Thrombolytics and Intermediate Risk PE

 

Thrombolytics and Intermediate Risk PE

Rob Orman MD and Jeff Kline MD

Pearls

• Treatment of submassive PE with thrombolytics is controversial.

• Three studies published on the treatment of submassive PE have found little improvement in mortality but improved quality of life for patients. However, there is an increased risk of bleeding complications.

• Response to thrombolytics is heterogeneous and affected by the presence of inhibitors.

CASE

You are wading through the hordes of chest pain patients in the ED when you come across one who doesn’t look good. The story is concerning for PE. The patient is stable but there is something about the presentation that makes you uneasy. The CT shows a large PE. You perform an ultrasound and note mild RV strain. Blood pressure remains stable. What is your disposition? Admit to the floor on heparin? Should we use thrombolytics in patients with submassive PE?

• Massive PE is defined as any PE that causes hemodynamic instability. The size does not matter but rather the effect on hemodynamics. Submassive PE is any clot that causes right ventricular dysfunction but the patient remains hemodynamically stable. The size of the clot does not matter.

• Most agree that massive PEs should be treated with thrombolytics.

• Treatment of submassive PE with thrombolytics is much more controversial. Eventually, right ventricular dysfunction can lead to left ventricular dysfunction resulting in shock or death. This is rare. Most patients will break down the clot eventually with the help of heparin. This is why mortality is low and it is difficult to find benefit from treatment. There is also the issue of long term outcomes. Patients with right ventricular strain can go on to develop pulmonary hypertension which can be debilitating. We need to assess quality of life after submassive PE which is difficult to study.

• Three studies published in the past few years have received a lot of attention.

1. (PEITHO)  

• Meyer, G et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. (PEITHO). PMID: 24716681

• In the PEITHO trial, approximately 1000 patients were randomized to receive tenecteplase plus heparin or placebo plus heparin. These were normotensive patients with intermediate risk PE. Intermediate risk was defined as confirmed PE with abnormal right ventricle noted on echocardiogram or CT and positive troponin.

• The primary outcome was death or hemodynamic decompensation or collapse within 7 days after randomization. Safety outcomes were major extracranial bleeding or ischemic or hemorrhagic stroke within 7 days of randomization.

• The combined endpoint of death or hemodynamic decompensation occurred in 2.6% of the tenecteplase group compared to 5.6% in the placebo (heparin only) group. Difference in the death rate between these two groups was not statistically significant. The real difference was in the rate of hemodynamic decompensation.

• Complications were much higher in the tenecteplase group.

• The authors concluded that fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage or stroke in patients with intermediate risk PE.

• This study is unlikely to change practice; those in favor of thrombolytics will point out the decrease in hemodynamic decompensation while those against thrombolytics will point out the ten-fold increase in hemorrhagic stroke with tenecteplase. This is likely the best study we are going to get. It continues to show a low rate of mortality of submassive PE. We should move more towards assessing quality of life. When the investigators release the data of 1-2 year follow-ups with endpoints more similar to the MOPPET or TOPCOAT such as right ventricular function and quality of life surveys, there will likely be better data. One of the criticisms of this study is that they were looking at the wrong outcome and had too short duration evaluating for outcome.

2. (TOPCOAT)

• Kline, J et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial.  J Thromb Haemost. 2014 Apr;12(4):459-68. (TOPCOAT) PMID:24484241

• Unlike the PEITHO study done by pulmonologists which looked at short term outcomes, this looked at long term outcomes.

• A previous study enrolled 200 patients who were normotensive. Those who decompensated were not randomized but did receive thrombolytics. They found that the patients who received thrombolytics had better right ventricular function.Patients were interviewed about what was important to them and found that it was independence and the ability to do things they cared about.  (Kline, JA et al. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest. 2009 Nov;136(5):1202-10.) PMID: 19542256

• In response, they devised a short term endpoint of death, need for intubation or rescue mechanical or surgical thrombectomy within 5 days. They had the patients return in three months and had a 94% follow-up rate. The patients received a repeat echocardiogram and 6 minute walk test. Patients were questioned about their wishes to develop a long term composite endpoint of right ventricular dysfunction, exercise intolerance and the patient’s perception of wellness measured with the survey SF-36. SF-36 is well known in the literature for a variety of disease endpoints. Patients wanted to be free of thrombotic complications.

• Patients who received thrombolytics had increased probability of a favorable composite outcome. However, there was one intracranial hemorrhage in the 43 patients that received tenecteplase. There was also one death secondary to PE in the placebo group. This demonstrates the equipoise between giving thrombolytics versus not. The difference is that more people feel better after getting thrombolytics.

• What were the inclusion criteria? In this study, patients had to have a positive biomarker (elevated troponin, BNP or pro-BNP) or positive echocardiogram with right ventricular hypokinesis. Patients had to be normotensive (although episodic hypotension was permitted) with a PE proven on CT scan.

• Low molecular weight heparin was used instead of unfractionated heparin along with tenecteplase. Does it matter which is given if the patient is receiving thrombolytics? Most of the study protocols use unfractionated heparin. This is likely due to the belief that a heparin drip can be stopped and reversed with protamine. However, this doesn’t matter. Enoxaparin was used in this study due to steadier anticoagulation with fewer ups and downs associated with a bolus. There is less heparin induced thrombocytopenia and these patients will be discharged home on enoxaparin as they are bridging to warfarin.

• Should a patient with a massive PE and hemodynamic compromise who will receive thrombolytics be given low molecular heparin? The only situation in which Kline would not give the patient low molecular heparin is if they were to go to interventional radiology. This would be a patient with some type of contraindication such as age >70. Kline would give unfractionated heparin as it is preferred by the interventionalists.

• One of the biggest factors of quality of life is recurrent thrombosis. Patients’ quality of life surveys plummet if they have to go back to the emergency room with symptoms. Patients who received thrombolytics had fewer recurrences and emergency room visits.

• It makes sense that if you get rid of the fibrin nidus, it reduces the scarring of the endothelium underlying the clot and reduces the inflammatory response. Residual scarring could serve as a trigger for recurrent clot formation at that site and the use of thrombolytics may lead to a vascular system less prone to clots. More studies are needed to figure out the exact mechanism of the reduction in recurrence rate.

3. (MOPETT)

• Sharifi, M et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7. PMID: 23102885

• This study received a lot of attention when it was first released as the results were almost too good to be true.

• The authors asked if there was benefit to giving a low dose thrombolytics to a patient with a moderate sized pulmonary embolism. They concluded that giving thrombolytics may not prevent patients from dying of PE but may lead to improved quality of life after PE.

• Thrombolytics dramatically diminished the post-PE incidence of pulmonary hypertension as measured by echocardiogram at 28 months.  

• They used half dose thrombolytics. Instead of using massive PE, severe hypotension, right heart dysfunction or biomarkers, they used submassive clot burden alone as inclusion criteria. Much of the methodology was not published. It was a single center study. There was no control or comparison group. No functional outcome was assessed.  Reducing pulmonary hypertension on echocardiogram is probably a good thing, but what does it mean to the patient’s quality of life and exercise tolerance. No short term outcomes were reported.

• 121 patients were enrolled; none had a bleeding complication or a severe complication due to PE such as death. This is unusual.

• Klein: It is ridiculous that we use a standard dose of thrombolytics for all patients with PE. There is extreme heterogeneity in the way that patients respond alteplase based on their own genetics. We will one day soon use biomarkers to let physicians know which patients require twice the dose and which only need a tenth of the dose. The appropriate dose is probably less dependent on clot burden than you might think.

• CASES: Would you give thrombolytics and what is the benefit?

CASE  1

A 60 year old, status post total hip replacement with a big fat swollen red leg, acute chest pain and syncope followed by cardiac arrest. CPR is in progress when the patient arrives. You have high pretest probability but will be unable to get a CT to confirm the diagnosis. Bedside echocardiogram shows a dilated right ventricle. Would you give thrombolytics?

• Kline would bolus alteplase (there is no need to infuse it). However, this has never worked for Dr. Klein and it is expensive ($20,000 acquisition cost).

• Is there any evidence of a mortality benefit for patients with cardiac arrest who receive thrombolytics? A systematic review of case reports found a survival rate of 60%. There is a bias in favor of those who survived.

• Stein, PD et al. Trends in case fatality rate in pulmonary embolism according to stability and treatment. Thromb Res. 2012 Dec;130(6):841-6. PMID: 22909825

CASE 2

A 50 year old patient with a massive PE seen on CT. The patient is hypotensive with a blood pressure of 80 and severe right heart dysfunction. The patient is still conversant. Would you give thrombolytics?

• Klein: Yes, if there are no complications.

• What can you tell the patient? “The chance of you deteriorating to the point where you need life support; infusion of chemical to sustain the blood flow to your body and brain and a breathing machine without this drug is about 50%. The chance of you dying without this drug is about 25%. We can cut those chances in half by giving this drug. However, your chance of severe bleeding (including in your brain) will be about 1 in 50.” This risk increases with age; 1 in 40 at age 60 and 1 in 20 at age 70.

• The American College of Chest Physicians, AHA and ACEP all endorse giving thrombolytics to patients with massive PE.

CASE 3

A 26 year old woman on birth control just had a scope of her knee. She has pleuritic chest pain. Vital signs are normal. CT shows large clot burden with a saddle PE. Echocardiogram is normal. BNP and troponin are normal. Would you give her thrombolytics?

• Klein: No. The proximal location of the clot has predictive value that is significant.  However, she will likely do very well with just heparin. The risk of thrombolytics outweighs the benefit.

• If she had an increase in her troponin? Give thrombolytics. The risk of death increases from 2% to 20% with the increase in troponin. Troponin is the most specific and has the highest likelihood ratio of positives. The overall best screening tool is the BNP. Echocardiogram is qualitative not quantitative.