Journal of Thrombosis and Thrombolysis 13(1), 5–7, 2002. C 2002 Kluwer Academic Publishers, Manufactured in The Netherlands. 

Home International Normalized Ratio Monitoring: Where Evidence-Based Medicine is Exemplified in the Medicare Coverage Process Mitchell I. Burken MD, MPP, John J. Whyte MD, MPH Coverage and Analysis Group, Centers for Medicare and Medicaid Services, Mailstop C1-09-06, 7500 Security Blvd., Woodlawn, Maryland 21244, USA

Key Words. international normalized ratio, home monitoring, medicare

N early three years ago, the Centers for Medicare & Medicaid Services (CMS), formerly the Health Care Financing Administration, announced a new process for making national coverage determinations [1]. Prior to this time, the process had been criticized as inconsistent, closed, and based on a “blackbox” methodology. The new process is designed to be evidence-based, as well as open and inclusive, and relying upon scientific and clinical literature to make coverage determinations. One controversial issue that prompted the creation of the new process was the topic of home prothrombin international normalized ratio (INR) monitors. At that time, CMS was considering issuing a national noncoverage determination. Within the past year, a coalition of manufacturers, physicians, specialty societies, and patients successfully used the evidence-based process to obtain coverage of home prothrombin (INR) monitoring for patients with mechanical heart valves. This communication explains the reasoning behind this decision, particularly with respect to the coupling of testing and outcomes, and it also explores ways to possibly expand coverage, as additional information becomes available. A detailed explanation of this decision can be found on CMS’s website at www.hcfa.gov/coverage. The recent CMS Decision Memorandum on home INR monitoring embodies the use of a rigorous evidence-based approach to CMS policy decisionmaking. The construction of a desirable analytical framework for assessing the clinical effectiveness of any diagnostic test is predicated upon the notion that the results of such a test will influence patient outcomes. The ideal, randomized controlled trial for effectiveness occurs when results of the diagnostic test alter a treatment intervention, and the health outcomes associated with such treatment are included within the boundaries of that same study. However, there are possibilities

where appropriate linkages of randomized controlled trials can demonstrate a similar, strong relationship between testing and health outcomes. In this latter instance, there is a coupling of surrogate (or intermediate outcomes) with eventual health outcomes. The presence of key clinical trials, particularly among patients with mechanical heart valves (MHVs) who require long-term anticoagulation, afforded CMS the opportunity to evaluate both types of analytical frameworks, which are described above. In the first case, the typical study design was comprised of a home INR test group vs. a “standard” care control group, and health outcomes are event rates (bleeding and thromboembolism). In the second analytical framework, a home INR test group was still compared against a standard care control group, but, in this instance, time-in-therapeutic range (TTR) was a more achievable surrogate outcome, given the much larger sample sizes needed to adequately compare event rates. However, since a separate body of literature has established a causal relationship between TTR and event rates, particularly as highlighted by Samsa and Matchar [2], CMS was able to rely upon such an indirect approach which is contingent upon the use of surrogate outcomes. It should be emphasized that CMS does not restrict its review of evidence to only include randomized controlled trials, but in this evaluation of home INR testing where several trials were available, it is reasonable to emphasize the strongest type of evidence that was considered. Studies involving diagnostic technologies are usually represented by crosssectional, two-by-two table analyses, which in spite of generating useful sensitivity and specificity values, do not often afford the opportunity to address outcomes, even those which are surrogate and usually more accessible. Although the Decision Memorandum contains further details, some representative supportive trials in the MHV setting (i.e., at least 50% MHV patients in both study arms) are summarized below. Horstkotte conducted one of the first randomized prospective trials related to home INR testing [3]. 5

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He examined outcomes of patients with mechanical valves between those that self-tested and selfmanaged with a home device, versus those that underwent laboratory testing by their physicians. Home INR patients tested once every four days versus once every 19 days in the usual care group. At the conclusion of the study, the authors determined that patients using the home INR device and who selfmanaged were more often in therapeutic range, and had fewer bleeding/thromboembolic events, although reduction in events was not statistically significant. The home testing patients also demonstrated a high degree of compliance with the testing schedule and treatment algorithm. Sawicki investigated the effects of self-management on patients receiving anticoagulation [4]. In a randomized, single-blinded, multi-center trial, the author randomized 179 patients (151 patients with mechanical heart valves) to either an anticoagulation self-management group, based upon a structured teaching and treatment program (lasting three to five hours per patient), or conventional care provided by family physicians, including referral to specialists. Ninety-two percent were followed for 6 months (83 in the self-management, 82 in the control group). The main outcome measure was the squared deviation of INR values from the individual INR target range. Patients in the self-testing and self-management group had an INR in the therapeutic range 1.5 times more often than the usual care group. There was also a significant reduction in the percentage of INR below range. Treatment-related quality-of-life measures (i.e., general treatment satisfaction, and self-efficacy) were significantly higher in the intervention group compared with controls. Limited information was provided on the process of care in the controls. Watzke compared weekly self-testing and selfdosing with standard management [5]. In a prospective clinical trial, he enrolled 49 patients in the self-testing group, and 53 patients in the standard management group. Only patients with stable anticoagulation were included in the study. Patients included those with mechanical heart valves (57%), atrial fibrillation, or venous thromboembolism, and were either high-intensity or low-intensity anticoagulation patients. However, it was not possible to determine the percentage of MHV patients in the standard management group. Patients were followed for one year. Self-managed patients tested weekly, while standard management patients tested every 4 to 8 weeks. Patients in the self-management arm were in therapeutic range more often than patients allocated to the usual care group. In addition, the mean-square deviation was nearly double in the usual care group compared to the test group. The individual INR deviations were dependent on the type of management using a generalized linear model.

Whereas the above three studies illustrate the indirect analytical framework in which home INR monitoring is associated with an improved surrogate outcome (TTR or variations thereof ), the ESCAT (Early Self-Controlled Anticoagulation Trial) offered sufficient sample size to compare actual health outcomes (event rates), and, in turn, illustrate the direct analytical framework presented above. ESCAT was a randomized prospective trial of 1200 patients who received mechanical heart valves. Half used patient self-testing and management with a home device, and the other half were treated and controlled conventionally by a physician. Koertke looked at the first 600 patients who completed followup of at least 2 years, with the observation period ranging from 25 to 51 months [6]. 295 patients were part of the conventional treatment group, and 305 patients were in the INR self-management group. The self-management group was trained 6– 11 days after surgery. In addition to demonstrating superior TTR in the self-management group, the authors also evaluated event rates (complications) on a four-step scale. Data were only reported for Grade III complications (i.e., patient complaints leading to a hospital admission): 9.5% of patients in the selfmanagement group had a Grade III complication versus 15.3% in the conventional treatment group ( p < 0.05). In turn, the authors inferred that the rate of thromboembolism could be decreased from 2.1% to 1.2% via self-management. Although the original request for coverage included a desire to cover patients with atrial fibrillation, we are only covering, at this time, patients with mechanical heart valves. The details are explained in our decision memorandum, but we did not believe that the data on patients with valves is easily generalizable to patients with atrial fibrillation. We are very interested in engaging in a dialogue to discuss the type of data that would be necessary to expand coverage, and we invite interested parties to come speak with us. Furthermore, such early clinical trials on home INR use raise additional questions on how such testing can be best configured to improve health outcomes via emerging delivery-of-care models, both in home and provider settings.

References 1. 64 Fed. Reg. 22619 [April 27, 1999]. 2. Samsa GP, Matchar DB. Relationship between test frequency and outcomes of anticoagulation: a literature review and commentary with implications for the design of randomized trials of patient self-management. J Thromb Thrombolys 2000;9:283–292. 3. Horstkotte D, Piper C, Wiemer M, Schulte HD, Schultheiss H-P. Improvement of prognosis by home prothrombin estimation in patients with life-long anticoagulant therapy. Eur Heart J 1996;9:Abstract suppl. 4. Sawicki PT. A structured teaching and self-management

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program for patients receiving oral anticoagulation: a randomized controlled trial. JAMA 1999;28:145–150. 5. Watzke HH, Forberg E, Svolba G, Jimenez-Boj E, Krinninger B. A prospective controlled trial comparing weekly self-testing and self-dosing with the standard

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management of patients on stable anticoagulation. Thromb Haemost 2000;83:661–665. 6. Koertke H, Minami K, Bairaktaris A, Wagner O, Koerfer R. INR self-management following mechanical heart valve replacement. J Thromb Thrombolys 2000;9:S41–S45.