Venous thromboembolism is considered the third most common cardiovascular disorder in North America. Each year, it affects 1 to 2 per 1000 people.1,2 It manifests as either deep vein thrombosis or pulmonary embolism. The management of acute venous thromboembolism consists of the prompt initiation of anticoagulation. Over the years, multiple parenteral and oral anticoagulant and thrombolytic agents were developed and approved for the management of venous thromboembolism. To date, unfractionated heparin is considered the most common parenteral anticoagulant initiated in the setting of deep vein thrombosis or pulmonary embolism.3
According to the current American College of Chest Physicians guidelines, it is recommended to use anticoagulant therapy alone over thrombolysis for most patients with an acute deep vein thrombosis, with the exception for patients with extensive iliofemoral or proximal deep vein thrombosis at a high risk of limb ischemia.4 Previous evidence that evaluated and compared thrombolytic therapy versus anticoagulant therapy showed that thrombolytic therapy may facilitate and enhance clot lysis and reduce the incidence of postthrombotic syndrome compared with anticoagulation alone.5 The major drawback of thrombolytic therapy is that it increases the risk of major bleeding, and that has led to underusing this treatment modality.5
Catheter-directed thrombolysis (CDT) is a relatively new and emerging management modality that involves the introduction of a catheter percutaneously into the venous system with subsequent fluoroscopic guidance to the target vessel and then a prolonged infusion of a thrombolytic agent directly into the thrombus site.6 In patients with pulmonary embolism, the use of CDT was associated with a decrease in right ventricular dysfunction, reduced pulmonary hypertension, and decreased anatomic thrombus burden.7 In patients with deep vein thrombosis, the use of CDT was proven to be an effective modality for restoring venous patency and reducing symptoms.8
Most reports that evaluated the use of thrombolytic therapy, including patients treated with CDT, used unfractionated heparin as a background anticoagulant. One of the major downsides of unfractionated heparin is heparin-induced thrombocytopenia (HIT), which is a serious and lethal complication of heparin therapy.9 Heparin-induced thrombocytopenia is an immune-mediated reaction that emerges as a result of heparin binding to platelet factor 4 to form an antigenic heparin–platelet factor 4 complex. The formation of antibodies to heparin–platelet factor 4 complex (HIT antibodies) could increase the risk of thrombocytopenia and thrombosis in 30% to 50% of the cases. It has been estimated that about 1% to 5% of patients exposed to unfractionated heparin or low–molecular-weight heparin can develop HIT.9 The pathological diagnosis of HIT remains challenging, and multiple screening instruments were developed to identify patients at risk of developing HIT. The most common screening instrument is the “4-Ts” Assessment Point System for patients with suspected HIT.10 In patients with a confirmed HIT, current practice guidelines recommend cessation of all heparin products for patients strongly suspected of having HIT and prompt initiation of a nonheparin direct-thrombin inhibitor (DTI) for anticoagulation.4
Unfortunately, none of the major reports that evaluated the use of CDT used any of the DTIs as a background anticoagulant. This review provides interventional radiologists, cardiologists, vascular specialists, hematologists, nurses, pharmacists, and other involved healthcare professionals with a summary of the available evidence in the literature that used DTIs in patients undergoing CDT to manage their venous thromboembolism in the setting of HIT.
We searched for peer-reviewed articles in MEDLINE, PubMed, and Scopus from inception to June 2018. We restricted our search to articles published in English. We used the following keywords in our search: “catheter-directed thrombolysis,” “heparin-induced thrombocytopenia,” “venous thromboembolism,” “deep vein thrombosis,” “pulmonary embolism,” “direct-thrombin inhibitors,” “bivalirudin,” “argatroban,” “desirudin,” and “lepirudin.” Citations from available articles were also reviewed for additional references. We only included articles that used DTIs to manage venous thromboembolism in patients diagnosed as having HIT.
Our search strategy yielded 322 records. We excluded 200 articles because of duplication. We also excluded 59 meta-analyses or reviews that addressed the evidence surrounding the use of CDT without examining the efficacy and safety of using DTIs during this management modality. A further 57 articles were excluded after a full-text review. Finally, 6 eligible case reports were included in our final review.11–16 The full identification and selection process is summarized in the Figure. We intended to review all articles that specifically investigated the use of DTIs in patients undergoing CDT. However, after extensive examination of the literature, only case reports were identified to address the main objective of this review. We reported patients' demographics, comorbid conditions, and venous thromboembolism risk factors. In addition, we reported HIT screening and diagnosis modalities, used CDT modality, and used DTI modality. Finally, we reported relevant patient outcomes including mortality, recurrent venous thromboembolism, and bleeding events after CDT.
Six case reports of patients who underwent CDT in the setting of HIT requiring DTI were identified. Of the case reports, 4 cases used argatroban and the remaining cases used bivalirudin. The median age was 67 years interquartile range, 29 years). Five patients (83%) had a history of hypertension, 1 patient (17%) had a history of heart failure, 1 patient (17%) had a history of diabetes mellitus, 3 patients (50%) had a history of venous thromboembolism, 1 patient (17%) had a history of active cancer, 1 patient (17%) had a history of recent trauma, and 3 patients (50%) had a history of recent surgery. Platelet counts on admission were reported in all cases, with a median platelet count of 204 000 (range, 150 000) platelets/μL. Four of the 6 cases reported the 4-Ts score with a median score of 6 (range, 4). Enzyme-linked immunosorbent assay HIT antibody test was reported in 5 cases, in which 4 of them (80%) were positive and 1 case (20%) was deemed negative but still was treated as an active HIT given previous positive HIT antibodies in multiple occasions. The patients' demographics, presentation, and medical history are summarized in the Table.
Thrombolytic and Anticoagulant Agents Used and Patient Outcomes
In terms of the thrombolytic therapy used in these cases, alteplase was used in all of the 6 cases. The average initial dose of alteplase ranged from 0.5 to 3 mg/h. A dose as high as 3 mg/h of alteplase was administered in patients with aggressive clot burden. Of the case reports identified, 4 cases used argatroban and 2 cases used bivalirudin. Overall, the rate of the anticoagulant agents used during CDT was individualized in all cases, and all activated partial thromboplastin time targets used were lower. The average CDT and anticoagulant infusion duration period was 26 hours (SD, 13 hours), with a longer period of infusion being used in patients with aggressive clot burden. The initial rate, rate adjustments, targeted activated partial thromboplastin time ranges, and fibrinogen levels for argatroban and bivalirudin during the CDT are summarized in the Table.
In terms of reported patient outcomes, 5 patients (83%) survived after the procedure and no recurrent venous thromboembolism or major bleeding events were reported. They were all initiated on long-term warfarin anticoagulation. One patient died as a result of aspiration pneumonia a few days after the CDT procedure (Table).
To the best of our knowledge, this is the first review to summarize the available clinical experience in using DTIs in patients undergoing CDT to manage their venous thromboembolism. The use of CDT modality to manage venous thromboembolism is relatively new and promising compared with the other management modalities. One of the major advantages of using CDT is the reduction in the total thrombolytic dose administered.17 Many institutions that perform CDT procedures have a certain experience to manage patients' anticoagulation given that most CDT procedures are performed in patients with no underlying conditions that prevent the use of heparin products. In our evaluation, there were diverse alteplase dose regimens and durations that were used in the presented reports. Most of the reports that used CDT in conjunction with DTI report using an alteplase dose ranging from 0.5 to 3 mg/h. The duration of infusion of alteplase during the CDT procedure ranged from 14 to 48 hours. It is important to highlight that the chosen CDT infusion durations in these cases were driven by the patients' specific clot burdens, with higher doses and longer durations being used in patients with higher clot burdens. Moreover, most of these cases used a lower activated partial thromboplastin time target to be achieved during the CDT to reduce the risk of bleeding. Using an intracatheter or intravenous route of administration to administer the DTI did not impact patients' outcomes. Theoretically, using the intracatheter approach might maximize anticoagulant delivery to the target clot site, still maintain some degree of systemic anticoagulation in the setting of HIT, and minimize the risk of bleeding. With the currently limited available evidence, we recommend individualizing CDT pharmacotherapy and dosages with close monitoring of coagulation parameters and potential adverse reactions. In addition, institutions should start to implement standardized protocols for anticoagulation during CDT. Finally, a multidisciplinary decision including but not limited to interventional radiologists, cardiologists, vascular specialists, hematologists, nurses, and pharmacists regarding the CDT pharmacotherapy and dosage modality to be used might be warranted because most of these cases used this approach. We acknowledge several limitations to our evaluation. First, the articles in this review were case reports. Second, it is difficult to generalize the efficacy and safety of this management modality given the heterogeneity and small sample size of the presented case reports. Third, there is a potential for the presence of a publication bias, given that research engines were not able to capture all relevant evidence. Finally, language restrictions might have resulted in the exclusion of some valid cases. However, on the basis of the presented evidence of case reports, the off-label use of DTIs might be safe and effective in selected patients with HIT undergoing CDT. Randomized controlled clinical trials and real-world or large data from registries are necessary to further evaluate this treatment strategy.
What's New and Important?
- We summarized the experience toward using DTIs in patients undergoing CDT to manage their venous thromboembolism in the setting of HIT.
- The use of DTIs might be safe and effective in selected patients with HIT undergoing CDT.
- Randomized controlled clinical trials and real-world or large data from registries are necessary to further evaluate this treatment strategy.
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