Follow-up data from the PEITHO trial shows that thrombolytics don't affect long-term morbidity. This simplifies management substantially.
PEITHO trial & long-term follow up
The PEITHO trial was a multi-center RCT investigating the effect of thrombolysis in submassive PE. Tenecteplase caused an increase in intracranial hemorrhage and a reduction in hemodynamic collapse. Overall there was a non-significant trend towards reduced all-cause mortality with thrombolysis.
This trial is discussed in further detail here. A major limitation of this study is that patients in the thrombolysis group were treated simultaneously with a loading bolus of heparin plus a full-dose bolus of tenecteplase. This is a very aggressive regimen, which produced bleeding complications substantially greater than other regimens that have been used for submassive pulmonary embolism. An unnecessarily aggressive thrombolytic regimen likely increased hemorrhagic complications, masking benefits from thrombolysis.
Recently, a follow-up study demonstrated that thrombolysis caused no long-term improvement in functional status or pulmonary hypertension (table above). This is strong evidence that thrombolysis doesn't affect long-term morbidity. The trial is explored in further detail by Rory Speigel here.
Revised goal of thrombolysis & how to achieve this safely
Goals of thrombolysis
Until recently, the goals of thrombolysis were essentially two-fold: reduction of morbidity related to chronic pulmonary hypertension and avoidance of PEA arrest. PEITHO simplifies this by eliminating concerns regarding long-term morbidity. This leaves the primary goal of thrombolysis as reducing the risk of PEA arrest (1).
Avoiding PEA arrest is a modest goal, which may be easier to accomplish. We don't need to normalize the pulmonary pressure, nor do we have to clear the pulmonary vasculature of all clot burden. All we need to do is relieve the pulmonary pressure enough so that patients don't drop dead. This is probably achievable with lower doses of thrombolytic than have been used historically.
What is the ideal dose of thrombolytic?
Two RCTs comparing full-dose alteplase (100 mg) versus reduced-dose alteplase both found equal efficacy from either dose (Goldhaber 1994, Wang 2010). Lower doses do cause less major bleeding (figure below). Thus, available evidence indicates that 100 mg alteplase is too much (Sharifi 2016).
The ideal dose of thrombolytic remains murky. The MOPETT trial utilized 0.5 mg/kg up to a maximal dose of 50 mg (giving many patients a dose of 30-40 mg). Aykan et al. used a regimen of 25 mg alteplase over 8 hours in patients with massive PE, causing an average 23 mm reduction in pulmonary artery systolic pressure (7). Studies from catheter-directed thrombolysis suggest that a slow infusion of 25 mg alteplase at 1 mg/hr can reduce the pulmonary artery systolic pressure by about 15 mm (2). The hemodynamic effects of 25 mg alteplase appear grossly similar to the effects of 50-100 mg alteplase (which reduce pulmonary pressures by ~15 mm; figure above). Although large prospective RCTs are lacking, this suggests that a slow infusion of 25 mg alteplase probably improves hemodynamics enough to avoid PEA arrest.
Risks: How dangerous is alteplase, really?
Conventional wisdom is that heparin is safe, whereas alteplase is dangerous. This dogma is propagated by circular logic:
Available evidence suggests that reduced-dose alteplase isn't actually more dangerous than heparin. Two small RCTs comparing heparin vs. heparin plus ~30-50 mg alteplase found exactly equal rates of major bleeding (Zhang 2014). Combining several studies of reduced-dose alteplase (table below), the rate of intracranial hemorrhage was 1/453 (0.2 %). This equals the rate of intracranial hemorrhage from heparin alone (1/500), suggesting that a few patients will develop ICH regardless of how they are anticoagulated (3,4).
How thrombolysis is given is probably important
Most attention is generally focused on the total dose of thrombolytic. However, the details of how this thrombolytic is administered are likely critical as well. Two factors in particular might improve safety:
1. Avoid combining thrombolytic with unfractionated heparin
Much of the risk which we have traditionally assigned to thrombolysis is probably due to clumsy combinations of alteplase plus unfractionated heparin infusions (heparin infusions being a veritable roller-coaster of anticoagulation, with wide swings between sub-therapeutic and supra-therapeutic anticoagulation). For example, the 2% rate of intracranial hemorrhage in PEITHO reflected a combination of full-dose tenecteplase plus a simultaneous loading bolus of heparin (a formula for disaster). Recent studies involving alteplase have minimized risks by giving alteplase more carefully, for example (5):
- Before and during alteplase infusion, the heparin infusion may be stopped or reduced substantially. After alteplase, heparin may be re-initiated several hours later without a bolus.
- Alteplase may be combined with low molecular-weight heparin (rather than a heparin infusion).
2. Slow infusion of thrombolytic with monitoring of fibrinogen levels
Fibrinogen levels are generally ignored during thrombolysis, blinding us to some very interesting dynamics. The response of fibrinogen levels to thrombolysis varies enormously between patients, reflecting variability in numerous proteins regulating fibrinolysis. If alteplase is given very slowly (e.g. 24 mg infused over 24 hours), this allows monitoring of fibrinogen levels during thrombolysis. If the fibrinogen level falls too rapidly, thrombolysis may be stopped before bleeding occurs. This strategy of controlled thrombolysis might be the safest approach to thrombolysis (extrapolating from extensive data about catheter-directed thrombolysis of PE and DVT).
Individual risk-stratification
Consideration of patient-specific risk factors for hemorrhage is also essential (e.g. using a contraindication checklist). The following factors in particular seem to predispose patients to develop intracranial hemorrhage (Chatterjee 2017):
- History of CVA or intracranial pathology
- Age
- Known vascular disease (prior myocardial infarction or peripheral artery disease)
- Coagulopathy
Who benefits from thrombolysis? Identifying patients at risk of dying from PE
Physiology of death due to PEA arrest
The two most common pathways whereby PE patients can present to a hospital alive and later arrest may be conceptualized as follows (6):
- Clot-throwing death: This is due to throwing additional emboli to the lungs. These patients look fine initially, with no hemodynamic instability. They may do great for a while, but then they suddenly have a PEA arrest.
- Teetering death: These patients present to the hospital with a very large clot burden in their lungs and severe RV strain. They are teetering on the brink of cardiac arrest. Any hemodynamic stress (e.g. fluid shifts, autonomic fluctuation, vasovagal episode, additional emboli) may push them into a death spiral, with progressive RV dilation and PEA arrest:
Identifying patients at risk of teetering death
These are your stereotypical high-risk submassive PE patients. They aren't hypotensive, but they have clinical signs of hemodynamic instability. The most notable examples of this are:
- Tachycardia, elevated shock index
- Syncope or presyncope (indicating lack of cardiac reserve)
- Patients being kept alive by a huge outpouring of endogenous catecholamines. Clinically, this may be manifested by one or more of the following:
- (a) Lactic acidosis (produced via aerobic metabolism stimulated by endogenous epinephrine)
- (b) Patients who look ill (endogenous epinephrine causes diaphoresis and pallor, makes people look and feel terrible)
Following PE diagnosis, these patients can be identified based on history and physical examination. Bedside echocardiogram should be consistent with right ventricular failure (showing both RV and IVC dilation), otherwise an alternative explanation should be sought for their instability (e.g. small pulmonary embolism plus volume depletion).
Identifying patients at risk of clot-throwing death
Proximal DVT is an independent risk factor for poor outcomes (Jimenez 2014). Meta-analysis confirms that DVT doubles 30-day mortality (Becattini 2016, above). Proximal DVT confers a threat of additional emboli to the lungs, causing hemodynamic collapse. Patients who are at the greatest risk of sudden death due to future embolic events meet the following description (Alviar 2016):
- Already have a submassive PE (e.g. RV dilation and troponin elevation).
- Significant residual clot burden in the legs (e.g. proximal DVT)
The combination of a submassive PE plus a proximal DVT is a formula for disaster. The RV is already strained, so it may be unable to tolerate additional emboli.
Time to stop performing “delayed” thrombolysis
Imagine that a man presents with dyspnea of one week's duration, which has been stable. He is found to have right ventricular strain and an elevated troponin. He is well-appearing and hemodynamically stable. Should he be lysed?
Previously I might have considered thrombolysis with a goal of reducing his long-term pulmonary morbidity. However, based on newer evidence, he shouldn't be lysed:
- He has been stable for several days, so the likelihood that he will suddenly have a PEA arrest is very low (he has already survived an extended trial of “observational therapy” at home).
- Over time, clot may mature and become less susceptible to thrombolytics.
The precise time frame during which thrombolysis may be beneficial remains unclear. Patients with accelerating instability might benefit from thrombolysis, even if they started experiencing symptoms some days earlier. However, patients with stable symptoms over several days probably don't derive much benefit from thrombolysis.
Pre-emptive vs. rescue thrombolysis
After identifying patients at risk of death from PE, two strategies are possible:
- Pre-emptive thrombolysis: Provide thrombolysis immediately and in a controlled fashion, with a goal of preventing decompensation.
- Rescue thrombolysis: Admit patients to the ICU, treat with heparin, and observe. If the patient deteriorates, then treat them with thrombolysis.
The best strategy may depend on the risks vs. benefits of thrombolysis for any individual patient. My general preference is for pre-emptive thrombolysis, for the following reasons:
- Even in the ICU, if the patient has a PEA arrest this is difficult to salvage. These patients often do survive, but may still suffer from anoxic brain injury.
- Observing patients in the ICU for a while doesn't protect them from subsequent deterioration. I've managed some patients who were admitted to the ICU, did great for 24-36 hours, felt better, and later died on the ward.
- Reduce-dose alteplase probably doesn't increase the risk of intracranial hemorrhage compared to a heparin infusion, if given very carefully (Sharifi 2016). For example, an infusion of 24 mg alteplase over 24 hours while monitoring fibrinogen levels is very safe. If a patient is so sick that they require ICU admission, it seems illogical not to treat them with a small, safe dose of alteplase.
Evidence: is there a mortality benefit to pre-emptive thrombolysis in submassive PE?
The largest meta-analysis by Chatterjee 2014 detected a 1.5% mortality benefit from pre-emptive thrombolysis, compared to anticoagulation with rescue thrombolysis as needed (p=0.03, above). However, a subsequent meta-analysis which excluded some studies due to concern about bias found a non-significant 1.4% mortality benefit (Nakamura 2014). The fact that these studies found any mortality reduction is impressive, given the following considerations:
- Most studies included all submassive PE patients (including low-risk submassive patients who are less likely to benefit).
- The meta-analysis found that thrombolysis caused a 1.3% increase in intracranial hemorrhage, which is much higher than rates obtained utilizing reduced-dose alteplase (0.2%). This high hemorrhage rate may reflect that many studies combined full-dose thrombolysis with simultaneous full-dose heparin infusion (e.g. PEITHO, TIPES). High hemorrhage rates would tend to mask any benefit from thrombolysis.
- Many studies included patients who had been symptomatic for several days (e.g. PEITHO included patients with symptoms for up to 15 days). Such patients are very unlikely to obtain any mortality benefit.
We may never have proof of a mortality benefit, since that this would require an improbably large clinical trial. However, extrapolation suggests that a meaningful mortality benefit could be obtained in a subgroup of submassive PE patients by:
- Restricting thrombolysis to patients at the greatest risk of death (high-risk submassive PE).
- Restricting thrombolysis for patients with acute PE, not patients who have had stable symptoms for several days.
- Mitigating the risk of hemorrhage by using a reduced dose of thrombolytic (25-50 mg alteplase) and avoiding the simultaneous use of thrombolytic and therapeutic heparin infusions.
Submassive PE schema 2017
Submassive PE tends to defy algorithms, because it seems that each patient is somehow unique. Nonetheless, having a general schema is useful. Previously, the following approach was proposed:
Based on the long-term results of PEITHO, this requires revision as shown below. There is no longer a rationale for lysing low-risk submassive PE patients.
- Long-term outcomes of patients in the PEITHO trial indicate that thrombolysis doesn't affect chronic pulmonary morbidity. This simplifies the approach to submassive PE, by making the primary goal of thrombolysis to avoid PEA arrest.
- Patients with low-risk submassive PE who are less likely to arrest probably don't benefit from thrombolysis. However, high-risk submassive patients may still benefit from thrombolysis.
- If our goal from thrombolysis is merely to avoid PEA arrest, all we need to do is reduce the pulmonary pressures somewhat (not normalize them). This may be achievable with lower doses of alteplase than have been used historically, with a superior safety profile.
Related
- PEITHO Followup study (EMNerd)
- 2016 series on quarter-dose TPA: Part I & Part II (PulmCrit)
- Submassive PE: are we treating it backwards? (PulmCrit)
- PERT team & risk sub-stratification (EMCrit)
- Sharifi M. Systemic full dose, half dose, and catheter directed thrombolysis for pulmonary embolism. When to use and how to choose? Curr Treat Options Cardio Med 2016; 18: 31.
Notes
- Some other arguments do exist in favor of thrombolysis (e.g. more rapid clinical improvement and reduced hospital length-of-stay). However, compared to concerns regarding PEA arrest and intracranial hemorrhage, these concerns are generally less pressing.
- It remains unknown whether this dose must be delivered to the pulmonary arteries, or whether it would be equally effective if administered via a peripheral vein. Given that 100% of the venous return goes directly to the lungs, location of infusion might not matter. This is explored further here.
- Statistic from the CHEST 2016 guidelines (Kearson 2016), Table 8.
- However, the precise rate of intracranial hemorrhage from reduced-dose thrombolysis remains unknown. Since the rate is so low, to precisely define this would require many more patients (e.g. ~5000 patients). Please also note that in real life, the rate of bleeding is often greater than in randomized controlled trials. However, the relative risk of bleeding would be expected to be similar (i.e. comparative danger of heparin vs. alteplase should be the same).
- Note that unlike alteplase, heparin has no proven immediate benefit during the acute phase of PE management. Therefore, interrupting or decreasing heparin infusion to give alteplase is a rational strategy.
- PE typically doesn't cause death due to respiratory failure, but this can occur in patients with chronic respiratory illness. In these cases, patients may manifest with respiratory failure (e.g. hypoxemia, tachypnea, exhaustion). These patients will obviously be ill and require aggressive therapy.
- This study currently is only available in abstract format: Aykan AC et al. Low dose prolonged infusion of tissue type plasminogen activator therapy in massive pulmonary embolism. European Heart J 2014; 35(Suppl 1): 69.
- PulmCrit Blogitorial – Use of ECGs for management of (sub)massive PE - March 24, 2024
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Josh- great follow-up to previous posts on submassive PE. Those posts are my go to when looking at treatment options for these patients. I have a dream study in regards to this issue- either half dose alteplase (ala MOPPETT) or 24mg over 24 hours alterplase and then followup looking at functional outcomes and development of pulmonary hypertension. Do you think there is enough of a signal from the literature that these lower dose strategies would reduce long term morbidity in regards to development of pulmonary hypertension without increasing bleeding risk? I know PEITHO’s long term followup did not show a… Read more »
Thanks Steve. I find the PEITHO follow-up study to be very persuasive *because* they used such a high dose of thrombolytic. I would expect a high dose of thrombolytic to increase short-term hemorrhagic complications slightly, but it should be more effective for avoiding chronic pulmonary hypertension. The fact that full-dose tenecteplase didn’t do anything for chronic pulmonary pressures suggests that a smaller dose of lytic (e.g. 25-50 mg alteplase) probably doesn’t either. For me, the PEITHO follow-up study is more definitive than the original PEITHO trial. So for now, I think we should probably operate under the premise that there… Read more »
In regards to your delayed thrombosis for subacute submassive PE. You mentioned that the risk of PEA arrest is lower due to the patient likely being out of the observational period and hard clot formation. Is there any benefit to still give lytics to this category of patients in hopes to limit the extent of their pulmonary hypertension that will develop?
Currently the best available evidence suggests there is no benefit regarding the risk of pulmonary hypertension (based on the follow-up results from PEITHO). I always have an open mind, but for now this seems to be the most evidence-based answer.
great post as always.
Is there any evidence for your proposal of alteplase 24mg over 24hrs given via a peripheral line because I have never heard of or seen this being done before.
thanks.
For a complete explanation about the 24mg/24hr regimen, see these posts: https://emcrit.org/pulmcrit/ultrasound-assisted-thrombolysis-pulmonary-embolism-alteplase/ and https://emcrit.org/pulmcrit/thrombolysis-submassive-pe-alteplase/
The short version is that this is the same exact regimen of alteplase that is generally used for catheter-directed thrombolysis. This provides us with extensive evidence regarding its safety (which is excellent). The efficacy of 24mg alteplase is less well established, but is supported by one case series and indirectly from other sources as well.
Do you think ECMO plays a role in the PE continuum outside of the salvage/ECPR state? Should patients with high-risk submissive PEs be managed in ECMO capable centres and should we be thinking of it earlier as a bridge to a definitive therapy?
First, I should say that I don’t work at an ECMO center, so I don’t have much experience with it. So I’d probably direct questions about ECMO to the ED ECMO podcast at http://edecmo.org.
That said, my guess is that ECMO’s role is limited to massive PE. Most patients with submassive PE (even high-risk submassive) are stable enough that there is some time window to provide therapy to stabilize them without needing ECMO.
Dear Josh,
thanks for this comprehensive and very practical approach. I have initiated the 24 mg/24 hrs strategy in an elderly ICU patient. He arrested in the hospital with PEA, ROSC after 20 minutes of CPR. Very unstable with low-dose pressors in the ICU. PEA again with CPR for 4 minutes under full-dose heparin. He had inguinal hernia repair about a week ago, I initiated alteplase at the rate above. Will see how it goes… What do you think of it? Best, – Peter
Thank you for this Josh. I am an emergency physician in Australia. Interestingly our national electronic therapeutic guidelines (updated 2016) state that the role of fibrinolysis is ‘limited’ and that there is a significantly increased bleeding risk compared to heparin. Heparin is the recommended first line treatment in patients with haemodynamic instability – bolus then infusion. The alteplase dosing is still the higher dosing regime – 10mg the 90mg over 2 hrs. A couple of questions for you: – with the 50mg over 2 hr dose, do you give any of that as a bolus in submassive/massive PE? – in… Read more »
Thanks. Guidelines vary on this, unfortunately I think some of them focus on black/white questions (e.g. “is TPA beneficial in submissive PE yes or no?”) while ignoring some of the subtleties in the data and individual studies. First question- for the 50 mg over 2 hours, will typically give 10 mg as a bolus dose with the remaining 40 mg over two hours. This is based of the MOPETT trial protocol. Would also note that the dose is lower than 50 mg for lighter patients (total dose 0.5 mg/kg up to a max dose of 50mg). Second question- agree with… Read more »
Josh, I am a emergency physician in rural America and I occasionally encounter patients with submassive PE. Given the lack of impact from thrombolysis on long term pulmonary hypertension, are there other therapies that can be given in the acute phase in an effort to exert some favorable outcome on long term PA pressures? I’m a fan of fish oils, and came across this: https://www.ncbi.nlm.nih.gov/pubmed/2732158 I don’t know how I could directly action this kind of therapy (short of some TPN infusion…), but outside of generalized hemodynamic support, I’m looking for something more. Great post, and thanks for all that… Read more »
I’m not aware of any therapies that affect long-term pulmonary pressures, unfortunately.
How does catheter thrombectomy or catheter directed thrombolysis fit in here? If these options are available, should they be pursued instead?
Yep, that’s the million dollar question (literally). This remains unknown, because industry-driven studies have only compared catheter-directed thrombolysis to heparin (a “straw-man” comparison). If there are large, bulky central clots then there might be some theoretical advantage of sinking a catheter into them and directly infusing the TPA into the clot. Maybe. Overall, my suspicion is that catheter-directed thrombolysis has similar efficacy compared to systemic thrombolysis with the same dose. More on this here: https://emcrit.org/pulmcrit/ultrasound-assisted-thrombolysis-pulmonary-embolism-alteplase/ This also depends on exactly which technologies your interventionists are using (e.g. some suction thrombectomy devices might be useful in patients who can’t tolerate anticoagulation).… Read more »
Hey Josh, fantastic review and more importantly, clinical synthesis. I’ve been using a similar “gestalt” for deciding, and so glad you put down how the IVC has to be dilated. I’ve ruffled feathers by POCUSing and telling docs flatly that it’s not a PE causing the instability (because of course we can’t r/o a non-hemodynamically significant PE) who had a syringeful of heparin to push STAT.
Keep up the awesomeness!
Dear Josh. I love your posts on submassive PE. I work as an ICU/CCU physician in a hospital in Austria. Inspired by your work I implemented Lysis- schemes for submassive PE. I use the 25mg alteplase over 24h via peripheral vein + subtherapeutic heparin infusion for my high Risk Patients and the 50mg over 2h without coadministration of heparin for the rest . Since last year I performed thrombolysis in 18 Patients without bleeding complications During those cases in witch I used 50mg alteplase I encountered the following. In about a quarter of Patients there was a quick resolution of… Read more »
Brilliant stuff. In general it is common practice to give a thrombolytic and then start anticoagulation without monitoring fibrinogen levels. However, as you point out, these levels are often severely depressed following thrombolysis. I’m not aware of any solid data on this. My opinion is that it is probably best to withhold anticoagulation until coagulation parameters are closer to normal as you have suggested (“sit tight and wait” approach). This may mean giving no anticoagulation for 10-12 hours after TPA, but the patient is probably still effectively anti-coagulated during this period due to the residual effects of the thrombolytic. My… Read more »
We are in the process of developing a “Rapid PE response team” at my hospital. But as of now, decisions are slow to come regarding lytics. So, in the ED, If I have a patient with a submassive PE that might need lytic tx, if they get worse, which is a safer choice to start, heparin or lovenox.
Thanks for great read!
Hi Josh – As many others have said, thanks for the excellent and thoughtful reviews!! What’s your feeling on thrombolytics for patients who have had pulmonary infarction and/or hemorrhage as a consequence of their PE? I would like to use 1/2 dose tpa systemically more liberally and currently have 2 patients in my unit with hemoptysis/hemorrhage and submassive PEs. While it seems that reducing the PA pressures and unloading the RV is hemodynamically beneficial, risking worsening respiratory failure from alveolar hemorrhage would be problematic (to say the least). We are probably risking this with heparin anyway, but “do no harm”…… Read more »
“Alteplase may be combined with low molecular-weight heparin (rather than a heparin infusion).”
Can you give us a reference and/or opinion on this? We are tempted to start anticoagulation before deciding on lytics in submassive PE. So which one, or none until we decide?
“Alteplase may be combined with low molecular-weight heparin (rather than a heparin infusion).”
Can you give us a reference and/or opinion on this? In a patient with PE not in shock, while workup is being done, we’re always tempted to starts anticoagulation. So which one or none to start?
Josh,
Brilliant post, and I agree wholeheartedly.
At the risk of being pedantic, PEITHO was not a “full dose” thrombolysis trial. Tenecteplase was dosed at 30-50 mg (weight based),given in a single bolus, often with concomitant anticoagulation…. which (for all of the reasons that you outline above) probably explains the high bleed rate..
FWIW, I don’t believe that 100 mg of tenecteplase would have changed the progression to CTEPH, and it almost certainly would have increased the number of bleeds.
Thanks much. According to the package insert (https://www.accessdata.fda.gov/drugsatfda_docs/label/2000/tenegen060200lb.htm) there is no indiction to ever give more than 50 mg tenecteplase. Most references recommend up to 50 mg tenecteplase for STEMI compared to ~100 mg alteplase for STEMI. So I would consider 50 mg tenecteplase to be a “full” lytic dose, equivalent to roughly 100 mg alteplase.
Great post !
Can I translate this to portuguese and post it on my blog ?
sure, please e-mail me a link to your translation (farkasmd@gmail.com) so I can index it. Also please contain a link back to the english version in your post.
Great review!!!
Thank you
Great post. Why risk complications of RHCath for CDT in patient with stressed RV (when a few PVCs can be disasterous) when same dose lytics can be delivered by peripheral iv? This is what’s done for right sided mechanical valve thrombus. If lytics gets to pulmonary valve thrombus, should also get to PA….right? What is fascination with CDT?
Cross-commenting from a different post:
I just saw this trial come up and thought of this post. Can’t wait to see the results when it comes out.
“Peripheral Low Dose Thrombolysis Versus Catheter Acoustic Directed Thrombolysis for Submassive PE”
EKOS vs Peripheral IV 2mg/hr
https://clinicaltrials.gov/ct2/show/NCT03581877
Have you seen any other papers about peripheral tPA in PE, or has your practice changed much recently?
Can’t wait for this study to come out. I haven’t seen anything new in the literature unfortunately, although I’m sure some pardigm-changing study will come out within the next couple of years.
Hi Josh. Thanks for the great summary of literature. In a low-risk bleeding patient, or someone in PEA, with a massive PE would you use 5-100 mg Alteplase as a bolus? How fast would you give it? Thanks!