Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension

Pharmacology of Thrombolytic Agents

In contrast to the passive reduction of thrombus size allowed by heparin, thrombolytic agents actively promote the hydrolysis of fibrin molecules.¹¹⁵ All fibrinolytic drugs approved by the US Food and Drug Administration (FDA) are enzymes that convert the patient's native circulating plasminogen into plasmin. Plasmin is a serine protease that cleaves fibrin at several sites, liberating fibrin-split products, including the D-dimer fragment. Table 3 qualitatively compares several clinically relevant features of fibrinolytic agents that have received approval for use by the FDA. In 2010, the FDA label for alteplase (Activase, Genentech, San Francisco, CA) explicitly stated that the agent is indicated for “… massive pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple segments of the lung, or for unstable hemodynamics, ie, failure to maintain blood pressure without supportive measures.”¹²¹

Potential Benefits and Harm

The decision to administer a fibrinolytic agent in addition to heparin anticoagulation requires individualized assessment of the balance of benefits versus risks. Potential benefits include more rapid resolution of symptoms (eg, dyspnea, chest pain, and psychological distress), stabilization of respiratory and cardiovascular function without need for mechanical ventilation or vasopressor support, reduction of RV damage, improved exercise tolerance, prevention of PE recurrence, and increased probability of survival. Potential harm includes disabling or fatal hemorrhage, including intracerebral hemorrhage, and increased risk of minor hemorrhage, resulting in prolongation of hospitalization and need for blood product replacement.

Quantitative Assessment of Outcomes

Patients treated with a fibrinolytic agent have faster restoration of lung perfusion.^79,122–125 At 24 hours, patients treated with heparin have no substantial improvement in pulmonary blood flow, whereas patients treated with adjunctive fibrinolysis manifest a 30% to 35% reduction in total perfusion defect. However, by 7 days, blood flow improves similarly (≈65% to 70% reduction in total defect). Table 4 summarizes the results of various fibrinolytic agents compared with placebo in the evaluation of the impact of therapy on mean pulmonary arterial pressure.

Thirteen placebo-controlled randomized trials of fibrinolysis for acute PE have been published,^{79,118,120,124,126–134} but only a subset evaluated massive PE specifically. These trials included 480 patients randomized to fibrinolysis and 464 randomized to placebo; 6 of the 13 trials studied alteplase, representing 56% of all patients (n=504). These 6 studies used variable infusion regimens. Two studies administered alteplase by bolus intravenous injection (100 mg or 0.6 mg/kg), and 4 infused 90 to 100 mg of alteplase intravenously over a 2-hour period. Three of the 4 used concomitant infusion of intravenous unfractionated heparin (1000 to 1500 U/h). Four studies used intravenous streptokinase, together enrolling 94 patients. All 4 studies of streptokinase used a bolus dose (250 000 to 600 000 U) followed by a 100 000 U/h infusion for 12 to 72 hours. Two studies that examined urokinase, published in 1973 and 1988, together enrolled 190 patients (Table 5). One study randomized 58 patients to receive weight-adjusted single-bolus intravenous tenecteplase (30 to 50 mg, with a 5-mg increase in dose for every 10 kg of weight from <60 kg to >90 kg) or placebo.

The odds ratios were calculated by use of fixed effects and random effects models.¹³⁵ Table 5 suggests that alteplase treatment was associated with a significantly higher rate of hemorrhage than anticoagulation alone, although these events included skin bruising and oozing from puncture sites. Neither recurrent PE nor death was significantly different in the alteplase versus placebo groups. Alteplase was associated with a trend toward decreased recurrent PE. Similar findings have been reported by Wan et al¹³⁶ and Thabut et al.¹³⁷ When Wan et al¹³⁶ restricted their analysis to those trials with massive PE, they identified a significant reduction in recurrent PE or death from 19.0% with heparin alone to 9.4% with fibrinolysis (odds ratio 0.45, 95% CI 0.22 to 0.90).¹³⁶

Number Needed to Treat

Wan et al,¹³⁶ in their analysis restricted to trials that included fibrinolysis for massive PE, found the number needed to treat to prevent the composite end point of recurrent PE or death was 10. This end point was not statistically significant when all trials, including those that studied less severe forms of PE, were included.¹³⁶ In this analysis, there was no significant increase in major bleeding, but there was a significant increase in nonmajor bleeding; the number needed to harm was 8.¹³⁶ On the other hand, Thabut et al,¹³⁷ using data from all trials regardless of PE severity but before the publication of the largest randomized trial to date, estimated the number needed to harm at 17.

Impact of Fibrinolysis on Submassive PE

At least 4 registries have documented the outcomes of patients with PE (MAPPET,¹⁰ ICOPER,^4,9 RIETE [Registro Informatizado de la Enfermedad TromboEmbólica],^71,139 and EMPEROR [Emergency Medicine Pulmonary Embolism in the Real-World Registry]¹⁴⁰), and the data from these are summarized in Table 6. The data suggest a trend toward a decrease in all-cause mortality from PE, especially massive PE in those patients treated with fibrinolysis. The 30-day mortality rate directly attributed to PE in normotensive patients in the recently completed EMPEROR registry was 0.9% (95% CI 0 to 1.6). Data from these registries indicate that the short-term mortality rate directly attributable to submassive PE treated with heparin anticoagulation is probably <3.0%. The implication is that even if adjunctive fibrinolytic therapy has extremely high efficacy, for example, a 30% relative reduction in mortality, the effect size on mortality due to submassive PE is probably <1%. Thus, secondary adverse outcomes such as persistent RV dysfunction, CTEPH, and impaired quality of life represent appropriate surrogate goals of treatment.

Impact of Fibrinolysis on Intermediate Outcomes

Among PE patients, to determine whether adjunctive fibrinolytic therapy can effectively reduce the outcome of dyspnea and exercise intolerance from PE caused by persistent pulmonary hypertension (World Health Organization [WHO] Group 4 pulmonary hypertension), it is first necessary to examine the incidence of persistently elevated RV systolic pressure (RVSP) or pulmonary arterial pressure, measured 6 or more months after acute PE. The current literature includes only 4 studies that report baseline and follow-up RVSP or pulmonary arterial pressures by use of pulmonary arterial catheter or Doppler echocardiography.^142–145 Table 7 summarizes these findings. These data suggest that compared with heparin alone, heparin plus fibrinolysis yields a significant favorable change in RVSP and pulmonary arterial pressure incident between the time of diagnosis and follow-up.

The largest study, accounting for 162 of the 205 patients, was the only one that was prospectively designed to assess outcomes for all survivors at 6 months.¹⁴⁵ All patients were normotensive at the time of enrollment. Follow-up included Doppler echocardiographic estimation of the RVSP, a 6-minute walk test, and New York Heart Association (NYHA) classification. The study protocol in that report recommended addition of alteplase (0.6 mg/kg infused over 2 hours) for patients who experienced hemodynamic deterioration, defined as hypotension, cardiac arrest, or respiratory failure requiring mechanical ventilation. Figure 1 shows the change in individual RVSP values for each patient in the study. Among the 144 patients who received heparin only, 39 (27%) demonstrated an increase in RVSP at 6-month follow-up, and 18 (46%) of these 39 patients had either dyspnea at rest (NYHA classification more than II) or exercise intolerance (6-minute walk distance <330 m). The mean 6-minute walk distance was 364 m for the alteplase group versus 334 m for the heparin-only patients. No patient treated with adjunctive alteplase demonstrated an increase in RVSP at 6-month follow-up, which suggests that thrombolytic therapy may have the benefit of decreasing the incidence of CTEPH.

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Figure 1.

Right ventricular systolic pressures at diagnosis and 6 months after acute submassive pulmonary embolism. Left Panel, Patients initially treated with heparin and alteplase. Right Panel, Patients who received heparin alone. Plots for patients with a net increase in systolic pressure are highlighted in red. Reprinted from Kline et al¹⁴⁵ with permission of the publisher. Copyright © 2009, American College of Chest Physicians.

Contraindications to Fibrinolysis

Because of small sample sizes and heterogeneity, the clinical trials presented in Table 5 provide limited guidance in establishing contraindications to the use of fibrinolytic agents in PE. Contraindications must therefore be extrapolated from author experience and from guidelines for ST-segment elevation myocardial infarction.¹⁴⁶ Absolute contraindications include any prior intracranial hemorrhage, known structural intracranial cerebrovascular disease (eg, arteriovenous malformation), known malignant intracranial neoplasm, ischemic stroke within 3 months, suspected aortic dissection, active bleeding or bleeding diathesis, recent surgery encroaching on the spinal canal or brain, and recent significant closed-head or facial trauma with radiographic evidence of bony fracture or brain injury. Relative contraindications to fibrinolysis include age >75 years; current use of anticoagulation; pregnancy; noncompressible vascular punctures; traumatic or prolonged cardiopulmonary resuscitation (>10 minutes); recent internal bleeding (within 2 to 4 weeks); history of chronic, severe, and poorly controlled hypertension; severe uncontrolled hypertension on presentation (systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg); dementia; remote (>3 months) ischemic stroke; and major surgery within 3 weeks. Recent surgery, depending on the territory involved, and minor injuries, including minor head trauma due to syncope, are not necessarily barriers to fibrinolysis. The clinician is in the best position to judge the relative merits of fibrinolysis on a case-by-case basis.

Synthesis of Data Into a Treatment Algorithm

Figure 2 summarizes the treatment options for acute PE. Patients with low-risk PE have an unfavorable risk-benefit ratio with fibrinolysis. Patients with PE that causes hypotension probably do benefit from fibrinolysis. Management of submassive PE crosses the zone of equipoise, requiring the clinician to use clinical judgment.

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Figure 2.

Suggested treatment algorithm for use of fibrinolytics to treat acute pulmonary embolism. PE indicates pulmonary embolism; RV, right ventricular; SBP, systolic blood pressure; RVSP, right ventricular systolic pressure; BNP, brain natriuretic peptide; and IV, intravenously.

Two criteria can be used to assist in determining whether a patient is more likely to benefit from fibrinolysis: (1) Evidence of present or developing circulatory or respiratory insufficiency; or (2) evidence of moderate to severe RV injury. Evidence of circulatory failure includes any episode of hypotension or a persistent shock index (heart rate in beats per minute divided by systolic blood pressure in millimeters of mercury) >1.¹⁴⁷ The definition of respiratory insufficiency may include hypoxemia, defined as a pulse oximetry reading <95% when the patient is breathing room air and clinical judgment that the patient appears to be in respiratory distress.^147,148 Alternatively, respiratory distress can be quantified by the numeric Borg score, which assesses the severity of dyspnea from 0 to 10 (0=no dyspnea and 10=sensation of choking to death); fewer than 10% of patients with acute PE report a Borg score >8 at the time of diagnosis.¹⁴⁹ Evidence of moderate to severe RV injury may be derived from Doppler echocardiography that demonstrates any degree of RV hypokinesis, McConnell's sign (a distinct regional pattern of RV dysfunction with akinesis of the mid free wall but normal motion at the apex), interventricular septal shift or bowing, or an estimated RVSP >40 mm Hg. Biomarker evidence of moderate to severe RV injury includes major elevation of troponin measurement or brain natriuretic peptides. A limitation of this approach is that these variables are generally presented as dichotomous, and there are no universally agreed on thresholds for minor or major abnormalities. Practical judgment of the bedside physician is required.

We recommend administration of a fibrinolytic via a peripheral intravenous catheter.¹⁵⁰ Figure 2 incorporates the FDA-recommended infusion dose of alteplase at 100 mg as a continuous infusion over 2 hours.¹²¹ The FDA recommends withholding anticoagulation during the 2-hour infusion period.

Two ongoing randomized controlled trials (RCTs) will help address the controversial question about which patients with submassive PE will benefit from fibrinolysis. Both trials use tenecteplase as the fibrinolytic, an agent that is not approved by the FDA for treatment of PE. The larger trial (the Pulmonary EmbolIsm THrOmbolysis Study [PEITHO]; ClinicalTrials.gov Identifier NCT00639743) is being conducted in Europe and has enrolled 500 of the planned enrollment of 1000 patients. Its inclusion criteria are RV dysfunction on echocardiography plus a positive troponin I or T measurement. The primary outcomes are development of circulatory shock or respiratory failure as an inpatient. The US trial (Tenecteplase Or Placebo: Cardiopulmonary Outcomes At Three Months [TOPCOAT]; ClinicalTrials.gov Identifier NCT00680628) will enroll 200 normotensive PE patients with either RV hypokinesis on echocardiography, an abnormal troponin measurement, a BNP >90 pg/mL or pro-BNP >900 pg/mL, or a pulse oximetry reading <95% when breathing room air (at altitudes <100 feet above sea level). The main outcome in TOPCOAT is evidence of RV dysfunction associated with an NYHA classification worse than II and a 6-minute walk distance <330 m at 3-month follow-up.

It is preferable to confirm the diagnosis of PE with imaging before fibrinolysis is initiated. When direct imaging is unavailable or unsafe because of the patient's unstable condition, an alternative approach favors aggressive early management, including fibrinolysis, of the patient with sustained hypotension (systolic blood pressure <90 mm Hg for at least 15 minutes or requiring inotropic support, not clearly due to a cause other than PE) when there is a high clinical pretest probability of PE and RV dysfunction on bedside transthoracic echocardiography.^2,151 We do not endorse the strategy of treating subjects with undifferentiated cardiac arrest with fibrinolysis, because this approach lacks clinical benefit.¹⁵²

Initial Anticoagulant Therapy

IFDVT patients should receive initial anticoagulant therapy for the prevention of PE and recurrent DVT.¹⁹⁰ Because there is no published evidence to support the use of different anticoagulant dosing schemes for IFDVT patients as opposed to other patients with proximal DVT, we recommend the initial use of 1 of the following regimens in adults: (1) Intravenous UFH at an initial bolus of 80 U/kg followed by a continuous intravenous infusion, initially dosed at 18 U · kg⁻¹ · h⁻¹, with dose adjustment to target a partial thromboplastin time prolongation that corresponds to plasma heparin levels of 0.3 to 0.7 IU/mL anti-factor Xa activity, for 5 to 7 days^191–194; (2) LMWH by subcutaneous injection, without routine anti-factor Xa monitoring (regimens such as enoxaparin twice daily at 1 mg/kg or once daily at 1.5 mg/kg, dalteparin once daily at 200 IU/kg or twice daily at 100 IU/kg, or tinzaparin once daily at 175 anti-Xa IU/kg)^195–202; or (3) fondaparinux by subcutaneous injection once daily at 5 mg for patients weighing <50 kg, 7.5 mg for patients weighing 50 to 100 kg, or 10 mg for patients weighing >100 kg.^203,204 Fixed-dose weight-adjusted subcutaneous UFH could also be considered, although data are more limited for this regimen.²⁰⁵ In children, the weight-based dosing of agents will vary with patient age.^206–209 No published studies directly address the appropriateness of outpatient therapy with UFH, LMWH, or fondaparinux for the IFDVT subgroup specifically. After consideration of the patient's overall medical condition, the presence of symptomatic PE, and the need for home support services, it is reasonable to administer LMWH or fondaparinux to selected IFDVT patients in the outpatient setting.^208–213 In IFDVT patients with suspected or proven heparin-induced thrombocytopenia, we recommend initial anticoagulation with intravenous direct thrombin inhibitors (eg, argatroban, lepirudin), as for other proximal DVT patients with heparin-induced thrombocytopenia.^214–217

Long-Term Anticoagulant Therapy for Patients With IFDVT

Most adult patients with IFDVT receive oral warfarin as first-line long-term anticoagulant therapy, overlapped with initial anticoagulant therapy for a minimum of 5 days and until the international normalized ratio (INR) is ≥2.0 for at least 24 hours, and then targeted to an INR of 2.0 to 3.0.^218–227 Recently published RCT data suggest that the oral direct thrombin inhibitor dabigatran is as safe and effective as warfarin for acute VTE and does not require laboratory monitoring,²²⁸ although data about dabigatran for IFDVT specifically are unavailable. Although it is possible that the higher risk of recurrent DVT and PTS in IFDVT patients^181,185 merits more rigorous therapy than for proximal non-IFDVT, there is no current evidence to support the use of a higher intensity or longer duration of warfarin, or longer-term use of parenteral anticoagulants, in this subgroup. Treatment duration decisions should be based on VTE risk factors, presence of recurrent VTE episodes, tolerance of anticoagulation, bleeding risk factors, and patient preferences.^229,230

Three major patient groups can be defined: (1) In general, anticoagulation may be safely stopped after 3 months in most patients with a first-episode of DVT related to a major reversible risk factor (ie, recent surgery or trauma).^{219,220,231–234} (2) Patients with recurrent DVT or unprovoked DVT should be considered for treatment of indefinite duration, with periodic reassessment of risk and benefit.^{221,224,235–237} (3) For most cancer patients with DVT, first-line therapy should be weight-based LMWH monotherapy for at least 3 to 6 months, or as long as the cancer or its treatment (eg, chemotherapy) is ongoing.^238–240 LMWH monotherapy regimens (without oral anticoagulation) studied in RCTs of adult cancer patients with normal renal function have included the following: (1) Dalteparin administered by once-daily subcutaneous injection at 200 IU/kg (maximum 18 000 IU) for the first 4 weeks, followed by ≈150 IU/kg thereafter; (2) tinzaparin administered by once-daily subcutaneous injection at 175 anti-Xa IU/kg; and (3) enoxaparin given by once-daily subcutaneous injection at 1.5 mg/kg. If there are barriers to long-term use of LMWH, the use of warfarin with a target INR of 2.0 to 3.0 is a reasonable alternative. The use of direct thrombin inhibitors for the initial and long-term treatment of DVT has also shown significant promise.²²⁸ If shown to be effective after further study, the use of these or other new agents may alter optimal medical therapy for IFDVT.

In children, the use of LMWH monotherapy as either the first-line or a second-line method for long-term DVT treatment may be reasonable.^241–243

Compression Therapy

IVC Filters in Patients With IFDVT

Systemic Thrombolysis

In adult RCTs, >50% clot lysis was seen more frequently in proximal DVT patients treated with systemic intravenous administration of streptokinase than in patients treated with heparin (62% versus 17%, P<0.0001).²⁷⁷ In limited long-term follow-up studies, the streptokinase-treated patients had significantly lower PTS rates (relative risk reduction 62% to 64%).^266,267 Turpie et al²⁶⁸ found that systemic tissue plasminogen activator infusion achieved ≥50% clot lysis more often than heparin alone in proximal DVT patients (58% versus 0%, P=0.002), with a trend toward reduced PTS in successfully lysed patients (25% versus 56%, P=0.07). However, major bleeding was increased significantly with use of systemic thrombolysis (14% versus 4% for streptokinase infusions, P<0.04).^268,277,278 These studies did not focus solely on IFDVT, but such patients were included in the subject populations. Therefore, we recommend against the use of systemic thrombolysis for the treatment of IFDVT in adult patients. If thrombolysis is desired but endovascular expertise is not locally available, patient transfer to an institution that offers access to endovascular thrombolysis is recommended in preference to attempts at use of systemic thrombolysis.

Catheter-Directed Thrombolysis

Catheter-directed thrombolysis (CDT) refers to the infusion of a thrombolytic agent directly into the venous thrombus via a multiple–side-hole catheter with the use of imaging guidance.^182,273 In a 473-patient prospective multicenter registry, the use of urokinase CDT resulted in successful fibrinolysis in 88% of patients with acute IFDVT.²⁷⁴ CDT was more often successful in patients with recent (≤10 to 14 days) onset of symptoms. In a follow-up study of 68 IFDVT patients from this registry who had initially successful CDT, Comerota et al²⁷¹ found these patients to have fewer PTS symptoms and improved quality of life at 16-month follow-up compared with a group of 30 retrospectively identified IFDVT patients who had received anticoagulation alone. AbuRahma et al²⁷² found more frequent 5-year symptom resolution (78% versus 30%, P=0.0015) in IFDVT patients receiving CDT plus anticoagulant than in those given anticoagulant alone in a small (n=51), prospective, nonrandomized study. In a small (n=35) RCT, Elsharawy et al²⁷⁵ reported that streptokinase CDT plus anticoagulation yielded a higher rate of normal physiological venous function (72% versus 12%, P<0.001) and less valvular reflux (11% versus 41%, P=0.04) at 6 months than anticoagulation alone. In an open-label multicenter RCT of 118 IFDVT patients, Enden et al²⁷⁶ found that rtPA CDT plus anticoagulation resulted in better 6-month venous patency (64% versus 36%, P=0.004), less functional venous obstruction (20% versus 49%, P=0.004), and no difference in femoropopliteal venous reflux (60% versus 66%, P=0.53) compared with anticoagulant alone.

In a 473-patient CDT registry²⁷⁴ that evaluated patients treated in 62 US centers in the 1990s with a variety of urokinase dosing schemes, major bleeding occurred in 11.4%, which diminished initial enthusiasm for this treatment. In the recently published 118-patient Norwegian RCT noted above,²⁷⁶ in which rtPA infusions of 0.01 mg · kg⁻¹ · h⁻¹ were used, CDT plus anticoagulation was associated with major bleeding in 2.0% (major bleeding occurred in 1.7% of patients treated with anticoagulant alone; statistics not provided). In 4 retrospective studies that used similar rtPA infusion dosing, major bleeding rates were 2% to 4%.^278–281 The lower major bleeding rates in contemporary rtPA studies than in the urokinase registry may reflect the use of different drug regimens, less access-site bleeding because of the incorporation of routine ultrasound-guided venipuncture into endovascular practice, the contemporary use of “subtherapeutic” heparin dosing while rtPA is being infused, different patient selection criteria, or a combination of these factors. In the 2 prospective studies noted above, the mean thrombolytic infusion time was approximately 54 hours. IVC filters were not routinely deployed, yet the rates of symptomatic PE were 1.3% (including 0.2% fatal PE) and 0%, respectively, with CDT.^274,276

Reteplase and tenecteplase have also been used as fibrinolytic drugs for CDT of IFDVT,^282–284 and a new form of CDT that incorporates low-power ultrasound to enhance fibrinolysis has been introduced²⁸⁵; however, there are no rigorous prospective studies of these methods. The clinical spectrum of IFDVT treated successfully with CDT is broad and includes patients with phlegmasia cerulea dolens,^286,287 patients with thrombus progression or symptom worsening despite initial anticoagulation,²⁸⁸ and patients receiving first-line CDT for PTS prevention.²⁷⁵

Percutaneous Mechanical, and Pharmacomechanical Thrombolysis

Percutaneous mechanical thrombectomy (PMT) refers to the use of a catheter-based device that contributes to thrombus removal via mechanical thrombus fragmentation, maceration, and/or aspiration.¹⁸² There is no evidence that any particular device is sufficiently effective as a stand-alone therapy for DVT, and use of some devices without concomitant thrombolytic agent administration may be associated with symptomatic PE.^289–291 However, retrospective comparative studies suggest that pharmacomechanical CDT (PCDT, or thrombus dissolution via the combined use of CDT and PMT), provides comparable clot-removal efficacy as drug-only CDT but with major (40% to 50%) reductions in the needed thrombolytic drug dose, infusion time, and hospital resource use.^292–294 Several nonrandomized studies suggest that with the use of some devices, thrombus removal can be accomplished in a single procedure session, which obviates the need for overnight infusion.^295–300 However, there are no rigorously performed prospective studies to validate this finding, and there may be risks associated with greater mechanical manipulation of the thrombus and vein.^295,300 No PCDT studies have systematically evaluated recurrent DVT and PTS.

Thrombolysis in Pediatric Patients

Limited clinical studies have demonstrated that PTS affects both children and adults.^301,302 In very limited populations, systemic thrombolysis and endovascular thrombolysis have been used to treat children and adolescents deemed to be at particularly high risk for PTS.^303,304 In small numbers of older adolescents, adult CDT and PCDT regimens were used.^288,297,305

Patient Selection for CDT or PCDT

Only operators experienced with these techniques should perform catheter-based intervention. The use of endovascular thrombolysis as an adjunct to anticoagulant therapy is reasonable for patients with acute IFDVT associated with limb-threatening circulatory compromise (ie, phlegmasia cerulea dolens), rapid thrombus extension despite anticoagulation, or symptomatic deterioration despite anticoagulation provided there is a low expected risk of bleeding complications. For first-line treatment of carefully selected patients with acute IFDVT, the use of CDT or PCDT (along with anticoagulation) to achieve more rapid relief of presenting DVT symptoms and to prevent PTS is reasonable. There are no published long-term outcome data from a multicenter RCT, so the potential benefits of therapy must be weighed carefully against the risk of bleeding. Patient selection should be based on a careful assessment of the severity of DVT symptoms, comorbidities, baseline capacity for ambulation, life expectancy, and patient preferences for an aggressive treatment approach. This approach should not be used for most IFDVT patients in whom the onset of DVT symptoms was >21 days before presentation or who are at higher expected risk for bleeding. In pediatric patients with occlusive IFDVT, the use of thrombolytic therapy to reduce the risk of PTS may be considered in carefully selected patients.

Choice of Endovascular Thrombolysis

No differences between the efficacy or safety of CDT, early-generation PCDT, or single-session PCDT have been established conclusively. Because PCDT reduces thrombolytic drug exposure and may therefore reduce bleeding, selection of PCDT instead of CDT may be reasonable in most patients undergoing endovascular thrombolysis. No differences between the efficacy or safety of different thrombolytic drugs used for CDT or PCDT have been established conclusively. When drug-only CDT is performed with rtPA, we suggest the use of 0.01 mg · kg⁻¹ · h⁻¹ rather than higher doses. When drug-only CDT is performed using urokinase, we suggest the use of 120 000 to 180 000 U/h. We recommend against the use of PMT without a thrombolytic drug unless there are contraindications to use of a thrombolytic drug.

Use of Other Standard DVT Treatments in Patients Undergoing CDT or PCDT

Before and after CDT or PCDT, therapeutic-level anticoagulation with similar dosing, monitoring, and treatment duration as for IFDVT patients who are not undergoing thrombolysis should be used. During CDT infusions, reduced-dose UFH may be safer than therapeutic-level UFH. This is based on indirect evidence from arterial thrombolysis trials,³⁰⁶ the finding that supertherapeutic heparin is associated with thrombolysis-related bleeding,³⁰⁷ the low major bleeding rate observed in an RCT in which reduced-dose heparin was used along with CDT for the treatment of proximal DVT,²⁷⁶ and expert consensus. However, during single-session PCDT or stand-alone PMT, both of which involve greater mechanical manipulation, it may be reasonable to use therapeutic-level UFH. LMWH has also been used along with PCDT, but there are no studies to support or refute this practice. No studies report on the concomitant use of fondaparinux or other parenteral anticoagulants, such as direct thrombin inhibitors, along with CDT or PCDT, or on the clinical outcomes associated with the use of antiplatelet therapies during or after thrombolysis. Like other patients with proximal DVT, IFDVT patients who undergo CDT or PCDT should wear 30– to 40–mm Hg knee-high ECS for at least 2 years after the diagnosis of DVT. We recommend against periprocedural IVC filter placement for most IFDVT patients undergoing drug-only infusion CDT.^274,276 Preprocedure placement and postprocedure removal of retrievable IVC filters may be reasonable in carefully selected IFDVT patients undergoing PCDT or stand-alone PMT, depending on the thrombus extent, patient factors such as baseline cardiopulmonary status, and the specific clot-removal methods that will be used.^295,300

Surgical Venous Thrombectomy

Contemporary surgical venous thrombectomy is an alternative method of removing thrombus in IFDVT. In 1 small RCT of 41 patients, the use of surgical thrombectomy as an adjunct to anticoagulation significantly reduced venous symptoms (58% versus 93%, P<0.005), venous obstruction (24% versus 65%, P<0.025), and valvular reflux (14% versus 59%, P<0.05) in acute IFDVT patients at 6-month follow-up.²⁶⁹ After 5 years, many patients were lost to follow-up, but in those available, absence of symptoms was more common in the surgical patients (37% versus 18%), although this difference was not significant.²⁷⁰ Operative intervention is invasive, requires general anesthesia, and may carry a small additional risk of PE. Nevertheless, given the potential to prevent PTS, in selected patients with acute IFDVT with contraindications to or failure of CDT or PCDT, surgical venous thrombectomy by experienced surgeons may be a reasonable strategy to decrease long-term morbidity due to PTS.

Acute DVT Setting

In a 473-patient CDT registry, patients who received iliac vein stents had greater venous patency at 1 year than those who did not, although these were not equivalent patient subsets.²⁷⁴ A study that included 52 patients with acute IFDVT who underwent thrombus aspiration and PMT followed by stent placement observed primary stent patency in 83% at 6-month follow-up.³⁰⁹ In 2 retrospective studies of 106 patients with acute IFDVT who had surgical venous thrombectomy, the intraoperative use of stents to treat iliac vein obstructive lesions was associated with 12% to 14% rates of early rethrombosis. In the larger study, a nonstented control group experienced postoperative early rethrombosis in 73% of cases (P<0.01).^310,311 In 1 of these studies, stent fracture with rethrombosis was observed in 1 pregnant woman.³¹¹ However, in a study of 62 women who received left iliac vein stents, later became pregnant, and received LMWH prophylaxis during pregnancy, no patient had recurrent VTE during pregnancy or the postpartum period.³¹² In that study, 4 patients had mechanical stent deformation shown by Duplex ultrasound late in pregnancy, but it resolved spontaneously postpartum without apparent clinical sequelae.

Treatment of PTS

The results of 2 large, nonrandomized, single-center experiences show that stent recanalization of chronically occluded iliac veins in patients with advanced PTS appears to offer significant potential to reduce PTS symptoms, improve quality of life, and enable healing of venous ulcers.^313–315 The anatomic success rate for stent-based recanalization of the occluded vein (without concomitant thrombolysis) was 83% to 98%.³¹⁴ Initial reduction in lower extremity pain and swelling occurred in >95% of patients and was maintained at 3 years in 79% and 66% of patients, respectively, in the larger study. Scores on the Chronic Venous Insufficiency Questionnaire, a validated venous disease–specific quality-of-life measure, were improved significantly, and ulcer healing occurred in 56% of affected patients. Another large study (n=493) found that in patients with PTS, self-expandable stent patency in those who required stent extension below the inguinal ligament to treat associated common femoral vein obstruction was reduced only slightly compared with patients in whom stents were limited to the iliac vein (90% versus 84%, P=0.0378).³¹³ Notably, stent fracture was rare (1 patient only), did not cause problems beyond thrombosis of that vessel, and was treated successfully with insertion of a second stent.

Use of Percutaneous Transluminal Venous Angioplasty and Stents

The use of stent placement is reasonable to treat venous lesions that obstruct flow in the iliac vein after preceding CDT, PCDT, or surgical venous thrombectomy for acute IFDVT in adults and older adolescents. For obstructive iliac vein lesions that extend into the common femoral vein, caudal extension of stents into the common femoral vein is reasonable if unavoidable. The use of percutaneous transluminal venous angioplasty (without stent placement) to treat lesions that obstruct flow in the femoral vein after initial CDT or PCDT in adults and older adolescents is reasonable. The use of percutaneous transluminal venous angioplasty in children may be reasonable, but this practice has not been well studied and may be associated with a greater risk of vasospasm. The placement of iliac vein stents to reduce PTS symptoms and heal venous ulcers in patients with advanced PTS and iliac vein obstruction is reasonable. After stent placement, the use of therapeutic-level anticoagulant therapy using similar dosing, monitoring, and duration as for IFDVT patients who do not have stents is reasonable for most patients. After stent placement, the use of concurrent antiplatelet therapy (ie, along with therapeutic anticoagulation) may be reasonable in selected patients believed to be at particularly high risk of rethrombosis (eg, because of poor inflow vein quality or an imperfect anatomic result after intervention) after an individualized assessment of the patient's bleeding risk.^310,314,316

Incidence of CTEPH

The true incidence of CTEPH is unknown. Ribeiro et al³²³ prospectively assessed pulmonary hemodynamics using echocardiographic measures of pulmonary artery systolic pressure in a cohort of 78 patients with acute PE studied between 1988 and 1992 with up to 5 years of follow-up. In this cohort, 43.5% of patients had mild pulmonary hypertension, with a pulmonary artery systolic pressure >30 mm Hg or RV systolic dysfunction at 1 year, and 5.1% had a pulmonary artery systolic pressure >40 mm Hg at 1 year. Of those patients with pulmonary artery systolic pressure >40 mm Hg at 1 year, 75% underwent pulmonary endarterectomy surgery within 5 years, whereas no subjects with lower pulmonary artery systolic pressures required surgery. Pulmonary artery pressure declined to a plateau at approximately 38 days after the acute PE and then stabilized with no further resolution, with a similar plateau for RV function, which suggests that an echocardiogram 6 weeks after acute PE might predict subsequent CTEPH. Pengo et al³²⁴ evaluated a cohort of 223 patients properly anticoagulated for 6 months after acute PE over a follow-up period of ≈94 months. The study used a CTEPH case definition of systolic and mean pulmonary artery pressures exceeding 40 and 25 mm Hg, respectively; normal pulmonary capillary wedge pressure; and angiographic evidence of thrombotic pulmonary artery obstruction.³²⁴ Eighteen patients died within 2 days of the acute PE, for a case fatality rate of 8.1%. During follow-up, there were 23 additional deaths. Seven patients with a first-time PE developed CTEPH, for a cumulative 2-year incidence of CTEPH of 3.8%; no patients developed CTEPH later than 2 years after the index PE. These 2 studies suggest that as many as 1 in 25 patients with an initial episode of acute PE will subsequently develop CTEPH. Another estimate of CTEPH incidence, based on the 2003 US Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample Database, is 3.4%, which represents >5000 cases of CTEPH in the United States in 2003.³²⁵ However, because ≈60% of individuals diagnosed with CTEPH have no antecedent history of acute VTE,³¹⁹ the true incidence of this disorder may be higher.

Pathophysiology of CTEPH

Treatment of acute PE usually results in improved pulmonary hemodynamic status,³²³ but residual thrombus remains despite adequate anticoagulation at 1 year in as many as half of all patients.³²⁶ If the acute PEs have not resolved in 1 to 4 weeks, the embolic material becomes incorporated into the pulmonary arterial wall at the main pulmonary artery, lobar, segmental, or subsegmental levels.³²⁷ Over time, the initial embolic material is remodeled into connective and elastic tissue, which contains endothelial and smooth muscle precursor cells.³²⁸ Visualization of the pulmonary arteries by angioscopy a few weeks after unresolved PE reveals vessel narrowing at the site of embolic incorporation and vessel wall remodeling.³²⁹ In some patients, recanalization of some of the pulmonary arterial branches occurs, with the formation of fibrous tissue called bands and webs.³³⁰ In most cases, these changes do not result in CTEPH. However, by a mechanism that is poorly understood, chronic thromboembolic obstruction may also lead to a small-vessel arteriolar vasculopathy characterized by excessive vascular and inflammatory cell proliferation around small precapillary arterioles in the pulmonary circulation.³³¹ These pulmonary microvascular changes resemble the arteriopathy observed in WHO Group I or idiopathic pulmonary hypertension and are gaining increased recognition as contributors to disease progression in CTEPH.³³² Pulmonary hypertension results when the capacitance of the remaining healthy vascular beds cannot absorb the cardiac output, either because of the degree of primary obstruction by thromboembolic material and adjacent remodeling or because of the combination of a proximal obstruction and secondary small-vessel vasculopathy. The importance of pulmonary arteriolar remodeling in the development of CTEPH is supported by the following observations: (1) There is often a lack of correlation between elevated pulmonary arterial pressure and the degree of angiographic pulmonary vascular bed obstruction; (2) pulmonary hypertension can progress in the absence of recurrent thromboembolism; and (3) total PVR is still significantly higher in CTEPH patients than in acute PE patients with a similar degree of proximal vascular bed obstruction.^333,334

Thromboembolic Disease Classification

Four major types of pulmonary occlusive disease, which are based on anatomic location of thrombus and vessel wall pathology, have been described.³³⁵ This classification of disease may be useful in predicting outcomes after pulmonary endarterectomy^335,336:

1. Type 1 disease (≈25% of cases of thromboembolic pulmonary hypertension; Figure 3A): Fresh thrombus in the main or lobar pulmonary arteries.

2. Type 2 disease (≈40% of cases; Figure 3B): Intimal thickening and fibrosis with or without organized thrombus proximal to segmental arteries. In these cases, only thickened intima can be seen on initial dissection into the pulmonary arteries, occasionally with webs in the main or lobar arteries.

3. Type 3 disease (≈30% of cases; Figure 3C): Fibrosis, intimal webbing, and thickening with or without organized thrombus within distal segmental and subsegmental arteries only. This type of disease presents the most challenging surgical situation. No occlusion of vessels can be seen initially. The endarterectomy plane must be raised individually in each segmental and subsegmental branch. Type 3 disease may represent “burned out” disease, in which most of the proximal embolic material has been reabsorbed.

4. Type 4 disease (fewer than 5% of cases): Microscopic distal arteriolar vasculopathy without visible thromboembolic disease. Type 4 disease does not represent classic CTEPH and is inoperable. In this entity, there is intrinsic small-vessel disease, although secondary thrombus may occur as a result of stasis.³³² Small-vessel disease may be unrelated to thromboembolic events (misdiagnosed WHO Group I pulmonary arterial hypertension [PAH]) or occur in relation to previous (now resolved) thromboembolic vascular occlusion as a result of a high-flow or high-pressure state in previously unaffected vessels.

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Figure 3.

Representative pulmonary endarterectomy specimens. A, Type 1 disease (≈25% of cases of thromboembolic pulmonary hypertension): Fresh thrombus in the main or lobar pulmonary arteries. B, Type 2 disease (≈40% of cases): Intimal thickening and fibrosis with or without organized thrombus proximal to segmental arteries. In these cases, only thickened intima can be seen on initial dissection into the pulmonary arteries, occasionally with webs in the main or lobar arteries. C, Type 3 disease (≈30% of cases): Fibrosis, intimal webbing, and thickening with or without organized thrombus within distal segmental and subsegmental arteries only. No occlusion of vessels can be seen initially.

Predisposing Factors for CTEPH

The cohort of symptomatic post-PE patients studied by Pengo and colleagues³²⁴ suggested that predictors of CTEPH include multiple episodes of PE, larger perfusion defect, and younger age. Case series have suggested an increased risk of CTEPH in patients with prior splenectomy, permanent intravenous catheters, ventriculoatrial shunts, and chronic inflammatory conditions, including inflammatory bowel disease and osteomyelitis.^337–339 In addition to these observations, associations with sickle cell disease, hereditary stomatocytosis, Klippel-Trenaunay syndrome, thyroid hormone–replacement therapy, and history of malignancy have been described.³¹⁹ The approximate 2:1 predominance of CTEPH among women and the higher overall incidence of chronic thromboembolic disease in Japanese patients compared with cohorts in the United States³⁴⁰ suggest possible differences due to race, sex, or environmental exposure. Laboratory abnormalities that may predispose patients to CTEPH after prior PE include the lupus anticoagulant (10% of CTEPH patients),³⁴¹ antiphospholipid antibodies in general (20% of CTEPH patients),³⁴² elevated plasma levels of factor VIII (39% of patients),³⁴³ and inherited deficiencies of antithrombin III, protein C, and protein S.^344–346 Other hematologic abnormalities observed in CTEPH include heparin-induced platelet antibodies,³⁴⁷ increased resistance to fibrinolysis,³⁴⁸ and decreased thrombomodulin levels.³⁴⁹ However, the majority of cases of CTEPH are not linked to a specific coagulation defect or underlying medical condition.

Natural History of CTEPH

Traditionally, the prognosis of CTEPH has been presumed to be very poor, although the asymptomatic or less severe cases of CTEPH may have been unrecognized previously,¹⁴⁵ which would bias estimates of prognosis. The risk of death due to right-sided heart failure in patients with undiagnosed or untreated CTEPH is correlated with pulmonary artery pressure at diagnosis. In 1 series, the mortality rate was ≈70% among patients with a mean pulmonary artery pressure >40 mm Hg, increasing to 90% at >50 mm Hg.³⁵⁰ Despite improved understanding of pathogenesis, diagnosis, and management, untreated CTEPH is usually a fatal disease.

Clinical Presentation of CTEPH

Patients with CTEPH usually present with subtle or nonspecific symptoms. The most common symptom is progressive exertional dyspnea with exercise intolerance.³⁵¹ Because of the large area of the pulmonary vascular bed, 60% to 70% of the vasculature must be occluded before pulmonary hypertension is observed in a patient at rest.³⁵² Dyspnea experienced by patients with CTEPH is usually out of proportion to any abnormalities found on clinical examination. As the disease progresses, additional symptoms such as chest pain, light-headedness, and syncope may develop. Nonspecific chest pain occurs in ≈50% of patients with more severe CTEPH.³⁵³ Hemoptysis may result from abnormally dilated vessels distended by intravascular pressures. Peripheral edema, early satiety, and epigastric fullness or pain may develop as the right side of the heart fails. There are no consistent physical signs in patients with CTEPH, and the physical examination may be unrevealing if right-sided heart failure has not occurred. With advancing right-sided heart disease, typical signs of pulmonary hypertension are found, including large V waveforms in the jugular venous pulse, an RV heave palpable at the left lower sternal border, a loud P₂ sound of pulmonary valve closure, and an S₃ or S₄ gallop auscultated over the RV. Patients with advanced disease may be hypoxic and cyanotic.

Diagnostic Evaluation of CTEPH

Patients with a history of DVT, PE, or both who present with dyspnea, exercise intolerance, or clinical evidence of right-sided heart failure should undergo diagnostic evaluation for CTEPH. Pulmonary vascular disease should be considered in the differential diagnosis of unexplained dyspnea. The diagnostic evaluation for CTEPH has 3 aims: (1) To establish the presence and severity of pulmonary hypertension and resultant cardiac dysfunction, (2) to determine its cause, and (3) if thromboembolic disease is present, to determine to what degree it will be correctable surgically. The differential diagnosis of patients with possible CTEPH mandates a battery of tests to establish 3 criteria:

1. There is pulmonary hypertension. This requires measurement by right-sided heart catheterization of PVR >3 Wood units at rest and resting systolic and mean pulmonary artery pressures exceeding 40 and 25 mm Hg, respectively.³⁵⁵ An echocardiogram is useful for screening but insufficient for diagnosis.

2. Angiography or ventilation-perfusion scintigraphy shows evidence of obstruction in the main, lobar, segmental, or subsegmental arteries within the pulmonary arterial tree despite 3 months of therapeutic anticoagulation. A normal pulmonary angiogram or ventilation-perfusion (V̇/Q̇) scan excludes the diagnosis.³⁵⁶ Importantly, a relatively normal CT angiogram can be observed in CTEPH despite substantial V̇/Q̇ scan abnormalities; thus, a V̇/Q̇ scan is important in the evaluation of CTEPH.³⁵⁷

3. Other causes of pulmonary hypertension, such as WHO Group II (pulmonary hypertension associated with left-sided heart disease) and WHO Group III (pulmonary hypertension associated with a parenchymal lung disease), have been excluded. To exclude left-sided heart disease as a cause of pulmonary hypertension, a pulmonary capillary wedge pressure <15 mm Hg is generally required.³⁵⁸ In some patients, the wedge pressure may be higher because of severe RV dilation, interventricular dependence, and resultant LV diastolic dysfunction; in these cases, the PVR is usually high (>600 dyne · s · cm⁻⁵).

The workup for a patient with CTEPH should include a history, physical examination, pulmonary artery and lateral chest roentgenogram, electrocardiogram, pulmonary function testing, arterial blood gases, V̇/Q̇ lung scanning, right-sided heart catheterization, and conventional invasive pulmonary angiography. Pulmonary angiography may be deferred to the expert surgical center.

Chest radiography is often unrevealing in the early stages of CTEPH. As CTEPH progresses, several radiographic abnormalities may be found. These include hilar fullness caused by enlarged central pulmonary arteries, clear or oligemic lung fields, and RV enlargement. Peripheral lung opacities suggestive of scarring from previous infarction may also be seen.

Pulmonary function tests are necessary to evaluate dyspnea and are used to exclude the presence of obstructive airway or fibrotic lung disease. Single-breath diffusion capacity for carbon monoxide (Dlco) may be moderately reduced, and it has been reported that 20% of patients will have a mild to moderate restrictive defect that is caused by parenchymal scarring.³⁵⁹ Arterial blood oxygen levels may be normal even in the setting of significant pulmonary hypertension; hypercapnia is rare and generally indicates WHO Group III pulmonary hypertension related to severe chronic obstructive pulmonary disease, interstitial lung disease, or obesity-hypoventilation syndrome. Most patients, however, will experience a decline in Po₂ with exertion.³⁶⁰

Transthoracic echocardiography is used to provide objective evidence of pulmonary hypertension. An estimate of pulmonary artery pressure can be made by Doppler evaluation of the tricuspid regurgitant envelope.³⁶¹ Additional echocardiographic findings vary depending on the stage of the disease and include enlargement of the right side of the heart, leftward displacement of the interventricular septum, and encroachment of the enlarged RV on the LV cavity, with abnormal systolic and diastolic function of the LV.³⁶² Contrast echocardiography may demonstrate a PFO, the result of high right atrial pressures opening the previously closed intra-atrial communication.³⁶³

Radioisotope V̇/Q̇ lung scanning is critical to establish the diagnosis of CTEPH.³⁵⁷ V̇/Q̇ scanning typically demonstrates 1 or more mismatched segmental defects caused by obstructive thromboembolism.³⁶⁴ This is in contrast to the normal or “mottled” perfusion scan seen in patients with WHO Group I PAH.³⁵⁷ Any lobar, segmental, or subsegmental defect should lead to further evaluation. V̇/Q̇ scanning may underestimate the magnitude of perfusion defects in CTEPH because partial recanalization of the vessel lumen can occur while still leaving significant obstruction to flow.³⁶⁵

Invasive cardiac evaluation and coronary arteriography are required in the evaluation of patients with CTEPH. RV catheterization quantifies the severity of pulmonary hypertension and assesses right- and left-sided heart filling pressures. Measurement of oxygen saturations in the superior and inferior vena cava, right-sided chambers, and pulmonary artery may document previously undetected left-to-right shunting.³⁶⁶ Response to vasodilator challenge, such as administration of inhaled nitric oxide, may be tested.³⁶⁷ For patients >50 years of age, coronary angiography and left-sided heart catheterization provide additional evidence about those at risk for coronary artery or valvular disease.³⁶⁸ This information is necessary for the preoperative risk assessment of patients deemed candidates for pulmonary endarterectomy and to determine whether concomitant coronary artery bypass grafting or valve repair/replacement needs to be undertaken at the time of pulmonary endarterectomy.

Pulmonary angiography is the “gold standard” test for definition of pulmonary vascular anatomy and is performed to identify whether chronic thromboembolic obstruction is present, to determine its location and surgical accessibility (operative planning), and to rule out other diagnostic possibilities.³⁶⁹ In angiographic imaging, thrombi appear as unusual filling defects, pouches, webs, or bands or as completely thrombosed vessels that may resemble congenital absence of a vessel. Organized material along a vascular wall produces a scalloped or serrated luminal edge.³⁷⁰ Because of both vessel wall thickening and dilatation of proximal vessels, the contrast-filled lumen may appear normal in diameter. Despite concerns about the safety of performing pulmonary angiography in patients with pulmonary hypertension, pulmonary angiography can be performed safely at specialized centers, even in patients with severe pulmonary hypertension.³⁷¹ Biplane imaging is preferred, which offers the advantage of lateral views that provide greater anatomic detail than the overlapped and obscured vessel images often seen with the anterior-posterior view.³⁷² Pulmonary angiography to assess operability should be performed at the center where surgery would be performed or at centers with an established cooperation with the surgical team.

Pulmonary angioscopy may be performed in conjunction with pulmonary angiography to confirm the diagnosis in cases in which the diagnosis of CTEPH is equivocal. The pulmonary angioscope is a diagnostic fiber optic device that was developed to visualize the intima of central pulmonary arteries. It is placed into the pulmonary arteries under fluoroscopic guidance.³²⁹ Inflation of a latex balloon affixed to the tip of the angioscope results in obstruction of blood flow in the artery and permits visualization of the arterial intima.³⁷³ The presence of embolic disease, occlusion of vessels, or gross thrombotic material is also diagnostic. Despite the potential benefits of angioscopy, this test is uncommonly performed in the evaluation of CTEPH.

Other studies that may be performed to distinguish CTEPH from other lung diseases include multidetector CT angiography with 3-dimensional reconstruction,^374–376 single-photon emission CT fusion imaging,³⁷⁷ and magnetic resonance imaging scanning.^{355,378–380} Although magnetic resonance and CT imaging are frequently used as primary imaging techniques in selected patients before pulmonary endarterectomy, few comparative studies between diagnostic modalities have been published, and conventional angiography remains the “gold standard” for diagnostic and preoperative evaluation. Importantly, a relatively normal CT angiogram can be observed in CTEPH despite significant abnormalities on ventilation-perfusion scintigraphy.³⁵⁷ Features of chronic thromboembolic disease seen by these modalities include evidence of organized thrombus lining the pulmonary vessels in an eccentric fashion, enlargement of the RV and central pulmonary arteries, variation in size of segmental arteries (relatively smaller in the affected segments than in uninvolved areas), and parenchymal changes compatible with pulmonary infarction. The CT scan in CTEPH typically shows inhomogeneous perfusion with a mosaic that reflects areas of the lung that are hyperperfused (high attenuation) and others that are hypoperfused (low attenuation).³⁸¹ This “ground glass” or mosaic pattern can also be observed in pulmonary venoocclusive disease; however, in that disease, the ground glass appearance is coupled by thickening of the interlobular septa not usually seen in CTEPH.

Short-Term Outcomes

Table 8 lists the hemodynamic outcomes for a recent series of 1100 patients who underwent pulmonary endarterectomy with respect to hemodynamic improvement,³⁸⁴ whereas Table 9 presents results for the same patient group stratified for thromboembolic disease classification. Before the operation, >91.3% of the patients were in NYHA Functional class III or IV in this cohort; at 1 year after operation, 91.4% of patients were reclassified as NYHA Functional class I or II. In addition, other echocardiographic studies have demonstrated that with elimination of susatined pressure overload, RV geometry rapidly reverts toward normal.³⁶¹ In successful cases, right atrial and RV hypertrophy and dilatation regress. Tricuspid valve function returns to normal within a few days as a result of restoration of tricuspid annular geometry after the remodeling of the RV, and therefore, tricuspid valve repair is not performed with this operation.³⁶⁹ In the entire University of California, San Diego, cohort, overall perioperative mortality was 6.4% over a time span of >30 years (unpublished data). In the past 3 years, surgical mortality for pulmonary endarterectomy was 2.5%, which reflects the learning curve for safe performance of this operation and the refinements in surgical technique that have enhanced patient outcome (unpublished data). For the majority of patients undergoing pulmonary endarterectomy, the restoration of blood flow to previously occluded lung regions results in an immediate reduction in PVR, with a consequent increase in cardiac output. Table 10 summarizes survival and hemodynamic outcome after pulmonary endarterectomy from a growing body of surgical experience at centers worldwide.

Pulmonary Vascular Resistance

The most important prognostic factor in endarterectomy cases is the severity of elevation in PVR and the ability to lower it to a normal range at operation. Those patients with high PVR and minimal vascular obstruction on angiogram (type 4 small-vessel vasculopathy indistinguishable from WHO Group I PAH) have the worst prognosis, and surgery does not correct pulmonary hypertension in this population.^335,369 Arteriolar precapillary vasculopathy without larger-vessel thromboembolic diseases is not influenced by blind endarterectomy of the proximal pulmonary arterial tree. The majority of early deaths after this operation are in this subgroup, and efforts are being directed at better identifying these patients in the preoperative setting to avoid unnecessary operation.⁴¹⁹

RV Function

In the setting of severe CTEPH, the RV is almost uniformly enlarged, hypertrophied, and hypokinetic. Early studies found a rapid decrease in RV and right atrial dimension after successful pulmonary endarterectomy.⁴²⁰ More recent reports demonstrated a significant improvement in tricuspid regurgitation severity after pulmonary endarterectomy, particularly in patients with a favorable intraoperative classification of CTEPH and a significant postoperative drop in pulmonary artery pressure.^419,421 More novel Doppler echocardiographic parameters of RV function, including systolic velocity of the tricuspid annulus⁴²² and the RV myocardial performance index,³⁶¹ have been shown to correlate with PVR in CTEPH and can help predict postoperative improvement in PVR. There is no apparent “point of no return” in terms of RV enlargement or dysfunction that would disqualify a CTEPH patient for endarterectomy.⁴²³ Patients with massive RV enlargement and severe RV dysfunction show marked improvement in both parameters after successful pulmonary endarterectomy.⁴²⁴ Preoperative pulmonary angiography and intraoperative findings are better indicators of postoperative RV performance than preoperative RV size or function.⁴²⁵ Similar to the improvements seen in LV size and function after relief of severely elevated afterload (eg, aortic stenosis), the RV has the ability to remodel favorably and regain systolic function after pulmonary endarterectomy. Thus, patients with severe RV failure should not be excluded from referral to a center with experience in pulmonary endarterectomy.

CTEPH Classification

A large retrospective study has shown that patients with type 3 and 4 disease have more residual postoperative tricuspid regurgitation, higher postoperative pulmonary artery systolic pressures, and a higher postoperative PVR than those with type 1 or 2 disease.³³⁵ Patients with distal thromboembolic disease (types 3 to 4) also have a higher perioperative mortality, require longer inotropic support, and have longer hospital stays than patients with type 1 or 2 thromboembolic disease. The degree of improvement in pulmonary hypertension and tricuspid regurgitation after pulmonary endarterectomy is determined by the type and location of pulmonary thromboembolic disease.⁴²⁶

Emerging Biomarkers

Several small studies have been performed to examine the utility of serum cardiac markers, serum inflammatory markers, and endothelial surface markers as an adjunct to predicting mortality after pulmonary endarterectomy. BNP,^427,428 N-terminal pro-BNP,^{397,410,412,429,430} heart-type fatty acid–binding protein,⁴³¹ C-reactive protein,⁴³² and thrombomodulin³⁴⁹ all have been shown to correlate with other surrogate markers of disease severity in CTEPH patients undergoing pulmonary endarterectomy, such as PVR or RV function. Widespread use of these tests for risk stratification after pulmonary endarterectomy has not yet occurred. Preoperative risk stratification with these markers requires further development and testing in large cohorts of patients.

Postoperative Morbidity

Severe reperfusion injury manifesting as pulmonary edema is the most frequent complication after pulmonary endarterectomy, occurring in ≈5% to 15% of patients.⁴³³ Of patients with reperfusion injury, the majority recover after a short period of ventilatory support and aggressive diuresis. A minority of patients with severe lung reperfusion injury require prolonged periods of ventilatory support, whereas extreme cases require veno-venous extracorporeal support for oxygenation and blood carbon dioxide removal.⁴³⁴ Neurological complications from circulatory arrest have mostly been eliminated by shorter circulatory arrest periods and the use of a direct cooling jacket placed around the head, which provides even cooling to the surface of the cranium.⁴³⁵ Pulmonary hemorrhage after pulmonary endarterectomy is rare.⁴³⁶ In a cohort of 1100 patients undergoing pulmonary endarterectomy,³⁸⁴ reexploration for bleeding was only required in 3.8%. Average duration of surgery was 6.7 hours (range 3.5 to 13.1 hours), with a perioperative wound infection rate of only 2.4%.

Long-Term Outcome After Pulmonary Endarterectomy

A survey of surviving patients who underwent pulmonary endarterectomy between 1970 and 1995 at the University of California, San Diego, formally evaluated long-term outcome from this operation.⁴³⁷ Questionnaires were mailed to 420 patients, and responses were obtained from 308 patients. Survival, functional status, quality of life, and the subsequent use of medical assistance were assessed. Survival after pulmonary endarterectomy was found to be 75% at 6 years or more. Patients reported that their symptoms were permanently, markedly reduced after operation. Ninety-three percent of the patients were found to be in NYHA class I or II, compared with ≈95% in NYHA class III or IV before surgery. Of the population desiring employment, 62% of patients who were unemployed before the operation returned to work. Patients who had undergone pulmonary endarterectomy scored several quality-of-life components slightly lower than healthy individuals but significantly higher than the patients before their operations. Only 10% of patients used oxygen after the surgery. Although the response rate of this survey was low, and the fate of the nonresponders is unknown, these data suggest that pulmonary endarterectomy can offer substantial improvement in survival, function, and quality of life. Hemodynamic benefit after pulmonary endarterectomy has been reported by many groups in follow-up periods as long as 5 years. This is accompanied by improvements in gas exchange, functional status, quality of life, and survival.^{369,404,408,412,437–440} For comparison, the Scientific Registry of Transplant Recipients reports that the mean 1- and 5-year survival rates for lung and heart-lung transplantation for all isolated pulmonary hypertension are 75.1% and 51.9%, respectively.⁴⁴¹ Corresponding survival rates for pulmonary endarterectomy are 97.7% in the perioperative period and 75% to 92.3% after 6 years.^404,408,437

Pulmonary Endarterectomy

The treatment of choice for CTEPH is pulmonary endarterectomy. This recommendation echoes that of other recently published consensus documents^355,442 and is based on the fact that pulmonary endarterectomy is potentially curative, with nearly normalized pulmonary hemodynamics and substantial clinical improvement seen in many patients.⁴⁴³ Pulmonary endarterectomy should be considered in patients who have evidence of hemodynamic or ventilatory impairment at rest or with exercise. Patients with CTEPH should be referred for surgical evaluation at an experienced center as soon as possible, even if symptoms are mild. Patients undergoing surgery typically exhibit a preoperative PVR >300 dyne · s · cm⁻⁵, often in the range of 800 to 1400 dyne · s · cm⁻⁵.⁴³⁵ There is no upper limit of PVR or degree of RV dysfunction or tricuspid regurgitation that excludes a patient from surgery at a center experienced with this operation, and patients with suprasystemic pulmonary artery pressures can safely undergo pulmonary endarterectomy.⁴⁴⁴ Severe hemodynamic or echocardiographic abnormalities should not be used by physicians to deem a patient “inoperable.”^384,423

The preoperative differentiation of operable from inoperable CTEPH remains one of the most problematic issues of CTEPH management. The success of pulmonary endarterectomy is dependent on surgical expertise and the degree of microvascular disease present and its contribution to overall PVR. Surgical expertise is required to ensure that obstruction in the segmental and subsegmental vessels can be removed with this operation.^369,435 Beyond surgical expertise, a critical element in the preoperative assessment of CTEPH is the determination of the relative contributions from microvascular disease (inoperable, small-vessel, precapillary arteriopathy) compared with macroscopic disease in surgically accessible vessels. Patients with significant pulmonary hypertension but with little or no visible evidence of thromboembolic pathology are considered poor candidates for surgery.⁴⁴⁵ This latter group generally displays a significant mismatch between the degree of proximal obstruction and magnitude of hemodynamic impairment in terms of PVR. The presence of comorbid conditions that may affect early and long-term survival must be considered in the evaluation of patients with CTEPH for surgery. Currently, advanced age (ie, >80 years of age), renal insufficiency, and hepatic dysfunction are not considered absolute contraindications to pulmonary endarterectomy, although they do affect risk assessment.⁴⁴⁶ Severe underlying parenchymal lung disease is considered a contraindication for operation, because pulmonary endarterectomy may result in hemodynamic improvement but will not reverse the symptoms and progression of the underlying lung disease.³⁶⁹

Medical Therapy for CTEPH: Anticoagulation

Before evaluation for pulmonary endarterectomy, standard medical therapy includes warfarin targeted to an INR of 2 to 3. Supportive treatment with warfarin anticoagulation reduces the likelihood of recurrent PE, and lifelong anticoagulation after surgery is recommended.³⁶⁹ There are no data for novel anticoagulants in CTEPH, such as the oral direct thrombin inhibitor dabigatran.

Other Medical Therapy

Although PAH (WHO Group I)-specific medical therapy in patients with CTEPH has been tried as a bridge to pulmonary endarterectomy surgery,^447,448 this therapy should not delay referral for surgical intervention for this disease. A strategy of using these PAH-specific medical therapies to reduce perioperative risk by improving perioperative hemodynamics has not been tested in clinical trials. In a retrospective study, preoperative treatment of CTEPH with PAH-specific therapy did not result in improved outcomes after pulmonary endarterectomy and was associated with significant delay in surgical intervention.⁴⁴⁹ In addition, it has been reported that some degree of tissue alteration may occur with prolonged medical therapy, and this may affect operability. Increased fragility of thromboemboli has been noted after as little as 2 weeks of treatment with prostacyclins.⁴⁴³

The only multicenter, randomized, placebo-controlled trial for a PAH-specific therapy in CTEPH is the BENEFiT (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension) trial, which evaluated bosentan. This study enrolled 157 patients with inoperable CTEPH or residual disease after surgery. After 16 weeks of therapy, a modest reduction in PVR was observed,⁴⁵⁰ although the effect was less than reductions in PVR observed with pulmonary endarterectomy.³⁸⁴ There was no improvement in either exercise capacity or 6-minute walk distance. Thus, there are no data from RCTs of any medical therapy for CTEPH that clearly demonstrate a benefit in terms of symptoms, exercise capacity, or survival. Other data with PAH-specific medical therapy come from small, uncontrolled series and retrospective evaluations, including open-label trials assessing endothelin receptor antagonists, prostanoids, and phosphodiesterase-5 inhibitors in patients deemed inoperable and in patients who have residual pulmonary hypertension after pulmonary endarterectomy (Table 11). These data do not define whether one class of drugs might be superior to another or whether combination therapy is a rational approach. Survival benefit for the use of PAH-specific drugs in CTEPH has not been proven, either as sole therapy or in conjunction with pulmonary endarterectomy.^353,462 More clinical trials are needed to guide care in this field; specifically, trials are needed to demonstrate whether medical therapy is beneficial, in terms of quality of life, exercise capacity, and survival, for those unable to undergo pulmonary endarterectomy or who have residual PAH after surgery that is not amenable to endarterectomy at an experienced center.

In general, medical therapy should be considered only in carefully selected patients who (1) are deemed to be inoperable by a multidisciplinary team with extensive surgical experience or (2) have residual functional impairment or hemodynamic abnormalities after pulmonary endarterectomy. In these latter patients, consideration should be given to a repeat pulmonary endarterectomy at a more experienced center.^320,465 Under no circumstances should a trial of medical therapy delay prompt evaluation for surgery.