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 (e.g., dyspnea, chest pain, tachycardia, and psychological distress), stabilization of respiratory and cardiovascular function (hypotension) without need for mechanical ventilation or vasopressor support; in addition, reduction of right ventricular damage, improved exercise tolerance, prevention of PE recurrence, and increased probability of survival have been observed. Potential harm includes disabling or fatal hemorrhage, including intracerebral hemorrhage, and increased risk of minor hemorrhages, resulting in prolongation of hospitalization and need for blood product replacement [2].

Patients treated with a fibrinolytic agent have faster restoration of lung perfusion. At 24 h, patients treated with heparin have no substantial improvement in pulmonary blood flow, whereas patients treated with adjunctive fibrinolysis manifest a 30–35 % reduction in total perfusion defect. However, by 7 days, blood flow improves similarly (~65–70 % reduction in total defect). Thirteen placebo-controlled randomized trials of fibrinolysis for acute PE have been published, 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 (no = 504). These six studies used variable infusion regimens. Two studies administered alteplase by bolus intravenous injection (100 mg or 0.6 mg/kg), and four infused 90–100 mg of alteplase intravenously over a 2-h period. Three of the four used concomitant infusion of intravenous unfractionated heparin (1000–1500 U/h). Four studies used intravenous streptokinase, together enrolling 94 patients. All four studies of streptokinase used a bolus dose (250,000–600,000 U) followed by a 100,000 U/h infusion for 12–72 h. Two studies that examined urokinase, published in 1973 and 1988, together enrolled 190 patients [2].

One study randomized 58 patients to receive weight-adjusted single-bolus intravenous tenecteplase (30–50 mg, with a 5-mg increase in dose for every 10 kg of weight from <60 to>90 kg) or placebo. The odds ratios were calculated by use of fixed effects and random effect models. The evidence suggesting 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 [2].

Alteplase was associated with a trend toward decreased recurrent PE. Similar findings have been reported by Wan et al. [4] and Thabut et al. [5] When Wan et al. [4] 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 0.22–0.90) [1].

Wan et al. [4] 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 patients. This end point was not statistically significant when all trials, including those that studied less severe forms of PE, were included [4]. In this analysis, there was no significant increase in major bleeding, but there was a significant increase in no major bleeding; the number needed to harm was 8 [4]. On the other hand, Thabut et al. [5], 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.

At least four registries have documented the outcomes of PE patients (MAPPET [6], ICOPER [7], RIETE [8] and EMPEROR [9]). The data coming from these registries 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 0–1.6). 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 right ventricular dysfunction, chronic thromboembolic pulmonary hypertension, and impaired quality of life represent appropriate surrogate goals of treatment [2].

Among PE patients, to determine whether adjunctive fibrinolytic therapy can effectively reduce the outcome of dyspnea and exercise intolerance caused by persistent pulmonary hypertension (World Health Organization, WHO Group 4 pulmonary hypertension); it is first necessary to examine the incidence of persistently elevated right ventricular systolic pressure or pulmonary arterial pressure, measured 6 or more months after acute PE. The current literature includes only four studies that report baseline and follow-up right ventricular systolic pressure or pulmonary arterial pressures by use of pulmonary arterial catheter or Doppler echocardiography [10–13]. These data suggest that compared with heparin alone, heparin plus fibrinolysis yields a significant favorable change in right ventricular systolic pressure and pulmonary arterial pressure incident between the time of diagnosis and follow-up [2].

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 [13]. All patients were normotensive at the time of enrollment. Follow-up included Doppler echocardiographic estimation of the right ventricular systolic pressure, 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 h) for patients who experienced hemodynamic deterioration, defined as hypotension, cardiac arrest, or respiratory failure requiring mechanical ventilation.

Among the 144 patients who received heparin only, 39 (27 %) demonstrated an increase in right ventricular systolic pressure 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 right ventricular systolic pressure at 6-month follow-up, which suggests that thrombolytic therapy may have the benefit of decreasing the incidence of chronic thromboembolic pulmonary hypertension [13].

Because of small sample sizes and heterogeneity, the clinical trials 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-elevation myocardial infarction patients. Absolute and relative contraindications are showed in Table 6.3. 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 [2].

Low-risk PE patients 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. 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 [2].

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. 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. 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 [2].

Evidence of moderate to severe right ventricular injury may be derived from Doppler echocardiography that demonstrates any degree of right ventricular hypokinesis, McConnell’s sign (a distinct regional pattern of right ventricular dysfunction with akinesis of the mid-free-wall but normal motion at the apex), interventricular septal shift or bowing, or an estimated right ventricular systolic pressure >40 mmHg. Biomarker evidence of moderate to severe right ventricular 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 [2].

This panel of experts recommends fibrinolytic administration by peripheral intravenous catheter (Table 6.4). FDA-recommended infusion dose of alteplase at 100 mg as a continuous infusion over 2 h. The FDA recommends withholding anticoagulation during the 2-h infusion period. Two ongoing randomized controlled trials 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) [14] and the trial (Tenecteplase Or Placebo: Cardiopulmonary Outcomes At 3 Months, TOPCOAT) [15].

The methodology used for the Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9), incorporates current evidence-based approaches to the appraisal and synthesis of evidence and to the formulation of clinical practice recommendations. The process thus ensures explicit, transparent, evidence-based clinical practice guidelines [16].