Risk factors for bleeding after thrombolysis (in PE and STEMI)

How do we explain the increased incidence in bleeding complications for PE? There are little data on the risk factors for bleeding after thrombolysis in PE. As mentioned above, age (with a possible threshold at 65 years) is a preponderant factor. Although not statistically significant, one randomised trial found that both age >75 years (OR 2.8, 95% CI 1 to 7.86) and female gender (OR 11.49, 95% CI 2.67 to 49.53) could be associated with higher rates of major extracranial bleeding (11.1% vs 8%, respectively).34

In a retrospective cohort of 104 patients receiving alteplase, major bleeding was observed in 20 patients (19.2%), with one death. In the multivariate analysis, independent predictors of major bleeding were cancer (OR 16, 95% CI 3.2 to 80 P=0.004), diabetes (OR 9.6, 95% CI 1.7 to 54, P=0.01), an increased international normalized ratio (INR) before fibrinolysis (OR 6, 95% CI 1.5 to 22, P=0.012) and catecholamine administration due to systemic hypotension (OR 115, 95% CI 9.4 to 1.411, P<0.001).36 One recent study focused on identifying the risks for major bleeding in patients who received 100 mg of alteplase as a treatment for PE at a single institution. Significant risk factors in this analysis included major surgery within the previous three weeks (OR 9.00, 95% CI 1.01 to 79.99), INR >1.7 (OR 13.20, 95% CI 1.54 to 113.52), weight <100 kg (OR 1.18 for each 10 kg below 100 kg, 95% CI 1.01 to 1.37) and at least one of the following characteristics (OR 5.02, 95% CI 1.78 to 18.55): internal bleeding in the previous four weeks, hypertension, acute MI, positive occult stool sample, presence of an intra-aortic balloon pump, African-American origin, gastrointestinal bleeding in the preceding three months, aortic dissection, acute pancreatitis, cardiopulmonary resuscitation that exceeded 10 min, bilirubin >3 mg/dL or dementia.37

In a large population-based study including 9705 patients with PE receiving thrombolysis, of which 176 experienced intracranial bleeding (1.8%), a logistic regression model identified four independent prognostic factors: peripheral vascular disease, age >65 years, MI and previous stroke with residual deficit. The latter being by far the most significant risk factor (OR 1.99, 95% CI 1.97 to 2.01, P=0.007).38

Interestingly, in the context of MI, important predictors of bleeding were similar to those found in the PE population and included increased age, lighter weight, female gender, African ancestry and those that had invasive procedures.20

Improving patient selection for thrombolysis in PE

The variable clinical results for thrombolysis in PE have been influenced by inappropriate patient selection, for which adverse events and bleeding risks have outweighed the benefits of clot fragmentation. An important challenge in PE management is patient risk stratification.52 Cho et al showed that in haemodynamically stable patients with PE 37% had evidence of right ventricular (RV) dysfunction on ultrasound assessment.53 Grifoni et al confirmed in their prospective clinical outcome study that 30% of normotensive patients had RV dysfunction with 10% progressing to shock with a hospital mortality of 50%. These patients with latent haemodynamic impairment may require more aggressive therapeutic strategies.54

Offering thrombolysis as a rescue therapy in decompensating patients?

One approach is to treat patients with RV dysfunction but no shock with a heparin infusion, and use thrombolysis as a bailout therapy for the decompensating patient. The risk–benefit analysis would be easier to justify. However, the results of the PEITHO randomised trial did not favour this approach, probably because the key treatment of cor pulmonale is removal of the causa prima. More than 1000 patients with moderate to severe (but all intermediate-risk) PE with RV dysfunction who received thrombolysis showed a statistically significant reduction in morbimortality within the 7 days after randomisation (death or haemodynamic decompensation: OR 0.44, 95% CI 0.23 to 0.87, P=0.02). Moreover, in the heparin-only group, 23 patients died despite 15 of them receiving thrombolysis (with tenecteplase) as rescue therapy.34 We may also emphasise that causes of death at 30 days in the placebo group included three haemodynamic collapses, three recurrent PEs, three respiratory failures and two sudden and unexplained deaths, and haemodynamic collapses were three times more frequent in the heparin-only group (1.6% vs 5%, OR 0.30, 95% IC 0.14 to 0.68), P=0.002). Therefore, the PEITHO randomised trial demonstrated that in patients with RV dysfunction heparin infusion without thrombolysis or with delayed thrombolysis may increase mortality and morbidity. Nevertheless, any potential advantage of thrombolysis was counterbalanced by a five times increased risk of major bleeds and a 10-fold increased risk of (mainly haemorrhagic) stroke.

Considering new fibrinolytic agents or regimens?

The use of thrombolytic agents is heterogeneous. Streptokinase was, historically, the main agent due to low cost and limited evidence in favour of other agents.55 Pharmaceutical engineering then developed ‘second generation’ fibrin-specific thrombolytic agents.56 The ‘third generation’ thrombolytics is characterised by improved pharmacokinetic properties, including a longer half-life due to a resistance to natural inhibitors; improved fibrin specificity and binding, which increased resistance to plasminogen activator inhibitors (PAI-1) and reduced immunogenicity.56 57 However, despite a massive investment of the pharmaceutical industry, the effects of second-generation and third-generation thrombolytics are somewhat disappointing.58 Both fundamental and in vitro data from animal studies have not shown significant improvements. Streptokinase is still the most widely used thrombolytic for the treatment of acute MI and by extension, PE. As pointed by Levine 25 years ago, ‘The risk of extracranial bleeding is virtually identical, regardless of the thrombolytic agent used within the approved dose ranges. Thus, the concept that relative fibrin specificity per se would protect against serious systemic bleeding has been proved incorrect.’59 The incidence of the three major conditions requiring thrombolysis, namely STEMI, PE and ischaemic stroke, is unlikely to decrease in the following years. We can only hope for further drug or drug regimen developments with better targeting of fibrin clot and decreased haemorrhagic events.60

Reconsidering targets for the management of PE using tailored heparin and thrombolytic infusions?

The PEITHO study also emphasised the challenge of the concomitant use of heparin infusions. All patients from both the tenecteplase and control groups received a significant heparin bolus, which resulted in an activated partial thromboplastin time of 2.0–2.5 times the upper limit of the normal range. The safety outcome results in the intention-to-treat analysis were an 11.5% rate of major bleeding, a 6.3% rate of major extracranial bleeding and a 2% rate of haemorrhagic stroke. This high incidence of bleeding associated with thrombolysis is in contrast to the International Cooperative of Pulmonary Embolism Registry, which reported a 22% incidence of major bleeding and a 3% incidence of intracerebral haemorrhage.14 The major bleeding rate associated with heparin infusion alone in the same registry was approximately 15%.14

In another literature review of 559 patients treated for PE with r-tPA (mostly between 50 and 100 mg), the frequency of intracerebral haemorrhage was 2.1%.61 Interestingly, in a randomised trial from Konstantinides et al, the alteplase + heparin versus heparin alone bleeding rate were 0.8% and 3.6% (P=0.29), respectively.29 Moreover, in the MOPPET trial, there was no major or minor bleeding after the use of a ‘low dose’ thrombolytic (maximum 50 mg tPA) with the aim of an activated partial thromboplastin time of maximum two times the upper limit of normal range.33 Anticoagulation with heparin infusion alone increases the risk of bleeding. Recent meta-analyses have included heterogeneous studies, some of which used outdated heparin protocols (both for administration and monitoring). We suggest that lower heparin bolus, strict aPTT (activated partial thromboplastin time), or better, anti-Xa and fibrinogen monitoring may be necessary. Moreover, a targeted approach with tailored thrombolytic dosage is paramount.

Both cardiologists for STEMI and neurologists for ischaemic stroke have addressed the benefit of adjusted or tailored thrombolysis. Studies assessing the efficiency of low-dose thrombolysis for both stroke62 63 and STEMI64 65 have shown comparable results to the standard-dose treatment in terms of effectiveness and safety. The same protocol used in the MOPPET trial was performed by the same authors in another cohort of 98 patients with moderate to severe PE with no bleeding due to this ‘safe personalised half-dose tPA thrombolysis’.66 The administration of weight-adjusted, reduced-dose rt-PA bolus seemed to produce less coagulation anomalies than current US Food and Drug Administration (FDA)-approved regimens.67 Moreover, clinicians now have access to additional point of care testing such as viscoelastometric testing of whole blood or sonic estimation of elasticity via resonance technology, which can complete the initial workup and guide therapy.68 One can imagine both titration of the heparin infusion and thrombolytic treatment. These hypotheses however remain to be confirmed in properly designed clinical trials.

Potential long-term benefits of thrombolysis

Once again, the beneficial impact of thrombolytic therapy is based on scarce data. If immediate mortality seems to be improved in high-risk PE,11–13 the effect on long-term outcomes is uncertain. In the randomised controlled TOPCOAT study, there were less adverse outcomes and less patients with dyspnoea in the thrombolysis group versus the placebo group. The study was unfortunately terminated prematurely.35 In the MOPPET trial, through a mean follow-up of 28±5 months, there were fewer patients with pulmonary hypertension after thrombolysis compared with placebo (16% vs 57%). However, the clinical relevance of systematic ultrasound assessment in asymptomatic patients is questionable. Finally, recently published long-term outcome evaluation performed on the PEITHO trial population recommends caution to be taken regarding potential beneficial impact of thrombolytic therapy at distance.69 Indeed, no differences were reported between the thrombolysis and placebo arms, regarding mortality rate, functional limitation, residual dyspnoea, residual pulmonary hypertension and RV dysfunction, in this population with intermediate-risk PE.70

The need to team up to decide if and when to administer thrombolysis

Thrombolysis for high-risk PE is mandatory whenever possible.16

Despite the abovementioned risk factors, a major shortcoming is the absence of a well-validated scoring system to predict the risk of bleeding in patients with PE.71 For patients with no absolute contraindications and deemed at moderate to high bleeding risk, half-dose thrombolysis could be started and then titrated to efficacy. If the administration of lytics is contraindicated, venoarterial extracorporeal membrane oxygenation can offer haemodynamic support in selected patients as a bridge to either recovery or interventional therapy. Urgent surgery is still an option for those patients who are decompensating, even if the published data on morbidity and mortality are limited, and probably biased (unfavourable outcomes being under-reported).

Several decades ago, local administration of alteplase in the pulmonary artery did not offer any benefit compared with systemic intravenous administration.72 However, catheter-assisted thrombolysis, whereby thrombolysis is administered locally, could be of interest in patients at high bleeding risk. In a review, Kuo et al concluded that it was a safe and effective treatment for acute and high-risk PE.73 One example is the EkoSonic Ultrasound-Accelerated Thrombolysis System (EKOS) technique, which uses ultrasonic energy to disrupt the structure of the thrombus, leaving it more susceptible to thrombolytic agents. The catheter combines numerous side-holes that infuse thrombolytics with a filament that includes multiple miniature ultrasound transducers. This recently FDA-approved technique should be delivered only in expert centres.74 The ULTIMA study demonstrated that for patients with PE at intermediate risk of adverse events EKOS treatment was clinically superior to anticoagulation with heparin alone in the improvement of RV function at 24 hours. The SEATTLE II study confirmed these results also showing an improvement in RV function and pulmonary pressure, while decreasing the number of ICHs.32 74 75 However, there are no solid data on hard and longer-term outcomes such as chronic pulmonary hypertension and mortality, and it is still unknown whether focused thrombolysis using catheter assistance is more efficient and less risky than systemic thrombolysis.73 76 77

There is now a broader spectrum of management strategies for patients with intermediate-risk and high-risk PE. We suggest that the management of patients with high-risk PE could undergo a developmental approach analogue to that observed in MI, with systemic thrombolysis being used in patients at low risk of bleeding or not accessible to catheter therapy because of time delay or haemodynamic instability while focused catheter-assisted thrombolysis will be restricted to patients at high risk of bleeding. In our view, thrombolysis should be administered only to high-risk patients with PE at low risk of bleeding. However, catheter-based therapies could be preferred for high risk of bleeding patient presenting with intermediate–high-risk PE. Its place in intermediate-risk patients with PE remains to be established in proper clinical trials. At this stage, however, any treatment that would be at variance with the 1B recommendation of the 2016 guidelines of the American College of Chest Physicians that ‘in most patients with acute PE not associated with hypotension, we recommend against thrombolytic therapy’ should be considered with extreme caution.78

In conclusion, PE management is challenging in many ways starting with, at times, deceptive clinical presentations. Thus, a decompensating patient may seem compensated but present with a life-threatening RV dysfunction. The same high-risk patient with PE may be treated completely differently depending on concomitant factors such as age, context and local resources. For these reasons, a multidisciplinary approach should be attempted, for example, a pulmonary embolism response team (PERT), to best manage patients with acute, severe disease.79 80 This shift of approach should to be adjusted according to the usefulness and timing of the intervention; in particular, PE management needs to be tailored to pathophysiology.

Acute cor pulmonale due to PE has a very specific pathophysiology, where patient characteristics and haemodynamic features interact, and may contribute to an increased risk of bleeding following thrombolysis. Future challenges to decrease the bleeding risk and improve clinical outcomes include better bleeding risk stratification, tailored heparin and thrombolysis dosage, improved treatment monitoring, adjunctive catheter-based therapies and implementing multidisciplinary PERTs.