes between these two categories. Marginally threatened patients have minimal sensory loss and no motor loss, whereas immediately threatened patients have a sensory loss that involves more than the toes, as well as a mild-to-moderate motor loss. Patients with irreversible ischemia have profound motor and sensory losses. With rare exception, revascularization of this patient group is contraindicated as reperfusion and can lead to multiorgan failure and quite possibly death.
A critical component in evaluating a patient with acute limb ischemia is the determination of risk factors for thrombolysis. A history of a recent stroke or TIA is an absolute contraindication to thrombolysis. Recent surgery, peptic ulcer disease, hematuria, and GI bleeding are relative contraindications to thrombolysis. A determination on whether or not to proceed with thrombolysis needs to be made on an individual basis when relative contraindications to lysis exist.
RATIONALE FOR LYSIS
To date, there have been three randomized, prospective trials that have established the efficacy of catheter-directed lysis when compared to surgery. In the Rochester Trial,4 Ouriel et al randomized 114 patients presenting with acute limb ischemia to receive either catheter directed thrombolysis with Urokinase (UK) (Abbott Laboratories, Abbott Park, IL) or surgery. 84% of the patients who received UK were alive at 1 year, whereas only 58% of the surgical patients were alive at 1 year. The difference in mortality was attributed to cardiopulmonary complications in the periprocedural period. The rate of limb salvage was the same in the two treatment groups (80%).
In the STILE trial,5 patients with acute limb ischemia were randomized into three treatment groups. Patients received either Alteplase (rt-PA, Genentech, San Francisco, CA), UK, or primary surgery. Three hundred ninety-three patients were eventually enrolled in the study. Within the 30-day follow-up period, death (4% lysis, 5% surgery) and amputation rates (5% lysis, 6% surgery) were nearly identical. Further analysis of the data showed that patients with acute occlusions had a lower rate of amputation when treated with thrombolytic drugs; those patients with more chronic disease had a lower amputation rate if treated by surgery. Although not statistically significant, at 6 months, the death rate was higher in the surgical group (10% vs 5.6%).
In the TOPAS trial6 funded by Abbott, 544 patients were randomized to a recombinant form of UK versus surgery. Within this study, patients with native artery occlusions that were treated with thrombolysis had a 1-year amputation-free survival of 61% as compared to 71% in the surgical group. Those patients with thrombosed bypass grafts had identical amputation-free 1-year survival at 68%. Death rates were higher in the surgical cohort (5% vs 0% in the thrombolytic group).
With the exception of the Rochester Trial, the results of the randomized trials failed to demonstrate a superiority of thrombolysis over surgery. However, it is important to note that in the STILE and TOPAS trials, thrombolysis was generally as equally efficacious as surgery. Moreover, it is critical to note that those patients who underwent thrombolysis were spared open surgery and the associated risks and recovery period. Therefore, in most centers, thrombolysis has become the treatment modality of choice in appropriately selected patients that present with acute limb ischemia.
BASIC MECHANISMS OF COAGULATION AND LYSIS
The mechanism of action for both thrombolytic agents is best understood within the context of the process of blood coagulation (hemostasis) and clot lysis (thrombolysis). This dynamic balance maintains normal blood flow in the vascular system. The coagulation cascade is a very complex series of steps and may be activated in two ways: (1) via the intrinsic pathway, stimulated by intravascular mechanical disturbances that disrupt laminar flow and induce platelet aggregation (ie, atherosclerotic plaque); or (2) via the extrinsic pathway, initiated by the intravascular chemical messengers released by injured tissues, (ie, thromboplastins or Factor III), such as in a state of prolonged muscle ischemia.
Ultimately, both routes lead to the conversion of prothrombin to thrombin, which catalyzes the conversion of fibrinogen (stimulated by fibrin stabilizing factor) to fibrin. Fibrin is the insoluble substance that forms the adhesive matrix of a clot. Along with other blood elements such as platelets, fibrin solidifies the thrombus formed within a vessel. The dynamic balance requires that, after hemostasis, the fibrinolytic pathway must also be activated to prevent the entire vascular system from thrombosing unchecked. Fibrinolysis maintains blood fluidity by dissolving the fibrin component of thrombus. The inactive enzyme precursor plasminogen is converted to plasmin, which is a powerful proteolytic enzyme. This step in the cascade is catalyzed by tissue plasminogen activator (tPA). tPA is a single-chain, glycosylated, serine protease and an endogenous plasminogen activator. It is secreted by human endothelial cells in response to arterial wall injury.
Plasmin has an affinity for multiple components of the coagulation cascade, such as factors V and VIII, prothrombin, fibrinogen, and others.7 Its principle substrate, however, is fibrin. Plasmin converts the insoluble fibrin content of thrombus into soluble, degradable fibrin monomers, or fibrin degradation products.
All clinically available thrombolytic agents are forms of plasminogen activators. That is, they do not directly degrade fibrin. Rather, these agents act to convert plasminogen to plasmin. It is this plasmin that degrades the fibrinogen to fibrin.
The first clinically available thrombolytic agent was streptokinase (SK). Its mechanism of action is different than that of the other thrombolytic agents. Unlike the other agents in which plasminogen is directly converted to plasmin, a molecule of SK must first bind with a molecule of plasmin or plasminogen to form an activated molecule. Once this is accomplished, this activated molecule then acts upon a second plasminogen molecule to form plasmin. Because SK is derived from the Streptococcus bacteria, it carries with it an antigenic potential. It is estimated that 2% of patients treated with SK develop some sort of an allergic reaction. Therefore, SK is in limited use today.
UK, which is produced in the human kidney, was first isolated from urine in 1946.8 Its thrombolytic properties were elucidated by Williams9 who, in 1951, identified it as an activator of plasminogen. Its great advantage over SK is that as a protein derived from humans, it is not antigenic. Although UK is only currently approved for treating pulmonary embolism, it was for years the de facto standard of treatment of acute limb ischemia. However, because of concerns about production standards, the FDA ordered Abbott to cease distribution in 1999. In October 2002, the issues were corrected to the satisfaction of the FDA, and UK was reintroduced to the marketplace.10,11
With the withdrawal of UK from the marketplace, peripheral interventionalists were forced explore alternative thrombolytic drugs. In large part, two drugs already approved for use in acute myocardial infarction were adopted for use in peripheral applications. Although there had been some earlier studies using Activase in peripheral trials (the STILE trial), little was known about the proper dosing of this or Reteplase, a new drug for peripheral applications. Following some evaluation with different dosing regimens, clinical success with bleeding complication rates near that of UK were observed.12,13 In addition, there are now some early reports of clinical success using Tenecteplase (TNK, Genentech) in the periphery.
THROMBOLYTIC AGENT PROPERTIES
Although a complete overview of the properties unique to each thrombolytic agent is beyond the scope of this review, it is important to address some of the characteristics of the various thrombolytic drugs. Fibrin specificity is defined as the ability of the plasminogen activators to distinguish between circulating and bound plasminogen. SK has the lowest fibrin specificity, whereas TNK has the highest.
Given the ability of high-fibrin-specific thrombolytic drugs to bind to bound plasminogen, it would seem to follow that those drugs with higher fibrin specificity would have a lower bleeding rate as they are directed only against thrombus. However, large series such as the GUSTO I trial14 have shown this to not be the case. In GUSTO I, 41,021 patients with acute MI were given either SK or rt-PA. Major bleeding rates were the same at 0.4%, and the incidence of intracranial hemorrhage was slightly higher in the rt-PA group (0.7% vs 0.5%). Clearly, other factors beyond fibrin specificity must be at work as SK has low fibrin specificity and rt-PA has high specificity. One theory is that the body has a number of “protective hemostatic plugs” that prevent spontaneous bleeding. These protective plugs are then subject to the fibrin-specific agents that act upon the bound plasminogen in the plugs. An alternative theory is that in the process of fibrin degradation, the different classes of thrombolytic drugs result in different fibrin degradation products. These byproducts can then cause a systemic lytic state that can lead to remote bleeding complications. Factor X is one of these degradation products that have been identified that can potentially induce a systemic lytic state.15
To date, there have been little data comparing the various lytic agents in the same patient population. Mahler et al16 has conducted a trial comparing UK to rt-PA. In this study, bleeding complications were nearly equal (12.8% rt-PA vs 9.1% UK). Because of a relative paucity of data, decisions to use one thrombolytic drug over another are based on more personal experience. Certainly, many peripheral interventionalists have strong beliefs that one drug is more efficacious and safe than the other; however, these beliefs have yet to be proven in any definitive scientific manner.
Through various trials and individual reports, the use of thrombolytic drugs has gained widespread acceptance as the treatment of choice for appropriately selected patients with acute limb ischemia. The temporary removal of UK from the market led many investigators to explore the use of Alteplase, Reteplase, and even TNK in the periphery. This experience has shown that all of these agents are at least as effective as UK in treating patients with acute thrombosis. The use of these agents, however, has lead to bleeding rates that are at least as high as those encountered with UK. Although the future may hold an ideal thrombolytic agent that will not result in bleeding complications, much work has yet to be done with the agents that exist today. A randomized trial comparing the all of the various agents currently available will likely never be performed, but additional work experimenting with different dosing rates and regimens such as bolus administration may yield results that equal or exceed those seen today with a lower rate of bleeding complications. Adjunctive therapy with the various mechanical thrombectomy devices available today may also yield similarly impressive results. Again, much of the work has yet to be done.
Alex Powell, MD, is a staff interventional radiologist at the Miami Cardiac and Vascular Institute in Miami, Florida. He is also a voluntary assistant professor of radiology at the University of Miami School of Medicine. Dr. Powell has previously been compensated by Abbott Laboratories for delivering lectures. He may be reached at (305) 598-5990; AxPowell@yahoo.com.
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