SGEM#184: We Weren’t Born to Follow-Up – The PEITHO Long-Term Follow-up Study

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Date: June 21st, 2017

Reference: Konstantinides et al. Impact of Thrombolytic Therapy  on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. JACC March 2017

Guest Skeptic: Dr. Kirsty Challen (@KirstyChallen) is a Consultant in Emergency Medicine at Lancashire Teaching Hospitals Trust (North West England). She did her Medical School at Manchester, with a History of Medicine BSc at the same time. Kirsty did her residency in North West England and has a PhD in Health Services Research from Sheffield. Kirsty is also the creator of a knowledge translation project called #PaperinaPic.

Case: A 22-year-old patient presents to the emergency department with sudden onset shortness of breath. She takes the oral contraceptive pill and was placed in a below-knee plaster cast for a fibula fracture 2 weeks ago. She is alert and talking, with a systolic blood pressure of 110 mmHg, but CTPA demonstrates bilateral pulmonary artery thrombus with right ventricular dilatation, and her troponin is raised. When you explain this, she asks if there isn’t something she could have to break up the clot.

Background: We have discussed pulmonary embolism (PE) a number of times on the SGEM. In episode #51 and #126 we talked about managing some patients with PEs at home. Then in episode #163 we shuffled off to Buffalo and discussed ultrasound-facilitated, catheter directed, low-dose fibrinolysis for acute massive or submassive PEs.

The 2015 Chest Guidelines recommend systemically administered thrombolytic therapy in patients with acute PE associated with hypotension (systolic BP<90mmHg) who do not have a high risk of bleeding (Kearon et al 2016).

In patients with acute PE associated with hypotension (eg, systolic BP <90 mm Hg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B).

In addition, this guideline still suggests systemic thrombolytic therapy using a peripheral vein over catheter directed thrombolysis (CDT) in patients with acute PE who are treated with thrombolytic agents. They do note that patients with a higher risk of bleeding and have access to CDT are likely to choose CDT over systemic thrombolytic therapy.

In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombolytic therapy using a peripheral vein over catheter directed thrombolysis (CDT) (Grade 2C).
- Remarks:Patients who have a higher risk of bleeding with systemic thrombolytic therapy and who have access to the expertise and resources required to do CDT are likely to choose CDT over systemic thrombolytic therapy.

Swami vs. Beardsell

However, we’ve been left not sure what to do about submassive PE – hence the highly memorable Swami vs. Beardsell cage match at SMACCDub.

Previous trials have suggested a reduction in clinical decompensation (MAPPET-3) and long-term pulmonary hypertension (MOPETT) in patients who are given systemic thrombolytics. The largest trial to date was the Pulmonary Embolism Thrombolysis (PEITHO) trial published in the NEJM 2014. It showed an number needed to treat (NNT) of 33 to prevent death or haemodynamic decompensation in the first 7 days but an number needed to harm (NNH) of 11 for major bleeding. The authors of the PEITHO trial conclude:

In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke.

Clinical Question: Does systemic thrombolysis in patients with submassive PE improve long-term mortality or morbidity?

Reference: Konstantinides et al. Impact of Thrombolytic Therapy  on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. JACC March 2017.

Population: Adult patients with objectively confirmed acute PE, within 15 days of first symptoms. RV dysfunction on echo or CT chest; myocardial injury by positive troponin (I or T).
- Exclusion Criteria: Haemodynamic decompensation at presentation (SBP<90 for 15 minutes or drop in SBP of 40mmHg for 15 minutes with evidence of end-organ hypo-perfusion, need for catecholamines), known significant bleeding risk (not including antiplatelet agents but including Vitamin K antagonist or platelets <100,000/mm3), thrombolysis in preceding 4 days, SBP>180 or DBP>110, pregnancy or childbirth in last 30 days or breastfeeding.
Intervention: Single weight-based IV bolus of tenecteplase (range 30-50mg).
Comparison: Placebo: bolus matched for appearance and volume. All patients received unfractionated heparin.
Outcome:
- Primary: Long-term mortality
- Secondary: Persistent symptoms of heart failure and echo findings

Authors’ Conclusions: Approximately 33% of patients report some degree of persistent functional limitation after intermediate-risk PE, but CTEPH is infrequent. Thrombolytic treatment did not affect long-term mortality rates, and it did not appear to reduce residual dyspnea or RV dysfunction in these patients.

Quality Checklist for Randomized Clinical Trials:

The study population included or focused on those in the emergency department. Unsure
The patients were adequately randomized. Yes
The randomization process was concealed. Yes
The patients were analyzed in the groups to which they were randomized. Yes
The study patients were recruited consecutively (i.e. no selection bias). Unsure
The patients in both groups were similar with respect to prognostic factors. Yes
All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes and No
All groups were treated equally except for the intervention. Yes
Follow-up was complete (i.e. at least 80% for both groups). No and Yes
All patient-important outcomes were considered. Yes
The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: As stated previously they were only able to get about 71% (709/1,005) of the entire study population consented to obtain two-year survival data and prospectively conduct long-term clinical and ECHO follow-up of their patients. The mean age was about 67 years with just over 50% being female.

No difference in all-cause or cause-specific long-term mortality.

Primary Outcome: Long-term mortality
- 20.3% (73/359) tenecteplase vs. 18.0% (63/350) placebo (p = 0.43)
- Median follow-up 37.8 months (interquartile range: 24.6 to 54.8 months)

Secondary Outcomes: No statistical difference

1) Were these Emergency Department Patients: From the paper this was not clear, but we reached out to Professor Konstantinides, who confirmed this:

“The vast majority of the PEITHO patients were recruited in Emergency Departments. Although this type of information was not explicitly requested in the eCRF and thus not directly obtained, we showed in the original NEJM paper back in 2014 that only 6% of the patients had surgery in the previous month, and of those only a small minority were actually still hospitalized in the same hospital in which surgery was performed. Clearly, most surgical patients were excluded because they had (or at least considered to have) contraindications to thrombolysis. We also had no medically ill patients who suffered acute PE in the same hospital in which they were admitted for an acute disease.”

2) Consecutive Recruitment: This is often a problem in emergency medicine research. If you only recruit at convenient times, like daylight hours, it is possible that you get a different patient group. This could introduce bias and limit external validity. Patients who get out of bed to see us at 4am might be sicker than those who wait till morning. It isn’t explicitly stated in either PEITHO papers or the methodology paper but there isn’t any mention of convenience sampling or restricted researcher hours.

3) Allocation Blinding: This was well done in the initial paper, with placebo that matched tenecteplase and blinding throughout the research team. However, they broke the allocation code to write up the original paper in 2014, so it’s possible that the researchers at the centres who did long term clinical and echocardiographic assessment knew which group the patient was in. This would tend to inflate any benefit of the treatment, though, which makes it less of an issue given their results.

4) Completeness of Follow-Up: This is a mixed bag. Initially 1,006 patients were randomised. The 28 sites which planned to do long-term follow-up randomised 709 patients (71%). They got good follow-up on mortality (696/709, 98.1%). However, clinical assessment was only done in 358 of the 578 long-term survivors (62%) and echo in 290 (50%). This could seriously affect the validity of the results.

At worst case, all the missing patients in the intervention group could have done really well (maybe they didn’t attend because they were busy skiing across Antarctica?), while all those in the placebo group were so breathless they couldn’t get to clinic. This would leave you with much different results:

5) A Priori: This is another threat to the study validity and is often a problem with outcomes that weren’t considered before the study was started. Ideally, we like to see a preplanned study, powered for long-term outcomes, which is resourced to carry out long-term assessment on all the patients who are randomised. Fortunately the UK national funding network, the NIHR, has recognised this and just issued a call for projects.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: Systemic thrombolysis in submassive PE cannot be recommended to reduce long-term mortality or morbidity at this time.

Case Resolution: The patient was treated with low molecular weight heparin, and admitted to a high care area so that thrombolysis could be reconsidered if she deteriorated.

Kirsty Challen

Clinical Application: In patients with submassive PE, treat with low molecular weight heparin, unless you can recruit them to a well-designed trial of thrombolysis.

What do I tell my patient? Although it sounds sensible to give you a drug to break up the clot, the evidence we have at the moment is that it will not improve your survival or how well you are in the long term. We may need to reconsider that if your blood pressure drops.

Keener Contest: Last weeks’ winner was David Hedman. He knew the first nationally recognized curriculum for EMS was published in 1969.
Listen to the episode on iTunes to here the question for this week. If you think you know the answer then send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

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