Treatment Options for Severe Manifestations of Venous Thromboembolism

Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a significant health problem affecting 1 in 1,000 in the United States annually.[1,2] After acute coronary syndrome and stroke, it is the third most common cardiovascular illness.[3] Although guidelines for management of VTE exist, there is a subset of severe manifestations of VTE where evidenced-based treatment options are less clear. Importantly, these manifestations may be associated with significant morbidity and mortality and represent a challenge for physicians providing care for these patients. In this issue of Circulation, McMurtry et al. provide a practical and comprehensive review of the literature for clinicians regarding treatment for three of these critical manifestations: massive and submassive PE, iliofemoral DVT (IFDVT), and chronic thromboembolic pulmonary hypertension (CTEPH). Concise definitions for each of these VTE subsets are described in the article to importantly help to contextualize the recommendations relative to patient characteristics and risk profiles.

For massive and submassive PE, several approaches are reviewed with the caveat that administration of pharmacologic therapies should occur with careful evaluation of risks/benefits and concomitant conditions of the individual patient. Regarding the management of patients with acute PE, those with a confirmed diagnosis and the absence of contraindications should receive prompt heparin (or fondaparinux) anticoagulation.[4,5] For submassive and massive PE, indications for the addition of fibrinolytics are considered. In patients with massive PE, fibrinolysis is considered "reasonable" with an acceptable risk of bleeding complications (Class IIa, Level of evidence B).[6-11] Use of fibrinolytics for patients with submassive PE remains equivocal and still represents a significant clinical conundrum in the hemodynamically stable patient. To aid in this determination, however, the authors offer two criteria that suggest patients likely to receive benefit from fibrinolysis. These include evidence of RV injury (moderate to severe) and/or evidence of respiratory or circulatory insufficiency. Further fibrinolytic therapy in this subset is not indicated in those with only minor myocardial necrosis and no clinical worsening. Findings from two ongoing randomized controlled trials (RCTs) (the Pulmonary Embolism THrOmbolysis Study, PIETHO and Tenecteplase or Placebo: Cardiopulmonary Outcomes At Three Months, TOPCOAT) evaluating the use of tenecteplase for acute PE may help to further elucidate indications for fibrinolytics in cases of submassive PE.

Catheter-based interventions that reduce thrombus burden or allow for removal of PE may be life saving as primary or adjunctive therapy in patients with massive or submassive PE.[12]. Notably, the expertise of the operator in implementation of these therapies remains of great importance. Further, McMurtry and colleagues conclude that catheter embolectomy and fragmentation or surgical embolectomy, when provided by an experienced, competent interventionalist, are reasonable for patients with massive PE and contraindications to fibrinolysis or hemodynamic/respiratory instability after fibrinolytics (Class IIA, Level of evidence C).[13-16] Again, the data for submassive PE are less clear - similar therapy for these patients may be considered in certain circumstances suggesting adverse prognosis. Of note, the use of inferior vena cava filters in these subsets of patients with acute PE were still considered as indicated for patients with confirmed acute PE and active bleeding complications or contraindications to anticoagulation therapy (Class 1, Level of evidence C).[7,17,18]

As IFDVT, thrombosis of the common femoral and/or iliac vein is associated with an increased risk of worse outcomes [e.g., recurrent VTE, postthrombotic syndrome (PTS)] and impaired quality of life, management options were evaluated in this scientific statement of severe manifestations of VTE. Of particular importance, identifying the optimal treatment approach for these patients may be challenging for the treating clinicians as prior trials often report on less extensive proximal DVT and neglect to report on subgroup analysis outcomes for IFDVT. In the absence of clear data to support alternate treatment regimens for IFDVT, the authors recommend that initial anticoagulation therapy model that of proximal DVT therapy.

After therapy in the initial acute phase, the treatment plan for long-term anticoagulation is of importance for patients and providers, particularly because of the risks associated with prolonged use and potential for intensive laboratory monitoring. A practical and straightforward treatment approach for use of anticoagulation in three subsets of patients is outlined in the review: "1) most patients with a first episode of IFDVT secondary to a reversible risk factor warrant medication for 3 months, 2) for patients with recurrent or unprovoked IFDVT, therapy is indefinite with periodic reassessment, 3) patients with cancer and IFDVT should receive low molecular weight heparin monotherapy for 3 to 6 months or as long as the cancer or cancer treatment is occurring." Notably, other factors that could impact treatment duration were patient tolerance and preferences, as well as VTE recurrence and bleeding risk. Concomitant daily use of elastic compression stockings for 2 years was also recommended for IFDVT to reduce the frequency of PTS.[19-21].

Catheter-directed thrombolysis (CDT) has been used for IFDVT in the context of phlegmasia cerulean dolens, worsening thrombus burden, and prevention of PTS. Based on available data, the authors recommended CDT or pharmacomechanical CDT for IFDVT associated with limb threatening circulatory collapse (Class 1, Level of evidence C).[22-28] Following CDT, or surgical venous thrombectomy, iliac vein stent placement was also considered reasonable therapy (Class IIa, Level of Evidence C).

The final VTE manifestation reviewed in this scientific statement is CTEPH. Pulmonary endarterectomy is still considered the treatment of choice for CTEPH, but preprocedural determination of which cases of CTEPH will benefit from operation compared with operative management still warrants further investigation. Overall pharmacologic or procedural/surgical management of massive PE, submassive PE, IFDVT, and CTEPH can be complex and require careful consideration of multiple factors such as patient comorbidities, risk factors, tolerability of therapy, disease severity, disease recurrence, patient preference, and operator expertise. Still needed in future studies of these VTE disease subsets are evaluations in pediatric populations, RCTs and subgroup analyses focusing on meaningful outcomes, and further determinations of comparative effectiveness and patient quality of life. The McMurtry et al. scientific review in this issue comprehensively evaluates the literature in a manner that is interpretable and implementable for clinicians providing care for patients with severe manifestations of VTE.