A Contrarian’s View – Top Five Alternative Things Every Clinician Should Know About the 2018 Antithrombotic Therapy Atrial Fibrillation Guidelines

Drs. Rieser and Lindsay recently provided a succinct (and well written!) overview of the Top Ten Things Every Clinician Should Know About the New Antithrombotic Guidelines for Stroke Prevention in Atrial Fibrillation.  While it may be true that most clinicians may embrace the new guidelines, I believe that there are several reasons why an alternative viewpoint should be considered.

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1. 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).

Argument 1a. 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 in the landmark DOAC trials.^1,3-8  See Table 1.  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 those studies.

The table below presents the ranges of events (% per year) reported in the DOAC trials and the event rates reported from sites that addressed the factors that are necessary for optimal VKA therapy as well as the calculated event rates based on regression equations generated by Wan and colleagues.

Table 1.  Range of event rates reported (%/yr) in DOAC Studies and Other Analyses

^{*Data for Wan, et al are calculated from 2 regression equations that were developed by analysis of numerous atrial fibrillation studies conducted mainly in North America and Western Europe.  The “stroke” rate is actually the thromboembolic rate and ICH/Hem. Stroke rates were estimated based on average percentages of major bleeds.}

^{TE = 8.313 – 0.098 x [TTR], (p = 0.03).  Intracranial hemorrhage (ICH) and hemorrhagic stroke were estimated based on their percentages of MB from the 4 DOAC trials5-8}

Points to note from Table 1:

• In the four landmark clinical trials that lead to the approval of four DOACs for stroke prevention in non-valvular atrial fibrillation (AF), the absolute differences in event rates between the DOAC and VKA groups are not large (even though warfarin was poorly managed in many centers).^5-8
• The European Action on Anticoagulation (EAA) is a network of clinics which report outcomes on 5,939 patients with AF found dramatically lower event rates with a VKA than has been reported in any of the DOAC trials.³
• In the Sweden-VKA 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 in the DOAC trials.⁴

Argument 1b. VKA therapy can be successfully managed in most patients but many centers failed to successfully manage warfarin. 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.  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.  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.⁹  Evidence indicates that a TTR of < 50% results in a greater rate of major events when compared to no treatment at all!  Furthermore, again from ROCKET-AF, the 5 (of 7) geographic regions with poor TTR also had more variable TTRs and were less attentive to 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 2018 Guidelines recommend 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 poorly managed 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 patients¹⁰ and a higher rate than with no treatment at all.^1,2

The Guidelines also identify 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.  Indeed, 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 outcome 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

Argument 1c. Intracranial hemorrhage and/or hemorrhagic stroke, although rare, were twice as high with VKA therapy in the DOAC trials.  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).¹³  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.¹³  According to the Guidelines, 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 EAA³ (see table above) would suggest that the ICH rate with well-managed VKA therapy is not greater than that reported with the DOACs.

Argument 1d. New approaches to VKA management keep FAR more patients in their goal INR range.  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 once enrolled in the study, each patient quickly achieved and maintained an iTTR > 70%.¹⁸  Such an approach also can eliminate the hassles, time, and expense of traditional VKA management.  One such system has been adopted by a network of 160 community pharmacies in New Zealand which now manages more than 6,000 VKA patients and is reimbursed by the New Zealand Health Ministry (personal communication with Dr. Paul Harper).

2. 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 as a way to determine what target INR ranges would produce adequate protection from clotting while minimizing major bleeding in patient populations taking a VKA for various indications.²¹  It was not intended to be a measure of the quality of anticoagulation and it is not an adequate measure of anticoagulation management in individual patients.  For example, a patient with a stable INR between 3.0 and 3.0 (iTTR = 0%) over the past 6 months would have similar benefits and risks when compared to a similar patient who had a stable INR between 2.7 and 2.9 (iTTR = 100%).  On the other hand, 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, a single 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.

3. The CHA₂DS₂-VASc Score can be misleading.  The Guidelines considered males with a score of 0 or females with a score of 1 to be “low risk” and, thus, do not require anticoagulation.  The difference in the gender score, according to the Guidelines, 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, lifetime risk.  Second, it has only three age categories (< 65, 65-74, and > 75) and two 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 likely has 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 1.3 %/yr by the CHA₂DS₂-VASc Score (depending on whether the female gender is counted).  Using the Framingham score, her risk would be 6% per 5 years … or 12% per 5 years (if the 6 pts for being female is included).  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 compared to a 5-year stroke risk of 24% based on the Framingham score. The 1-year risk estimates probably doesn’t sound very high to most patients but the 5-year risk estimates makes a much more compelling case in favor of treatment.  Personally, I give my patients a 5-yr risk estimate. The various scores for assessing stroke and bleeding risks in patients with atrial fibrillation are available here: Assessing Stroke and Bleeding Risk in Atrial Fibrillation

4. The SAME-TTR score is recommended but may be irrelevant in a site with a good VKA management system.  The SAME-TTR is put forward as a way to determine which patients may or may not achieve a good iTTR.  But it seems likely that some patients require more support than others … and a good VKA management system can make all the difference.  In our experience, every patient (even those in the bottom quartile with a TTR of only 23% during the 6 months before enrolling in our program) can quickly achieve and maintained an iTTR > 70% if given the right tools and feedback!

5. Coronary artery disease and atrial fibrillation:  The Guidelines provide 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 detail at ClotCare in this commentary: Rivaroxaban or Warfarin in Stable Coronary Artery Disease – Should the COMPASS Study Lead Us Back to the Future?