American Society of Hematology

Ask the Hematologist: May-June 2013

Charles S. Abrams, MD Director
PENN-CHOP Blood Center for Patient Care and Discovery

Published on: May 01, 2013

Dr. Abrams indicated no relevant conflicts of interest.

The Question

What is your view of the safety and efficacy of novel oral anticoagulants?

My Response

When Richard Nixon “opened the door” to China in 1971, he met with Zhou Enlai, the first Premier of the People’s Republic of China. Many of their conversations were focused on developing trade between their two countries, but some discussions were designed to gain insight into each other’s culture and perspectives. At one point, Nixon queried the Premier on his opinion of the French Revolution of 1789. Zhou Enlai’s response was that it was “too soon to say.” Many interpreted this remark as exemplary of a nation that exhibits extreme patience (although the response may have been merely an example of international miscommunication). But the philosophy of patience is one that often serves its followers well, including physicians. When patients query me about whether they should switch their warfarin anticoagulation to a novel oral anticoagulant (NOAC), I find myself echoing the Chinese Premier and stating that it is still too soon to say with confidence.

For well over a decade, pharmaceutical companies have attempted to replace vitamin K antagonists such as warfarin. In the United States alone, more than 2 million people are treated with anticoagulation, making this avenue of pursuit quite lucrative. All of us who manage patients on warfarin easily understand the desire to replace warfarin with a drug with less complicated dosing. But, are we there yet? The initial contender was an oral thrombin inhibitor, ximelagatran. However, liver failure in several recipients of this medication caused the drug to be removed from clinical evaluation. Now, there are three NOACs that have been approved by the FDA. These are the oral thrombin inhibitor dabigatran and two factor Xa inhibitors, rivaroxaban and apixaban. But, what do we know about these novel agents, and, more importantly, what don’t we know?

What Do We Know?

A lot, but not all of what we know about the NOACs is good. Dabigatran, rivaroxaban, and apixaban each have the obvious advantage over warfarin of fixed doses that do not require laboratory monitoring. They also exhibit similar, or even improved, efficacy when compared with warfarin. But, if there is improved efficacy for any of these drugs when compared to warfarin, such advantages are modest.

To date, the safety of these agents when used in clinical trials also appears to be acceptable. However, one would have anticipated that fixed dosing and relatively fewer drug interactions would have resulted in a vastly superior safety profile and far fewer hemorrhagic complications. Consistent with this assumption, the risk of the dreaded intracranial hemorrhage is significantly reduced in patients taking an NOAC when compared with warfarin. Improvement in other types of hemorrhages, however, has not been a consistent finding. In fact, in the calendar year 2011, dabigatran replaced warfarin as the drug most frequently reported to the FDA as being associated with adverse events, and when compared with warfarin, both dabigatran and rivoroxaban appear to increase the risk of gastrointestinal bleeding.1,2 Further, it must be emphasized that there are existing treatment strategies for reversing anticoagulation induced by warfarin but not for anticoagulation induced by any of the available NOACs. Similar to warfarin, non-hemorrhagic adverse effects appear to be rare in patients taking NOACs. However, as post-marketing data have accumulated, dabigatran, when compared with warfarin, has been found to be associated with a small, but definite, increased risk of myocardial infarction.1,3,4 Finally, we know that patient compliance is not great. For all of the NOACs, failure to adhere to the dosing schedule is in the range of 20 to 25 percent, even in the setting of clinical trials.1,3,5

What Don’t We Know?

Almost all of the available evidence for NOACs is derived from patients enrolled in clinical trials, many of whom who were treated for only a few months. Because clinical outcomes for patients treated in “real-world” settings may differ from those for patients enrolled in clinical trials, I find it difficult to inform my patients about the true risks and benefits of these new agents.

A big question is how these drugs will perform in patients who receive less intensive, non-continuous education. In a typical clinical practice, the average time spent educating a patient about the rationale, efficacy, and safety of a new medication is less than a minute.6 This short amount of time spent educating real-world patients is in striking contrast to the amount of time spent educating patients enrolled in clinical trials who are informed and re-informed about the properties of the new agents. What impact brief patient education will have on adherence to treatment with an NOAC and what the risk of bleeding will be in a less-than-ideally informed patient are completely unknown.

Although patients and health-care providers grumble about monitoring the INR in patients treated with warfarin, this action actually offers a tremendous educational opportunity. As a consequence of encounters mandated by the monitoring requirement, patients on warfarin are continuously re-educated about the warning signs of excessive bleeding. This process also helps monitor patients who are actually taking their medication and affords an opportunity to intervene when they are not. In contrast, given that monitoring is not required, the NOACs have the danger of being categorized as prescribe-and-forget drugs. Since no drug works when it is not taken, and since patients frequently do not openly report their non-compliance, the absence of a monitoring requirement might, ironically, turn out to have a major negative impact on the safety and efficiency of these drugs in the everyday clinical setting. The compliance issue is especially concerning given that all three of the NOACs have a half-life much shorter than warfarin, and two of them (dabigatran and apixaban) require twice-daily dosing to maintain a therapeutic level.

When compared with warfarin, the long-term outcome of NOACs in patients who are elderly and who have suboptimal renal function is also incompletely understood. On average, the patients in clinical studies of NOACs have been younger than those found in typical clinical practices. Patients in clinical studies are also not on drugs that might impact their renal function or otherwise affect the pharmacodynamics of the NOACs. Common drugs such as NSAIDs can affect the glomerular filtration rates of patients. Drug-induced changes in kidney function can lead to changes in the drug levels, which in turn may lead to changes in anticoagulation status that will go unrealized because monitoring is not part of the standard management of patients taking NOACs.

Caveat Emptor

When I speak with my patients, I can confidently state the adverse effects of warfarin in patients that have been treated for not only months, but also for decades. In recent years, we have seen several drugs that have significant toxicity that only became detected after more widespread use by the public. Some examples include rosiglitazone and rofecoxib. The link between dabigatran and myocardial infarctions was also discovered in post-marketing studies that followed FDA approval. Elucidation of the true efficacy and safety of NOACs requires still more time. Perhaps the Chinese Premier Zhou Enlai was right after all.

1. Connolly SJ, Ezekowitz, MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

2. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with two doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123:2363-2372.

3. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

4. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med. 2012;172:397-402.

5. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

6. Tarn DM, Paterniti DA, Kravitz RL, et al. How much time does it take to prescribe a new medication? Patient Educ Couns. 2008;72:311-319.

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