Evolving clinical conundrums in modern cardiology require insights from many sources. In this spirit, I’d like to present another ‘conversation in cardiology’ about a real dilemma involving a woman, a stent, and dual anti-platelet therapy. My colleagues generously contributed their thoughtful opinions to assist the treating physician in his decision-making. The conversation addresses the pros and cons, and puts the issue into perspective for a best clinical decision. Let’s see what happened
[Disclaimer: The opinions expressed below are those of the authors of the comments. These opinions are not intended to be used as authoritative sources, which may be obtained from standard reference literature regarding the problem.]
The Clinical Problem
A referring cardiologist called me today. His patient, a 40-year-old female, had a 2.75 mm/28 mm Promus stent placed in her mid-left anterior descending artery (LAD) 5 months ago. She presented to him today, stating that she is 5 weeks pregnant. What would you do about her dual anti-platelet therapy (DAPT)?
Aspirin is a class D agent for pregnancy. The baby may already have sustained teratogenic effects. After 32 weeks, the prostaglandin effect could lead to placenta blood flow abnormalities and failure to close the ductus. The FDA has a warning in the last trimester.
Clopidogrel (Plavix) is listed as class B in pregnancy. Hence, there is probably a low risk of teratogenicity. There is limited experience with its use, however. There may be increased bleeding relating to delivery or a c-section. Since it is not a prostaglandin inhibitor, those concerns are not operative. I would work closely with an obstetrician in this case. Given that the stent is 5 months old and the mother in the first trimester, for the last trimester, I would probably lean toward stopping the aspirin and going with 150mg clopidogrel. Until then, and for the next 7 months, the FDA warning provides a judgment call in regard to risk vs. benefit. Perhaps a low dose of aspirin could be given until that time. Too bad a bare metal stent was not placed — that would have been so much easier!
Lloyd W. Klein
From Duke University:
This is definitely a conundrum. Aspirin (ASA) is relatively contraindicated in pregnancy. At high doses in animal models it is teratogenic. In humans, aspirin can cause abnormal closure of the ductus, and therefore should not be given in the last trimester. It can cause problems with hemostasis at the time of delivery. The good news is that low-dose ASA has been explicitly tested in tens of thousands of pregnant women in formal clinical trials, so there actually is a body of data about ASA and pregnancy.
Much less is known about clopidogrel. The package insert lists it as a Class B pregnancy risk (I looked it up), which basically means that nobody knows, because it hasn’t been studied. There isn’t even enough known about clopidogrel to determine whether it is teratogenic.
So here’s my thoughts — a discussion should occur with the mother and father to determine the psychosocial aspects related to this pregnancy — how many children she has borne, what their mindset is about this pregnancy, etc. She needs to be counseled about the risks (including mortality) to both her and her child. The stent that was implanted is long and small, not a great device to leave relatively unprotected. If it helps in our thinking about management, the date of delivery should be around the 1-year anniversary following the stent implantation. The hemodynamic stresses of pregnancy and delivery can be quite scary. I would think that a spontaneous vaginal delivery would be out. I’d be very worried about spontaneous coronary dissection in the last trimester or just after delivery. If she makes it through the pregnancy and wants to breast feed, she’ll need to consider that at least she’ll be put back on ASA after delivery and this is associated with child developmental issues. In summary, there are both cardiac and obstetrical risks to consider, including a relatively high potential for serious morbidity and mortality (both mother and baby).
Management options: This is collectively in the unacceptable risk category, so termination of the pregnancy should be recommended as the first choice. If termination of the pregnancy is not an option, then the situation becomes much more difficult. The usual DAPT question is “when to stop the clopidogrel.” But I would think about stopping the aspirin instead — perhaps even now — leaving her on clopidogrel only. She is 5 months out from stent implantation, so now is as good time as any to stop the ASA. I would keep the clopidogrel going up to 3-4 days before a scheduled c-section, and then restart ASA just after delivery. And I would make sure that I have documented all discussions with her, and have my malpractice insurance paid up.
This is a great response, Jimmy...no surprise to anyone that your comments are so insightful. Couple of questions/points:
- What do people believe is the actual percent risk of stent thrombosis on ASA 81mg alone, on clopidogrel plus 81mg, on clopidogrel alone? Is there any way to put numbers on these? Probably not, but worth trying. I would guess it is in the single digits for all, and probably less than 5%...even in pregnancy.
- Does pregnancy increase or decrease clotting?
I think this is a case, as you point out, for shared decision-making with the patient, her family, and her high-risk OB doc. It is very hard for us to make a judgment as to what is “unacceptable risk” or not.
- Why do you think she is at higher risk of coronary dissection? Unless that was the original pathology, I would not put her in a particularly high-risk category for that rare entity.
- Yes, seems that a C-section would make sense in many ways...certainly more predictable. But, I wonder...if this is not her first pregnancy, she might even be a candidate for vaginal delivery (though I am sure few OBs would feel comfortable with it!)
Would anybody consider optical coherence tomography (OCT) to verify strut endothelization? There is no prospective data that I know of for this particular problem, but makes sense. We have had a couple of cases in which we stopped clopidogrel based on OCT results. Of course, these cases were not pregnant patients and the extra radiation was not an issue.
From Aalst, Belgium:
Depending on the mass of myocardium distal to the mid-LAD, the type of lesions and the final result, I would stop clopidogrel after 2 or 3 months.
From New York City:
This is a very difficult situation. Emerging data suggests that the risk of stent thrombosis is very low with everolimus-eluting stents with clopidogrel discontinuation after 6 months (same as on DAPT – ~0.1%). That being said, I would suspect (without much data) that the epinephrine excess with either vaginal or surgical delivery would be a major risk for stent thrombosis. A long discussion needs to be had with the patient. If termination is not an option (which does need to be considered), I would discontinue the clopidogrel after 6 months and continue aspirin 81 mg per day. If an epidural can be performed on low-dose aspirin, I would prefer that route of delivery; if not, a C-section on low-dose aspirin.
Gregg W. Stone
From the University of Southern California:
The following is the information on antiplatelet therapy in pregnancy taken from our recent review (Roth A, Elkayam U. J Am Coll Cardiol 2008; 52:171–180):
“Aspirin (Risk Category C). The safety of aspirin during the ﬁrst trimester of pregnancy is questionable because animal studies have shown birth defects, including ﬁssure of the spine and skull; facial and eye defects; and malformations of the central nervous system, viscera, and skeleton. The safety of high-dose aspirin during pregnancy is also debatable, and its chronic use should be avoided because it may lead to increased maternal and fetal hemorrhage, increased perinatal mortality, intrauterine growth retardation, and premature closure of the ductus arteriosus. On the other hand, the safety of low-dose aspirin (150 mg/day) has been suggested by a meta-analysis and a large randomized trial that enrolled more than 9,000 patients during both the second and third trimesters.
“Thienopyridine derivatives are in Risk Category B. Information on the use of clopidogrel or ticlopidine in pregnancy is very limited. Clopidogrel was administered in 6 patients for a period of several weeks during weeks 6 to 37 of pregnancy. One case of intrauterine mortality was reported; this patient’s clinical condition was complicated by CABG, and thus no conclusion could be reached regarding the effects of the drug on the fetus.”
We have recently reviewed 116 new cases with pregnancy-associated acute myocardial infarction published since 2008, 54 during pregnancy. Many of them received antiplatelet therapy, including clopidogrel, without reports of side effects, so this increases the experience with the use of clopidogrel somewhat. There is no information regarding the use of everolimus in human pregnancy. The following is a statement taken from drugs.com regarding everolimus in pregnancy:
“Everolimus Pregnancy Warnings:
“Based on the mechanism of action of everolimus, the drug may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while using everolimus and for up to eight weeks after ending treatment.
“Everolimus has been assigned to pregnancy category D by the FDA (benefits may be acceptable despite the risk). Animal studies have revealed evidence of embryo fetal toxicities. There are no controlled data in human pregnancy. Everolimus should only be given during pregnancy when there are no alternatives and benefit outweighs risk.”
In summary, because of the limited data, the risk of clopidogrel and everolimus on the fetus at this early stage of pregnancy is not a known fact. That needs to be shared with the patient who will need to decide if she is willing to accept the unknown risk or elect for termination.
I recommend performing “upstream” genetic testing, perhaps she is a hyper-rapid metabolizer and may require less clopidogrel. Perform “downstream” PRU testing; perhaps she is below 170 that might be a marker of overall low events. Of course both outcomes are unknown and this is speculation. But then again, pregnancy is a hypercoagulable state, so both of those tests may have little value in that setting.
An addition thought. No anesthesiologist will perform spinal/epidural for labor analgesia or Cesarean delivery on a patient on DAPT due to risk of epidural hematoma. The patient should be made aware of that prior to labor or if an emergent delivery were necessary for which she would require general anesthesia.
Mladen I. Vidovich
[Dr. Vidovich asked Dr. Cynthia Wong, leading obstetric anesthesiologist, to comment on this case.]
I have the following comments that you are welcome to post:
- Definitely one must consider pregnancy as a hypercoagulable condition, and therefore, data regarding the timing of discontinuing DAPT probably cannot be applied to the pregnant patient. This is especially true in the postpartum period (even more hypercoagulable). On the other side, pregnancy is a “vasodilated” state, and adrenergic receptors are down regulated.
- From a surgical/anesthetic standpoint, a patient on low-dose ASA is easier to deal with than a patient on clopidogrel. The most recent American Society of Regional Anesthesia guidelines for patients receiving anticoagulant therapy suggest neuraxial (spinal or epidural) anesthesia is not contraindicated in patients receiving ASA only. Clopidogrel needs to be discontinued for 5 days before the procedure. (Available online at http://journals.lww.com/rapm/Fulltext/2010/01000/Regional_Anesthesia_in_the_Patient_Receiving.13.aspx)
- I am not sure I agree with the statement that a Caesarian section (CS) is less stressful/better option than a vaginal delivery. In terms of risk of postpartum thromboembolism, a CS is more risky. In terms of bleeding while anticoagulated, a CS is more risky. In terms of “stress” of delivery, I am not sure there is any evidence that an elective CS is less stressful than carefully managed labor with good neuraxial analgesia and an assisted second stage, especially for a parous patient.
- If a CS is chosen for route of delivery, a neuraxial anesthetic technique is definitely less stressful than the run-of-the-mill general anesthetic that is usually administered for a CS. The usual GA [general anesthesia] technique would need to be altered — probably include high-dose opioids, which would likely/possibly result in a depressed neonate requiring resuscitation (this should not affect long-term outcome). A neuraxial procedure could be done on someone on ASA, but not clopidogrel.
- Oxytocin (used routinely for third stage prophylaxis) causes ST-segment depression in a significant proportion of patients. The clinical significance of this in healthy patients, or patients with coronary artery disease, is not known.
- I agree with all the comments about joint decision-making. The “joint” should include patient/family, cardiologist, MFM [maternal fetal medicine], and obstetric anesthesiologist.
Cynthia A. Wong, MD, Professor and Vice Chair, Department of Anesthesiology, Northwestern University Feinberg School of Medicine
From New York City:
Great conversation. Unfortunately, the right recommendation [I believe] is to terminate the pregnancy. Losing your LAD at age 40, even if you survive it, is catastrophic. The fetus may already be harmed; she could die along with her baby, or the father could be left with a (possibly disabled) child that has no mother. There is no option that doesn’t put both her and the fetus at great risk. It’s very early in the pregnancy; termination should be advised in the strongest terms possible.
If termination not an option, and since ASA has known teratogenic effects in first trimester and undesirable vascular effects later, you’ll have to go with single anti-platelet therapy. Clopidogrel and prasugrel are category B; ticagrelor, pentoxifylline and cilostazol are category C. The bleeding anxiety with prasugrel would likely push everyone toward clopidogrel, but I’d take that risk to protect the LAD. I’d choose prasugrel monotherapy, schedule elective C-section (to control delivery date, not limit stress), and stop drug 7 days before. Admit patient 3 days before and begin eptifibatide (Integrilin) therapy (also category B), which can be shut off for operation and resumed as soon as surgeon says it is safe. This is what I do for non-pregnancy situations when the drug-eluting stent is in a critical location. The patient should resume DAPT afterward. Mother cannot breast feed while taking ASA + thienopyridine.
Kirk N. Garratt
Some of the comments about aspirin are not consistent with I’ve read about it in pregnancy. It is indeed teratogenic. Moreover, as I understand it, before birth, a fetus receives oxygen through blood from the placenta. At birth, a natural drop in prostaglandin levels in some of the fetus’s blood vessels drives its circulatory system to reroute blood flow to the lungs. Since aspirin blocks the production of prostaglandins, taking aspirin during pregnancy — especially after 32 weeks — could trigger the fetus’s blood flow to be rerouted in the uterus. This could cause potentially fatal problems for the baby.
So the next question is how to terminate the pregnancy in someone on DAPT? I searched PubMed [www.pubmed.com] on “pregnancy termination and dual antiplatelet therapy” without success. Medical vs. surgical? Misoprostol has been associated with myocardial ischemia. Both techniques are associated with vaginal bleeding. I think a gynecologist needs to weigh in on the remaining management conversation.
From Long Beach, California:
Dr. Oliver Bertrand from Lavalle Hospital, Quebec City, sent me the “The European Society of Cardiology guidelines on the management of cardiovascular diseases during pregnancy: The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC)” which is just now is available online. As with much of the discussion above, there is very little specific commentary on the type of patient discussed here. From the section 6.2 on CAD/ACS management, “b-Blockers and low dose acetylsalicylic acid are considered to be relatively safe, while this is unknown for thienopyridines. Clopidogrel should therefore only be used during pregnancy when strictly needed (e.g. after stenting) and for the shortest duration possible.”
I agree with stopping the clopidogrel at 6 months, continuing low-dose aspirin, and consulting the family and team about continuation to term.
This is no easy case and I’m sure we all learned a great deal from this interchange. I hope our ‘conversations’ will be of benefit to our colleagues, nurses and techs, and patients having some of these unusual problems.