Outcome of Acute Deep Venous Thrombosis Using Standard Treatment versus Thrombolytics: A Literature Review.

Deep vein thrombosis (DVT) is a major health problem affectinga significant portion of population. Primary complications are Pulmonary Embolism (PE) in the short term and Post-Thrombotic Syndrome (PTS) in the long term. Thrombolytic drugs act by activating plasminogen which in turn forms the enzyme plasmin. Plasmin consequently degrades blood clots by breaking down the fibrin molecules which make up the clots help to degrade the already formed clot. They can be used using different route of administration, doses and durations. The purpose of this systematic review was to assess the outcome of thrombolytic therapy in terms of the efficacy, safety and effectiveness of the medicines. Electronic searches of databases (MEDLINE and Google Scholar) were queried for articles written in English since 2000 GC. A total of 760 results were obtained using the search keys, and after excluding duplicates, 275 articles were selected. Finally, 9 randomized controlled trials (RCTs) which met the language of publication, study design and exclusion criteria were included in this systematic review. The data were obtained from nine trials (6 countries), providing a study-level data of 1309 participants. Almost all studies revealed that thrombolytic treatment was effective in the management of acute DVT. In most of the studies, the rate of rethrombosis was lower in case of thrombolytic than standard management. Hence, addition of thrombolytic results in persistence and increases the clinical benefits. Thrombolytic therapy was very effective in reversing closed veins, in boosting the patency rate,whilereflux was higher in patients treated with anticoagulants. Thrombolytic offers potential advantages over the standard treatment of DVT by reducing the proportion of patients with chronic disabling leg symptoms (such as PTS) by triple in the longer term. However, the incident of major bleeding was higher in patients receiving thrombolytics than anticoagulants.


INTRODUCTION
Deep Vein Thrombosis (DVT) is a major health problem affectinga significant portion of population. Primary complications are Pulmonary Embolism (PE) in the short term and Post Thrombotic Syndrome (PTS) in the long term 1 . Standard treatment using propagation, but does not treat the occlusion itself 2 . However, over half of patients may suffer PTS in the long term, manifested by some 202 International Journal of Hematology Oncology and Stem Cell Research ijhoscr.tums.ac.ir degree of pain, swelling, skin pigmentation or venous ulceration of the affected leg in the follow up period of therapy despite of taking anticoagulants 3 . Elastic compression stockings had also been recommended by the American College of Chest Physicians Evidence Based Clinical Practice Guidelines as non-pharmacologic alternative for DVT patients to prevent PTS 4 . However, a meta-analysis (six random controlled trails including 1462 patients) recently indicates that elastic compression stockings are not sufficient to prevent PTS 2 . Thrombolytic drugs act by activating plasminogen which in turn forms the enzyme plasmin 5 . Plasmin consequently degrades blood clots by breaking down the fibrin molecules which make up the clots to degrade clots already formed. They may be administered using different doses and durations as well as different route of administration. The theoretical advantage behind the loco/regional and catheter-directed methods is that they may reduce the necessary amount of thrombolytic (uses lower doses) and may reduce the risk of bleeding compared to systemic route 6 . A randomized trial comparing recombinant tissue plasminogen activator (rt-PA) versus anticoagulation alone demonstrated that 58%of the patients receiving rt-PA achieved greater than 50% clotlysis compared to 0% in those receiving anticoagulation alone and that rt-PA-treated patients had a trend toward reduced PTS if lysis was successful (56%vs 25%) 7 . However, the incident of major bleeding was higher in patients receiving thrombolytic than anticoagulants 8 . The goals of therapy for acute DVT are minimizing the incidence of recurrent thrombosis, PE, decreasing the risk of chronic venous insufficiency and PTS in order to achieve the goals in which thrombolytic therapy plays a major role 9 . Conventional anticoagulant therapy which aimed at the prevention of PE and recurrent venous thromboembolism (VTE) has been largely ineffective at treating PTS 10 . Current recommendation on treatment of iliofemoral venous thrombosis is percutaneous catheter-directed thrombolysis (CDT), either pharmacologic or pharmacomechanical as first-line therapy 11 . Current reviews indicate that thrombolytic use increases the proportion of participants with any improvement in venous patency and complete clotlysis, and reduces the risk of PTS. So, the purpose of this systematic review is to assess the efficacy, safety and effectiveness of thrombolytic therapy in the treatment of acute DVT.

Rationale
Currently,the use of thrombolytic therapy as firstline therapy for acute DVT is not recommended in most treatment guidelines despite their use is appreciated through different studies. All studies included in this review are RCTs to maximize the quality of the results.

MATERIALS AND METHODS
In this review, an attempt was made to include all published articles that were reported on the use of thrombolytic for acute deep venous thrombosis (DVT) by searching the PubMed and Google scholar electronic database. The following key words were used: thrombolytic, thrombolysis, fibrinolysis, fibrinolytics, therapy, tissue plasminogen activator and venous thrombosis.

Eligibility criteria
The following documents were not included: Unpublished documents, articles written in languages other than English, study design used other than RCT and articles published before 2000.

Searching strategy
Searching of articles from electronic database system of PubMed and Google Scholar was done from July 6 to July 13, 2018. A total of 760 articles were identified by systematic search strategy. After screening of the title and abstract using the predefined inclusion and exclusion criteria, 275 studies were retrieved for more detailed information. 518 articles were excluded for the following reasons: not written in English (n=44), not relevant to the topic (n=469), not consistent with study design (n=261, not RCT) and published before 2000 (n=5). Finally, 9 RCTs were included in this review.

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International Journal of Hematology Oncology and Stem Cell Research ijhoscr.tums.ac.ir

Key outcomes
Efficacy, safety and effectiveness werethe key outcomes.

Planned methods of analysis
The validity of randomized trials with adequate reliability determined the adequacy of randomization and concealment of allocation, blinding of patients, health care providers, data collectors, and outcome assessors and extent of loss to followup (i.e. proportion of patients in whom the investigators were not able to ascertain outcomes.)

RESULTS
The studies included in this systematic review were different types of interventions, ranging from nonpharmacologic management (compression stocking) to various pharmacotherapy managements (Urokinase, Alteplase, Heparinization, streptokinase, warfarin, enoxaparin, UFH and Actilyse). In studies which were tried to compare thrombolytic with standard management: almost all uses of heparin were followed by warfarin as standard therapy and most of the studies (five out of nine) use alteplase as thrombolytic agent during the study period. The data were analyzed from 7 countries, providing studylevel of 1309 participants from previously published studies. Surveys were broadly distributed across the three regions with more participants from Europe. Of 9 articles, 3 were conducted in Norway and the rest were carried out in China, Germany, Turkish, Egypt, the United States, and Brazil (Table  1). Regarding result presentation, three studies presented their data by comparing thrombolytic therapy with the standard anticoagulants treatment, two studies by dealing with post thrombotic complications after anticoagulants and thrombolytic therapy, and two other studies by concerning shortand long-term effectiveness of thrombolytic treatment, whereas the rest of the studies used catheter-directed thrombolysis for the treatment of DVT. All publications were produced during the period 2000 and 2016. Most of the studies were conducted in a single study site (6 out of 9), and their results were presented by comparing standard anticoagulants with thrombolytic treatment. Five studies were done using catheter-directed thrombolytic therapy, while four of which employed systemic thrombolytic therapy. Three out of 9 studies compared standard treatment (anticoagulants) with thrombolytic therapy; two studies emphasized on the impacts of thrombolytic therapy in prevention of PTS, again 2 of which focused on short-and long-term results of thrombolytic treatment. 849 of 1309 patients were treated by thrombolytic therapy (urokinase, alteplase or streptokinase) and 460 of the patients were treated by standard anticoagulants (parenteral heparin followed by oral warfarin).

DISCUSSION
DVT treatment includes anticoagulant therapy, pharmacologic thrombolysis (systemic thrombolysis, flow-directed thrombolysis, and catheter-directed thrombolysis), percutaneous mechanical thrombectomy, surgical thrombectomy and physical therapy 3 . Current guideline of antithrombotic therapy for VTE disease suggests that acute lower extremity DVT patients are most likely to benefit from thrombolytic therapy due to its efficacy 13,19 .
Thrombolytic therapy has been showed very effective in reversing closed veins, improving patency rate and reducing reflux 8,17 . Many studies agreed that lower dose of recombinant tissue plasminogen activators (tPA) was safe and effective in various forms of DVT 7,18,20,21,22 . Thrombolytics are less likely to cause complication in later stages of treatment compared with standard treatment which composed of heparin and warfarin therapy. One study observed that the most effective mechanism for thrombolysis was the penetration of the  19 . Rethrombosis was also lower among patients on thrombolytics (n=849, 2.4%) than standard management (n= 460, 39%) 15,17,19,21 . A study on Short-and Long-Term Results After Thrombolytic Treatment of DVT, High-dose thrombolysis led to better rates of complete recanalization after seven days than loco-regional lysis 19 . The addition of thrombolytics on DVT management was resulted in persistence and increased clinical benefits 24 . The incidence of VTE was also lower in patients treated with thrombolytic than anticoagulant alone 18,25 . However, considering the safety issue, thrombolytic therapy associated with major bleeding and PE in most patients compared with traditional treatment (10.4% and 4.1%), respectively, especially with higher doses the occurrences of such events are increased 16 . one study underlines that the use of thrombolytic needs further study and investigation to decide about their long-term effects 8,15 . The utilization of these agents in the assessment of the quality of life in patients and their use specifically for endovascular thrombosis need further investigation (n=849 ,54%) compared to patients on anticoagulants (n=460 , 53%) 14 .
One study reported increased rate of serious bleeding and PE after thrombolytic use 24 and out of 12 patients receiving thrombolysis (9 systemic, 3 local); 9 patients on systemic treatment developed PE 1, 2 . Furthermore, the study revealed that higher doses of thrombolytic were associated with serious adverse events (major bleeding and PE) and these agents can be resulted in better clinical outcome when given in catheter-directed route than systemic administration 21,24 . Moreover, one study pointed out that these agents should only be considered in patients with high proximal DVT and lower risks of bleeding 26 .

CONCLUSION
The use of thrombolytic therapy offers potential advantages over the standard treatment of DVT by reducing the proportion of patients with chronic disabling leg symptoms (from PTS) by one-third in the longer term. However, the safety issues of these drugs in terms of risk of bleeding and PE require further investigation.