The Non-Stroke TPA Debate: What else should we be giving TPA for?

 

TPA for MI when PCI is not available – recommended so thoroughly it’s in textbooks.

TPA for clotted AV fistulas – surgeons do it.

TPA in stroke…not going anywhere near it.

TPA for PE…Interested?

 

After a lit search [1] done under the tutelage of Dr. Shahriar Zehtabchi, here’s what I learned.

 

Let’s start at the extremes.

Patient arresting from PE – Give fibrinolytics (Class IIa, LOE B). They may improve survival and long term neurologic function. [2,3]

For undifferentiated arrest, though, do NOT give fibrinolytics. (Class III, LOE A). [3]

 

Massive PE (defined by a PE causing hemodynamic instability)

– Per European guidelines [4], give fibrinolytics. They report “haemodynamic” benefits in the first few days after and lower mortality (RR 0.20; 95% CI 0.19-0.22; p< 0.0001).

 

Low Risk PE (without right heart strain, elevated troponin or hemodynamic instability).

-These PE’s have low mortality (see Dr. Freedman’s wonderful post on this from last week) and tpa may not be the safest drug. Seems like the risk of bleeding outweighs any potential benefit in my humble opinion.

 

The Tricky One – Submassive PE

Defined as PE without hemodynamic instability, BUT with elevated troponin, right heart strain on echo, or both. The literature for fibrinolytics in this subset is a bit more…confusing.

To start, Cochrane Review, 2009 [5] – Using 8 trials, they found no significant difference in mortality, major bleeding, minor bleeding, or PE recurrence. They conclude that the evidence for fibrinolytics in PE is limited and more studies are needed.

Since then, we have had a major study with two meta-analysis following.

PLEITHO [6]

A large RCT on fibrinolysis in submassive PE. Finally! Yaay! 1005 patients with PE and both elevated trop and right heart strain randomized to receive fibrinolysis with vs without heparin/lmwh. Excluded pregnant, allergy to fibrinolytics, BP >180/110, known coagulation disorder (including plt < 100,000 or on Coumadin), known significant bleeding, or ED physician felt unsafe.

Outcomes (tenecteplase vs placebo)

No change in 7 day mortality: 6 (1.2%) vs 9 (1.8%), p = 0.42, or 30 day mortality: 12 (2.4%) vs 16 (3.2%) p =0.42, BUT a significant decrease in hemodynamic decompensation: 8 (1.6%) vs 25(5%), p = 0.002. They combined these outcomes, which doesn’t make that much sense to me, and got a P = 0.02 in favor of tenecteplase: 11 (2.6%) vs 28 (5.6%). I’m not sure how useful this combination is. If someone has hemodynamic decompensation without dying, how important is their decompensation?

The tenecteplase group had more ICH: 10 (2%) vs 1 (0.2%), p =0.003, and more major extra-cranial bleeding: 32 (6.3%) vs 6 (1.2%), p<0.001. Wierdly, 2 in the tenecteplase group had ISCHEMIC strokes while on heparin/lmwh after tenecteplase.

Subgroup analysis

Turns out there is an increased risk of bleeding in patients older than 75. Unfortunately, they didn’t present the data for mortality and hemodynamic decompensation separately. All we know is, for patients < 75 yo, the combined outcome remains significant: 6 (1.7%) vs 17 (5.1%) OR 0.33 (0.13-0.85). For patients >75 yo the combined outcome is not statistically significant.

Extra-cranial bleeding on the other hand, showed a trend without statistical significance for <75 yo: 14 (4.1%) vs 5 (1.5%), p = 0.09 and remained statistically significant for > 75 yo.

Looking at the appendix data, of the 10 patients with hemorrhagic stroke, only one was younger than 75 years old…She was 73. Which means 344 patients younger than 75 years old got TPA and only 1 had an ICH!

 

Since then, two meta-analyses have come out.

The first, from China and in the journal “Patient Prefer Adherence [7], included 7 studies and reported no statistically significant difference in mortality and no increase in major hemorrhage with fibrinolytics

The JAMA one [8] found 16 RCTs and concluded that fibrinolysis had lower mortality (OR 0.53; CI 0.32-0.88) with an NNT 59. They computed a NNH 18 for major bleeding and an NNH 78 for ICH. Importantly, major bleeding was NOT significantly increased in patients < 65 yo.

The 2014, European guidelines [4] conclude that full dose fibrinolytics for submassive pe are “controversial”. They quote a 1.9%-2.2% risk of intracranial hemorrhage with a beneficial improvement in symptoms WITH NO conclusive increased mortality.

 

Tired of TPA again? Well what about half dose tpa?
Some literature supports the use of “half dose” fibrinolysis. Theory has it; you could get the same benefit without as much pesky ICH.

MOPETT [9]

After excluding those with plt <50k, major bleeding within 2 months, surgery or major trauma within 2 weeks, brain mass, neuro surgery, ICH of SDH < 1 year, or end stage illness, 121 patients with “moderate” PE were randomized to half dose TPA vs control, they had less pulmonary htn in 30 months: 9 (16%) vs 32 (57%), P<0.001 and less recurrent pe: 0 vs 3 (5%),p=0.08, less days in the hospital: 2.2 vs 4.9, p <0.001, with NO difference in mortality: 1 (1.6%) vs 3 (5%), p = 0.3. Interestingly, they had 0 episodes of bleeding in the TPA group. Obviously this is a small study, but the data sure is tantalizing.

 

So what are you going to do with your next submassive PE patient? What factors will influence whether or not you give fibrinolytics? What about half-dose thrombolytics? What’s your age cut-off? Do you use an age cut-off?

 

 

By Dr. Andrew Grock with special thanks to Dr. Ian deSouza and Dr. Shahriar Zehtabchi

[1] Lit Search:

Pop. – (embolic or embolism or thromboembolic or thrombus, or vte or venothromboembolism or thromboembolism) AND (lung or pulmonary)

Int. – Thombolysis or tpa or alteplace or fibrinolysis

Resulted in 1013 articles. Narrowed to 186 articles when limited to human studies, less than 5 years old, clinical trials, meta-analysis, RCTs, or systematic reviews. All 186 articles titles reviewed, 27 abstracts reviewed with 18 being reviewed for the above analysis.

 

References

[2]Robert W. Neumar, et al. Part 8: Adult Advanced Cardiovascular Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010; 122: S729-S767

[3] Terry L. Vanden Hoek, et al. Part 12: Cardiac Arrest in Special Situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation.2010;122:S829-S861           

[4] Stavros V. Konstantinides, et al.  2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). European Heart Journal (2014) 35, 3033–3080

[5] Dong BR¹, Hao Q, Yue J, Wu T, Liu GJ.Thrombolytic therapy for pulmonary embolism.Cochrane Database Syst Rev. 2009 Jul 8;(3):CD004437. doi: 10.1002/14651858.CD004437.pub3.

[6] Guy Meyer, M.D., et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med 2014; 370:1402-1411. April 10, 2014

[7]Yaoqian Cao, et al. Systematic review and meta-analysis for thrombolysis treatment in patients with acute submassive pulmonary embolism. Patient Prefer Adherence. 2014 Feb 28;8:275-82

[8] Saurav Chatterjee, et al. Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial HemorrhageA Meta-analysis.JAMA. 2014;311(23):2414-2421.