Revascularization Procedures

It is often possible to revascularize an organ or limb using intravascular thrombolytic therapy (i.e., Urokinase) and/or mechanical revascularization devices such as dilators, balloons, extraction catheters, lasers, atherectomy devices and vascular stents. These procedures are done commonly in both the peripheral and visceral arteries, and in the peripheral and central veins of the upper extremities. Thrombolytic therapy, balloon angioplasty, and vascular stenting are the most important of these procedures in current practice.

Thrombolytic Therapy

The advent of modern thrombolytic therapy has had a dramatic impact on the treatment of acute vascular thrombosis. Over the last decade, thrombolytic techniques have evolved, and indications have expanded to now include acute and chronic arterial thromboses, arterial grafts, hemodialysis fistulas and grafts, acute and chronic central venous thromboses, and some peripheral venous thromboses. Streptokinase (SK), tissue plasminogen activator (TPA), and urokinase (UK) are the 3 thrombolytic agents currently available. Of these, UK has been the most useful agent in peripheral vascular work.

TPA is the newest, and most expensive agent to become available for treating acute arterial thrombosis. This agent is produced by recombinant DNA technology. The hope that TPA would have greater clot specificity and less potential for producing systemic lytic effects has not been borne out in clinical trials. In fact, hemorrhagic complications with TPA have been more frequent and significantly more severe than those seen with UK. In one comparison of TPA versus UK for peripheral arterial occlusion, TPA demonstrated faster clot lysis and a higher incidence lysis. However, patients receiving TPA had a 2% incidence of intracranial hemorrhage. By comparison, intracranial bleeding did not occur in over 1000 similar uses of UK.

SK was the first thrombolytic agent to be used clinically. The early work was with systemic infusions given for thrombotic and thromboembolic peripheral arterial occlusions. Although clot lysis was successful in 20-50% of patients, hemorrhagic complications were unacceptably high. In an attempt to improve results and reduce complications, investigators began exploring the efficacy of local intraarterial infusions. The first local intraarterial infusions of SK were reported by McNicol in 1963. Dotter described the angiographic technique of SK infusion in 1974. Katzen and van Breda reported an exceptionally high success rate (11/12 acute or recent arterial thromboembolic occlusions) in 1981, using "intermediate dose" (i.e., 5000 units per hour) SK given by local intraarterial infusion. Use of SK decreased significantly when UK became widely available. There are currently a number of SK derivatives under investigation.

UK was isolated from human urine and shown to have thrombolytic activity in 1946. Although most reports considered UK safer and more effective than SK, the cost of recovering the enzyme from urine was prohibitively high. UK did not see widespread use until methods evolved for obtaining the enzyme from fetal kidney cell cultures. In 1985, McNamara and Fischer reported their experience with intraarterial UK in a series of 85 patients. This was followed by numerous reports of successful thrombolysis in arterial and bypass graft occlusions using UK.

UK differs from SK in several respects. First, since UK is a human product there are no antibodies to cause inactivation or allergic reactions. Consequently, no loading dose is necessary. In contrast, SK is derived from group c beta hemolytic streptococci. Since exposure to this bacteria is common, many patients will have high titers of neutralizing antibodies. The antigenicity of SK occasionally produces febrile reactions and serum sickness. Anaphylaxis has been reported but severe reactions are relatively rare. UK activates plasminogen directly. In contrast, SK must first bind with plasminogen. This SK-plasminogen complex then binds with another plasminogen molecule to produce plasmin. SK is thus less efficient than UK in forming plasmin, and it has a much greater potential for plasminogen depletion. The SK-plasminogen complex appears to be a stronger plasminogen activator than UK. Therefore, fibrinogen degradation is also greater during SK infusion. UK has a distinct peak of activity with a half life of 14-20 min. SK has a bimodal activity peak. The early peak has a half life of 16 min. and the later peak a half life of 83 min. The cost of UK is roughly 6 to 10 times that of SK. Nevertheless, because of its greater efficacy and safety, UK is the preferred agent among interventional radiologists.

Catheter directed thrombolysis uses direct intrathrombus infusion of the lytic agent. With this technique, the frequency of significant bleeding complications is very low (5-10%) and successful clot lysis occurs in 85-95% of patients with acute thrombosis. Selection of appropriate patients for thrombolytic therapy is of critical importance. Patients who have had recent intracranial or spinal surgery, recent stroke, metastatic disease in the brain, or active GI bleeding are not considered for thrombolytic therapy. The absolute and relative contraindications for thrombolytic are shown in Table 3.

Acute arterial thromboses that have progressed to anesthesia or motor deficits in the affected limb require immediate surgical revascularization. Therefore, the decision to proceed with arterial thrombolysis is made jointly by the interventional radiologist and the referring or consulting vascular surgeon. Patients receiving intraarterial thrombolytic therapy require monitoring in an intensive care setting. Because of the risk of bleeding, frequent observation of vital signs, puncture sites, and sensorium is required in addition to testing all urine, emesis and stool for blood. The treated extremity must be evaluated frequently for loss of neurological function, loss of previously present pulses, or swelling that could result in a compartment syndrome. Lytic therapy frequently gives rise to showers of thromboemboli that produce a marked increase in pain. Appropriate analgesics including morphine or Demerol should be ordered PRN. Emboli which occur during therapy generally will lyse within an hour or two. Any change in sensorium or level of consciousness requires immediate discontinuation of therapy and a CT examination of the head. Significant GI bleeding will be obvious. Hypotension with tachycardia and no obvious source of bleeding should also prompt discontinuation of therapy and a CT scan to rule out intra-abdominal or retroperitoneal hemorrhage. If bleeding has occurred, epsilon amino caproic acid (Amicar), fresh frozen plasma and cryoprecipitate are UK antagonists. Monitoring of PTT is required when adjunctive heparin is given. Fibrinogen is monitored during high and intermediate dose therapy, and the UK infusion rate is titrated to maintain a fibrinogen level of greater than 150. Although most patients will maintain adequate fibrinogen levels during treatment, we have seen precipitous drops that could not have been predicted prospectively. Nevertheless, fibrinogen monitoring is controversial, and some investigators believe it is unnecessary.

Although UK is considered to be nonantigenic, some patients will experience shaking chills early in their course of therapy. In most cases, these reactions have been self limiting and have ceased without discontinuing the infusion. The cause of this type of reaction has not been determined, but the reaction occurs more commonly with high initial infusion rates. There is currently no way of determining prospectively which patients will experience chills. Acetaminophen 650 to 1000 mg PO and diphenhydramine (Benedryl) 50 mg PO given 30 minutes prior to beginning the infusion has been recommended for prophylaxis. Should shaking chills still occur, Demerol 50 mg IV is recommended for symptomatic relief. Symptomatic treatment with H2 blockers has also been recommended. We have found Zantac 50 mg IV to be effective.

Successful thrombolytic therapy requires the utmost cooperation among the referring physician, vascular surgeon, interventional radiologist, and the ICU nursing personnel. Patience and caution are mandatory in these cases. Lytic therapy may continue for 36 to 48 hours or more, during which time the patient experiences waxing and waning ischemic symptoms. Limited angiography is repeated intermittently during the therapy to assess progress. Underlying fixed vascular lesions are often uncovered and treated concurrently with balloon angioplasty. Intraarterial thrombolytic therapy is complementary to surgical thrombectomy, particularly in cases where thrombectomy results have been unsatisfactory (i.e., in salvage of thrombosed venous bypass grafts and in cases where thrombosis extends into the tibial vessels and/or important side branches).

Thrombotic occlusion of the major veins is also amenable to catheter directed lytic therapy using techniques similar to those employed for arterial thromboses. Venous thromboses tend to lyse more slowly than their arterial counterparts, often requiring longer duration of therapy at lower infusion rates.

The decision to treat venous thromboses with thrombolytic agents remains somewhat controversial. Treatment is always warranted in symptomatic central venous thromboses and in peripheral venous thrombosis where impending venous gangrene is a concern. The controversy arises in cases of DVT with only mild symptoms and no immediate limb threat. These patients have traditionally been treated with heparin and coumadin. However, there are now several studies that have shown significant long term clinical benefit derived from thrombolytic therapy in such patients. In a study of symptomatic lower extremity DVT by Amensen, et al, only 4% of patients treated with anticoagulation alone had complete resolution of the thrombus. In 82%, follow up venography showed either no change or propagation of thrombus, and 80% subsequently developed post-phlebitic symptoms. Patients treated with anticoagulation plus systemic thrombolytic therapy had complete lysis in 45%, only 37% had no improvement, and 36% developed post-phlebitic symptoms.

Percutaneous Transluminal Angioplasty

Percutaneous transluminal angioplasty (PTA) has become the procedure of choice for treatment of stenoses of the renal arteries, focal aortic stenosis, focal stenosis or occlusion of the iliac arteries, and, in selected cases, lesions of the superficial femoral and popliteal arteries. Angioplasty of the brachiocephalic vessels is somewhat controversial, although carotid and vertebral artery angioplasty is becoming more commonplace in both general interventional and interventional neuroradiology practice. Many authorities now consider PTA the procedure of choice for fibromuscular dysplasia of the carotid arteries. Small vessel angioplasty, i.e., peripheral extremity and intracranial branch vessels, remains very controversial and is generally advocated only in the context of limb salvage or life threatening intracranial arterial spasm following subarachnoid hemorrhage.

Patency rates following PTA are strongly dependent on the size of the vessel treated and the quality of inflow and outflow through the treated vessel. Focal aortic lesions probably have the best response to angioplasty, however the reported series of aortic angioplasty are small. Iliac angioplasty is technically successful in >95% of cases and has a long term patency rate comparable to aortobifemoral grafting (>85% at 2 years). Superficial femoral and popliteal procedures have a >90% technical success rate and patency of 50-75% at two years. The patency rate here is lower than bypass grafts using autologous vein (either in-situ or reversed saphenous vein) but the procedure can be repeated multiple times if necessary whereas the failed vein graft often may not be salvageable. The poorest angioplasty results are in the tibial vessels and the coronary arteries. These procedures are technically successful in 80-90% of cases but early restenosis or occlusion is common with two year patency rates of 30 to 50%. Nevertheless, distal angioplasty for limb salvage appears to do as well as surgery in patients with advanced disease. Two year cumulative limb salvage rates of 70% are reported.

Visceral angioplasty has been extensively studied in the renal arteries where >90% technical success and patency rates of 90-95% at two years for fibromuscular dysplasia and 80- 85% for atherosclerosis are commonly reported. Angioplasty of other visceral arteries has been reported infrequently but appears similar to renal artery angioplasty in success and patency. Because of the excellent results obtained with renal angioplasty, it has become the procedure of choice for symptomatic renal artery stenosis (either renovascular hypertension or chronic renal insufficiency). In the past, angioplasty was considered contraindicated in patients with a solitary or transplanted kidney. This is no longer the case and, in fact, angioplasty is now considered the procedure of choice for treatment of renal artery stenosis in either of those settings.

Venous angioplasty has not been highly successful due, in part, to the low volume of flow seen in veins, the highly elastic nature of the vein wall, and the underlying pathologies which lead to venous stenosis. The most common site for venous angioplasty is in the outflow of a hemodialysis fistula. These stenoses and occlusions are due to a form of fibrointimal hyperplasia which appears to arise in response to elevated venous pressure and turbulence from the shunt. These lesions often require extremely high dilatation pressures (20-30 atm.) and have a high rate of early recurrence (3-6 months). Nevertheless, given all of the problems in maintaining a hemodialysis access site, and the small number of potential sites available in a patient, most surgeons and interventional radiologists agree that repeated angioplasties are worthwhile in these cases. It is hoped that vascular stents will prove valuable in treating these lesions.

Apart from hemodialysis access problems, venous angioplasty has been used infrequently. The technique has been used successfully in treating Budd Chiari syndrome due to hepatic vein or IVC webs. However, in most cases of Budd Chiari the venous lesions have been extensive and venous hypertension recurred early. Similarly, venous angioplasty for central venous (subclavian, brachiocephalic and SVC) stenoses has had less impact than arterial angioplasty due primarily to the elasticity of these lesions or their resistance to dilation. Many investigators have found endovascular stents to be an invaluable adjunct in treating these and similar veno-occlusive problems.

Vascular Stents

Vascular stenting is a new technology that is complementary to PTA. The currently available vascular stents are metallic devices which are either self expanding or balloon expandable. The Palmaz stent and Wallstent have FDA approval for use in the iliac arteries, Cook and Palmaz-Schatz stents are approved for coronary arteries, and Schneider WallStents have recently been approved for Transjugular Intrahepatic Portosystemic Shunt (TIPS) procedures. There are several other stents which are under investigation in the U.S. and Europe. Vascular stents have also been combined with thin walled vascular graft materials for percutaneous endoluminal grafting of aortic and iliac aneurysms, and for peripheral revascularization procedures.

To date, the most compelling evidence for stents is a comparative study of angioplasty alone versus primary iliac stenting using the Palmaz device. In this study, Richter, et al, showed a 4 year patency rate of 95% for primary stenting compared to 76% for angioplasty alone. It is of interest that, while Richter's iliac angioplasty results are poorer than most published angioplasty series, his primary stenting results are better than many published series of aortoiliac bypass grafts.

While stents seem to improve the results in the iliac arteries, the same cannot be said for superficial femoral, popliteal, and other smaller arteries. In studies from both the U.S. and Europe, stenting of smaller vessels has resulted in an unacceptably high incidence of thrombosis. These problems are being addressed in the development of new stenting materials and coatings. While the ultimate role of stents in the treatment of vascular disease is yet to be determined, these devices have already had a dramatic impact on the practice of interventional radiology.

Other Revascularization Tools

There has been a proliferation of revascularization devices including rotational and directional atherectomy catheters, RF thermal wires, thermal balloons, low frequency sonotrobes, etc. To date, none of these devices has proven superiority to conventional balloon angioplasty, and, in many cases, the results have been inferior. For example, laser angioplasty initially received a lot of attention because of its "high tech" profile. However, in well controlled clinical trials the laser has been very disappointing and the device has generally served best for its public relations and advertising "hype". At a cost of $200,000 to more than $1,000,000, lasers have successfully accomplished what a $15 guide wire does, with only a 10-30% increase in complications! One prominent interventional radiologist described the current status of laser angioplasty as analogous to "digging a ditch with a B-52".

In order to improve the results of both PTA and vascular surgical procedures, new methods of treating or preventing the vessel response to injury must be developed. Immediate or early failure is uncommon and usually due to technical problems. The vast majority of failures occur late and are due to restenosis or progression of disease. Following PTA, atherectomy, endarterectomy, or bypass grafting, the surgical injury to the vessel incites a response mediated by platelets, endothelial cells, and other factors, which interact in a complex way to induce smooth muscle cells in the media to divide and migrate to the intima. The end result of this complex interplay is fibrointimal hyperplasia which is the common denominator in most cases of restenosis. Various techniques designed to blunt or inhibit this response to injury are currently under investigation. Other investigations aimed at halting or reversing the progression of atherosclerosis are also in progress. These are areas of active and ongoing research in vascular medicine.