The Case Against Trasylol

[coprolalia]

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So, there has been a lot of press lately about the dangers of Trasylol (aprotinin) being used in cardiac surgery. The television show "60 Minutes" even recently did a piece on this (which is a "must-see" for those not in the know)...

http://www.cbsnews.com/stories/2008/02/14/60minutes/main3831900.shtml

The insinuation is that Bayer Pharmaceutical knew about the "problems" with this drug yet suppressed reporting to the FDA. As many of you know, there is now a marketing ban on it.

Why is this important? Because Trasylol was (and continues to be) an important adjunct in cardiothoracic surgery where the patient goes on cardiopulmonary bypass. Aside from tranexemic acid and aminocaproic acid, there are really no other drugs that prevent bleeding while on pump... and both of those drugs have their own issues too.

So, who is still using aprotinin during bypass? I know we do. Problem is, we only have a small stockpile of the drug left. In the past month since this story came out, I've probably used it four or five times (including recently on a 4-year-old boy who had a completion of his Fontan).

The consensus at our program on this drug is that the data is somehow suspect; that this is a retrospective analysis and is not reflective of the full population of patients that are exposed to this drug. Bayer clearly was not forthcoming with their data, but did they have the right to reserve blowing the whistle on themselves before they knew the whole story? And, there is also suggestion by some of my colleagues that Mangano is more interested i promoting his own career than he is the truth.

I don't know what to think. In the times I've used Trasylol, I haven't noticed inadequate renal function post-op (except for one patient who was an ASA-5 salvage procedure and would've died anyway because of the severity of her underlying disease).

I'm interested to know if people out there are still using it and what your thoughts are on the subject. Our practice is to defer to the surgeon's preference. In that sense, we are simply administering a drug they've prescribed. Should we as practitioners be clearly documenting that in the record?

Discuss.

-copro

 

[swpm]

I'm interested to know if people out there are still using it and what your thoughts are on the subject. Our practice is to defer to the surgeon's preference. In that sense, we are simply administering a drug they've prescribed. Should we as practitioners be clearly documenting that in the record?

We have it in stock, but I don't think it's been used since October or November. None of our surgeons seem to think it's worth the liability. Aminocaproic acid was the drug of choice around here, last time I did a heart.

As for deflecting blame in the record ... I doubt a b-b-b-but-he-prescribed-it note would amount to much if it came to a lawsuit (after all, we're doctors, not CRNAs), but I'd put that note in the chart anyway.

 

[coprolalia]

As for deflecting blame in the record ... I doubt a b-b-b-but-he-prescribed-it note would amount to much if it came to a lawsuit (after all, we're doctors, not CRNAs), but I'd put that note in the chart anyway.

I think you have to put something like, "Surgeon requested administration of aprotinin during the cardiopulmonary bypass and clinical decision was deferred to primary service." I think you are likely still on the hook if you have a bad outcome and get sued. But, this is clearly more defendable. After all, you are a consultant.

I always ask well before. And, since we've established which surgeons still like to use Trasylol and those that steer away from it, it's pretty much a no brainer at this point. But, I still ask. After all, I'm just the resident. If my attending wants to take responsibility for it, so be it. I probably will not do hearts when I finish residency anyway.

-copro

 

[pd4emergence]

We used it for redos until november when it was pulled. I haven't liked using it since the first data came out a few years ago but our CV guys wanted it. I would always put in a trasylol disclaimer but it probably would not keep you off the suit. In residency, we used it for everybody at first, then the first major study came out showing that the only subset it seemed to be beneficial in were the cabg redo's. Then, we changed and started using amicar for all except the redos and for those we used aprotinin. I was happy when the new data came out in November and we stopped using it. I honestly do not know if I have had any patients develop renal failure after they left the ICU. I can think of a few that became long term unit players that did end up with renal failure. I do not know if aprotinin was a factor. If I had to guess I would say probably not. I am glad it is gone so now I don't have to fight over the latest data on the safety of trasylol. Our hospital pharmacy is extremely happy also.

 

[coprolalia]

It's clearly an expensive drug. We primarily used it for our redo's, and used Amicar for our primaries. Now we are using a lot more [SIZE=-1]Cyklokapron, for some reason. Both are about the same drug. And, there's even a lot of our CT guys who think it's all voodoo anyway.

-copro
[/SIZE]

 

[UTSouthwestern]

Aprotinin is still available at the hospitals I cover but most of it is sitting largely unused. The one time I heard it was used in the past two months, the anesthesiologist used it for a patient who had full dose Plavix up until the day of surgery, the patient did fine and was extubated after a 5V CABG and MVA, but postop, clotted off his circ. This was previously a 95% patent vessel.

For my cases, I don't use it anymore. Amicar or tranexemic acid with or without DDAVP as necessary. I have also taken to underdosing the heparin boluses on my hearts to prevent ACT's > 600, to ensure that they lay within a 450-600 range for on pump cases, 300-450 for off pump. I also titrate in protamine to prevent over reversal with protamine and subsequent protamine induced coagulopathy.

 

[coprolalia]

Thanks for responding, UT. So, do you use Amicar or Cyklokapron even on re-do's?

-copro

 

[urge]

I have also taken to underdosing the heparin boluses on my hearts to prevent ACT's > 600, to ensure that they lay within a 450-600 range for on pump cases

What is the reasoning behind it? Is there any evidence?

I don't like aprotinin. I only use it when the surgeons ask for it and cannot wait for the day when we deplete our stock. I think we'll get our asses sued so badly one of these days.

 

[UTSouthwestern]

Thanks for responding, UT. So, do you use Amicar or Cyklokapron even on re-do's?

-copro

Yes, I use them even on redos.

 

[UTSouthwestern]

What is the reasoning behind it? Is there any evidence?

I don't like aprotinin. I only use it when the surgeons ask for it and cannot wait for the day when we deplete our stock. I think we'll get our asses sued so badly one of these days.

What I have found is that the ACT machines tend to overestimate the amount of heparin that a patient should receive. When I gave the full dose recommended by the machine in my first two years of practice, my ACT's would invariably be greater than 600 with a heparin level much higher than 3.0 and many times the ACT would be greater than 999.

By giving the patient 60-70% of the calculated dose, I have been able to keep the ACT's below 600, while rarely having to give additional heparin to achieve an adequate level for CPB. I have talked to the manufacturer about this problem as in my first two years, post procedure or post CPB bleeding was a problem I seemed to have quite a bit, whereas in the last year since altering my practice toward careful titration and multiple ACT readings, I have very little post op bleeding in even redo/redo hearts.

This also applies to the protamine dosing that the ACT machines calculate. I give only 40-50% of the recommended dose and 90+% of the time, I get normal ACT's. I have argued with several colleagues about the heparin rebound phenomenon which they argue is a reason to give 1:1 or even 2:1 protamine:heparin dosing, but my argument is that since excessive doses of protamine can act as an anticoagulant, you are not giving the patient any reasonable post procedure time period during which they can form a sustainable clot. There is literature to support it, but some of my surgeons are trying to strictly follow protocols they picked up at their training institute.

With TEG and platelet mapping pretty much standard at the heart hospitals I cover, I can back up my arguments with post protamine TEG's showing normal tracings after a titrated protamine regimen. You also need to give at least 10 minutes after administration of protamine to see adequate clot formation systemically, so I tend to ignore surgeon complaints of oozing within 10 minutes after protamine administration.

Of my last 82 hearts, I have only given FFP once and that was not entirely necessary as after I spiked it, the surgeon noted that the oozing had stopped, but I had already started infusing it not even a minute prior. I have given platelets twice and both times due to preoperative thrombocytopenia with moderate post procedure coagulopathy by TEG with platelet mapping indicating weaker clot stability.

 

[coprolalia]

Doing a TEG is a good tool. We use it routinely in our liver room. Not in our heart room. Problem is that by the time you get your answer, whatever bad that was going to happen has already happened. Although, TEGs and an oximetric Swan are standard in our LVADs.

I haven't seen that many "bring back" hearts lately. We usually give the 1:100 dose of protamine to heparin (i.e. if you give 25,000 units of heparin, you'll give 250mg of protamine when off-pump and clearly not going back on). I haven't seen a particular problem with this, although my experience is clearly limited.

But, we do occassionally get the "ooze" as they're closing. Usually this is treated with platelets and sometimes FFP. Maybe we're overdoing it with the protamine. However, my experience is that doing it this way will usually get your ACT back to within the 10% of the baseline. And, we dose 300units/kg of heparin before going on pump which usually gets us an ACT between 500-600 pretty consistently. Haven't seen any post-op MI's so far from this regimen either, even when giving Trasylol. And, we follow-up post-op 24 hours religiously on all of our pump cases.

Not suggesting that I have nearly the experience you do. Just haven't been burned yet.

-copro

 

[rsgillmd]

Doing a TEG is a good tool. We use it routinely in our liver room. Not in our heart room. Problem is that by the time you get your answer, whatever bad that was going to happen has already happened. Although, TEGs and an oximetric Swan are standard in our LVADs.

I haven't seen that many "bring back" hearts lately. We usually give the 1:100 dose of protamine to heparin (i.e. if you give 25,000 units of heparin, you'll give 250mg of protamine when off-pump and clearly not going back on). I haven't seen a particular problem with this, although my experience is clearly limited.

But, we do occassionally get the "ooze" as they're closing. Usually this is treated with platelets and sometimes FFP. Maybe we're overdoing it with the protamine. However, my experience is that doing it this way will usually get your ACT back to within the 10% of the baseline. And, we dose 300units/kg of heparin before going on pump which usually gets us an ACT between 500-600 pretty consistently. Haven't seen any post-op MI's so far from this regimen either, even when giving Trasylol. And, we follow-up post-op 24 hours religiously on all of our pump cases.

Not suggesting that I have nearly the experience you do. Just haven't been burned yet.

-copro

My experience is the same as Copro's. Except we don't have oxi-metric Swans and only recently got a TEG (still trying it out).

Except for the extra-long pump runs (usually aortic dissection/circ arrest), I haven't had to give FFP recently. Probably been lucky.

We used to use Trasylol for some re-do's (usually redo double valves), but stopped a couple of months ago. Amicar for everyone now.

 

[UTSouthwestern]

Doing a TEG is a good tool. We use it routinely in our liver room. Not in our heart room. Problem is that by the time you get your answer, whatever bad that was going to happen has already happened. Although, TEGs and an oximetric Swan are standard in our LVADs.

I haven't seen that many "bring back" hearts lately. We usually give the 1:100 dose of protamine to heparin (i.e. if you give 25,000 units of heparin, you'll give 250mg of protamine when off-pump and clearly not going back on). I haven't seen a particular problem with this, although my experience is clearly limited.

But, we do occassionally get the "ooze" as they're closing. Usually this is treated with platelets and sometimes FFP. Maybe we're overdoing it with the protamine. However, my experience is that doing it this way will usually get your ACT back to within the 10% of the baseline. And, we dose 300units/kg of heparin before going on pump which usually gets us an ACT between 500-600 pretty consistently. Haven't seen any post-op MI's so far from this regimen either, even when giving Trasylol. And, we follow-up post-op 24 hours religiously on all of our pump cases.

Not suggesting that I have nearly the experience you do. Just haven't been burned yet.

-copro

It may not be coincidental that you are giving platelets post CPB for oozing as one of the primary mechanisms of coagulopathy caused by protamine is platelet dysfunction from excessive amounts of protamine.

Which ACT machine are you using out of curiosity? Just interested in seeing if it is the same as ours.

 

[Gas]

No one should be using aprotinin. Just throw away what your hospital has left. Type in "trasylol" or "aprotinin" to google, and all the top hits and advertisements are law firms.

Where I trained, it is largely a surgical decision which anti-fibrinolytic to use, but unfortunately we could probably be held liable. Once you get sued, they try to bring down the whole ship and all its passengers. Not to mention, you are doing your patients a disservice.

 

[coprolalia]

It may not be coincidental that you are giving platelets post CPB for oozing as one of the primary mechanisms of coagulopathy caused by protamine is platelet dysfunction from excessive amounts of protamine.

Could be. It has always been described to me that the reason for the platelets (not given every time) is because they are "chewed up" when they go through the bypass machine. But, the protamine theory is interesting. Will have to be more observant as I do more pump cases.

Which ACT machine are you using out of curiosity? Just interested in seeing if it is the same as ours.

The Hemochron "Response" machine.

-copro

 

[coprolalia]

No one should be using aprotinin. Just throw away what your hospital has left.

I read an interesting article criticizing the retrospective studies done to date, and using a different methodology looking at the data. I will try to find it, but the gist of it was that aprotinin was better at controlling major bleeding than anything else. In the cases where some patients died (in the "all cause mortality" analysis done by Mangano), there was a suggestion that "major bleeding" was the reason in many of the cases. This is counterintuitive, and suggested another mechanism at play not easily elucidated by these retrospective studies.

Keep in mind that this drug was used for almost 14 years before it was voluntarily pulled from marketing. I don't think that even the best jury necessarily gets it right even with the supposedly best data they are presented. They only get to see what they are presented and have to make a judgment. How many murderers later have been cleared with DNA evidence, i.e. better data, that shows that they clearly did not commit the crime?

A moratorium perhaps. But, throwing it out? We're not talking about healthy 25-year-olds coming in off the street to get bypass surgery. These patients are complex and have a lot of underlying comorbidities. I don't think it's as black-and-white as some would have you believe.

-copro

 

[rsgillmd]

Did a re-op MVR and graft from previous ascending aortic graft to innominate artery. It was supposed to be arch replacement, but the surgeon decided not to do it.

Interestingly enough the right radial pulse was present in the HA, but not in the OR shortly after induction. Surgical exploration confirmed suspicion of dissection of innominate.

The surgeon also hit the IVC during the dissection of the dense adhesions. Luckily he was able to repair it quickly. Total circ arrest = 8.5 minutes. Case was still going (but off bypass) and we were giving factors when I was let go.

Anyway, to make a long story short, no Trasylol. Only used Amicar. This surgeon has asked for Trasylol for similar cases in the past, but he didn't say a word today.

 

[Gas]

I read an interesting article criticizing the retrospective studies done to date, and using a different methodology looking at the data. I will try to find it, but the gist of it was that aprotinin was better at controlling major bleeding than anything else. In the cases where some patients died (in the "all cause mortality" analysis done by Mangano), there was a suggestion that "major bleeding" was the reason in many of the cases. This is counterintuitive, and suggested another mechanism at play not easily elucidated by these retrospective studies.

Keep in mind that this drug was used for almost 14 years before it was voluntarily pulled from marketing. I don't think that even the best jury necessarily gets it right even with the supposedly best data they are presented. They only get to see what they are presented and have to make a judgment. How many murderers later have been cleared with DNA evidence, i.e. better data, that shows that they clearly did not commit the crime?

A moratorium perhaps. But, throwing it out? We're not talking about healthy 25-year-olds coming in off the street to get bypass surgery. These patients are complex and have a lot of underlying comorbidities. I don't think it's as black-and-white as some would have you believe.

-copro

Of course it's not black and white. But in a courtroom, that doesn't matter. All the lawyers have to do is play that 60 minutes special and you're doomed. The jury does not care about patient comorbidities, underlying conditions, the circumstances of the surgery, or the fact that aprotinin was voluntarily pulled. That is too complex for a jury. I still say, if you want to stay out of the courtroom, throw away the rest of your stash.