Key Questions to be Answered

Statements and recommendations made in this document are based on a literature review using clearly defined levels of evidence. This process has revealed a number of key questions that need to be addressed by future studies. They are summarized in this final section.

Patient Populations

Although venous thromboembolism (VTE) is an appealing target for maximally effective prevention, there is still a low rate of appropriate prophylaxis worldwide, particularly for acute medically ill patients. Continuing efforts to educate combined with hospital-wide protocols, local audits for VTE prevention, electronic alerts, and use of clinical nurse specialists have been shown to result in a marked increase in appropriate application of guidelines.

The risk of deep venous thrombosis (DVT) after various minimally invasive abdominal surgical procedures and advanced laparoscopic surgery, as well as upper limb surgery, needs to be established.

Recurrence rates of DVT in relation to the residual thrombus, increased d-dimer or risk factors following treatment of the first episode needs to be determined. A database needs to be created to establish the risk of pulmonary hypertension in patients with pulmonary embolism (PE). The value of spiral computed tomography evidence of right heart failure as predictor of a high-risk group in patients with PE requiring thrombolysis needs to be determined.

Prophylaxis

Further studies are needed to assess additive effects on the efficacy, cost-effectiveness and safety of chemical agents (oral and injectable), and mechanical methods in high- and medium-risk patients for various medical and surgical specialities.

Possible differences in the efficacy of mechanical devices of different design need to be determined such as thigh length versus knee length stockings and pneumatic sleeves, and sequential gradient versus uniform pressure sleeves.

In the 1970s and 1980s when the efficacy of electrical calf muscle stimulation was assessed, the equipment used produced painful stimuli so that it could be used only during general anesthesia. Modern equipment now commercially available produces muscle contractions as a result of electrical impulses that are painless and can be tolerated by patients throughout the day. The efficacy of such modern equipment used not only during surgery but also during the postoperative period should be determined in adequately powered randomized controlled trial (RCT).

In a cost-constrained system, the relative efficacy, cost, and safety of aspirin and the new oral agents requires proper and definitive study with a randomized trial in various groups, particularly knee replacement and hip fracture.

Now that the fatal PE rates after arthroplasty are so low, the equivalence of symptomatic VTE events and symptomatic bleeding events with different prophylactic modalities should be evaluated with regard to morbidity, cost, and medicolegal liability.

Prophylaxis for patients in plaster casts requires further study, in particular establishing those at risk and delivering prophylaxis for an adequate duration in a safe, cost-effective, and pragmatic way. New oral agents should be studied in this group.

Prophylaxis for those at high risk of VTE having day case surgery need further study. The day surgery environment may preclude administration of inhospital chemical prophylaxis due to the bleeding risk with proximity to surgery. This will require administration for an adequate period of time, as yet unknown, in an out-of-hospital environment. Oral agents have a pragmatic advantage in this group, but their safety and efficacy require study.

The RCTs in high-risk patients having plastic surgery are needed to determine the efficacy and safety of pharmacological and mechanical prophylaxis.

The RCTs in patients having prostatectomy are needed to determine the efficacy and the safety of pharmacological and mechanical prophylaxis.

The RCTs in patients having elective spine surgery are needed to determine the efficacy and safety of pharmacological and mechanical prophylaxis.

The RCTs in patients having spinal cord injury are needed to determine the efficacy and safety of combined pharmacological and mechanical prophylaxis. The RCTs in patients with burns are needed to determine the efficacy and safety of pharmacological and mechanical prophylaxis. The RCTs are needed to determine the optimal duration of extended prophylaxis and whether or not mortality is influenced in general surgical patients. Further studies are needed before recommendations can be made for prophylaxis beyond 35 days in patients having hip surgery.

The value of new oral anticoagulants in the prophylaxis for different groups of patients having nonorthopedic surgery needs to be determined. The RCTs in patients with acute stroke are needed to determine the efficacy and safety of combined pharmacological and mechanical prophylaxis.

A multicenter trial assessing efficacy, cost-effectiveness, and safety of thromboprophylaxis in high-risk pregnant patients is required. The optimum prophylactic therapy in patients having laparoscopic surgery needs to be determined. There is a need for further studies to assess the efficacy of mechanical methods in medical patients.

Well-designed RCTs are needed to determine the optimal duration of thromboprophylaxis in high-risk medical patients. There is a need to adequately validate VTE and bleeding risk assessment models in hospitalized medical patients.

Phase 4 studies (postmarketing surveillance) to address long-term potential harm from prophylactic methods should be encouraged.

The value of routine thromboprophylaxis in those receiving radiotherapy needs to be evaluated. Adequately powered studies are needed to determine the benefits and harms of new anticoagulant drugs in patients with cancer with indwelling central venous catheters and in specific subgroups of patients.

Treatment Regimens

The value of extended treatment with aspirin in patients who are at high risk of bleeding when taking vitamin K antagonist (VKA) needs to be confirmed by further studies.

The efficacy and safety of thrombolytic therapy in patients with PE and right ventricular dysfunction require confirmation by randomized trials.

A randomized study comparing catheter-directed thrombolysis (CDT) of proximal DVT with conventional anticoagulation therapy in preventing the postthrombotic syndrome (PTS) is required.

Studies comparing postthrombotic morbidity in patients treated with CDT versus those treated with pharmacomechanical lysis are needed.

The best approach for low-molecular-weight heparin (LMWH) use (eg, dose adjustment or anti Xa monitoring) in pregnancy, obesity, and patients with renal impairment needs to be determined (Note: there are increasingly clear guidelines for dose adjustment without anti-Xa monitoring).

How do we manage bleeding in patients treated with LMWHs, fondaparinux, and the new oral anticoagulants? Studies should explore the efficacy of protamine sulfate in patients bleeding due to the use of LMWH.

The role of long-term LMWH versus VKA in the treatment of DVT and prevention of PTS should be determined by further randomized trials.

The value of prognostic markers such as d-dimer, C-reactive protein, and extent of residual clot burden in guiding the duration of long-term oral anticoagulant therapy needs to be studied further.

New drugs in terms of production of heparin-induced thrombocytopenia (HIT) antibodies and their use as an alternative to UFH or LMWH in patients with HIT need clinical evaluation.

More RCTs are needed to determine the complications or harm produced by prophylatic methods. Further trials are needed to clarify whether LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer.

The improved survival in patients with cancer treated with LMWH needs to be confirmed by further prospective clinical trials with appropriate design and power to assess cancer outcome before recommendations can be made.

The safety and efficacy of inferior vena cava filters for the management of cancer-associated thrombosis need to be evaluated. The relative benefit/harm from the new oral anticoagulants needs to be further determined.

The RCTs are needed to determine the efficacy of percutaneous endovascular venoplasty and stenting to relieve chronic venous obstruction and whether this may alleviate symptoms of PTS.