Vitamin K antagonists (VKAs) such as warfarin inhibit the enzyme vitamin K epoxide
reductase and consequently the recycling of inactive vitamin K epoxide back to its
active, reduced form 1]. Vitamin K in its active form is required for the synthesis of various clotting factors
(II, VII, IX and X) involved in the coagulation cascade (as well as the anti-clotting
proteins C and S); and thus, VKAs result in the depletion of these factors (within
72–96 h after dosing) and an anticoagulated state.
VKAs are indicated for the prevention of thrombotic events in patients with atrial
fibrillation (AF) and following venous thromboembolism (VTE) 2], 3]. For stroke prevention in AF patients, VKA therapy that is dose-adjusted to maintain
an international normalized ratio (INR) range of 2.0 to 3.0 is associated with a 64 %
reduction in the risk of stroke compared to placebo 4]. In patients suffering an acute VTE (either deep vein thrombosis (DVT) or pulmonary
embolism (PE)), adjusted-dose VKA use (preceded by a parenteral anticoagulant) significantly
reduces the risk of recurrence of thrombotic events 3], 5], 6]. Adjusted-dose VKAs are included in clinical guidelines for AF and VTE 2], 3], 7], 8] with a target INR range of 2.0–3.0.
The objective of this paper is to provide an assessment of “INR stability” with VKA
use and patient outcomes in contemporary practice. INR stability refers to achieving
and maintaining target INR range (typically 2–3, but not always). Therefore, if target
INR range is not achieved or maintained this would be considered INR instability.
We will determine: 1) to what extent INR instability can be anticipated, 2) whether
INR instability is predictable, and 3) the consequences of INR instability.
Metrics of INR
Despite 60 years of clinical experience, the maintenance of stable INR in patients
using VKA remains a challenging task. While numerous metrics have been used in clinical
studies of VKAs to assess the quality of anticoagulation control 9], 10], time in therapeutic range (TTR) (most commonly calculated using Rosendaal’s method
of linear interpolation 11]) is the most frequently reported. Experts have suggested that the minimum target
TTR should be no less than 65 % 12]–15] but this goal is often not met 16]–22] even in modern day RCTs 23]–32] (Table 1). A large observational assessment of 40,404 patients in the VA population demonstrated
that 42 % of patients had INR stability (defined as TTR??70 %) while 34 % had moderate
instability (TTR 50 to 70 %), and 23 % had high instability (TTR 50 %) 33]. A recently published retrospective analysis from the CoagClinic™ database assessed
9433 patients who met the inclusion criteria and had been using warfarin for over
6 months 34]. In these chronic warfarin patients, more than 90 % had at least one value below
2 and 82 % had at least one value above 3 (Fig. 1).
Table 1. Mean time in the therapeutic range observed in recent atrial fibrillation and venous
thromboembolism randomized controlled trials of novel target oral anticoagulants
Fig. 1. Percent of patients with ?1 INRs outside the normal therapeutic range. This figure
displays the % of people in an analysis 34] of the CoagCheckTM database with at least one INR value outside of the normal therapeutic
range with blue boxes showing the percent of patients who were either below 2.0 (90 %)
or above 3.0 (82 %). The red, green, purple, and orange boxes display the percent
of people who ever achieved a level of 3.0–4.0, 4.0–5.0, 5.0–6.0, and 6.0, respectively.
The same individual could be represented in multiple categories given their INRs achieved
over time including being below 2.0 and above 3.0
Using data from the multicenter ORBIT-AF (Outcomes Registry for Better Informed Treatment
of Atrial Fibrillation) registry, the INR stability of 3749 patients on chronic warfarin
therapy for 6 months was assessed 35]. Only 26 % (95%CI: 24 to 27 %) of patients had 80 % or more of their INRs between
2 and 3. Among this subgroup with INR stability, 92 % (95%CI: 90 to 94 %) had at least
one value outside of the normal INR range while 36 % (95%CI: 33 to 39 %) had an INR
below 1.5 or above 4 over the subsequent year. Thus, even the “cream of the crop”
– those patients able to achieve most of their values within target range within a
6-month period – had at least occasional out-of-range values over longer-term follow-up.
Multiple meta-analyses of randomized and real-world studies have been performed in
order to estimate the quality of INR control in AF and VTE populations receiving VKAs
16]–20], 22]. These meta-analyses demonstrate poor INR control to be ‘the rule rather than the
exception’ with TTRs and proportion of INR measurement in range typically falling
near or below 60 % and nearly twice the amount of time being spent below versus above
the therapeutic INR range (Table 2) 16]–20], 22].
Table 2. Results of meta-analyses evaluating the international normalized ratio stability in
atrial fibrillation or venous thromboembolism patients
The literature from clinical trials and observational studies substantiate that INR
stability is not readily attainable and when it occurs, is rarely sustainable over
time.
Consequences of INR Instability
Outcomes
The consequences of INR instability are multifaceted. INR instability was associated
with clinical events, higher level of medication non-persistence and discontinuation,
utilization of more healthcare resources, and therefore, higher costs. According to
meta-analyses of AF or mixed populations assessing INR control and associated events
18], 36]–38], greater than half of all thromboembolic events occurred when patients have an INR??2.0,
while over 40 % of all hemorrhagic events occurred at an INR 3.0. In VTE patients,
subtherapeutic INRs were found to be present during 58 % of recurrent VTEs 17].
An observational study by Nelson et al, 38] using the Veterans Health Administration (VHA) dataset, explored the relationship
between out-of-range INRs and clinical outcomes in 34,346 patients with non-valvular
AF (NVAF) who were newly initiated on warfarin therapy. When INR values were below
range (2), patients were much more likely to experience adverse thrombotic or embolic
events (Fig. 2). Patients were at an increased risk of major bleeding with both subtherapeutic INR
values (RR?=?2.58 95%CI: 2.19–3.03) as well as supratherapeutic INR values, (RR?=?1.55,
95%CI: 1.21–1.97). All event rates were qualitatively the highest when patients had
an INR??2. While most of these events were stroke associated with sub-therapeutic
values, increased bleeding events were also observed. While only speculative (and
we could not identify supportive literature) it is possible the increased bleeding
associated with sub-therapeutic INRs is due a lag in time between the actual event
and the true INR value. This emphasizes the need for close INR monitoring to prevent
subtherapeutic warfarin dosing.
Fig. 2. Risks of adverse outcomes for people with INRs 2.0 or 3.0. Adapted from data from
an observational study using the Veterans Health Administration dataset 38] showing the relative risk (RR) of adverse thrombotic or embolic events in patients
with subtherapeutic INRs versus normal INRs and then major bleeding vents with supertherapeutic
INRs versus normal INRs. The diamond represents the actual RR with the line representing
the 95 % confidence interval and the blue dashed line representing a RR of 1.0, where
the risk of outcomes would have been the same as those with normal INRs
Further evidence showed the link between INR instability and clinical events. In meta-analyses
that examine the relationship between TTR and the prediction of adverse events, a
significant negative relationship has been observed 19]. In patients with AF, 1 thrombotic or major hemorrhagic event per 100 patient-years
could be avoided by improving TTR by 7 % or 12 %, respectively 19]. Likewise in patients with VTE, for every 1 % increase in TTR, recurrent thromboembolic
events may be reduced by 0.46 % per year and major hemorrhagic events reduced by 0.30 %
17]. Furthermore, in a nested case control analysis of the Atrial fibrillation Clopidogrel
Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) study, patients
who experienced an ischemic stroke had a TTR 9.5 % lower than those without any ischemic
event 39]. The TTR of patients with a major hemorrhage was 7.2 % lower when compared to those
without an event, again, suggesting that TTR is a useful predictor for both hemorrhagic
and thromboembolic events. Of note, ACTIVE W also found that patients spent a greater
amount of time out of range in the 1–2 months preceding a major bleeding event or
stroke which suggests even a temporary period out of range can lead to a bleeding
event or stroke.
Inability to achieve high TTR in clinical practice is associated with non-persistence
and medication discontinuation 40]. In an analysis of longitudinal anticoagulation management records from 15,276 US
patients with NVAF, discontinuation of therapy occurred in less than 4 months among
patients with unstable INR. Patients who achieved INR stabilization were 10 times
more likely to remain on warfarin therapy beyond 1 year. In another observational
study using the Symphony Health Solutions’ Patient Transactional Database, patients
who were prescribed rivaroxaban had a lower risk of treatment nonpersistence [HR 0.66
(95%CI: 0.60–0.72)] compared to patients who were prescribed warfarin 41]. A similar analysis of the Truven Health Market Scan Research Databases showed comparable
findings, that NVAF patients who received rivaroxaban were 46 % less likely to discontinue
therapy compared to those receiving warfarin 42]. Continued protection by anticoagulation is particularly important for patients with
NVAF, since the risk of stroke is expected to increase with age and additional comorbidities
43].
Costs
INR instability was associated with higher healthcare utilization and costs. In an
observational study using the Premier Perspective Comparative Hospital Database, hospital
length of stay was 5.27 days vs. 4.46 days, leading to significant differences in
hospitalization costs ($13,255 vs. $11,993, P??0.001) 44], 45]. In another comprehensive cost analysis of 23,588 patients with NVAF who were on
warfarin for at least 30 days from the US Veteran’s Administration, investigators
randomly selected an INR value from a patient and classified it as being below 2,
2–3, or above 3 and then evaluated total direct costs (i.e. inpatient, outpatient
medical, and outpatient pharmacy costs) over the next 30 days. Mean direct costs over
30-days after exposure to an INR 2.0, between 2 and 3, and 3.0 were $5126, $2355
and $3419 (Fig. 3) 46]. These findings remained robust in a sensitivity analysis with a more stringent definition
of the cohort. The substantial cost difference between in-range and out-of-range time
is significant across a broad warfarin population with atrial fibrillation.
Fig. 3. Costs Associated with In Range and Out of Range INRs. Adapted from data from a US
Veterans Administration dataset 46] where the total costs are displayed in blue and the constituent costs of inpatient,
outpatient, and outpatient pharmacy costs are in red, green, and purple, respectively.
The total costs in the therapeutic INR group is significantly lower than those with
abnormally low or high INR groups. Note that the highest costs were associated with
suboptimal INR values (i.e., INR 2.0)
The literature suggests that INR instability has important clinical and financial
consequences which underscore the need for greater vigilance on achieving INR stability
or the use of a novel oral anticoagulant which provides more consistent pharmacologic
effects.
Predicting INR Instability
Predictors
Based on data from adjusted meta-regression or multivariate analyses of large datasets,
INR stability is known to vary greatly based upon various study- and patient-level
factors (Table 3) 15]–17], 21], 47], 48]. The use of anticoagulation clinics can positively impact higher TTR attainment but
only ~1/3 of VKA patients have access to these advanced services 49]. Therefore, a broad understanding of factors predicting INR instability is beneficial
for clinical practice.
Table 3. Summative assessment of factors shown to positively or negatively impact INR stability
Two of the most extensive studies were conducted by Apostolakis et al. (SAMe-TT2R2)
14] and Rose et al. (VARIA) 48] and provided insight into factors affecting anticoagulation control. Apostolakis
and colleagues 14] used data from the 1061 patients in the Atrial Fibrillation Follow-up Investigation
of Rhythm Management (AFFIRM) trial to identify clinical factors associated with TTR.
Based upon these results, the SAMe-TT2R2 score was derived (and eventually validated)
whereby 1 or 2 points are assigned for important patient factors (Table 4). Scores ?2 were found to be associated with decreased odds of achieving a TTR ?65 %
(previously described as the minimum target TTR) 14].
Table 4. SAMe-TT2R2 scoring system and implications
The Veterans AffaiRs study to Improve Anticoagulation (VARIA) 48] used data from over 124,000 veterans receiving warfarin for any indication (55 %
AF, 35 % VTE, 10 % other) between 2006 and 2008; and evaluated the effect of various
patient characteristics on TTR in those starting warfarin (first 6 months of therapy)
and who were experienced (on therapy for 6 months). Like the SAMe-TT2R2 derivation/validation
study, female gender, younger age, minority status and co-morbid physical conditions
were also found to be associated with lower TTR in VARIA (in both the inception or
experienced cohorts) but there were a large number of additional factors which were
identified, such as alcohol abuse, number of hospitalizations, and various comorbidities,
such as heart failure, diabetes, chronic kidney disease, and others. The VARIA investigators
also created a clinical prediction tool but eliminated race because they did not wish
to perpetuate disparities in care, eliminated poverty and distance to drive to receive
care because they felt it was hard to assess, and eliminated other factors to simplify
the model. Their model is available in a downloadable excel spreadsheet from Supplemental
Appendix 3S at http://onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2010.03996.x/full. In addition to the factors in the SAMeTT2R2 score, this tool also assesses the indication
for use, total number of chronic medications, substance abuse, mental illnesses, number
of hospitalizations, and the general quality of TTR attainment in other patients within
that healthcare setting. Even with all of these additional factors, the R-squared
value only ranged from 3.2 to 6.8 % suggesting that the much of the variability in
TTR is not explained by this model. Furthermore, while the study assessed TTR at therapy
initiation and after chronic therapy, the authors stated that the prediction tool
is not to be used as a means to assess long term control, and that clinical experience
from past VKA therapy is the preferred method 48].
Factors that effect INR instability
Two reasons why the clinical prediction tools are inadequate may be related to genetics
and adherence to therapy. Patient genotype plays an important role in INR stability
12], 50]–52]. At least 30 genes contribute to the anticoagulant effects of VKAs, with one third
of the variance in warfarin dosing related to mutations in genes leading to the synthesis
of CYP2C9 and vitamin K epoxide reductase (VKORC1) 12], 50]–52]. Patients with CYP2C9*2 and CYP2C9*3 polymorphisms have decreased enzymatic activity,
metabolize warfarin (and to a lesser extent acenocoumarol) more slowly, have a 1.4-
to 3.6-fold increased risk of supratherapeutic INR, and often take longer to achieve
stable dosing 53]–55]. VKORC1 polymorphisms can result in either a heightened (group A haplotype) or reduced
effect (group B haplotype) of warfarin which alters the risk of thromboembolism and
bleeding accordingly 12]. Based on this data, the Food and Drug Administration altered the package insert
recommending clinicians consider genetic testing before initiating warfarin therapy
56]. However, the cost-effectiveness of this approach is questionable; with economic
models suggesting genotyping of patients would cost more than $170,000 per AF patient
quality-adjusted life-year (QALY) gained (far above the commonly accepted willingness-to-pay
threshold of $50,000 per QALY) 57].
Medication adherence was highlighted as an important variable in VKA INR stability
in the American College of Chest Physicians (ACCP) guidelines 12]. Identified predictors of VKA nonadherence include not being married, not having
a vehicle for transportation, education levels beyond high school, currently employed,
lower levels of mental health functioning, poor cognitive functioning, and greater
drug regimen complexity 58], 59]. In addition, studies have identified patient dissatisfaction with care as a cause
of medication non-adherence in patients with cardiovascular disease states 60]. This is noteworthy since patient satisfaction with warfarin therapy has been shown
to be poor in recent studies of AF 61] and VTE patients 62]. In the above-mentioned studies, poor patient satisfaction in either AF or VTE patients
(measure by the Anti-Clot Treatment Scale) was related to the burden and frustration
of taking VKAs resulting from fear of bleeding/bruising, diet and alcohol interactions
and the perceived hassle of INR monitoring. One of the frequently cited studies evaluating
the association between VKA non-adherence and INR control is the International Normalized
Ratio Adherence and Genetics (IN-RANGE) Study 63]. IN-RANGE was a prospective cohort study conducted at 3 US anticoagulation clinics
and assessed warfarin adherence using a medication electronic monitoring system (MEMS).
The study followed 136 patients taking warfarin for a variety of reasons (but predominantly
AF and VTE) for a mean of 32-weeks and found that missed warfarin doses (missed MEMS
bottle openings) were common, with 92 % of patients missed at least 1 dose, and one-third
missed more than 20 % of their doses. A total of 1490 INRs values were collected,
with 40 % out of range and 26 % being below range. Upon multivariable regression analysis,
researchers found that for every 10 % increase in missed warfarin doses (days without
a dose), there was a 14 % increase in the adjusted odds of under-anticoagulation (having
an INR??2.0); and patients who missed 20 % of their doses (missed 20 days of warfarin
therapy) had a 2.10-fold (95%CI: 1.48–2.96) increase in their odds of having an INR??2.0
63].
Existing research provided good understanding of the drivers behind poor INR control.
The research findings indicate that many of the patient factors are not modifiable
and are also not sufficiently reliable to predict whether VKA will perform well for
a particular patient.
Modalities to optimize clinical management of VKAs
There are several modalities to improve the clinical management of patients on VKAs
including computer assisted dosing and patient self-testing or management. In a randomized
study of 13,219 patients conducted in 32 centers around the world, the impact of software
program guided VKA therapy was compared with experienced clinician dosing 64]. Unadjusted INR time in range was 67 and 66 % with computer-assisted versus experienced
clinician dosing. However, in order to elicit these comparable results, the experienced
medical staff randomized to use the computer assisted program provided 11 % of the
dosages because the computer failed to provide it and the dose was changed 11 % of
the time because the results were felt inaccurate. In addition, the computer-advised
appointment intervals were changed by experienced clinicians 34 % of the time. More
data is needed to truly determine the impact of computer assisted dosing in less experienced
clinicians versus very experienced clinicians/anticoagulation specialists.
Point of care testing by the patient or clinician allow rapid determination of the
INR without the need for a centralized laboratory to acquire and analyze the samples.
In a meta-analysis of 22 studies, including 4 studied deemed of high methodological
quality, the precision and accuracy of the CoaguChek XS, INRatio, ProTime/ProTime3,
and Smartcheck INR coagulameter systems were assessed 65]. The CoaguChek system was the most commonly assed and yielded a coefficient of variation
that ranged from 1.4 to 5.9 and the concordance ranged between 93 to 100 % showing
congruence. The other systems have coefficients of variation ranging from 3.7 to 8.4
and concordance values ranging from 81 to 97 % (with the exception of one trial of
the ProTime system where the concordance was only 39 %. In general, point of care
testing is accurate and can facilitate patient self-testing (where the patient self-tests
the INR but clinician doses) or patient self-management (where the patient self-tests
and self-adjusts VKA therapy based on the INR.
In an 8-month open label crossover trial conducted in Canadian primary care offices,
patients (n?=?11, 99 patient months, 122 INR determinations) underwent patient self-management
or physician management for 4 months 66]. Patients were trained and given an algorithm to follow that specified the new dose
and the timeframe for which to reassess the INR. The mean proportion of INR values
in therapeutic range among subjects in the PSM and physician-management groups was
82 and 80 %, respectively (p?=?0.82). Ten of the 11 patients preferred PSM to physician management and elected
to continue with this strategy after study completion (P?=?.001). No calls or visits were made to the physician regarding dose adjustment
during the patient self-management period. There were no episodes of major bleeding
or thromboembolic events. Studies like this are promising but preliminary and it is
unclear whether this is an effective therapy for highly motivated and intelligent
patients or patients with health disparities or care barriers.