Journal of Thrombosis and Thrombolysis

, Volume 31, Issue 3, pp 265–274

Transforming oral anticoagulation by combining international normalized ratio (INR) self testing and online automated management

Authors

    • College of PharmacyThe University of Texas at Austin and the University of Texas Health Science Center at San Antonio
    • Genesis Clinical Research
    • ClotCare.org
Article

DOI: 10.1007/s11239-011-0564-y

Cite this article as:
Bussey, H.I. J Thromb Thrombolysis (2011) 31: 265. doi:10.1007/s11239-011-0564-y

Abstract

Because of the number and complexity of issues addressed, this manuscript is divided into two major sections. The first section focuses on how new technology can transform vitamin K antagonist therapy. Specifically, evidence suggest that combining INR self testing with online automated management (STOAM) can greatly reduce the time, expense, and hassle of managing VKA therapy; improve the quality of INR control to a degree that, in large studies, has been associated with a 50% or more reduction in major events (such as stroke, myocardial infarction, major hemorrhage, and death); reduce health care costs by an estimated $4 million per 1,000 patients per year; and improve quality of life and patient satisfaction. Such improved VKA therapy should be safer, more effective, and more cost-effective than the new oral anticoagulants. The improved efficiency and outcomes also should prompt reconsideration of indications in which VKA therapy may not be the current standard of care. Although new reimbursement models are clearly needed for STOAM, the current Medicare reimbursement model for patient self testing can be utilized to make VKA management financially viable and sustainable. The second section of this article focuses on additional considerations that may be important in optimizing VKA therapy and/or selecting an online management system. A brief review is provided to examine why a recent meta analysis and a large randomized trial of self testing did not find the same degree of improvement as reported in the four STOAM trials described in the first section of this article.

Keywords

Vitamin K antagonistWarfarinOral anticoagulationInternational normalized ratioInformation technologySelf testingAnticoagulation management

Introduction

Because of the number and complexity of issues addressed, this discussion is presented in two parts. The first part focuses on the potential value and impact of combining INR self testing and online automated management (STOAM). The second part focuses on several considerations that are important to optimizing vitamin K antagonist (VKA) therapy and/or selecting a system for automated online management. Also addressed in the second section is why recent studies of self testing have yielded somewhat disappointing results compared to those reported in STOAM trials.

Part 1 of 2, examining STOAM

Over the past 3 years new studies have illustrated how all facets of (VKA) therapy can be improved by combining INR self testing with online automated management (STOAM) [15]. Each of four trials reported an impressive improvement in the INR time in therapeutic range (TTR) of approximately 10–23% (Table 1). The reported improvement in TTR is considerably better than the less than 4% improvement reported in two large trials that evaluated either self testing [6] or computer dosing [7] as methods to improve INR control. Further, the achievement of 70–80% TTR in three of the four studies would suggest that most patients in the STOAM trials achieved a level of INR control that was found to be associated with a 50% reduction in major events (stroke and system embolism, myocardial infarction, pulmonary embolism, major hemorrhage, and death) in three recent large atrial fibrillation trials [811]. White et al. [8] evaluated INR control in a pooled analysis of the SPORTIF III and V trials. In that analysis, the one-third of patients with “poor” INR control were found to have individual TTR values (iTTR) of less than 60%; while the one-third with “good” control had iTTR values above 75%. This difference of as little as 15% in the iTTR (less than 60% vs. greater than 75%) was associated with a more than two-fold difference in stroke, myocardial infarction, major hemorrhage, and death (Table 2) [8]. Similarly, in the RE LY trial, the 25% of patients with an iTTR below 53% had twice the major event rate as the 50% of patients with an iTTR above 67% (Table 3) [911]. It is noteworthy, that these two reports which included almost 10,000 VKA treated patients, had such consistent findings in that as little as a 15% difference in iTTR (60 vs. 75% in SPORTIF III & V and 53 vs. 67% in RE LY) was associated with a two-fold difference in major events. The net clinical benefit associated with a 15% difference in iTTR was virtually identical with 65 and 66 fewer major events per 1,000 patients per year in the SPORTIF and RE LY studies, respectively (Table 4). Using the excess event rate from the SPORTIF trials, it was estimated that better INR control (>75% iTTR) was associated with a reduction in health care costs of more than $4 million per 1,000 patients per year (Table 5). Although these differences are based on retrospective analysis, the results are derived from very large data sets, are remarkably consistent with each other, and are consistent with early studies which reported on the relationship between TTR and event rates in other populations [1215].
Table 1

Results of studies combining self testing and automated online monitoring

 

% TTR

% T < INR 1.5

% T > INR 5

Study

Control

Study

% Diff.

Control

Study

Control

Study

Ryan et al. [1] n = 132

60.2

71.4

11.2

Harper et al. [2] n = 43

71

80.4

9.4

  

0.6

0

Ferrando et al. [3] n = 102

55.7

64.9

9.2

Bussey et al. [4, 5] n = 55

56.8

79.7

22.9

2.41

0.4

0.1

0.1

%TTR percent of time that the INR was in the therapeutic range, %T < 1.5 percent of time that the INR was less than 1.5, %T > 5 percent of time that the INR was above 5

Table 2

INR percent time in the therapeutic range (mean) vs. clinical event rates as %/year

 

Poor TTR < 60% (48%)

Moderate TTR 60–75% (68%)

Good TTR > 75% (83%)

Combined VKA group

Ximelagatran

Stroke + SEE

2.1

1.34

1.07

1.5

1.6a

Maj. bleed

3.85

1.96

1.58

2.46

“no difference”

Mortality

4.2

1.84

1.69

2.58

 

M.I.

1.38

0.89

0.62

0.96

 

Total

11.53

6.03

4.96b

7.5

 

Adapted from pooled analysis of SPORTIF III & V trials by White et al. [8]

M.I. myocardial infarction, SEE system embolic event, VKA vitamin K antagonist

aIn the two studies the stroke + SEE event rates with warfarin were 2.3 and 1.2%, major bleeding was not different with warfarin vs. ximelagatran

bGood TTR vs. poor TTR number needed to treat for 1 year to prevent one event: 15

Table 3

INR percent time in the therapeutic range (TTR) vs. clinical event rates (%/year)

Event (%/year)

Warfarin n = 6022

Warf. Q 4 TTR < 53%

Warf. Q 1–2 TTR > 67%

Dabi. 110 mg n = 6015

Dabi 150 mg n = 6076

Strokea + SEE

1.69

2.2

1.3

1.53 (NI)

1.11b

Maj. bleed

3.36

4.6

2.7

2.71b

3.11

M.I.

0.53

Na

Na

0.72

0.74b

Total

5.58

Na

Na

4.96

4.96

Death

Na

7.5

2.4

Na

Na

Composite

7.64

11.9

5.3

7.09

6.91

NNT

23

15.2

20.7

20.0

Adapted from Connolly et al. [9]; Gage [10]; and Wallentin [11]

Comp Stroke, systemic embolism, MI, PE, death, major bleeding. TTR percent of time that the INR was in the therapeutic range, Warf 4th quartile those with TTR < 53.4%, 1st and 2nd quartile those with TTR > 67.1%. NNT number needed to treat for 1 year to prevent a composite event vs. warf. 4th quartile

aStroke includes hemorrhagic stroke

bstat. sig. vs. warfarin

Table 4

Excess events per 1,000 patients/year among those with poor vs. good INR control

Event (%/year)

Top 1/3 vs. bottom 1/3 (>75% vs. <60% TTR) total n = 3587 [8]

Top ½ vs bottom ¼ (>67% vs. <53% TTR) total n = 6,022 [911]

Stroke + SEE

10

9

M.I.

8

Not reported

Maj bleed

22

20

Death

25

50

Total/composite

65

66

NNT

15.4

15.2

Adapted from White et al. [8]; Connolly et al. [9]; Gage [10]; and Wallentin [11]

SEE systemic embolic event, M.I. myocardial infarction, Composite Stroke, systemic embolism, M.I., pulmonary embolism, death, major bleeding. NNT number needed to treat for 1 year to prevent one composite event compared to “poor” INR control

Table 5

Costs of excess events per 1,000 patients per year

Fewer events

Cost/event

Total

Strokes, 10

$140,000a

$1,400,000

Myocardial infarctions, 8

$147,500a

$1,180,000

Major bleeds, 22

$25,000b

$550,000

Deaths, 25

$50,000b

$1,250,000

Total

 

$4,380,000

Event rate differences taken from White et al. [8]

aCost from 2010 American Heart Association Statistics

bPersonal rough estimate

If such improved anticoagulation control can be achieved easily with STOAM in atrial fibrillation, one should also consider how those with other indications might benefit. Currently, the recommendation for patients with unprovoked deep vein thrombosis or pulmonary embolism is to treat for at least 3 months and then evaluate for long-term therapy [16]. If long-term anticoagulation is substantially safer and more readily achievable, then offering such patients the benefits of long term therapy becomes more attractive. Similarly, for post-myocardial infarction without coronary artery stenting [1719] and for stroke due to intracranial disease [14, 15] where well-managed warfarin has been shown to reduce major events by approximately 50% compared to aspirin, STOAM should make it feasible for patients to receive the greater benefits of oral anticoagulation therapy.

In addition to improved INR control, patient satisfaction and quality of life improved in at least two of the trials [3, 5]. For example, when patients were asked if they would recommend anticoagulation therapy to a friend with their same condition, the percent who indicated that they would recommend such therapy improved from only 62% before STOAM to 100% after 3–6 months of STOAM [5]. Further, the average clinician management time was less than 10 min per patient per month in two trials [2, 4]. The improved clinician efficiency was due in large part to the ability to safely automate a large number of “virtual visits” that did not require clinician intervention (discussed below), and the fact that an online automated system can gather and evaluate information from patients, document the visit, provide instructions to patients, and schedule the next virtual visit.

The potential to improve efficiency, as well as patient satisfaction and quality of life, has been documented, in part, by studies which provide some quantification of how wasteful contemporary VKA management is. In 1989 we assessed the value of adhering to frequent follow-up for warfarin-treated patients by evaluating the percent of patients who achieved INR stability and their duration of stability [20]. From eight-two patients who provided almost 200 patient-years of data, we found that 67 (82%) achieved anticoagulation stability which lasted for an average of more than 8 months with 12 patients having more than 2 years of therapy without a required dosage change. Further, once patients achieved stable anticoagulation, the likelihood of requiring a dosage change at any subsequent monthly visit was less than 8%. These data certainly challenged the value and associated expense of monthly follow up visits. Much later, in a different setting, a somewhat similar evaluation of almost 200 patient-years of data found that 77% of the time patients were going an average of more than 5 months between required dosage changes [21]. And even more recently, Witt et al. [22] in two studies reported that 41% of 6,073 patients and 17% of 3,088 patients [23] had all of their INRs in range for 6 and 12 months, respectively. Providing numerous monthly management visits for months at a time without any clear impact consumes a lot of resources, time, and expense for both the patient and clinician. Therefore, our group in 1989 and Witt’s group 20 years later questioned the value of seeing stable patients month after month and suggested that less-frequent follow-up might be appropriate for the very stable patients. Extending visits to longer intervals, however, is very likely a misguided approach because one can not predict when a given patient is going to require a change in warfarin dose. If a required dosage change is not recognized promptly as the INR is changing, the outcome for the patient can be catastrophic. Implementation of STOAM provides a way to offer more frequent INR testing and close follow-up with minimal use of time and resources until the online system alerts the clinician to the fact that his/her expertise and intervention may be needed.

So, if it is feasible to reduce catastrophic and fatal events by 50% and to do so while substantially reducing the time, expense and hassles of management; while also improving patient satisfaction and quality of life; what are the deterrents to adopting STOAM? Issues that may need to be addressed are patient capabilities to perform self-testing and/or online management, lack of internet access, and reimbursement.

Although some early self testing studies were criticized because they were limited to highly selected patients, that certainly was not the case in at least one of the four new trials [4]. Potential subjects were recruited from eleven different practices and were excluded only if they had a diagnosis of HIV/AIDS (a requirement from the Institutional Review Board), were less than 18 years of age (for reasons related to obtaining informed consent), or had a diagnosis of antiphospholipid antibody syndrome (since such antibodies can interfere with the INR whether performed by point of care device or traditional laboratory). Patients had to be able to perform a point of care (POC) INR and communicate through the online system, or have a family member or care giver who could do so for them. Patients underwent a single patient education and training session with re-training only if needed. In general, those patients who were not able to perform a POC INR test and/or use the online system had a family member, neighbor, or care giver who was willing to assist them. In most instances, that same individual was the person who typically accompanied the patient to the laboratory and/or clinic visit. Therefore, the STOAM approach actually reduced time and travel commitments for two people; the patient and the care giver.

Availability of internet access also was not a problem. Seventy-five to 82% of households in the US have Internet access [24, 25]. Internet home access and individual use have increased every year for at least the past 10 years. For example, the percent of the US population that uses the Internet increased from 50% in 2001 to 77% by 2010 [26]. Those who do not have Internet access from home may have access at work, at a neighborhood library, or through a relative or neighbor. STOAM also could be facilitated by providing centralized testing stations with Internet access in wellness clinics, in the work place, or in the community in pharmacies or other easily accessible locations.

Clinician reimbursement is probably the single biggest deterrent to adopting self testing, but Medicare (CMS) reimbursement does offer a potential solution. The issue of reimbursement for anticoagulation services has been reviewed in more detail in an earlier publication [27]. Under the CMS reimbursement model the very low reimbursement to the clinician for oversight of four tests per month is inadequate in view of the considerable cost of traditional management models. In Texas, physician reimbursement is less than $10 for the evaluation of 4 INR results per month for an annual amount of less than $120 ($10/4 test/mo × 12 months). Telephone management is estimated to require at least 10 min of clinician time per “visit” at an estimated total cost of at least $30 for an annual cost of $1,440 per patient ($30/phone “visit” × 4 “visits” per month × 12 months/year). Therefore, the annual cost for patient follow up at $1,440 is several times the annual physician reimbursement of $120. The reimbursement for training the patient (~$130) and for providing the device and test strips (~$115/4 test) appears to be adequate. If a physician or medical practice elected to provide a complete self-testing service and bill all three G codes (G 0248, 249, and 250), the estimated revenue per patient per year would be approximately $1,630. If that same practice utilized an on online automated management system that requires less than 10 min of clinician time per 4 “visits” per month, then the revenue should be more than adequate to cover the monthly pro-rated cost of the POC device and other expenses such as the cost of test strips and supplies, the cost of the software, and the clinician’s management time. In addition, some payers may reimburse self-testing at a higher level than what CMS does. If one has a patient “mix” that yields an average return that is 20% above the CMS reimbursement rate, that 20% increase in reimbursement is estimated to increase revenue by 30–45%, depending on expenses. The 20% increase in reimbursement yields a substantially greater percent increase in revenue because no additional expenses are incurred. Lastly, if the previously projected reductions in health care costs of more than $4 million per 1,000 patients per year can be confirmed in further studies, then payers may be persuaded to provide more equitable reimbursement.

It would appear, therefore, that the potential exists to improve all facets of anticoagulation management with STOAM which can improve efficiency of management; improve quality of life and patient satisfaction; reduce clinician time and resources required for management; improve INR control and thereby reduce major bleeding, major thromboembolic complications, deaths, and health care expenses. Based on data available at this time, it would appear that such improved management would be safer, more efficacious, and more cost-effective than the new oral agents.

Reviewing the available systems for STOAM is beyond the scope of this discussion, but the automated online systems used in the four trials discussed above were INR Online (INR Online Ltd. Palmerston North, New Zealand) [1], CoagCare (Zycare, Chapel Hill, NC) [2], SintromacWeb (Grifols, Barcelona, Spain) [3], and ClotFree (Genesis Advanced Technologies, Inc., Lakehills, TX) [4, 5]. The reader is encouraged to conduct his/her own review of these systems, perhaps, with the following considerations kept in mind.

Part 2 of 2, important considerations for optimizing VKA therapy and/or selecting an online management system

The need to change how we assess the quality of INR control

There is a clear need to use quality indicators other than the group or clinic mean TTR. In 1995, Cannegieter et al. [12] demonstrated that the major event rates in VKA-treated patients were quite low as long as the INR was within the target range. This led to the adoption of the group mean TTR as the primary measure of the quality of anticoagulation management within a given practice or anticoagulation clinic. It has been advocated that TTR can be used as a surrogate endpoint for clinical events, but this approach has serious flaws. There is a need to assess measures of INR control other than the TTR and there is a need to evaluate INR control in the individual patient (rather than the group or clinic mean values).

Assessing ranges other than the TTR: The use of the TTR ignores the fact that event rates increase exponentially beyond certain extremes of the INR range (such as below 1.5 or above 5) while limited excursions outside of the target range may carry very little risk [12, 14, 15]. Consequently, recent studies have reported TTR, time in the therapeutic range that has been expanded by ±0.2 to 0.3 INR units (TExTR), and time in the extreme range of less than 1.5 or above 5 (TEtR). It would seem that TEtR may be the strongest surrogate for clinical events because of the exponential increase in event rates as the INR control moves beyond the thresholds of 1.5 or 5.0. The TExTR and TTR may be less predictive, but still useful in assessing quality of care. Therefore, because INR control is so critically linked to risk of major events, providing an accurate assessment of the quality of anticoagulation management may require that all three indicators be considered. Clinical settings that can not provide these measures of INR control should modify their systems to do so or, perhaps, refer patients to a setting that can provide such quality measures.

Assessing the INR control of the individual patient: Use of the TTR, TExTR, and TEtR to evaluate the INR control for a given clinic or group of patients presumes that individual patients have INR control that is similar to that of the group. Veeger et al. [13] emphasized the need to consider the INR control of the individual patient when they reported on individual INR time in therapeutic range (iTTR) versus event rates in approximately 4,000 patients in a clinic in The Netherlands. In their report, the 25% of patients with the lowest iTTR had major event rates that were approximately three to seven times the event rates of the other 75% of the clinic population (Table 6). Somewhat similar results were reported by Witt et al. [22, 23] in two studies from an even larger clinic population in the US. A minority of patients had 100% iTTR for either 6 or 12 months while the remainder of patients had TTRs of less than 50% and experienced two to three times the event rates of those with 100% iTTR (Table 7). These results from two large clinics are consistent with the results of the three recent trials of new oral anticoagulants versus VKA in patients with atrial fibrillation as reviewed above [811]. In fact, if one considers that the overall annual risk of stroke in patients with atrial fibrillation is about 5%, one must question whether the combined major event rate of more than 11% per year in the patients with poor iTTR of less than 60% indicates that these patients are experiencing more harm than benefit from VKA therapy (Tables 2, 3, 4, 5). It would seem to be critically important to be able to identify patients with such low iTTR values so that they can be targeted for more aggressive anticoagulation management. If improved iTTR can not be achieved, then perhaps therapy should be discontinued or changed to one of the new oral anticoagulants. Therefore, systems should be able to readily identify individual patients with sub-optimal iTTR values.
Table 6

INR percent time in the therapeutic range (TTR) vs. clinical event rates (%/year)

End points

M.I. (n = 1012)

A. Fib (n = 2614)

MHV (n = 838)

INR TTR (%)

39

42

44

1st–3rd quartiles

48

51

52

Upper limit 4th quartile

25

30

34

4th quartile

10

16

20

Thromboembolism

4

1.7

1.4

1st–3rd quartiles

2.3

1.3

1.1

4th quartile

19.2

4.1

3.4

Major bleeding

0.9

1.6

1.7

1st–3rd quartiles

0.8

1.3

1.4

4th quartile

1.9

4.1

3.9

Combined Events

4.9

3.3

3.1

1st–3rd quartiles

3.1

2.6

2.5

4th quartile

21.1 (RR 6.8)

8.2 (RR 3.2)

7.3 (RR 2.9)

Adapted from Veeger et al. [13]

M.I. myocardial infarction, A. Fib atrial fibrillation, MHV mechanical heart valve, TTR % of time that the INR was within the therapeutic range, RR relative risk of having a given event

Table 7

Event rates for patients with all INRs within the therapeutic range for 6 or 12 months

 

%TTR

% Bleed

% TE

% Combined

Six month study [22], n = 6073

64

   

6 mo stable n = 2504 (41%)

100

0.8

0.4

1.1

Not stable n = 3569 (59%)

46.9

2.8

0.7

3.6

Twelve month study [23], n = 3088

65

   

12 mo stable n = 533 (17%)

100

2.1

0.2

2.3

Not stable n = 2555 (83%)

42.1

4.1

1.3

5.4

Adapted from Witt et al. [22, 23]

%TTR percentage of time in the therapeutic INR range

Raise the standard of acceptable INR control: Traditionally, INR TTR values in the 50% to 60% range have been considered acceptable while values of approximately 65% have been considered optimal. As reviewed above, such values do not produce optimal outcomes and, in fact, may obscure unacceptably low TTRs in individual patients. We can do better. Exactly which measures—or combination of measures—of INR control (the individual’s TTR, TExTR, and/or TEtR) are most valuable in defining optimal INR control remains to be determined.

Other shortcomings of contemporary management

Approximately 60 years ago, Askey and Cherry [28] pointed out that there are three essential factors for safe and effective oral anticoagulation: a readily available and reliable laboratory, a cooperative patient, and a vigilant clinician. A fourth component of thorough documentation of all actions and decisions probably should be added. The following paragraphs will examine these issues in view of the role of patient self-testing.

A readily available and reliable laboratory. Over a decade ago our group found that approximately 10–15% of INR results from two different university-affiliated laboratories were erroneous and would have led to unwarranted dosage changes [29]. In that setting, POC INR results were more reliable, more reproducible, and less likely to lead to unwarranted dosage changes. Further, laboratory INR results often took hours to obtain even if ordered “stat” and repeating questionable INR results within the same day was very difficult. Even under the best of circumstances in more reliable laboratories, repeating a questionable INR result is still time consuming. The POC device, therefore, offers a reliable method that can yield an INR within approximately 2 min and a method by which the INR can be readily repeated should the initial result appear questionable. With the advantages of the POC method of INR measurement, one has to question why sites are still using the traditional laboratory method for obtaining INR results. Clearly, self-testing is an attractive way of making a “reliable laboratory” readily available; and the portability of the device allows the patient to travel with their “lab”.

A cooperative patient: In order for the patient on anticoagulation therapy to be fully cooperative, he/she needs to be thoroughly educated on a variety of aspects of anticoagulation management. The patient should understand the importance of tight INR control, the need to adhere to all instructions, and the importance of communicating any of a number of important changes to their anticoagulation clinician. For those experienced in anticoagulation management, the importance of this level of patient education would seem self-evident; yet patients on anticoagulation therapy are often deficient in this information. In 2004, Kagansky et al. [30] reported that patients on VKA therapy who had not been well-educated about their therapy had a lower TTR and an almost ninefold increase in the major bleeding rate compared to those who had been well-educated. Clearly, thorough education—and re-education—is important if the patient is to fully cooperate. Such education may be provided in face-to-face discussions, through printed materials, CDs, and online. In our own setting, we have patients sign a “Patient Adherence Agreement” which explains what the clinician expects from them, what they should expect from the clinician, and why they must agree to thoroughly review an online training session on ClotCare.org at http://www.clotcare.com/newtowarfarincoumadin.aspx. The initial education efforts in our setting are reinforced in how various questions are presented to patients when they report an INR and through re-education efforts whenever a deficit in their knowledge is recognized. Being able to provide patient education through written materials, CDs, and/or a web-based resource substantially reduces clinician time and allows the patient the opportunity to review the material as often as needed. Verifying and documenting that such patient education takes place may be especially important for self-testing patients who may have less frequent clinician contact than patients seen in a traditional clinic.

A vigilant clinician: What constitutes appropriate “vigilance” for the anticoagulation clinician is a complex issue that has been further complicated by some recent efforts to improve the quality and/or efficiency of anticoagulation management. Appropriate vigilance should include (a) utilizing a system that assures that patients are not lost to follow-up and that they test as often as warranted, (b) gathering all relevant information when needed to assure optimal care and outcomes, (c) considering all relevant factors in making the most appropriate dosage adjustments and other clinical decisions, (d) avoiding reliance on dosing nomograms, and (e) avoiding telephone management and providing thorough documentation for optimal care and medical legal reasons.
  1. a.

    Assuring patient follow-up. In too many settings follow-up is based on the patient initiating the INR measurement, the INR result being called or faxed to the clinician’s office, and the INR result—perhaps with patient specific data—being delivered to the clinician for evaluation. Any breach in this process can result in follow-up being delayed or omitted. If follow-up does not occur, then the patient may be lost to follow-up; especially if the patient has not been fully educated about their condition and anticoagulation. For self-testing patients who receive their POC device and test strips from an IDTF (independent diagnostic testing facility), the IDTF has the responsibility of being sure that the patient tests on schedule and that the INR is reported promptly to the clinician. Unfortunately, communications regarding patients who are overdue for testing may be delayed and, in some settings, prompt notification of INR results occurs only if the INR is out of range. Such an approach may undermine close follow-up and/or the ability to quickly identify significant changes in the INR for patients on self-testing.

     
  2. b.
    Gathering all relevant information needed often times is not done. In some settings the only information transmitted to the clinician is the INR result. Table 8 contains a series of questions that I believe should be addressed with each INR report. Additional information, such as pulse rate, blood pressure, weight change, etc. may be in order for patients with certain conditions or complications. This information, together with a well-designed INR versus warfarin dose flow chart, is necessary in order to maintain optimal INR control and to identify potential problems or trends early before they worsen. Self testing systems that provide only the INR to the clinician would seem to be deficient in this area.
    Table 8

    Patient information requested with each reported INR in one anticoagulation management system

    Enter your daily dosing schedule in mg per day for each day of the week

    Enter the strength(s) of the warfarin tablets that you are using

    Changes in lifestyle may alter the response to warfarin, therefore tell us:

    Have you missed any doses or taken extra dose of warfarin?

    Have you had a change in any prescription or non-prescription medications or doses?

    Have you changed your diet, vitamins, food supplements, or herbal supplements?

    Have you been ill, had a fever, or received any injections?

    Have you changed your level of physical activity?

    Have you changed your level of alcohol consumption or smoking/tobacco use?

    Have you had a change in your bowel habits (i.e. diarrhea or constipation)?

    Have you noticed any evidence of bleeding such as unusual bruising, red or black bowel movements, pink or brown urine, nose bleeds, gum bleeds, blood in your eye, heavy vaginal bleeding, coughing up blood)?

    Have you noticed any new symptoms that might suggest a mild stroke such as numbness, tingling, weakness, change in vision, new problems with balance or speaking, or headache?

    Have you noticed evidence of blood clots such as new pain, swelling or tenderness in the leg; difficulty breathing, chest pain, or shortness of breath?

    Since you completed this questionnaire last, have you been to the emergency room, been hospitalized, or given instructions by any of your other doctors?

    If you experienced any of the above changes, did you notify the anticoagulation service and, if so, what date did the notification take place?

    Adapted from the ClotFree system (Genesis Advanced Technologies, Inc., Lakehills, TX)

     
  3. c.

    All relevant factors should be considered. In order to make the most appropriate dosage decision, or other clinical decisions, it is imperative that the clinician consider all pertinent information. Obviously, if the information outlined above is not obtained, then it can not be utilized. Other factors that should be considered include additional risk factors for thrombosis or bleeding. Such factors may include additional indications for anticoagulation (such as a patient with atrial fibrillation who also has a prosthetic heart valve and experienced a recent stroke), additional risk factors for thrombosis (such as hypertension, thrombophilias, heart failure, etc.), and additional risk factors for bleeding (such as a history of bleeding problems, cerebrovascular disease, excessive alcohol consumption, concomitant medications, etc.). All too often a given patient is identified as being on anticoagulation for one single indication even though the net clinical benefit of anticoagulation and the appropriate intensity and duration of therapy may be altered by a variety of factors. Systems with built in clinical “flags” and a clinically useful drug interaction alert system may also be useful. It may be important for the clinician to have ready access to the patient’s medical chart if such information is not included in the system used for monitoring self testing patients.

     
  4. d.

    Avoiding reliance on dosing nomograms. Perhaps a less obvious problem is the use of dosing nomograms to adjust therapy. There are three problems with using such nomograms. First, their use may improve poor TTR but nomogram use usually does not achieve optimal TTR. In a recent large, multinational study by Poller et al. [7] the use of a popular computer-based dosing nomogram resulted in improvement of the TTR from 63.4 to 66.8% TTR. The two reports by Witt et al. [22, 23] used the same nomogram system and achieved similar group TTR values, but the majority of patients had a TTR of less than 50%. Clearly, if we need to achieve iTTRs above 67 or 75% for optimal outcomes, the values in these three studies do not represent optimal INR control. The second problem is that nomograms sometimes fail to provide a dose recommendation and, in other instances, the nomogram-generated dose has to be over-ridden by a “supervising expert”. In the report by Poller et al. [7], the nomogram failed to provide a dose recommendation 5.7% of the time and the supervising expert had to over-ride the nomogram-recommended dose 27% of the time. One has to wonder what the outcomes might have been if the recommended doses had not been over-ridden; and what is the value of the nomogram if a supervising expert is required? Thirdly, the use of a nomogram may lead to less careful consideration of dosage changes and/or delegating management to less experienced clinicians; factors that may increase the likelihood of failing to recognize the need to over-ride a nomogram-recommended dose. Dosing nomograms, therefore, are not employed in our setting.

     
  5. e.

    Avoiding telephone management and providing thorough documentation for optimal care and for medical legal reasons. In some clinics, almost all visits are face-to-face with a complete progress note documenting each encounter. Further, dosage instructions and a follow-up appointment may be provided in writing at the end of each visit. Self testing patients are often managed by telephone which creates the potential for incomplete data gathering and miscommunication of information including dosage instructions. For example, one of our home-bound patients who was being managed by telephone confused her dosing regimen and started taking three 2 mg tablets daily rather than the prescribed 3 mg (one and one-half of the 2 mg tablets) daily. Fortunately, the error of 6 mg daily vs. 3 mg daily was recognized before serious harm was done. But had such harm occurred, we would have had no written confirmation of what the patient was told or what she thought she heard. Perhaps if we had required her to read the dosing instructions back to us and if we had documented that confirmation, that might have avoided the misunderstanding. Of course, thorough documentation of the course of action at each visit and the rationale behind such changes is critically important for continuity of care as well as medical legal considerations.

     

Why have we not seen better results with other recent self-testing studies?

In 2010 two key articles examined the impact of how INR self-testing is currently done in most settings and arrived at somewhat different conclusions [6, 31]. An extensive meta-analysis by the Cochrane Collaboration, evaluated 18 trials that compared standard management with self testing (either self-monitoring or self management) [31]. The findings, as presented in Table 9, found substantial reduction in some, but not all, major events with self-testing. Only 12 of 18 studies reported an improvement in TTR and the improvement was not large in most cases [31]. Further, for the self-monitoring group, all cause mortality was not significantly lower and in the self-management group there was actually a trend toward an increase in major bleeding.
Table 9

Summary of Results from the Cochrane Collaboration Meta Analysis of Self-Testing

End Point

Relative Risk with Self-testing or Self-management

Combined self-testing and self-management studies—n = 18 trials

 Thromboembolism

0.50 (95% CI 0.36–0.69)

 All cause mortality

0.64 (95% CI 0.46–0.89)

 Major hemorrhage

0.87 (95% CI 0.66–1.16)

Self-monitoring (without self-management)—n = 7 trials

 Thromboembolism

0.57 (95% CI 0.32–1.0)

 All cause mortality

0.84 (95% CI 0.50–1.41)

 Major hemorrhage

0.56 (95% CI 0.35–0.91)

Self-management—n = 12 trials

 Thromboembolism

0.47 (95% CI 0.31–0.70)

 All cause mortality

0.55 (95% CI 0.36–0.84)

 Major hemorrhage

1.12 (95% CI 0.78–1.61)

Adapted from Garcia-Alamino et al. [31]

Relative Risk is the proportional risk of a given event occurring in the self testing patient compared to the standard management patient

95%CI the statistical 95% confidence interval around the listed relative risk factor

The second article described the results of The Home INR Study (THINRS), which was a large randomized trial that failed to show a difference in major event rates between self testing and “high-quality” clinic-based INR testing [6]. THINRS randomized 2,922 patients to clinic management or self testing and accrued 8,730 patient-years of data. Although INR TTR was 3.8 percentage points higher in the self testing group (66.2 vs. 62.4%, P = 0.002), the primary end points of stroke, major bleeding, or death were not different.

Close scrutiny of these two reports suggests that there is room for substantial improvement in patient self testing. Apparently, the studies included in the Cochrane Collaboration analysis and the THINRS trial involved telephone management with the associated potential short comings as outlined above. Specifically, in the THINRS, patients called into report their INR results and apparently were instructed to contact their clinician only if the INR was out of range or if the patient had been hospitalized recently. Event rates and concomitant medication changes were assessed only quarterly. This approach would seem not to fit with the discussion above regarding a “vigilant clinician”.

Conclusion

INR self testing with online automated monitoring represents a transforming advancement in the management of oral anticoagulation. Such an approach offers the potential of making VKA therapy simple and easy to manage while also making it twice as safe and effective. STOAM can be provided under the existing CMS reimbursement model, but realignment of reimbursement could further facilitate implementation of STOAM. Realizing the full potential of STOAM, however, requires careful attention to detail regarding exactly how patients are trained and educated, how information is gathered and utilized, and how quality management is assessed and continually improved.

Potential conflicts of interest

Consultant to Genesis Advanced Technologies, Inc. in development of the ClotFree system, Research support from Roche Diagnostics, Inc., Advisory board member for Boehringer-Ingelheim and Daiichi-Sankyo, minor share holder of Alere, Inc.

Copyright information

© Springer Science+Business Media, LLC 2011