Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide and increases the risk of ischemic stroke by nearly 5-fold [1, 2]. Studies have demonstrated that adjusted-dose vitamin K antagonists (VKAs) significantly decrease the risk of stroke in AF patients versus placebo or aspirin therapy [3, 4]. However, VKA use can be challenging given the narrow therapeutic international normalized ratio (INR) range, requirement for periodic INR monitoring, high inter-patient variability in response, numerous drug and food interactions and risks related to non-adherence [5].

In previous meta-analyses [6‐9] the quality of anticoagulation control with VKAs has proven to be poor; with an estimated time spent in the therapeutic INR range (TTR) between 55% and 64%. Numerous study-level factors (e.g., VKA dosing setting) have been shown to be an important determinant of the quality of INR control. Thromboembolic events may occur more frequently at an INR <2.0 and major hemorrhagic events at an INR >3.0 [10]. No previous meta-analyses have examined INR control in VKA-experienced as compared to naïve patients as a study-level factor, not all analyses have looked at AF alone, and few have assessed the percentage of INRs in therapeutic range (PINRR) as a quality measure of INR control. Moreover, there has been a substantive increase in the number of studies assessing INRs in patients with AF receiving VKAs in the past few years, lending more power and validity to a systematic assessment of INR control being conducted now.

The primary objective of this systematic review with meta-analyses and meta-regression analyses was to assess VKA INR control in AF patients and the effect of selected study-level factors (including prior VKA treatment experience) on TTR and the PINRR, and to evaluate the relationship between the proportion of VKA-associated hemorrhagic and thromboembolic events that occurred when the INR was above or below the therapeutic range.

We identified 5,326 citations, of which 5,231 were excluded (Figure 1). Ninety-five articles met our inclusion and exclusion criteria [11‐103]. Sixty-eight studies reported measures of INR control representing 87 VKA study arms, and 43 studies reported an INR at or near the time of the adverse event (16 studies reported both and were included in both analyses).

Of the 87 VKA study groups that reported a measure of INR control, 17 reported data on patients with no prior VKA exposure whereas 47 enrolled patients who were VKA-experienced and 23 did not report prior VKA exposure data or had mixed enrollment. Twenty-eight VKA groups were from RCTs, 27 were conducted in an anticoagulation clinic setting, and 32 were in a community practice setting (Table 1). Thirty-nine VKA study groups were recruited in Europe/UK, 5 from Asia, 13 were multinational, 1 from Israel and 29 from North America. The mean age ranged from 62 to 92 years (median, 72 years), the number of VKA-treated patients ranged from 55 to 11,770 (median, 249), and the person-years of VKA therapy ranged from 17 to 30,188 (median, 399). Of the 43 identified studies that reported an INR with an adverse event, 16 were RCTs, 14 were conducted in an anticoagulation clinic, and 13 were from community practice with the number of VKA-treated patients ranged from 55 to 9,217 (median, 288) (Table 1).

For the first meta-analysis, 78 out of 87 (90%) study groups reported a TTR and 55 (63%) reported the time spent below and above range; 22 of 87 (25%) study groups reported a PINRR and 21 (24%) reported the percent of INR measures below and above range (Table 2). Thirteen study groups (15%) reported both TTR and PINRR. Overall, patients spent 61% of their TTR (95% CI, 59–62%), 25% (95% CI, 23–27%) below, and 14% (95% CI, 13-15%) above range. Similarly for PINRR, 56% of INR measurements were in the therapeutic range (95% CI, 53–59%), 26% (95% CI, 23–29%) below and 13% (95% CI, 11-17%) above range. Statistical heterogeneity was observed to be high between the groups included in these analyses (I² ≥ 97%). The likelihood of publication bias appeared low for TTR, time above range, PINRR, and proportion of INR measurements below and above range. However, publication bias was deemed more likely for the time below range analysis (Egger’s p = 0.03) (Additional file 1).

Upon meta-regression to determine how study-level factors influenced TTR, community VKA management was associated with less time in range than therapy managed in an anticoagulation clinic or RCT setting, European/UK study patients spent more time in range than North American study patients, and the VKA-naïve (and mixed/not reported) spent less time in range than VKA-experienced patients (Table 3). For PINRR, no study-level factor was found to be significantly different than the referent upon meta-regression (p > 0.05) (Table 4).

In the second meta-analysis, 30 of 43 studies (70%) reported an INR measure with thromboembolic events, 21 (49%) reported an INR with ischemic stroke, 32 (74%) reported INRs with major hemorrhage, and 16 (37%) reported an INR with ICH. INR data was incomplete in 58% of the studies that reported adverse events; not all events were reported with an INR measure. Thirty percent of the studies used previously reported INRs, allowing INR measures from 3 days up to 12 days prior to be considered as temporally related to the adverse event.

Overall, 57% of the thromboembolic events occurred at an INR <2.0 (95% CI, 50-64%) and 42% of hemorrhagic events occurred at an INR >3.0 (95% CI, 35 – 51%) (Figures 2 and 3). A high degree of heterogeneity was present for studies that reported thromboembolic and hemorrhagic events (I² = 80% and 77% respectively); however, the presence of publication bias was deemed low (Egger’s p = 0.31 and p = 0.69, respectively) (Additional file 1). When ischemic stroke and ICH were evaluated separately from other events, we found that 56% of ischemic strokes (95% CI, 48 – 64%) and 45% of ICHs (95% CI, 29-63%) occurred at INRs <2.0 and >3.0, respectively, but a high degree of heterogeneity was still present (I² = 76% and 85%, respectively) (Figures 4 and 5). Furthermore, when studies that allowed previously reported INRs (more than 48 hours prior to an event) were excluded, we found a higher proportion of events that occurred outside the therapeutic range for 59% of thromboembolic events (95% CI, 51 – 66%) and 47% of hemorrhagic events (95% CI, 37 – 58%).

In a pooled analysis of AF studies performed worldwide between 1990 and June 2013, we found patients spent only 61% of their TTR and only 56% of their measured INRs were in range. Moreover, when patients were out of range, they were more likely to be below range and at an increased risk of thrombosis, as compared to being above range with an increased risk of bleeding. While, thromboembolic and hemorrhagic events did occur in patients with a therapeutic INR; we demonstrated more than half of all thromboembolic events occurred when the INR was less than 2.0 and more than 40% of all hemorrhagic events happened at an INR > 3.0. As such, the efficacy and safety of VKAs appear strongly tethered to the quality of INR control achieved.

Our meta-regression analyses showed three important findings. First, patients having their VKAs managed in the community setting spent significantly less TTR when compared to patients managed in an anticoagulation clinic or in a RCT setting. This data supports the growing body of literature demonstrating that patients whose care is managed in an anticoagulation clinic have better outcomes (improved TTR, lower rates of major bleeding and thrombosis, and decreased health care costs) than those managed in community practice [104‐106]. The improved INR control in RCTs and anticoagulation clinics may be the result of increasing the frequency of monitoring, providing more organized care and focusing more on improving poor VKA-drug persistence (as low as 68% at 6-months) [107, 108] than typically done in community settings. Unfortunately, not all patients receiving a VKA have access to anticoagulation clinics [109]. In fact, it is estimated that only about one-third of patients receiving a VKA in the US have access to an anticoagulation clinic due to time, distance, economic or other access-to-care issues. Second, patients who were VKA-naive spent significantly less time in the therapeutic range than VKA-experienced patients. This is likely a result of poorer INR control early on in treatment, as clinicians attempt to control the INR within the narrow therapeutic window without any prior knowledge of the patient’s-specific dosing requirements. It may also suggest that patients learn to manage their VKA better over time. This observation may warrant researchers to stratify analyses according to whether patients are newly initiated to warfarin or experienced warfarin patients. Finally, people in North America spent significantly less time in the therapeutic range than those in Europe or the UK. This may be a result of North America’s near exclusive use of warfarin, which has been shown in previous analyses to result in as much as a 9% lower TTR compared to other VKAs [6], as well as, North America’s less wide-spread use of proven strategies to increase TTR such as and anticoagulation clinics as noted above [6, 8, 9, 109] and patient self-monitoring [6].

Our systematic review and meta-analysis supports and extends the knowledge of VKA use in contemporary practice. Our TTR or PINRR results are in general agreement with the systematic reviews by van Walraven et al. [6] and Cios et al. [9], but these analyses included all therapeutic indications for VKAs, which lowers their applicability for an AF-specific population. The meta-analyses by Baker et al. [8] and Wan et al. [7] focused on AF only populations, but each had some limitations. The Baker meta-analysis was limited to a United States population, and therefore, contained only 8 studies. Despite this, they did find that care within an anticoagulation clinic yielded a higher TTR than usual care in the community, a finding we extend into the worldwide AF population as well. The Wan meta-analysis was published in 2008, evaluated a worldwide AF population and found similar TTR and PINRR results to our own. However, they only included 47 VKA groups from 38 published studies. They found that TTR was significantly correlated with PINRR in retrospective studies and TTR was significantly negatively correlated to both major hemorrhage and thromboembolic events. Given the intense focus on thromboembolism in contemporary practice, our literature search was able to almost double the number of articles included in the Wan et al. by updating the search to 2013. Over the 5 years since the publication of Wan et al.’s meta-analysis, we found the TTR and PINRR to be only slightly increased (overall TTR increased from 57% to 61% and PINRR from 51 to 56%) [7]. This suggests that we still have a long way to go to enhance the quality of INR control. Our findings that the majority of thromboembolic events happen in AF patients when the INR is less than 2.0 and more than 40% of hemorrhages occur when an INR is greater than 3.0 confirms the findings from the systematic review of Oake et al. [10]. Their systematic review did not limit the studies to an AF population and was published in 2009, so our findings through June 2013 in the target AF population extend knowledge in this area as well.

There are several limitations of our meta-analysis worth discussion. First, the potential for publication bias and possibility of missed eligible articles could exist. However, we consider this risk to be minimized due to our systematic search strategy and manual backwards citation tracking. In addition, having such a large cadre of studies, as we do in our meta-analysis, minimizes the impact that a missed individual study might have on our pooled result. Another limitation of our analysis includes the fact that very few identified studies evaluated PINRR. As a result, our meta-regression analysis was likely underpowered; although similar trends could be seen to TTR. Future evaluation of PINRR should be conducted when there is a sufficient literature base to make firmer conclusions. Another limitation of our analysis is the possibility of a language bias; as we only included English language studies which may not represent all of the published evidence. Finally, there was a high degree of statistical heterogeneity observed in our analyses, suggesting that the included studies varied clinically and/or methodologically. However, this was one of our rationales for conducting meta-regression. In our meta-regression analyses, we found some potential explanations for the identified heterogeneity; although there may still be additional factors that we could not think to evaluate or for which there is insufficient data to allow evaluation.

Patients on VKAs for thromboembolism prevention in AF are frequently outside the normal INR range and tend to be under-anticoagulated rather than over-anticoagulated. While, thromboembolic and hemorrhagic events do occur patients with a therapeutic INR; patients with an INR < 2.0 make up many of the cases of thromboembolism, while those with an INR > 3.0 make up many of the cases of major hemorrhage. Managing anticoagulation outside of a clinical trial or anticoagulation clinic is associated with poorer INR control as is initiation of therapy in patients who are VKA-naïve. Patients in Europe/UK have better INR control than those in North America.