Why we should be very wary of using clotbusting drugs to treat acute strokes

This is Part 1 of three posts

• a basic overview of thrombolysis in stroke
• a detailed overview of evidence based research into thrombolysis and CVA
• Schrödinger’s Fence

Author: Prof Daniel Fatovich

Let’s compare the treatment of strokes, to the treatment of heart attacks. Heart attacks are caused by a sudden blockage of a blood vessel supplying oxygen to heart muscle. This is nearly always caused by a new blood clot that forms on a hardened and diseased blood vessel.

Background

It took trials and studies on 60 000 heart attack patients to work out that clot busters prevent deaths in heart attacks, but that they only worked on one type of heart attack (which is only about 5% of all heart attacks). So we took the time to get it right, refining study after study, until we were sure that introducing a potentially dangerous drug had benefits that outweighed the harms.

Every type of clot buster that was studied worked, and the earlier it was given, the better. Interestingly, the one that caused the most brain bleeding was tPA.

Studies have been done on clot busters in stroke. Strokes are also caused by a blockage to a blood vessel (in the brain), but there are important differences to heart attacks:

1. About 30% of the time, the cause of the blockage is never worked out.
2. There are two very different types of blood clots that cause strokes: new blood clots (like in heart attacks) & old blood clots (eg an old blood clot that has formed in the heart & travelled to the brain & blocked off a blood vessel) – called embolic clots.
3. This difference between new & old blood clots is very important, because clot busters do not work on old blood clots.
4. How many strokes are caused by new blood clots? No one knows for sure because we can’t work out what kind of clots (or other causes) are causing the stroke. The best guess is that it is a little less than half.

“It is important to note that the efficacy of thrombolytic drugs depends on the age of the clot. Older clots have more fibrin cross-linking and are more compacted; therefore, older clots are more difficult to dissolve. For treating acute myocardial infarction, the thrombolytic drugs should ideally be given within the first 2 hours. Beyond that time, the efficacy diminishes and higher doses are generally required to achieve desired lysis.” [Reference: CV Pharmacology Thrombolytics]

Things you need to know about the stroke clot busting studies:

1. There are 12 important studies: 10 were negative (ie they showed that clot busting did not work in stroke). Of these 10 studies, 4 had to be stopped early because of harm ie they were killing people. So far, they have only studied this in about 1/6^th the number of stroke patients compared to the heart attack studies.
2. This is a completely different situation to the heart attack studies, where it worked in every study & every clot busting drug they tried worked.
3. The 2 positive stroke studies (ie they suggest a statistical benefit) have been widely criticised in the medical literature because of their scientific flaws. One of these 2 studies looked at giving tPA within 3 hrs of the stroke. Interestingly, this study proved that there was no benefit in the first 24 hrs, which again, is different to the heart attack studies. The other study looked at giving tPA from 3-4.5 hrs after the stroke. This second study also contains some major errors.
4. The biggest flaw is that there was an imbalance in baseline stroke severity. The placebo group(those that didn’t get tPA) were sicker, with more severe stroke; the tPA group were less sick & had much more mild strokes. Everyone understands that people with milder strokes do better than people with more severe stroke. So obviously, the study favoured tPA, because the tPA group had milder strokes, which will do better anyway.
5. This study was re-analysed later. If tPA really worked to improve the outcomes in sudden stroke, then there should be a much larger improvement in outcome compared to the placebo group.  But there was no difference.
6. The studies show that tPA causes brain bleeding in about 6% of patients. Brain bleeding is the other type of stroke. It is strange that some people would advocate a treatment for stroke that can cause a (worse) stroke. Brain bleeding is very severe, and if this happens, almost half the people die.
7. Why does brain bleeding happen with a clot buster? Doctors think of clot busters as being like ‘drano’, a plumbing product that is used to unblock pipes. In strokes, you have a damaged blood vessel inside a damaged part of the brain. So if you put ‘drano’ in there, it’s no surprise that it sometimes dissolves through the blood vessel & bleeds into the brain.
8. The largest study on clot busting in stroke was published in 2012. This again was a negative study ie it showed that tPA did not work, but confirmed the increase in early deaths with tPA.
9. Interestingly, the time to give the drug from the stroke studies is completely different to the heart attack studies. In heart attacks, after studying 60 000 patients, every study showed that the earlier the clot buster was given, the better. In the stroke studies, the majority of the studies do not show this effect. The reason for this is unclear, but may be because the patients who get to hospital earlier are somehow different to the ones who arrive later.
10. However, one must always remember that once the blood vessel is blocked, the brain cells will be dead in about 3 min. So giving a clot buster later shouldn’t have any effect, & this may be what we’re seeing. It’s also worth remembering that heart muscle cells & brain cells are very different.
11. People have used statistical techniques (called meta-analysis) to ‘prove’ that clot busting works. The simple summary of the problem with this, is that garbage in = garbage out. Badly done studies, when put into a meta-analysis, do not magically become good studies. There is at least one review of this that concludes: “there is no consistent or proven benefit” to clot busters in stroke. [Reference: Thrombolytics for Stroke]

What is the problem here?

Why is there controversy in the medical world? Shouldn’t it be black and white? Either tPA works, or it does not.  Easy.

Sadly it is not so easy.  Statistical analysis of any medical treatment is rarely black and white. It is about the interpretation of the research. This is where the controversy has occurred here.

So why is this being pushed? 

1. We really want it to work.
2. Unfortunately, many of those pushing this treatment have conflicts of interest with the manufacturer of the drug. [Reference: Why we can’t trust clinical guidelines and Ensuring the integrity of clinical practice guidelines]

So how do we resolve this problem?

• We think that patients, & society in general, expect that an offered medical treatment will have passed the test of science. The test of science requires: elimination of bias, healthy scientific debate, & replication.  Replication means repeating the study that suggested a statistical benefit, to see if we can get that result again, which would make it more believable. Time & time again, in medical research we find that when larger more decisive studies are done (ie replication) the initial exciting result becomes a disappointing one – it doesn’t work. This replication has not happened for stroke, but needs to, if we want to maintain our trust in medicine. [Reference: Do risks outweigh benefits in thrombolysis for stroke?]

Has anyone else raised concerns about this?

• Recently, the British Medical Journal published a debate & poll on this very subject. Other experts have also expressed similar concerns.
• Further reading: Delusions of Benefit; The Guideline, The Science, and The Gap

So is there anything else that can be done if I have a stroke?

We know that having your care in a stroke unit is much more powerful than any drug. And taking part in stroke research will help us to answer these unanswered questions.