Options To Rat Poison – Other Mousetraps?
“The policy of being too cautious is the greatest risk of all.” Jawaharlal Nehru
Of all the potential complications associated with atrial fibrillation (AF), stroke is the most feared. Attempting to predict a stroke has proven to be a daunting task. The mechanism by which AF leads to a stroke is undoubtedly due to the formation of a thrombus within the left atrium, in particular the left atrial appendage (LAA). The latter structure serves to enhance the atrial contribution to ventricular diastolic filling. When AF sets in, effective atrial contractions are greatly minimized, and blood can become stagnant within the LAA and form a thrombus. Should parts of the thrombus embolize, a stroke can result. Such cerebrovascular events can be devastating.
My thoughts today will focus not on the symptoms caused by AF, and their treatments but to summarize medical options in stroke prevention. The mainstay of stroke prevention with this arrhythmia is the use of an anticoagulant. For many years, warfarin was the only anticoagulant available. Although this agent can be a forgiving drug if a dose is missed, it can also be the most fickle. Not uncommonly, patients often perceive this agent to be “rat poison.” Historically, this was its previous use. The drug’s notoriety can be appreciated by the numerous interactions with certain foods (particularly ingredients which have a high content of vitamin K which inhibit its actions), or with other medications such as antibiotics. Additionally, excessive anticoagulation may result with ceratin cardiac medications such as the widely used antiarrhythmic amiodarone. Unfortunately, when the anticoagulant level, colloquially known as the INR, increases above the desired clinical range, bleeding may occur1. Frequent, at least monthly office monitoring is recommended. As such, the quality of life may be impacted for many patients.
In my practice, I have encountered numerous patients that were very determined to avoid warfarin despite facing a risk of stroke. The anticoagulation landscape changed with the introduction of the “novel oral anticoagulants” (NOACs) which exert their effects at different levels of the coagulation cascade. The development of the direct thrombin inhibitor dabigatran (marketed as Pradaxa) was a welcome option to warfarin. However, true to the nature of the class of drugs with which it belongs to, bleeding complications still occur. Since its approval approximately seven years ago, dabigatran is no longer the only NOAC2. The last several years saw the emergence of the factor Xa inhibitors rivaroxaban (Xarelto), apibixan (Eliquis) and most recently edoxoban (Savaysa)3-5.
With that being said, the clinical studies used to obtain FDA approval for use in the United States concluded that collectively these agents have relatively low rates of bleeding. However, the post-marketing experience may be very different than what is observed in the safe confines of a clinical trial. It is vital that there exists medically equivalent options to prevent an AF-related stroke. In general, The NOACs have the clinical advantage of not commonly interacting with other medications, and typically do not require any change in dietary habits or such constraints. Frequent monitoring is not universally required, and other than adjusting for renal function, dosing is often straightforward. With the exception of dabigatran, the other NOACs do not have any readily available reversal agent to counter an acute bleeding event or hemorrhage. This is potentially a serious limitation, and a clinically relevant factor which must be discussed with patients when counseling them on anticoagulation. The ideal “drug” would be completely effective at preventing an atrial thrombus from occurring, and yet lead to no bleeding6. Neither of those objectives are tangible options yet. At the end of the day, both the clinician and patient need to decide which medicine is most likely to be protective and be an acceptable risk.
- Seet RC, Rabinstein AA, Christianson TJ, Petty GW, Brown RD. Bleeding complications associated with warfarin treatment in ischemic stroke patients with atrial fibrillation: a population-based cohort study. J Stroke Cerebrovasc Dis. 2013;22:561-9
- Larsen TB, Rasmussen LH, Skjøth F, Due KM, Callréus T, Rosenzweig M, Lip GY. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61:2264-73
- Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91
- Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-92
- Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-104
- Deshpande CG1, Kogut S, Laforge R, Willey C. Impact of medication adherence on risk of ischemic stroke, major bleeding, and deep vein thrombosis in atrial fibrillation patients using novel oral anticoagulants. Curr Med Res Opin. 2018 Jan 16:1-17. doi: 10.1080/03007995.2018.1428543. [Epub ahead of print]
Christian Perzanowski is an electrophysiologist in Tampa, FL. His main interests are in ablation techniques for atrial fibrillation and device therapy for congestive heart failure.
Apollo Beach, FL 01/18 CP.