Any Point in Higher Doses of Clopidogrel or Aspirin in ACS?
Any Point in Higher Doses of Clopidogrel or Aspirin in ACS?
Hi, I'm Dr. Henry Black. I'm a Clinical Professor of Internal Medicine at the New York University School of Medicine and a member of the Center for the Prevention of Cardiovascular Disease. I'm also immediate past President of the American Society of Hypertension.
What I want to talk about today is: what do we do with acute coronary syndromes? Should we use a high or low dose of aspirin, or a high or low dose of clopidogrel? This is a very important problem for people who deal with this issue because clinical trial evidence has shown the value of the usual dose of clopidogrel vs aspirin at a modestly high dose. A loading dose is 150 mg plus 75 mg per day. The problem is that some people have tried using higher doses and thought they had better results. This is an important issue for this very common problem because, as you give higher doses of both aspirin and clopidogrel, you end up with a greater likelihood of bleeding and sometimes major or fatal bleeding.
To test this question, the sponsors (ie, the people who market this drug) decided to do a large clinical trial comparing, at the same time, high-dose aspirin (the dose used in the United States -- 162 mg to 325 mg at the initial presentation of the patients) with low-dose aspirin (75 or 100 mg, which is the commonly used dose in Europe and the rest of the world). To do this, they planned to enroll 14,000 people and ended up needing 25,000. So, this is a huge study lasting several years in recruitment and outcomes.
The outcomes were as you'd expect: the 30-day incidence of acute myocardial infarction (MI), cardiovascular death, and strokes. They looked at safety issues in particular, namely major or fatal bleeding. They also looked at stent thrombosis. This is an issue especially for the use of high-dose clopidogrel, or platelet inhibitors in general, because this can certainly make all this effort and expense and risk not worth it.
They enrolled 25,000 people who presented to an emergency room. They planned to have percutaneous coronary invasion after cardiovascular proof that they needed this. The anatomy had to be described. The patients got a loading dose of clopidogrel (either 150 or 300 mg), and then if they had the appropriate coronary anatomy and they were candidates, they went ahead. Those who turned out to be candidates for coronary artery bypass graft surgery had only 1 dose of the drug, because having this relatively longer-acting platelet inhibitor on board is a problem when you're performing coronary artery bypass graft surgery.
It turned out that approximately 70% of the people who were originally looked at had non-ST-elevation MIs and approximately 30% had ST-elevation MIs. The average time before the catheterization was done was about 4 hours, which is excellent. Approximately 30% of people didn't have any need for either procedure and approximately 23% needed coronary bypass surgery. That left about 17,000 people who were randomized to the 2 groups.
At the end of the observation period of about 30 days, there was no benefit from the higher dose of either drug -- no benefit from higher dose aspirin, slightly increased risk and no benefit from higher dose clopidogrel -- making the higher dose maybe unnecessary. There was a reduction in stent thrombosis, but this was one of a large number of secondary endpoints, and those of us who do trials are not sure that you should even do them unless a primary endpoint was shown. The primary endpoint assumed that the higher dose would be better.
So, right now, this is still up in the air, especially with the advent of some newer platelet inhibitors that may not have this problem. So if you're going to send your patient in for an emergency catheterization and angioplasty or surgery, be pretty careful about what dose they're going to get. If the angioplasty patient wants to use a high dose, he or she can use it, but I think this is not necessarily showing any benefit. I think Americans can stop using the higher dose aspirin that we've been using because you seem to do just as well with the lower dose. Thank you very much.
Hi, I'm Dr. Henry Black. I'm a Clinical Professor of Internal Medicine at the New York University School of Medicine and a member of the Center for the Prevention of Cardiovascular Disease. I'm also immediate past President of the American Society of Hypertension.
What I want to talk about today is: what do we do with acute coronary syndromes? Should we use a high or low dose of aspirin, or a high or low dose of clopidogrel? This is a very important problem for people who deal with this issue because clinical trial evidence has shown the value of the usual dose of clopidogrel vs aspirin at a modestly high dose. A loading dose is 150 mg plus 75 mg per day. The problem is that some people have tried using higher doses and thought they had better results. This is an important issue for this very common problem because, as you give higher doses of both aspirin and clopidogrel, you end up with a greater likelihood of bleeding and sometimes major or fatal bleeding.
To test this question, the sponsors (ie, the people who market this drug) decided to do a large clinical trial comparing, at the same time, high-dose aspirin (the dose used in the United States -- 162 mg to 325 mg at the initial presentation of the patients) with low-dose aspirin (75 or 100 mg, which is the commonly used dose in Europe and the rest of the world). To do this, they planned to enroll 14,000 people and ended up needing 25,000. So, this is a huge study lasting several years in recruitment and outcomes.
The outcomes were as you'd expect: the 30-day incidence of acute myocardial infarction (MI), cardiovascular death, and strokes. They looked at safety issues in particular, namely major or fatal bleeding. They also looked at stent thrombosis. This is an issue especially for the use of high-dose clopidogrel, or platelet inhibitors in general, because this can certainly make all this effort and expense and risk not worth it.
They enrolled 25,000 people who presented to an emergency room. They planned to have percutaneous coronary invasion after cardiovascular proof that they needed this. The anatomy had to be described. The patients got a loading dose of clopidogrel (either 150 or 300 mg), and then if they had the appropriate coronary anatomy and they were candidates, they went ahead. Those who turned out to be candidates for coronary artery bypass graft surgery had only 1 dose of the drug, because having this relatively longer-acting platelet inhibitor on board is a problem when you're performing coronary artery bypass graft surgery.
It turned out that approximately 70% of the people who were originally looked at had non-ST-elevation MIs and approximately 30% had ST-elevation MIs. The average time before the catheterization was done was about 4 hours, which is excellent. Approximately 30% of people didn't have any need for either procedure and approximately 23% needed coronary bypass surgery. That left about 17,000 people who were randomized to the 2 groups.
At the end of the observation period of about 30 days, there was no benefit from the higher dose of either drug -- no benefit from higher dose aspirin, slightly increased risk and no benefit from higher dose clopidogrel -- making the higher dose maybe unnecessary. There was a reduction in stent thrombosis, but this was one of a large number of secondary endpoints, and those of us who do trials are not sure that you should even do them unless a primary endpoint was shown. The primary endpoint assumed that the higher dose would be better.
So, right now, this is still up in the air, especially with the advent of some newer platelet inhibitors that may not have this problem. So if you're going to send your patient in for an emergency catheterization and angioplasty or surgery, be pretty careful about what dose they're going to get. If the angioplasty patient wants to use a high dose, he or she can use it, but I think this is not necessarily showing any benefit. I think Americans can stop using the higher dose aspirin that we've been using because you seem to do just as well with the lower dose. Thank you very much.
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