Understanding Treatment Options for Severe Manifestations of Venous Thromboembolism in the Absence of Definitive Guidelines
Pub Date: Friday, May 6, 2011
Author: Raina Merchant, MD MS
Jaff MR, McMurtry MS, Archer SL, et al; on behalf of the American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Peripheral Vascular Disease, and Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011: published online before print March 21, 2011, 10.1161/CIR.0b013e318214914f.
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. 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.. 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.
- Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151(5):933-938.
- Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158(6):585-593.
- Goldhaber SZ. Pulmonary embolism thrombolysis: a clarion call for international collaboration. J Am Coll Cardiol 1992;19(2):246-247.
- Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29(18):2276-2315.
- Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008;133[Suppl 6]:454S-545S.
- Kasper W, Konstantinides S, Geibel A, et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997;30(5):1165-1171.
- Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006;113(4):577-582.
- Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386-1389.
- Laporte S, Mismetti P, Decousus H, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008;117(13):1711-1716.
- Lobo JL, Zorrilla V, Aizpuru F, et al. Clinical syndromes and clinical outcome in patients with pulmonary embolism: findings from the RIETE registry. Chest 2006;130(6):1817-1822.
- Academic Emergency Medicine. 2009;16:S77.
- Kucher N. Catheter embolectomy for acute pulmonary embolism. Chest. 2007;132(2):657-663.
- Skaf E, Beemath A, Siddiqui T, Janjua et al. Catheter-tip embolectomy in the management of acute massive pulmonary embolism. Am J Cardiol 2007;99(3):415-420.
- Chechi T, Vecchio S, Spaziani G, et al. Rheolytic thrombectomy in patients with massive and submassive acute pulmonary embolism. Catheter Cardiovasc Interv 2009;73(4):506-513.
- Sukhija R, Aronow WS, Lee J, Kakar P, et al. Association of right ventricular dysfunction with in-hospital mortality in patients with acute pulmonary embolism and reduction in mortality in patients with right ventricular dysfunction by pulmonary embolectomy. Am J Cardiol 2005;95(5):695-696.
- Leacche M, Unic D, Goldhaber SZ, et al. Modern surgical treatment of massive pulmonary embolism: results in 47 consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg 2005;129(5):1018-1023.
- Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med 1998;338(7):409-415.
- White RH, Zhou H, Kim J, Romano PS. A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism. Arch Intern Med 2000;160(13):2033-2041.
- Partsch H, Kaulich M, Mayer W. Immediate mobilisation in acute vein thrombosis reduces post-thrombotic syndrome. Int Angiol 2004;23(3):206-212.
- Brandjes DP, Buller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349(9054):759-762.
- Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004;141(4):249-256.
- Lin PH, Zhou W, Dardik A, et al. Catheter-direct thrombolysis versus pharmacomechanical thrombectomy for treatment of symptomatic lower extremity deep venous thrombosis. Am J Surg 2006;192(6):782-788.
- Elsharawy M, Elzayat E. Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial. Eur J Vasc Endovasc Surg 2002;24(3):209-214.
- Enden T, Klow NE, Sandvik L, et al. Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency. J Thromb Haemost 2009;7(8):1268-1275.
- Comerota AJ, Throm RC, Mathias SD, et al. Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life. J Vasc Surg 2000;32(1):130-137.
- AbuRahma AF, Perkins SE, Wulu JT, Ng HK. Iliofemoral deep vein thrombosis: conventional therapy versus lysis and percutaneous transluminal angioplasty and stenting. Ann Surg 2001;233(6):752-760.
- Vedantham S, Vesely TM, Sicard GA, et al. Pharmacomechanical thrombolysis and early stent placement for iliofemoral deep vein thrombosis. J Vasc Interv Radiol 2004;15(6):565-574.
- Mewissen MW, Seabrook GR, Meissner MH, et al. Catheter-directed thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999;211(1):39-49.
-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association