, Benjamin Hohlfelder2 and Samuel Z. Goldhaber3
(1)
Cardiovascular Division, Harvard Medical School Brigham and Women’s Hospital, Boston, Massachusetts, USA
(2)
Department of Pharmacy Services, Brigham and Women’s Hospital, Boston, Massachusetts, USA
(3)
Thrombosis Research Group, Harvard Medical School Brigham and Women’s Hospital, Boston, Massachusetts, USA
Abstract
Selection of patients with venous thromboembolism (VTE) for advanced therapies requires recognition of high-risk deep vein thrombosis (DVT) and pulmonary embolism (PE) syndromes. Advanced therapies for acute PE include systemic fibrinolysis, catheter-based “pharmacomechanical” intervention, and surgical pulmonary embolectomy. Choosing a particular advanced therapy depends on the individual patient’s risk for adverse outcomes due to VTE and for major bleeding, specifically intracranial hemorrhage. Multidisciplinary PE Response Teams may facilitate access to advanced therapies and appropriate patient selection.
Keywords
Catheter-based interventionDeep vein thrombosisFibrinolysisPulmonary embolismSurgical embolectomyTherapySelf-Assessment Questions
1.
Which of the following statements regarding systemic fibrinolysis for acute PE is correct?
(a)
Compared with anticoagulation alone, systemic fibrinolysis reduces mortality only in patients with massive PE.
(b)
Compared with anticoagulation alone, systemic fibrinolysis reduces mortality in patients with massive and submassive PE at the cost of increased risk of intracranial hemorrhage.
(c)
Compared with anticoagulation alone, systemic fibrinolysis for acute PE reduces the risk of hemodynamic collapse but does not impact mortality.
(d)
Compared with anticoagulation alone, systemic fibrinolysis reduces the risk of recurrent PE and shortens length of stay but does not improve mortality.
2.
Which of the following advanced therapies would be most appropriate in a 55-year-old man with acute dyspnea, tachycardia, and hypotension requiring vasopressor support who is diagnosed with “saddle” PE 1 week following laparotomy for small bowel obstruction?
(a)
Full-dose systemic fibrinolysis
(b)
Half-dose systemic fibrinolysis
(c)
Surgical pulmonary embolectomy
(d)
Inferior vena cava (IVC) filter insertion
Clinical Vignette
A 57-year-old obese man with severe three-vessel coronary artery disease status post coronary artery bypass graft surgery 5 years prior and history of heart failure with a left ventricular (LV) ejection fraction of 40–45 % presented to the Emergency Department with 5 days of progressive exertional dyspnea and an episode of syncope. Earlier in the week, the patient had seen his Primary Care Physician who increased his outpatient diuretic regimen. On the morning of presentation, he was walking to the bathroom when he felt lightheaded and then lost consciousness. On physical examination, he was tachycardic to 124 beats per minute, hypotensive with a blood pressure of 86/48 mmHg, and profoundly hypoxemic with an oxygen saturation of 94 % on a non-rebreather mask. His electrocardiogram was remarkable for sinus tachycardia. His chest X-ray demonstrated cardiomegaly without pulmonary edema. Contrast-enhanced chest computed tomogram (CT) demonstrated a large “saddle” PE (Fig. 7.1) and right ventricular (RV) enlargement with an RV diameter-to-LV diameter ratio of 1.3 (Fig. 7.2). Upon return from Radiology, the patient developed worsening hypoxemia and hypotension requiring bolus intravenous fluids. An urgent transesophageal echocardiogram demonstrated RV dilation, hypokinesis, and pressure overload (Fig. 7.3) and PE in the proximal pulmonary trunk (Fig. 7.4). The hospital PE Response Team was activated, and representatives from Pulmonary Medicine, Cardiovascular Medicine, and Cardiac Surgery convened at the bedside. After a consensus decision was made, the patient was administered recombinant tissue-plasminogen activator (t-PA) 100 mg via peripheral IV over 2 h with prompt improvement in oxygenation and hemodynamics.
Fig. 7.1
Contrast-enhanced chest computed tomogram (CT) demonstrating large “saddle” pulmonary embolism (PE) (arrows) in a 57-year-old man with dyspnea on exertion and syncope
Fig. 7.2
Contrast-enhanced chest computed tomogram (CT) demonstrating right ventricular (RV) enlargement as defined by an increased RV diameter-to-left ventricular (LV) diameter ratio (4.9 cm/3.8 cm = 1.3; normal ≤ 0.9) in a 57-year-old man with acute pulmonary embolism (PE)
Fig. 7.3
Transesophageal echocardiogram, transgastric view, demonstrating right ventricular (RV) dilation in diastole with an underfilled left ventricle (LV) (panel a) in a 57-year-old man with acute pulmonary embolism (PE) and hypotension. In systole, the interventricular septum deviated toward the LV (arrows) consistent with RV pressure overload (panel b)
Fig. 7.4
Transeso-phageal echocardiogram demonstrating pulmonary embolism (PE) (arrows) in the proximal pulmonary trunk in a 57-year-old man with acute pulmonary embolism (PE) and hypotension
Spectrum of Disease
Deep Vein Thrombosis
DVT describes a wide spectrum of conditions, including massive DVT, proximal lower extremity DVT, isolated calf DVT, and upper extremity DVT.
Massive Deep Vein Thrombosis
Massive DVT most often describes thrombus that originates in the proximal veins of the lower extremity and extends into the iliac veins. Such extensive thrombus may result in severe post-thrombotic syndrome if not treated with advanced therapies such as pharmacomechanical catheter-directed fibrinolysis or thrombectomy.
Proximal Lower Extremity Deep Vein Thrombosis
Proximal DVT is the most common type of DVT and generally describes thrombus involving the common femoral, proximal femoral, distal femoral, or popliteal veins.
Isolated Calf Deep Vein Thrombosis
The previous practice of serial diagnostic testing with lower extremity ultrasound has been largely replaced by routine anticoagulation of symptomatic, isolated calf DVT. Patients with isolated calf DVT are at elevated risk for proximal propagation of the thrombus as well as for development of PE. Calf veins include the gastrocnemius, soleal, peroneal, posterior tibial, and anterior tibial veins. A proportion of patients will have duplicated venous segments that can contribute to underdiagnosis of DVT if the duplicated vein is not imaged.
Upper Extremity Deep Vein Thrombosis
Upper extremity DVT most often affects the subclavian, internal jugular, axillary, and brachial veins as a result of chronic indwelling foreign bodies such as central venous catheters and pacemaker or defibrillator leads [1]. Superior vena cava syndrome may complicate an upper extremity DVT secondary to venous foreign bodies or may result from thoracic malignancy with extrinsic compression of the upper extremity veins. Catheter-based fibrinolytic therapy is recommended for patients with acute proximal upper extremity DVT and severe symptoms, low risk for bleeding, and good functional status [2].
Pelvic Vein Thrombosis
Pelvic vein thrombosis describes DVT of the inferior vena cava (IVC), gonadal veins, and common, internal, and external iliac veins.
Mesenteric Vein Thrombosis
Mesenteric vein thrombosis describes DVT of the superior mesenteric vein most commonly but may also involve the inferior mesenteric vein, splenic vein, and portal veins [3].
Cerebral Venous Thrombosis
Cerebral venous thrombosis, including thrombosis of cerebral veins and major dural sinuses, is an uncommon disorder in the general population. However, it has a higher frequency among patients younger than 40 years old, patients with hypercoagulable states, and women who are pregnant or receiving hormonal contraceptive therapy [4].
Pulmonary Embolism
Acute PE describes a number of clinical syndromes, including massive PE, submassive PE, and PE with normal blood pressure and preserved RV function.
Massive Pulmonary Embolism
Massive PE accounts for approximately 5–10 % of cases and describes a subset of patients with PE who present with syncope, systemic arterial hypotension, cardiogenic shock, or cardiac arrest. The patient in the Clinical Vignette would be categorized as having massive PE because of his syncope and systemic arterial hypotension on presentation.
Submassive Pulmonary Embolism
Normotensive patients with acute PE and evidence of RV dysfunction are classified as having submassive PE and account for approximately 20–25 % of cases. These patients represent a population at increased risk of adverse events and early mortality [5].
Pulmonary Embolism with Normal Blood Pressure and Preserved Right Ventricular Function
Patients with acute PE presenting with normal systemic blood pressure and no evidence of RV dysfunction represent the majority of PE patients (approximately 70 %) and generally have a benign course when treated with standard anticoagulation alone.
Advanced Therapy
Fibrinolysis
Deep Vein Thrombosis
Fibrinolysis plus mechanical disruption of thrombus should provide a greater chance of preserving venous valve patency and function, thereby preventing chronic venous disease including post-thrombotic syndrome. Fibrinolytic therapy should be catheter-directed rather than peripherally-administered in DVT to gain access to the obstructed deep venous system [6].
Pulmonary Embolism
Advanced therapy with systemic fibrinolysis is reserved for patients presenting with either massive or submassive acute PE. The rationale for systemic fibrinolysis administered through a peripheral vein is to rapidly reverse hemodynamic compromise, RV dysfunction, and gas exchange abnormalities. Fibrinolytic therapy reverses systemic arterial hypotension by alleviating RV pressure overload [7]. In patients with submassive PE, fibrinolysis is administered to avert impending hemodynamic collapse and death from progressive right-sided heart failure. Systemic fibrinolysis may also function as a “medical embolectomy” that reduces thrombus burden, pulmonary vascular resistance, and RV dysfunction [8–10], and improves pulmonary capillary blood flow and gas exchange [11]. Finally, systemic fibrinolysis may help prevent the development of chronic thromboembolic pulmonary hypertension [12, 13] by preserving the normal hemodynamic response to exercise [14].
Fibrinolysis is usually considered a lifesaving therapy in patients presenting with massive PE [15–17]. The 2012 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy for Venous Thromboembolism Disease suggest restricting the use of systemic fibrinolysis in submassive PE to a subset of these patients with a low risk of bleeding and a clinician-determined high risk of developing hemodynamic collapse (Grade 2C) [16]. The American Heart Association (AHA) Scientific Statement on Management of Massive and Submassive PE, Iliofemoral DVT, and Chronic Thromboembolic Pulmonary Hypertension recommends considering systemic fibrinolysis for submassive PE patients deemed to have evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis) and a low risk of bleeding (Class IIb; Level of Evidence C) [15]. The 2014 European Society of Cardiology (ESC) Guidelines on the Diagnosis and Management of Acute Pulmonary Embolism recommend systemic fibrinolysis for PE with shock or hypotension (high-risk) (Class of Recommendation I, Level of Evidence B) [17]. The 2014 ESC Guidelines state that fibrinolytic therapy should be considered for patients with intermediate-high risk PE and clinical signs of hemodynamic decompensation (Class of Recommendation IIa, Level of Evidence B).
The Europe-based Pulmonary Embolism International Thrombolysis Trial (PEITHO) is the largest randomized controlled trial of systemic fibrinolysis in submassive PE to date, enrolling 1,006 submassive PE patients. The study evaluated the impact of systemic fibrinolysis with tenecteplase followed by anticoagulation with heparin versus heparin alone on the primary outcome of all-cause mortality or hemodynamic collapse within 7 days of randomization [18]. Fibrinolysis reduced the frequency of the primary outcome (2.6 % vs. 5.6 %, p = 0.015) with the majority of the benefit due to a reduction in hemodynamic collapse within 7 days of randomization (1.6 % vs. 5 %, p = 0.002). However, the benefit of fibrinolysis came at the cost of increased major bleeding (6.3 % vs. 1.5 %, p < 0.001). More than 2 % of the tenecteplase-treated patients suffered intracranial hemorrhage, compared with 0.2 % in the heparin alone group.
Meta-analyses of trials of systemic fibrinolysis for acute PE have demonstrated both important benefits and critical limitations [19, 20]. Chatterjee and colleagues compared 1061 patients treated with fibrinolytic therapy with 1054 patients treated with anticoagulation alone [19]. Fibrinolytic therapy was associated with a reduction in all-cause mortality (2.2 % vs. 3.9 %; adjusted odds ratio [OR], 0.53; 95 % confidence interval, 0.32–0.88) and recurrent PE (1.2 % vs. 3.0 %; adjusted OR, 0.40; 95 % confidence interval, 0.22–0.74) compared with anticoagulation alone, resulting in a number needed to treat of 59 patients. The reduction in all-cause mortality with fibrinolytic therapy was sustained even when the meta-analysis was restricted to patients with submassive PE. Similar to the findings of PEITHO, the benefit of systemic fibrinolysis was offset by an increase in major bleeding (9.2 % versus 3.4 %; adjusted OR, 2.73; 95 % confidence interval, 1.91–3.91) in particular intracranial hemorrhage (1.5 % versus 0.2 %; adjusted OR, 4.78; 95 % confidence interval, 1.78–12.04).
Another meta-analysis by Marti and colleagues confirmed the finding of a reduction in all-cause mortality with fibrinolytic therapy for acute PE (adjusted OR, 0.59; 95 % confidence interval, 0.36–0.96) [20]. However, increased major bleeding (adjusted OR, 2.91; 95 % confidence interval, 1.95–4.36) and fatal or intracranial hemorrhage (adjusted OR, 3.18; 95 % confidence interval, 1.25–8.11) limited the benefit of fibrinolysis. Concern over the risk of intracranial hemorrhage, which approaches 3–5 % outside of clinical trials [21, 22], has dampened clinician enthusiasm for full-dose systemic fibrinolysis and has sparked development of alternative fibrinolytic strategies with lower bleeding risk.
One such alternative strategy focuses on half-dose systemic fibrinolysis [13, 23]. In the Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial, 121 hemodynamically stable patients with acute symptomatic and anatomically large PE were randomized to either half-dose fibrinolysis with t-PA and concomitant anticoagulation versus standard anticoagulation with enoxaparin or heparin [13]. The frequency of pulmonary hypertension at 28 months was lower in patients who received fibrinolytic therapy than in the standard anticoagulation group (16 % vs. 57 %, p < 0.001). No in-hospital bleeding events were reported in either study group. Mean length of hospital stay was decreased in those assigned to the fibrinolytic arm compared with standard anticoagulation (2.2 days vs. 4.9 days, p < 0.001).
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