Henry I. Bussey, Pharm.D. November 8, 2018
Recently Drs. Rieser and Lindsay reviewed the changes in the new Chest guideline for Antithrombotic Therapy in Atrial Fibrillation (AF) for the iForumRx website. Their review is available at https://iforumrx.org/commentary/top-ten-things-every-clinician-should-know-about-2018-antithrombotic-therapy-atrial
For those who would like to review the guideline, the complete report is:
Lip GYH, Banerjee A, Boriani G, Chiang Ce, Fargo R, Freedman B, Lane DA, Ruff CT, Turakhia M, Werring D, Patel S, Moores L, Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report, CHEST (2018), doi: 10. 1016/j.chest.2018.07.040. (available online at https://journal.chestnet.org/article/S0012-3692(18)32244-X/fulltext#sec7.3.1)
The following is my “contrarian” view. While it may be true that most clinicians may embrace the new guideline, I believe that there are several reasons why alternative and/or additional issues should be considered. Here are five issues:
- Direct-acting Oral Anticoagulants (DOACs) should not be preferred over vitamin K antagonists (at least not in North American, Western Europe, Australia, and Scandinavian countries).
VKA therapy in patients with atrial fibrillation, if poorly managed, is associated with an increase (not decrease) in the risk of thromboembolism, major bleeding, and death over no treatment at all.[1,2] However, reasonably well-managed VKA therapy reduces stroke, major bleeding, and death far more than what has been reported with the DOACs (see table below). [1,3,4] The guidelines identify several factors that are necessary for successful VKA therapy but they fail to point out that the absence of these factors from the DOAC studies undermine – and even invalidate – the conclusions of these studies.
The table below presents the ranges of events (% per year) reported in the DOAC trials, the event rates reported from sites that apparently address the factors that are necessary for successful VKA therapy, and the calculated event rates based on regression equations generated by Wan and colleagues. 
Range of event rates reported (%/yr) in the DOAC trials vs event rates from other reports.
|Study||Stroke||Maj. Bleeding||Death||ICH/Hem. Stroke|
|1.02 – 1.66||2.13 – 3.60||3.52 – 4.50||0.32 – 0.50 / 1.0 – 0.26|
|1.52 – 1.96||3.40 – 3.57||3.94 – 4.90||0.70 – 0.85 / 0.38 – 0.47|
|EAA – VKA||0.30||0.86||0.75||NA|
|Sweden – VKA||1.61||1.29||0.34 / NA|
|Wan, et al *||0.96*||1.10||NA||0.26/0.15|
*Data for Wan, et al are calculated using 2 equations that were developed by analyzing 38 atrial fibrillation studies for the relationship between the percent of time that the INR was in target range (%TTR) vs. major bleeding (MB) and thromboembolism (TE) events. The regression equations MB = 10.104 – 0.120x[TTR], (p = 0.004) and TE = 8.313 – 0.098x[TTR], (p = 0.03). Itracranial hemorrhage (ICH) and hemorrhagic stroke. (Hem. Stroke) were estimated based on their percentages of MB from the 4 DOAC trials[5-8]
Points to note in the above table:
- The range of absolute differences in event rates between the DOAC and VKA groups are not large (even though warfarin was poorly managed in many locations – discussed below).
- The European Action on Anticoagulation (EAA) is a network of clinics which reported on 5,939 patients with AF who had dramatically lower event rates with a VKA than was reported with either agent in the DOAC trials.
- In the Sweden report, where the mean time in the target INR range (TTR) was almost 70%, the more than 22,000 patients with an individual TTR (iTTR) of 70% or greater had dramatically lower event rates with a VKA than was reported with either agent in the DOAC trials.
Factors necessary for successful VKA therapy [Note: From details available at this time, it appears that each of the DOAC studies were conducted in approximately 40 or more countries with a minority of patients being enrolled from North America (NA) and Western Europe (WE). Therefore, it is likely that regional differences reported with one study apply to the other studies in some degree].
- The Chest guideline talks about differences in VKA management in various geographical regions, but it does not seem to consider this factor when making the recommendation of DOACs over a VKA. If we look at one example – the ROCKET AF trial – we find that only 2 of 7 geographic regions (NA and WE) had TTRs > 60% while the other 5 regions had an unweighted TTR of 49% – a level at which VKA therapy tends to be harmful rather than beneficial. Evidence indicates that a TTR of < 50% results in a greater rate of major events than no treatment at all! Furthermore, with the ROCKET-AF trial again serving as the example, the 5 (of 7) geographic regions with poor TTR also had more variable TTRs (discussed below) and were less attentive when patients experienced extreme INRs (where event rates increase exponentially). For example, for INRs < 1.5 or > 4, the time to follow-up in NA and WE was approximately 10 days vs. three weeks in the 5 regions with poor TTR. Approximately 65% of patients were enrolled from these countries with quite poor VKA management which clearly skewed the data in favor of the DOAC.
- The Guideline recommends monitoring each individual’s TTR (iTTR) and intervening if the iTTR is not > 65 – 70%. Such individualized monitoring and intervention was not part of the management in the DOAC trials; patients with poor INR control were allowed to continue poor therapy. In other analyses, the 25% of patients with the poorest INR control have been shown to have a 3 to 6 fold higher rate of major events than the other 75% of patients  and a higher rate than with no treatment at all.[1,2]
- The Guideline also identifies anticoagulation clinics and self-testing or self-management as measures that have been shown to improve outcomes and/or INR control. Self-testing and self-management were not utilized in the trials and, at least in the RE LY trial, fewer than 15% of patients were managed in an anticoagulation clinic.[11,12]
- Adherence to a dosing algorithm may improve INR control and outcomes but, at least in the RE LY trial, deviation from the algorithm was identified as a problem that resulted in a higher rate of clinical events. [11,12]
- Intracranial hemorrhage and/or hemorrhagic stroke, although rare, were twice as high with VKA therapy. This reported difference is frequently cited as an advantage of the DOACs; but is it really? In the ROCKET-AF trial, for example, the ICH rate with a VKA was 4 fold higher in Asian study sites (which enrolled only 6.5% of patients) than in other sites (2.5%/yr vs. 0.6%/yr). ICH was not statistically higher in the 93.5% of patients enrolled outside of Asian sites. In other words, the significantly higher ICH with warfarin was due entirely to the extremely high rate reported in the 6.5% of patients who were enrolled from Asian sites. According to the Guideline, Asian sites had the lowest rate of TTR > 65% at 16.7%. Furthermore, the ICH rate reported in Sweden with an iTTR > 70%  and even the major bleed rate reported by the EAA  – see table above – would suggest that the ICH rate with well-managed VKA therapy is not greater than that reported with the DOACs.
- New approaches to VKA management: From 2008 to 2013 there were at least 7 small studies that reported improved INR control and efficiency of VKA management by combining INR self-testing with online monitoring and management.[14-20] The TTR achieved in these 7 studies ranged from 74% to 81%. In our own series with an overall TTR of 81%, the bottom quartile of patients had a TTR of 23% for the 6 months preceding the study, but each patient quickly achieved and maintained an iTTR > 70%. Such an approach also can eliminate the hassles, time, and expense of traditional VKA management. One such system, which has been adopted by a network of 160 community pharmacies in New Zealand, now manages more than 6,000 VKA patients and is reimbursed by the New Zealand Health Ministry (personal communication with Dr. Paul Harper).
- Pharmacodynamic and pharmacokinetic differences allow one to verify and adjust the intensity of anticoagulation with a VKA using the INR, and the effect can be partially or completely reversed over various time periods depending on the reversal method employed. The direct-effect and rapid offset of the DOACs is almost certainly why these agents contain a warning against self-discontinuation. Similarly, the direct-effect and pharmacokinetic differences likely explain the substantially higher major gastrointestinal bleeding rate reported with each of the DOACs except apixaban.[5-8]
- Recommending that clinicians should strive for all VKA patients to have an iTTR > 65% -70% is a good start but it is inadequate and may be misleading. It should be recognized that the TTR calculation was developed by Dr. Rosendaal in the early 1990s as a way to determine what target INR ranges would produce adequate protection from clotting while minimizing major bleeding in patients with various indications. It was not intended to be a measure of the quality of anticoagulation and it is not an adequate measure of same. For example, a patient with a stable INR between 3.0 and 3.3 would have an iTTR of 0% but would have very little additional risks compared to a similar patient with a stable INR of 2.5 and an iTTR of 100%. Alternatively, we know that the rates of major events increase exponentially when the INR moves far out of range to “extreme values”. Even in a patient with a high iTTR, an excursion to an INR of 10 or higher carries a risk of major bleeding and, if over-corrected, may also result in an increased risk of clotting. Such wide swings in INR values almost certainly explain why several studies have found that event rates correlate better with measures of INR fluctuation than with the TTR.[22-24] In my own practice, we calculate the iTTR but we place a higher value on time in an expanded range (target range +/- 0.3 INR units) and on avoiding extreme INR of < 1.5 and > 5. It is entirely possible to have a patient with an iTTR that is well below the 65% Guideline target but may have an expanded iTTR of well over 80% with virtually no extreme INRs. That patient has very well controlled VKA therapy.
- Use of the CHA2DS2-VASc Score can be misleading. The various scores for assessing stroke and bleeding risks in patients with atrial fibrillation are available at http://www.clotcare.com/assessing_stroke_and_bleeding_risk_in_atrial_fibrillation_consensus_statement_on_appropriate_anticoagulant_use.pdf). The Guideline considered males with a score of 0 or females with a score of 1 to be “low risk” and not requiring anticoagulation. The difference in the gender score, according to the Guideline, is because being female is not a risk factor unless the individual is over 65 years of age. The reason I believe that the CHA2DS2-VASc score may be misleading is two-fold. First, the calculated risk is for only one year and may give the clinician and/or the patient the misimpression that the one-year risk is the total risk. Second, it gives only 3 age categories (< 65, 65-74, and > 75) and 2 hypertension categories (yes or no). The Framingham scoring system has 11 age categories and 5 blood pressure categories, but it does not count heart failure or vascular disease. So, each of these scoring systems may have its own limitations. But let’s consider a couple of examples: A 63 year old female with a systolic blood pressure of 125 mm Hg. would have a score of 1 pt (female) or zero if you discount the female gender because she is not yet 65. Her estimated stroke risk would be zero or 3 %/yr by the CHA2DS2-VASc Score (depending on whether the female gender is counted) vs. 6% or 12% per 5 years by the Framingham score (depending on whether the 6 pts for being female is included). Zero or 1.3%/yr vs. 6% or 12% per 5 years may be perceived differently. Four years later when that same patient has turned 67 years old, developed diabetes, and has a systolic blood pressure of 155 mmHg, her CHA2DS2-VASc Score of 4 would suggest an annualized stroke risk of 4%/year vs. a Framingham score of 16 points and a 5 year stroke risk of 24%. Again, a 24% 5-yr risk may be perceived differently than a 4%/yr risk. As best I can, I try to give my patients a 5-yr risk estimate.
- Use of the SAME-TTR score is recommended but may be irrelevant in a site with good VKA management: This scoring is put forward as a way to determine which patients may or may not achieve a good iTTR. As mentioned previously, in our experience, every patient (even those in the bottom quartile at a TTR of only 23% for the previous 6 months) can quickly achieve and maintained an iTTR > 70% if managed in a good system.
- Coronary artery disease and atrial fibrillation: The Guideline provides a nice update on combining anticoagulation and antiplatelet therapy in patients with stents. But for patients without stents, one should remember that a good body of evidence shows that warfarin alone (or with aspirin) offers protection in coronary artery disease patients. This issue is discussed in more detail at the ClotCare link: Rivaroxaban or Warfarin in Stable Coronary Artery Disease – Should the COMPASS Study Lead Us Back to the Future?
- Wan Y, Heneghan C, Perera R, et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: A systematic review. Circ Cardiovasc Qual Outcomes 2008; 1:84-91.
- Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa T-P. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011; 106:968-977.
- Poller L, Jespersen J, Ibrahim S (on behalf of the European Action on Anticoagulation – EAA). Warfarin or dabigatran for treatment of atrial fibrillation. J Thromb Haemost 2014; 12:1193-5.
- Bjorck F, Renlund H, Lip GYH, et al. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiology 2016; 1:172-180.
- Connolly SJ, Ezekowitz MD, Yusuf S, RE-LY Steering Committee Investigators et al. Dabigatran vs warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:113–151.
- Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. 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, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365(11):981-92.
- Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban vs Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2013; 369:2093-2104.
- Singer DE, Hellkamp AS, Piccini JP, et al. Impact of global geographic region on time in therapeutic range on warfarin anticoagulation therapy: Data from the ROCKET AF clinical trial. J Am Heart Assoc 2013, 2:e000067. doi: 10.1161/JAHA.112.000067.
- Veeger NJ, Piersma-Wichers M, Hillege HL, et al. Early detection of patients with a poor response to vitamin K antagonists: the clinical impact of individual time within target range in patients with heart disease. J Thromb Haemost 2006; 4:1625-1627.
- Van Spall HGC, Wallentin L, Yusuf S, et al. Variation in warfarin dose adjustment practice is responsible for differences in the quality of anticoagulation control between centers and countries; An analysis of patients receiving warfarin in the Randomized Evaluation of long-term anticoagulation therapy (RE-LY) trial. Circulation 2012; 126:2309-2316.
- Rose AJ. Improving the management of warfarin may be easier than we think. Circulation 2012:126:2277-2279.
- Wong KSL, Hu DY, Oomman A, et al. Rivaroxaban for stroke prevention in East Asian patients from the ROCKET AF trial. Stroke 2014; 45:1739 – 1747.
- O’Shea SI, Arcasoy MO, Samsa G, et al. Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation. J Thromb Thrombolysis 2008; 26(1): 14-21.
- Ryan F, Byrne S, O’Shea S, et al. Randomized controlled trial of supervised patient self-testing of warfarin therapy using an internet-based expert system. J Thromb Haemost 2009; 7:1284-1290.
- Harper PL, Pollock D. Improved anticoagulant control in patients using home international normalized ratio testing and decision support provided through the Internet. Internal Medicine Journal 2011; 41:332-7.
- Verret L, Couturier J, Rozon A, et al. Impact of a pharmacist-led warfarin self-management program on quality of life and anticoagulation control: a randomized trial. Pharmacotherapy 2012; 32:871-879.
- Bussey HI, Bussey M, Bussey-Smith KL, et al. Evaluation of warfarin management with international normalized ratio self-testing and online remote monitoring and management plus low-dose vitamin k with genomic considerations: a pilot study. Pharmacotherapy 2013; 33:1136-46.
- Bereznicki LR, Jackson SL, Peterson GM, et al. Supervised patient self-testing of warfarin therapy using an online system. J Med Internet Res 2013; 15(7):e138.
- Harper P, Shaw J, Harrison J, Harrison J. Evaluation of a community pharmacy anticoagulation management service utilizing point-of-care testing and online computer decision support (abstract ATT07). J Thromb and Haemostasis 2013; 11:11-12.
- Rosendaal FR, Cannegieter SC, van der Meer FJM, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69:236-239.
- Lind M, Fahlen M, Kosiborod M, Eliasson B, Oden A. Variability of INR and its relationship with mortality, stroke, bleeding and hospitalisations in patients with atrial fibrillation. Thrombosis Research 2012; 129:32-35.
- Razouki Z, Ozonoff A, Zhao S, Jasuja GK, Rose, AJ. Improving Quality Measurement for Anticoagulation Adding International Normalized Ratio Variability to Percent Time in Therapeutic Range. Circ Cardiovasc Qual Outcomes 2014;7:664-669.
- Van Den Ham HA, Klungel OH, Leufkens HGM, Van Staa TP. The patterns of anticoagulation control and the risk of stroke, bleeding, and mortality in patients with non-valvular atrial fibrillation. J Thromb Haemost 2013; 11: 107–15.