Clopidogrel [Plavix] & Seniors – the Risks & Benefits

What is clopidogrel (also called Plavix)?
Most heart attacks and strokes (“brain attacks”) are caused by a blood clot within an artery.  By preventing the formation of the blood clot, we can reduce the risk of the heart attack or stroke.  Plavix, like aspirin, is a type of “blood thinner” which means it makes it more difficult for blood to clot.  Both drugs do this by interfering with the ability of platelets to clump together; platelets are small blood cells which are needed to "stick together" so that a clot can form.

 



Major Studies/Research about Plavix (clopidogrel).

 

1.  The C.U.R.E. Trial. C.U.R.E. is short for:  Clopidogrel in Unstable angina to prevent Recurrent Events.  Published Oct.2000, it involved 12,562 patients, from 28 countries, who had a specific type of heart attack (“unstable angina” – damage to the heart muscle but no scar forms), and who each took aspirin and either a placebo (“sugar”) pill or clopidogrel (Plavix) for up to one year, to determine if the clopidogrel reduced the risk of cardiovascular death, heart attack, or stroke, more than aspirin alone did.


2.  The CHARISMA Trial. (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance.)  This was published in 2006.  It involved 15,603 patients with either known cardiovascular disease or multiple risk factors (diabetes, carotid artery narrowing, poor leg circulation, smoking, high cholesterol, hypertension).  Half the patients took aspirin plus clopidogrel and half took aspirin plus a placebo (sugar pill), for over two years, to see which group had fewer heart attacks, strokes, or death from a heart attack.


3.  Meta-analysis (a type of study which combines all the patients. results from many studies to give a more accurate analysis and conclusion).  This one involved the results from eight trials between 1966-2006 comparing Plavix + ASA with just ASA and included 91,744 patients.



What were the results of the studies?

1.  C.U.R.E. The number of events of cardiovascular death, heart attack, or stroke was reduced by clopidogrel regardless of the amount of aspirin taken, as follows:
ASA alone (any dosage) = 11.4% events, vs 9.3% events with clopidogrel, = 2.1% fewer events.
However, there were more bleeding side-effects both with increasing doses of aspirin and with clopidogrel:
ASA alone (any dosage) =  2.7%   vs  3.7% with clopidogrel = 1.0% additional risk with clopidogrel.

2.  CHARISMA. The number of events of cardiovascular death, myocardial infarction (heart attack), or stroke was not significantly reduced by clopidogrel, as follows:
ASA alone = 7.3% events, vs 6.8% events with clopidogrel, = 0.5% fewer events.
And, again there were more bleeding problems with the Plavix:  1.7% vs 1.3% = 0.4% additional risk.  If a person had only multiple risk factors and no known cardiovascular disease, the Plavix actually increased the risk of having a heart attack, stroke, or death from a heart attack:
ASA alone = 5.5% events, vs 6.6% events with clopidogrel, = 1.1% increased risk with Plavix.


3.  THE META-ANALYSIS. They concluded that patients with Acute Coronary Syndrome [chest pain related to heart disease] taking both Plavix + ASA had 15% fewer deaths [from heart disease], repeated heart attacks, or strokes, compared to those only on aspirin.  However, they found no difference in overall mortality between the Plavix/ASA and ASA only groups; and that there was a greater risk of a major bleed taking Plavix and ASA together.


What does this really mean?
We already know that taking a baby aspirin each day significantly reduces the risk of a person having another heart attack or stroke.  Considering these studies, adding Plavix to the aspirin, further reduces the risk by 0.5-2.1% but is offset by an increased risk of a major bleed (such as a stomach ulcer bleed requiring a transfusion) by 0.4-1.0%.  BUT, if you only have risk factors and do not have known heart disease, taking Plavix appears to actually increase your risk of dying or having a problem. This means, if 100 people who had „unstable angina. took just a baby aspirin daily, each year 7-11 of them would have either another heart attack, a stroke, or die from a heart attack (89-93 would not).  But, if that same 100 people were to also take Plavix, then only 7-9 of them would have such an attack – 0-2 fewer.  However, up to four of that 100 would have a major bleeding event (one more than with just ASA).



What is the risk of a major bleed for Seniors?

For anyone taking the drug there is an increased risk of bleeding.  In the under 75 age group, this risk is usually outweighed by the benefit provided by reducing the risk of a stroke or heart attack.  In both Trials, the average age was 64, with only 16% in CURE over the age of 75.  Thus, it is difficult to assess how beneficial this treatment really is just for seniors. For those over 75 years, that benefit may be lost because:  1) elders are more sensitive to all drugs, to drug interactions, and to their side-effects; 2) they are at greater risk of falling and having a head injury; 3) they have an increasing risk of Cerebral Amyloid Angiopathy (CAA), especially after age 80 when the incidence of CAA may be as high as 50%, meaning every other person over age 80 has it.  CAA refers to a hardening of the arteries in the brain which makes the vessels more likely to rupture spontaneously or with minimal trauma.  And if one is unsteady, tends to fall easily, or has Alzheimer.s Disease, the risk of bleeding may be 33%. Thus, because Plavix increases the risk of bleeding and a senior already has an increased risk of bleeding, the benefit gained by taking Plavix may be lost completely.



Should You Take Plavix?
It.s important for each person to determine their health goal.s:  to be kept alive for as long as possible regardless of the costs or pain or consequences; or, at the other extreme, to just live comfortably, eat and drink what you want (within reason), and accept whatever happens.  If you know your goals, the status of your health/disease, and the risks/benefits of a particular treatment, you can more easily determine whether that treatment will help you reach your goals. Equally important, you must consider your peace of mind: if you feel any additional possible benefit is worth YOUR peace of mind, then you should take that treatment.  But, if you don.t think the benefit is great enough, and you are prepared to live with your decision, then decline the treatment.  With the above evidence, there appears to be little benefit to Plavix except for those who have recently had a stent placed in an artery.  And, for those who have only the risk factors, Plavix may actually increase your risk of having a problem.



Summary of Factors against taking Plavix are if you are over age 75 and have:
1) Poor balance with a tendency to fall;
2) A history of bleeding ulcers or any bleeding disorder;
3) Alzheimer.s Dementia (or any other dementia);
4) Any terminal disease limiting your life expectancy or reducing your quality of living;
5) Several risk factors but no actual evidence of heart disease or stroke;
6) Taking the drug will not help you reach your healthcare goal.


You should consider taking Plavix, if you have:
1) had a stent placed in one of your arteries in your heart (take Plavix for three to 12 months);
2) an allergy to aspirin or if you already have been taking aspirin and still had a stroke or heart attack.


There is no treatment or drug which can guarantee that you will not have another heart attack or stroke.  Your risk is only reduced by two in a 100 (from 11 to 9 events) by taking the Plavix, but you have the added risk of major bleeding (from three to four in a 100).  Only you can determine if that gain outweighs the risks or problems.  For some elders, any reduction in risk is worthwhile, regardless of the potential problems and costs.  But for others, comfort, not having to “take more pills”, and not worrying about “a few extra weeks”, is more important.  Based on the evidence and on your own goals, ask yourself, “Will taking Plavix significantly improve my comfort and quality of life in my remaining years”.  [read other handouts available, or look on the comfortcarechoices.com website]

Discuss this with your family and with your doctor (give him this handout) and then make a decision that.s right for you.



References:


1.  Peters RJ, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes:  observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003 Oct 7;108(14):1682-7.
2.  Rosand J, et al. Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology 2000;55:907-8.
3.  Bob H. Oral anticoagulation in nursing home residents. JAMDA 2003;Mar/Apr:S50-S51.
4.  Hart RG, Bailey RD. An assessment of guidelines for prevention of ischemic stroke. Neurology 2002;59:977-82.
5.  Albers GW, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Sixth ACCP consensus conference on antithrombotic therapy. Chest 2001;119:300s-320s.
6.  Mehta SR, Yusuf S. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial programme; rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J. 2000 Dec;21(24):2033-41.
7.  Yusef S, et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med. 2001;345:494-502.
8.  Bhatt DL, et al.  Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. NEJW 2006;354.
9.  Bowry AD, et al.  Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevenetion of vascular events.  Am J Cardiol. 2008;102(2):248.


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