October 8th, 2012

Triple Antithrombotic Therapy: What — and When — Is the Bleeding Risk?


In a national registry study, researchers in Denmark studied the effect of multiple antithrombotic drugs — including triple therapy with warfarin, aspirin, and clopidogrel — in patients with atrial fibrillation and coronary artery disease (indicated by hospitalization for PCI or MI).

Among more than11,000 patients, 30-day bleeding rates were:

  • Warfarin + ASA + clopidogrel (triple therapy): 22.6 per 100 patient-years
  • Warfarin + single antiplatelet: 20.3 per 100 patient-years
  • ASA + clopidogrel: 14.3 per 100 patient-years.

The increased bleeding risk observed with triple therapy persisted for up to 1 year after the initiation of therapy.

CardioExchange’s John Ryan sat down with lead investigator Morten Lamberts, MD, to ask some questions about this study and its implications.

Ryan: Dr Lamberts, congratulations on this wonderful paper. Can you give our readers an idea of why you believed it was important to do this study?

Lamberts: Thank you very much. In everyday practice, we face the problem of bleeding complications when balancing the addition of antiplatelet(s) on top of oral anticoagulation therapy in AF patients who suffer MI or undergo PCI. We know that antiplatelet therapy is indicated for CAD and oral anticoagulant therapy for AF, and current guidelines support an additive approach, although no firm evidence of the safety of triple therapy (ASA, clopidogrel, oral anticoagulant) exists. Our perception that short-term triple treatment is safe is based on expert opinion, which, if unfounded, could potentially put patients at even greater hazard.

Ryan: The mean CHADS2 score in this study was 1.5 (SD, 1.5). I think it is important for people to recognize that these results were obtained in a well-treated cohort that is not necessarily at high risk for bleeding. Similarly, from what I understand, you did not observe any significant differences in risk between various subgroups. Can you expand on that for our readers?

Lamberts: We looked at several clinically relevant subgroups for any differences in our main finding of early serious bleeding with triple therapy use. Regardless of sex, age, CHADS2 score (≥2 or ≤1), or MI or PCI status at inclusion, the relative risk for bleeding events was increased, particularly within the first 90 days after the index MI or PCI.

Ryan: At inclusion, 13% of patients were on triple therapy, whereas by day 180, only 8% were. Do you have a sense as to why treatment was altered in almost 40% of patients? And also, which agent was typically stopped when physicians took people off triple therapy?

Lamberts: We defined antithrombotic treatment from ongoing medication, which allowed us to continually update exposure status based on actual redeemed prescriptions; thus, patients could change exposure status during the 1-year follow-up period. Current guidelines arbitrarily recommend triple therapy for 1 to 12 months, based on the severity of CAD presentation, type of stent implanted, and presumed bleeding risk. We also know from several studies that antithrombotic treatment in real-life patients after MI or PCI is fairly consistent and adheres to recommendations, but antithrombotic treatment in AF patients is highly variable. In this light I am not surprised that the proportion of triple therapy users declined. We did not specifically look at which agent was stopped, but it seems to be the case that if an oral anticoagulant is prescribed, this treatment is continued.

Ryan: It is noteworthy that the combined endpoint of cardiovascular death, MI, and ischemic stroke was similar in patients on triple therapy and in those on warfarin plus a single antiplatelet agent. Did this surprise you, and what recommendations can you make based on that data?

Lamberts: Although the study was designed to evaluate safety issues, it somewhat surprised us that we could not find a benefit for the combined thrombosis outcome with triple therapy. With regard to recommendations, I think we need further evaluation of specific treatments and more details on outcomes (i.e., ischemic stroke, death, stent thrombosis, and recurrent MI), before the data can support advice against use of triple therapy. Nevertheless, I believe these data raise important questions for patients with dual indications for antithrombotic therapy. When the patient is already anticoagulated, do we really need two drugs to inhibit platelet aggregation? And, are there differences between the available antiplatelet agents?

Ryan: So, let me pose a case: If I have a 71 year old man with AF and diabetes mellitus who needs PCI for critical LAD disease, should I be thinking about placing a bare-metal stent so I can discontinue his triple therapy as soon as possible?

Lamberts: This is a very difficult case; interventionalists especially know this problem well. I believe that in this setting, a BMS should be preferred, which also accords with current American and European guidelines. The reasoning, as you say, is that the risk for stent thrombosis is lower with a BMS compared with a drug-eluting stent; consequently, an earlier removal of an antiplatelet agent is possible. Although our study suggests that even 30 days of triple therapy is associated with increased bleeding risk, at this point, we cannot firmly say that an oral anticoagulant and a single antiplatelet are sufficient to protect from recurrent coronary events in the initial vulnerable period. Until solid evidence is available, treating physicians must assess bleeding and thrombosis risks individually. They should also be aware that our data suggests that triple therapy does not have a safe therapeutic window.

6 Responses to “Triple Antithrombotic Therapy: What — and When — Is the Bleeding Risk?”

  1. Jean-Pierre Usdin, MD says:

    wonderful discussion.
    The length of dual Anti Agregant Platlet therapy (AAP) is a cornerstone of this important every-day clinical practice.
    The results of the study “Dual Antiplatlet Therapy” are waited for December 2013. It will resolve the safety/efficiency of double AAP within the period of 12 and 30 months after initiation.
    But as you say the risk exists immediately and its nadir is 90 days after initiation!
    The same problem is seen in patients with a prosthetic cardiac valve suffering from AMI or undergoing PCI.
    We have to convince our interventional colleagues that some elective PCI should not be attempted and in some case medical treatment (or why not balloon ATL the return of single balloon angioplasty…I knowi will receive many critics) works. However, you will say Aspirin is a mandatory in chronic CAD.
    I think this story is not ready to end…
    Thank you for your precious remarks.

  2. Karen Politis, MD says:

    As an anesthesiologist, who often is called to the ER in case of traumatic brain injury, I must point out the often devastasting consequences of TBI (traumatic brain injury) for a patient on anticoagulant/antiplatelet therapy. Of course a massive stroke or stent thrombosis can be equally devastating. What to do? I would suggest that when in doubt, a physician should consider the patient’s history of falls or traffic accidents. Sometimes there are lifestyle factors (like excessive alcohol consumption, which is not unusual in seniors today), orthopaedic problems or orthostatic hypotension (which can be partly iatrogenic). I wonder if the statistics considering the side effects of anticoagulants even include the problems the patient and the caregivers face in case of trauma.

  3. David Powell , MD, FACC says:

    Just today a similar issue arose in an elderly patient with an fairly large apical infarct treated medically without PCI. No afib. DAT as per CURE. But how about warfarin for prevention of LV thrombus, at least for a few months? I imagine such patients with larger infarcts were more likely treated with triple therapy, illustrating the meaninglessness of judging efficacy in a retrospective study.

  4. Judith Andersen, AB, MD says:

    Triple therapy? I realize that this study was performed without benefit of rivaroxaban or dabigatran, but warfarin is not the darling of the future. In fact, many of us are hoping that we can relegate warfarin to exalted but antique status, since future critical studies of multiagent value and safety will employ agents with defined — not shifting –spheres of efficacy. And we may, by critically evaluating the data from these studies, identify the appropriate use of these individual agents, as well as the power of judicious combinations.

    This study may be useful for the developing world, in which warfarin may remain a treacherous but important mainstay of care — but for practice in countries in which target-specific anticoagulant agents can be used, the use of warfarin will hopefully disappear, leaving an historic and noble past, but a happy transition to new agents that may not create this “triple threat.” I have not yet had access to the “time within range” data for warfarin is this study, but if it resembles any of the recent drug comparison studies that have plagued the pivotal clinic trials of new agents, it it clear that warfarin anticoagulation remains far from ideal — and, in its difficult management, creates a risk that may disappear with the use of newer, more predictable agents. Warfarin has the advantage of using multiple targets to achieve a therapeutic goal, but it’s a rare individual who can intuit the likely mix of effects in real time. And head-scratching may be therapeutic for the scratcher, but not good for the patient.

    I realize that one of the most powerful means of identifying an old therapeutic agent’s value is to shelve it in favor of one or more new agents, but will stand by the sense that — although we do not understand all the contributors to thrombotic risk in many different patient populations– warfarin is a major contributor to antithrombotic instability and threats to safety in the patients who take it. Who ever said that rat poison was good for people!

  5. Davi’s point is very relevant- my practice in those settings is to opt for BMS with triple therapy for one month and warfarin thereafter. But the guidelines to this issue in my view are vague.

  6. Mario Maiese, DO says:

    What do we think about the WOEST study presented @ ESC 2012 in August? Based on study results recommendations were to drop ASA (major bleeding reduction in the study compared to triple tx without an increase in stent thrombosis.

    Clopidogrel + warfarin for 3 mo in BMS and 1 yr in DES then switch to ASA/warfarin. Only 573 pts but clinical implications very important and probably guideline changing. May be the best choice until we get more/better data.

    Unfortunately new OAC drugs not available and results are non-transferable.