February 18th, 2011
A Case of Clopidogrel Nonresponsiveness?
Tariq Ahmad, MD, MPH and James Fang, MD
This latest installment in our case discussion series is submitted by Tariq Ahmad, MD, MPH. We encourage members to submit cases that they believe warrant discussion. Selected cases will be presented to the community, and case authors will receive a $100 Amazon gift card.
A 70-year-old woman presents to the ED with an anterior STEMI. She had a stroke 3 months prior and an MI 5 months prior to that, with DES to the LAD. She is morbidly obese and has hypertension, hyperlipidemia, and peripheral artery disease with bilateral carotid stenosis. Soon after arriving in the ED, she goes into cardiac arrest and is found to be in ventricular tachycardia/fibrillation. After a 15-minute resuscitation that includes intubation, she is taken to the catheterization lab, where a thrombus is found in her LAD stent. She undergoes PCI with a BMS to the LAD. During the procedure, she has significant hemodynamic instability and requires an intra-aortic balloon pump. She is admitted to the CCU for further management.
According to her family, she has been adherent to her clopidogrel. A VerifyNow P2Y12 platelet function test shows 0% P2Y12 inhibition.
Questions:
- Do you feel fairly confident, based on the VerifyNow test, that this patient is a clopidogrel nonresponder?
- Would you perform any additional testing to assess whether she is a clopidogrel nonresponder?
- Would you increase the clopidogrel dose or give an alternate agent?
Response
The most common cause of clopidogrel “resistance” (and for that matter, aspirin “resistance”) remains noncompliance. The “0%” P2Y12 inhibition with VerifyNow is highly suspicious for noncompliance despite the report from the patient’s family. I am not confident that she is a clopidogrel nonresponder. I would recommend that she be given clopidogrel in the CCU and have her platelet reactivity retested in 48 hours.
If the test demonstrates nonresponsiveness, then I would consider using prasugrel despite the risks, which would need to be reviewed with the patient and family. The issue of increased intracerebral bleeding is not trivial with prasugrel (e.g., age, prior stroke). To further minimize risk, the duration of therapy with prasugrel could be limited since a bare metal stent was used. Another option is clopidogrel at 150 mg daily, although the findings of GRAVITAS and OASIS-7 make this choice less than ideal. Ticagrelor will soon be available as another option. Some would consider adding cilostazol. Finally, it should be kept in mind that stent thrombosis is not just an issue of P2Y12 inhibition; there are patient- and procedural-related factors, as well.
The issue of routine assessment of platelet function after PCI is evolving and is not yet the standard of care. The “negative” results of GRAVITAS and OASIS-7 have made this issue even more complicated, however, this may be more of an indictment of clopidogrel rather than the concept of measuring platelet reactivity.
Which platelet assay to use? VerifyNow has the greatest clinical data available in human studies, however, both VerifyNow and PlateWorks have good discriminating ability for important clinical endpoints and both are relatively easy to use at the bedside. The POPULAR study (JAMA 2010; 303:754) is worth reviewing in this regard.
4 Responses to “A Case of Clopidogrel Nonresponsiveness?”
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This is a more common problem than recognized. There should be routine monitoring of ALL patients taking clopidigrel. the “Veriy Now” test is not accurate because it does not detect microagregates. The “Platelet Works” test which electronically does a platelet count before and after addition of aggonist is cheap and a very accurate test as can be shown by doing a dose reponse curve of response of the test to increasing doses of a soluable glycoprotein IIb/IIIa inbhibitor such as Integrelin, Aggrastat or Reopro. When this is done, the “Verfy Now” test wil not respond to either of these agents at the critical 80-100% inhibition of platelet aggregation B.A Kottke MD,PhD Emeritus Professor of Medicine Mayo College of Medicine(details are in my editorial in JACC several years ago)
Competing interests pertaining specifically to this post, comment, or both:
no conflicts of interest other than concern for patients not being monitored
I thought there was no clear “winner” among 3 top platelet assays as far as predictive power in the POPULAR trial. And GRAVITAS didn’t show a benefit of increasing clopidogrel dose for nonresponders. So Im not sure what to do. Change to prasugrel? Add cilostizol? Await TRIGGER PCI? How often do you really get a 0% on VerifyNow?
Unfortunately there are no clear answers as far as routine monitoring of antiplatelet therapy because while low platelet inhibition by VerifyNow is associated with worse outcomes, (A) the positive predictive value is very low (most folks with low inhibition will still do fine) and (B) as GRAVITAS has suggested, there isn’t an unequivocal benefit of titrating therapy to the platelet assay test using higher doses of clopidogrel. What is not clear is whether the same titration using Prasugrel (or ticagrelor) would have been beneficial.
In this patient given a clear devastating event I’d :
1. Confirm and reconfirm that she was indeed compliant – perhaps ask the family to bring her tablet stock and show you (you may get a nasty surprise that there’s no Plavix in there anywhere – I say this because 0% inhibition is awfully odd on aspirin and plavix)
2. Discuss with the patient and family about pros and cons and go with Prasugrel. They’ll need to know higher risks given this lady has had a stroke and is elderly but those higher risks pertain to patients who haven’t had a stent thrombotic event, NOT to this patient. Some centers are using half dose Prasugrel (Sharma at Sinai for example) in high risk patients but I’d go with full dose in this obese lady and recheck platelet aggregation – if really high (say 80%) consider reducing dose to 5 mg. Ticagrelor would be another option. I won’t recommend cilostazol because the data with triple therapy isn’t a clear cut winner.
3. Get rid of any potential interacting drugs including PPIs
Competing interests pertaining specifically to this post, comment, or both:
None
I had a patient who was by his cardiologist 2 years prior noted to have 0% inhibition on Plavix. He was then given 150 mg po daily. He wasvrecently admitted and in the hospital on 150 mg daily po, he had 0 % inhibition.