Aspirin -proven in cardiac care to save lives

[D.P.Gumby]

Hi Gumby. I must say that is an excellent post, it has covered exactly the issues there are with plavix, thank you.

It is interesting to note that in the CURE study the methodology was actually changed half way through the trial, because the only results they were getting were negative. They moved the parameters to look only at the really high risk patients to try and salvage some sales. Oops, I meant salvage some results...

Thanks for the kind words, I enjoyed your thoughts as well.

I'm sure that sales had nothing to do with any of these studies [http://www.emtcity.com/uploads/emoticons/default_whistle.gif' alt=':whistle:'>]. Really I was pretty disappointed with the almost blatant salesmanship in some of the writing. As a more blatant example, look at the third paragraph of the CLARITY-TIMI trial: "Clopidogrel has been shown to prevent death AND [emphsis added] ischemic complications in patients with 1. symptomatic artherosclerotic disease, 2. patients who have undergone percutaneous coronary intervention, AND 3. PATIENTS WITH UNSTABLE ANGINA OR MYOCARDIAL INFARCTION WITHOUT ST-SEGMENT ELEVATION [numbers and emphasis added]."

No study has shown a "prevention of death" in NSTEMI, certianly not their flagship CURE trial. This is almost a blatant misrepresentation, but they cleverly list conditions for which a decrease in death has been found (I haven't read the other studies, so benefit of the doubt on that claim), and tack on NSTEMI on the end, implying to anyone not carefully reading that a mortality benefit was found in NSTEMI as well as in the other two. I'm sure the authors would claim they meant that in each of these three settings ischemic complications OR death were prevented, but this is really grammatical trickery. Is it fair to say that plavix prevents ischemic endpoints OR alien invasion?

I'm very new to this game, so I'm not sure how common nonsense like this is, but really, pretty disappointing.

[...]

The rebound effect from plavix certainly seems to be of concern. There has been a study published in JAMA in 2008 that was very compelling, showing adverse effects out to 90 days post cessation, but the authors recognize that further study is needed. It's certainly something that the cardiothoracic and general surgeons don't like.

I haven't seen that study, I'll have to read it, thanks. This issue actually may have be a bit relevant to the EMS world as well, at least as far as diagnosis, as I wonder if a history of recently discontinued Plavix should maybe increase our suspicion of thrombotic issues (stroke PE etc). Something to keep in mind.

I had heard somewhere along the line about the surgeons objecting as well. I assume this is predominantly in patients requiring CABG? I think 5 days is the time for plavix to clear, but I also think the Plavix people claim it's not much of an issue. I can't seem to find where I read that claim, though.

[...]

I think it was the COMMIT trial that had a list of exclusions for patients recieving beta-blockers, one of which was those with a high likelihood of devloping cardiogenic shock (or words to that effect - cardiogenic shock is what we give people when we give them beta-blockers). However one of the recommendations put forward is that beta-blockers should be given to patients with tachycardia. Now, what is a predictor of cardiogenic shock in ACS? That's right, tachycardia!

This is another trial I need to go re-read. I think you're right, but I have heard advocacy for retaining B blockers for some tachycardic patients (e.g. those with hypertension, good perfusion, clear lungs, no other s/s of failure/CHF), where maybe the goal of decreasing the myocardial oxygen demand down might outweigh the low chance of fialure. I'm not sure how the COMMIT data interacts with that proposal, or how well associated with failure tachycardia is, maybe you know more.

There is far too much evidence of harm and far too few beneficial effects to consider beta-blockers as a standard part of the treatment regimen for ACS.

[DartmouthDave]

Hello,

A very interesting thread.

Next, we should tackle IIb/IIIa Inhibitors.

Cheers...

BTW...excellent post DP

[Paramagic]

Hello,

A very interesting thread.

Next, we should tackle IIb/IIIa Inhibitors.

Cheers...

BTW...excellent post DP

The glycoprotein inhibitors studies have produced some excellent sales... oops, there I go again, I mean results! I haven't had a look at them for the last year or so, but there were about 4 studies done, all of them industry sponsored. The patients were all at low risk of bleeding and at high risk from death due to infarct, so these are the patients we would expect to see good results in. There were none.

No reduction at all in the re-occurence of MI at 6 months or death at 6 months, yet a reasonably significant (0.8% or about 1 in 115) patients suffered from a significant complication (cerebral haemorrhage or bleeding requiring transfusion)

There was a reduction in the need for repeat angioplasty, but as this was separate from and did not effect death or MI, it's really a waste of an endpoint.

No benefit, significant harm. No brainer really. Mind you, I'm not aware of any EMS that uses IIb/IIIa inhibitors, so it may be a moot point for us anyway.

If there are any studies newer than a year or so old that anyone knows of, please let me know, I haven't been very diligent in keeping up with this lately.

[Aussieaid]

Given the setting of the back of an ambulance (being on an EMS forum after all) beta-blockers are most definitely a no-go. They are also most likely a no-go after we get them to the hospital. Beta-blockers are a useful drug in patients with coronary artery disease, they have no place in the emergent treatment of evolving ACS, particularly in the back of an ambulance.

I think it was the COMMIT trial that had a list of exclusions for patients recieving beta-blockers, one of which was those with a high likelihood of devloping cardiogenic shock (or words to that effect - cardiogenic shock is what we give people when we give them beta-blockers). However one of the recommendations put forward is that beta-blockers should be given to patients with tachycardia. Now, what is a predictor of cardiogenic shock in ACS? That's right, tachycardia!

There is far too much evidence of harm and far too few beneficial effects to consider beta-blockers as a standard part of the treatment regimen for ACS.

Since I was responding to your initial comment on beta-blockers being a no-go I don't see how you made the leap that I was advocating BB's as pre-hospital treatment. Having reviewed the COMMIT trial and a large number of other trials and recent (=/> 2005) literature reviews however, I will stand by my opinion that there is not enough evidence that BB are a complete no-go. Yes, there definitely needs to be caution in their use but looking at tachycardia alone is not a basis for giving or withholding them. Although a significant variable, tachycardia is not an independent predictor of the development of cardiogenic shock. It does need to be assessed but as a risk factor by itself a pt has a <1% chance of developing shock. (GUSTO trials). One study shows harm and the next one shows benefit so I will withhold judgement until there is enough convincing evidence either way. We all know how statistics can be manipulated to support individual agendas.

I will add that though I would like to put a lot of faith in the COMMIT trial since it is a very large study, that having done medical missions to some of these countries my faith in their level of medical excellence is a little lacking. It would be good to know the level of medical care that goes along with the trials in general. It's easy to say we are going to do a trial and this person will have this drug and this one a placebo, when at the same time basic infection control is sadly lacking (not saying this is the case in all Chinese hospitals, just would be nice to know exactly what conditions were like in the included hospitals) it can have a huge influence on a study. (Just saying.... )

Thank you for the information on Plavix. Seems to me that there are way too many patients who are overtreated with antiplatelet and anticoagulant therapy in that they are not just given one medication but multiple. Then surprise, surprise we are called to transport them with significant head bleeds...now that has to mess with morbidity and mortality outcomes!

[D.P.Gumby]

The glycoprotein inhibitors studies have produced some excellent sales... oops, there I go again, I mean results! I haven't had a look at them for the last year or so, but there were about 4 studies done, all of them industry sponsored. The patients were all at low risk of bleeding and at high risk from death due to infarct, so these are the patients we would expect to see good results in. There were none.

No reduction at all in the re-occurence of MI at 6 months or death at 6 months, yet a reasonably significant (0.8% or about 1 in 115) patients suffered from a significant complication (cerebral haemorrhage or bleeding requiring transfusion)

There was a reduction in the need for repeat angioplasty, but as this was separate from and did not effect death or MI, it's really a waste of an endpoint.

No benefit, significant harm. No brainer really. Mind you, I'm not aware of any EMS that uses IIb/IIIa inhibitors, so it may be a moot point for us anyway.

If there are any studies newer than a year or so old that anyone knows of, please let me know, I haven't been very diligent in keeping up with this lately.

I'm not ready for the B-blocker discussion yet, but I did try to do my reading for GPIIb/IIIa inhibitors.

I think you covered it for the big 4 for NSTEMI (If we're talking about the same 4: PRISM, PRISM-PLUS, PURSUIT, and GUSTO-IV). David Schriger and Mel Herbert wrote a nice review of this data almost 10 years ago that I think nicely cover the myriad of problems with taking those 4 as proof of safety and efficacy (and provides a great example of how to do really good analysis):

http://www.ncbi.nlm.nih.gov/pubmed/11524643

As for new stuff, there seems to be a huge volume of literature on these drugs, and some of the studies are new, but from what I can tell they tend to be smaller and are using multiple divergent combinations of medications in a wide variety of settings. The truth is the volume of literature and diversity of interventions proved a bit overwhelming to me and I have to admit I'm especially not clear on the role of glyc. inhibitors in STEMI, maybe someone could point me in some sort of direction? I've heard that really glycoprotein inhibitors are being somewhat abandoned in practice, but I'm not clear on why that is. I agree that the initial studies were not as conclusive as touted, but (I think) those big 4 did lead to the widespread adoption of the drugs. What is driving the move away from them (have they gone generic or something?)?

Since we're in EMS I do think it bears mention that there was a recent (2008) RCT looking at prehospital use of tirofiban prior to PCI in the setting of STEMI published in the Lancet:

On-TIME 2:

http://www.ncbi.nlm.nih.gov/pubmed/18707985

I feel like this is getting rather repetitive, but the analysis here is not greatly different than other antiplatlet meds.

This study randomized PCI candidates either to "placebo" (600mg Plavix + 500mg ASA + 5000IU heparin all IV) or placebo plus 25mcg/kg loading and 0.15 mcg/kg/min infusion of tirofiban. Primary endpoint was resolution of ST elevation, with a couple of composite endpoints including death, MI, urgent revascularization (TVR), or bail-out use of tirofiban. They also looked at TIMI graded flow. N was 984.

They did find a significant improvement in ST-elevation, of course its up to the reader to determine the clinical relevance of that endpoint. They also found an improvement in their composite clinical endpoint, but that was driven largely by bail-out use of tirofiban being higher in the placebo group, which I think is a pretty mediocre surrogate measure. When they looked at Death/MI/TVR there was a slight trend to benefit with tirofiban, but nowhere near significant. There was also a marginal benefit in TIMI rated flow prior to PCI. Again, there was a trend towards greater rates of major bleeding (4% versus 2.9% placebo, p=0.363) and minor bleeding (6.1% versus 4.4%, p=0.233).

This study actually irked me a bit, it really read like an advertisement. A brief list of my biggest objections: They designed the study to look at ECG endpoints, but threw in a heap of other clinical endpoints as well, reported nonsignifigant trends towards clinical improvement in these endpoints (especially TIMI outcomes) without noting that these trends weren't significant, and at the same time claimed that there was "no significant increase in the rate of bleeding" ignoring the trend.

Second, they used this odd composite endpoint including bail-out use of tirofiban in order to achieve significance and claim improved clinical outcome (and to imply a significant improvement in mortality) despite marginal benefits in other endpoints.

Finally, they threw in a paragraph long "meta-analysis" of this study and unpublished pilot data from a non RCT to support the claim of a mortality difference.

Ah, I feel better.

Minor quibbles aside, I'm not sure how this study fits into the other glycoprotein inhibitor literature as applied to STEMI, but color me unconvinced about field usage. Of course there are issue of external validity here, as this was not conducted in the US and often involved physician staffed ambulances.

That aside, I'm still a bit confused about the issue with these druges. I'd love to hear more about GPiia/iiib in STEMI, as well as the reason for the move away from using these antiplatelet agents.

[Paramagic]

I'm not ready for the B-blocker discussion yet, but I did try to do my reading for GPIIb/IIIa inhibitors.

I think you covered it for the big 4 for NSTEMI (If we're talking about the same 4: PRISM, PRISM-PLUS, PURSUIT, and GUSTO-IV). David Schriger and Mel Herbert wrote a nice review of this data almost 10 years ago that I think nicely cover the myriad of problems with taking those 4 as proof of safety and efficacy (and provides a great example of how to do really good analysis):

http://www.ncbi.nlm....pubmed/11524643

I worship daily at the alter of Dave Schriger and Mel Herbet for bringing clarity and common sense to the world of medical literature!

As for new stuff, there seems to be a huge volume of literature on these drugs, and some of the studies are new, but from what I can tell they tend to be smaller and are using multiple divergent combinations of medications in a wide variety of settings. The truth is the volume of literature and diversity of interventions proved a bit overwhelming to me and I have to admit I'm especially not clear on the role of glyc. inhibitors in STEMI, maybe someone could point me in some sort of direction? I've heard that really glycoprotein inhibitors are being somewhat abandoned in practice, but I'm not clear on why that is. I agree that the initial studies were not as conclusive as touted, but (I think) those big 4 did lead to the widespread adoption of the drugs. What is driving the move away from them (have they gone generic or something?)?

You are right about some of the trials having dodgy methodolgy, and it's not just in the IIb/IIIa studies. I can't remember which one off the top of my head, but one of them was comparing plavix AND aspirin against plavix alone and against no treatment and then saying "Wow! look how good plavix is!" Well of course it's better than nothing, that's not really the point! My understanding is simply that on further examination of the data canny clinicans confirmend they had been conned (there's some nice alliteration for this hour of the day!) and simply haven't taken to

Since we're in EMS I do think it bears mention that there was a recent (2008) RCT looking at prehospital use of tirofiban prior to PCI in the setting of STEMI published in the Lancet:

On-TIME 2:

http://www.ncbi.nlm....pubmed/18707985

I feel like this is getting rather repetitive, but the analysis here is not greatly different than other antiplatlet meds.

This study randomized PCI candidates either to "placebo" (600mg Plavix + 500mg ASA + 5000IU heparin all IV) or placebo plus 25mcg/kg loading and 0.15 mcg/kg/min infusion of tirofiban. Primary endpoint was resolution of ST elevation, with a couple of composite endpoints including death, MI, urgent revascularization (TVR), or bail-out use of tirofiban. They also looked at TIMI graded flow. N was 984.

They did find a significant improvement in ST-elevation, of course its up to the reader to determine the clinical relevance of that endpoint. They also found an improvement in their composite clinical endpoint, but that was driven largely by bail-out use of tirofiban being higher in the placebo group, which I think is a pretty mediocre surrogate measure. When they looked at Death/MI/TVR there was a slight trend to benefit with tirofiban, but nowhere near significant. There was also a marginal benefit in TIMI rated flow prior to PCI. Again, there was a trend towards greater rates of major bleeding (4% versus 2.9% placebo, p=0.363) and minor bleeding (6.1% versus 4.4%, p=0.233).

This study actually irked me a bit, it really read like an advertisement. A brief list of my biggest objections: They designed the study to look at ECG endpoints, but threw in a heap of other clinical endpoints as well, reported nonsignifigant trends towards clinical improvement in these endpoints (especially TIMI outcomes) without noting that these trends weren't significant, and at the same time claimed that there was "no significant increase in the rate of bleeding" ignoring the trend.

Second, they used this odd composite endpoint including bail-out use of tirofiban in order to achieve significance and claim improved clinical outcome (and to imply a significant improvement in mortality) despite marginal benefits in other endpoints.

Finally, they threw in a paragraph long "meta-analysis" of this study and unpublished pilot data from a non RCT to support the claim of a mortality difference.

Ah, I feel better.

I haven't read this one yet, but my suspicion is that it is industry funded? In which case it probably read like an advert because it is an advert! It's very common for these sorts of studies to have lots of "slices" of data looked at in an attempt to come up with something that will sell the drugs. Strange endpoints, conclusions that aren't actually drawn from the data: it's all designed to get the product moving. The trouble is, it works. I suspect that most of us (and I am certainly guilty of this) grab a study, read the abstract and conclusion and say "Neato! We should be using this!" Actually burrowing through the data is time consuming and often very difficult, particularly for those of us without much of a mathematical bent (like me) so we take the easy way out.

They are certainly interesting outcome measures you mention in relation to that study. I struggle to see how ST segment changes are really a significant measure, given that they are dynamic in STEMI anyway. Does the drug help, or is it merely the natural progression of ST segments trending down (before skyrocketing up again!): a natural regression to the mean? Equally TIMI flow has shown to not necessarily correlate well with survival, so again, not sure how much use that is as a clinical endpoint.

May I ask what your background is? I assume sciences or mathematics? It is rare to find a paramedic student who is able to analyse data so effectively, but it is pleasing to see. Maybe there is hope for EMS after all!

[D.P.Gumby]

I worship daily at the alter of Dave Schriger and Mel Herbet for bringing clarity and common sense to the world of medical literature!

You are right about some of the trials having dodgy methodolgy, and it's not just in the IIb/IIIa studies. I can't remember which one off the top of my head, but one of them was comparing plavix AND aspirin against plavix alone and against no treatment and then saying "Wow! look how good plavix is!" Well of course it's better than nothing, that's not really the point! My understanding is simply that on further examination of the data canny clinicans confirmend they had been conned (there's some nice alliteration for this hour of the day!) and simply haven't taken to

I haven't read this one yet, but my suspicion is that it is industry funded? In which case it probably read like an advert because it is an advert! It's very common for these sorts of studies to have lots of "slices" of data looked at in an attempt to come up with something that will sell the drugs. Strange endpoints, conclusions that aren't actually drawn from the data: it's all designed to get the product moving. The trouble is, it works. I suspect that most of us (and I am certainly guilty of this) grab a study, read the abstract and conclusion and say "Neato! We should be using this!" Actually burrowing through the data is time consuming and often very difficult, particularly for those of us without much of a mathematical bent (like me) so we take the easy way out.

They are certainly interesting outcome measures you mention in relation to that study. I struggle to see how ST segment changes are really a significant measure, given that they are dynamic in STEMI anyway. Does the drug help, or is it merely the natural progression of ST segments trending down (before skyrocketing up again!): a natural regression to the mean? Equally TIMI flow has shown to not necessarily correlate well with survival, so again, not sure how much use that is as a clinical endpoint.

May I ask what your background is? I assume sciences or mathematics? It is rare to find a paramedic student who is able to analyse data so effectively, but it is pleasing to see. Maybe there is hope for EMS after all!

Sorry for the delay, was enjoying vacation. I think I'll join you at the alter of the great doctors (and a few others). I really enjoy that Dr. Schriger does the Annals of Em Med journal club writeups. A lot of what he writes flies straight over my head (especially where statistics are involved), but his way of looking at information and medicine is inspiring clever and robust

As for plavix,The big studies are all indeed drug company funded infomerci...err..studies. I like your take on all of this, and couldn't say it any better, so I won't try. I do remember reading the abstract to that aspirin/plavix study, and I think that's one situation where the abstract is all you need to read

Thanks again for the flattery (although it may be misplaced). I wish I could say that my partial paramedic education taught me how to read research, but the truth is I have a BS, the earning of which included much interpretation of research. It causes me much angst and frustration that there isn't the barest of a mention of research methodology or learning how to read evidence in my medic classes - it's a skill that takes time and practice to learn, and it bothers me that everyone isn't getting the same opportunity that I had.

My background is in a basic science, so this clinical stuff is a bit outside of my training, but the thought processes are similar and this is proving good practice for me. This thread has sort of died, but it was a useful exercise for me so I'm going to work on B-blockade for the end of the week.