Self-management of Oral Anticoagulation
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Background: Properly dosed oral anticoagulation effectively prevents thromboembolic events. It is unclear whether adult patients with an indication for long-term oral anticoagulation can benefit from self-management in terms of patient-oriented endpoints and improved coagulation values.
Methods: We selectively searched the Medline database for high-quality systematic reviews based on randomized controlled trials of self-measurement or self-management of oral anticoagulation, compared to standard treatment.
Results: We identified eight review articles based on overlapping sets of randomized clinical trials. In all of these systematic reviews, patients who performed self-measurement or self-management had a 40% to 50% lower rate of thromboembolic events; in six of them, the mortality was also significantly lower, by 30% to 50%. Subgroup analysis revealed that these effects were present exclusively in patients who performed self-management, and not in those who only performed self-measurement. None of the review articles revealed any difference in the frequency of severe hemorrhagic events. Quality of life and patient satisfaction were rated in five reviews, which, however, used different instruments, with the result that no clear conclusions could be drawn. All of the review articles documented an improvement in coagulation values, but information on statistical significance was mostly lacking.
Conclusion: Adults with an indication for long-term oral anticoagulation benefit from self-management, as compared to standard treatment with management of dosing by a physician. A limitation of this study is that the multiple review articles on which it is based were largely analyses of the same group of clinical trials.
Numerous indications for oral anticoagulation are associated with an increased risk of thromboembolic events, e.g. atrial fibrillation arrhythmia, artificial heart valves, cardiomyopathies, vascular prostheses, and status post thrombosis or embolism (1).
Currently, vitamin K antagonists (coumarin derivatives) are among the most commonly used drugs for long-term anticoagulation (2). The standard model of care for patients receiving oral anticoagulation (OAC) therapy comprises the collection of venous blood samples at regular intervals to determine INR values, followed by INR-guided dose adjustments typically made by general practitioners or other specialists.
The emergence of point-of-care devices (POCDs) paved the way for the development of new models of care, such as patient self-testing (PST) and, as the next step, patient self-management (PSM).
In the PSM model, the patient is responsible for INR self-measurement and the self-adjustment of the medication dosage. To prepare the patients for their new role they have to be educated and instructed in the use of the monitoring device; for structured training, several standardized and evaluated educational programs are available (3, 4). In contrast, patient involvement in the PST model is limited to INR self-monitoring—adjusting the anticoagulant dosage continues to be the responsibility of the physicians providing the care.
Potential advantages of PSM or PST include:
- Improved patient adherence with anticoagulation therapy (5)
- Enhanced treatment satisfaction (6)
- Fewer thromboembolic events along with an unchanged risk of bleeding due to more frequent checks and improved dosage adjustments (7).
It was the aim of this review to answer the question whether adult patients with a long-term indication for oral anticoagulation would benefit from patient self-management (PSM) with regard to patient-relevant endpoints and improved anticoagulation control.
Only systematic reviews summarizing analysis results from randomized controlled trials (RCTs) were included (e.g. meta-analyses). According to the methods of the Institute for Quality and Efficiency in Healthcare (IQWiG, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen) (8), such an approach may be regarded as reliable and time-saving as long as certain specific requirements, such as a sufficient number of high-quality reviews with concordant results, are met. The Cochrane Collaboration has recently incorporated this type of review, sometimes referred to as meta-review, too (9). The RCTs on which these results were based had to meet the PICO criteria:
- P: Population: adults with long-term indication for OAC (coumarin derivatives)
- I: Intervention: either PST or PSM
- C: Comparison: monitoring and dose adjustment by healthcare professionals
- O: Outcomes: patient-relevant endpoints, such as mortality, thromboembolic complications, major bleeding complications, and quality of life, plus surrogate parameters of anticoagulation control based on INR monitoring.
Collecting information, identifying relevant studies and evaluating quality
A literature search was conducted in Medline. Two experts independently performed abstract and full text screening as well as quality evaluation; subsequently, any discrepancies in evaluation were discussed and reconciled. With regard to methodology, the review had to be of high quality according to the quality index of Oxman and Guyatt (10, 11). Only reviews scoring at least 5 of 7 points when evaluated by two independent experts were included.
The extraction of relevant data was performed by one expert and controlled by a second.
Results of information collection
Altogether the database search identified 128 references (Figure 1). Of these, 9 publications about 8 high-quality systematic reviews were included after full text viewing and quality assessment using the Oxman and Guyatt index.
Systematic review characteristics
Table 1 provides information about the characteristics of the included reviews. Detailed information is available in the full report of the Federation of Austrian Social Insurance Institutions (HVB, Hauptverband der Österreichischen Sozialversicherungsträger) (12). Four reviews (7, 13–15) included studies evaluating PST or PSM. In 1 review, only studies on PSM were considered (16), while in another review additional studies with corresponding measurements by a practice nurse (near-patient testing, NPT) were also included (17). The remaining 2 reviews included studies in general in which the anticoagulation measurements were performed using a POCD (18, 19). Study durations ranged from a few months to several years. The number of included RCTs varied between 5 and 22, with each review considering a large proportion of the RCTs (Table 2). The total numbers of patients ranged from 2219 to 8413. Only 2 reviews (7, 13) reported the average age which was 65 years. The proportion of female subjects was stated in only 4 reviews; this was mostly smaller than that of male subjects.
Results for relevant endpoints
All-cause mortality—All 8 reviews report all-cause mortality results and also perform meta-analyses. In 6 reviews, statistically significant advantages of PST/ PSM over standard therapy were revealed regardless of the number of RCTs included in the calculations (4 to 16), with relative risk reductions between 25% and 52% (calculated from the data in Table 3 (Figure 2). The reviews by Heneghan 2012 and the Ontario HTA Group in 2009 showed only a numeric advantage of 16% and 34%, respectively, for the intervention group; however, these differences did not reach statistical significance (Table 3). Statistical heterogeneity was found increased in those 2 reviews (7, 13) with the highest number of patients included in the analyses (I2 = 51% and 37%, respectively).
In the context of subgroup analyses, 6 reviews (7, 14, 15, 17–19) reported separate results for PSM compared with standard therapy. In another review (16), the general focus was exclusively on PSM as an intervention. All in all, statistically significant all-cause mortality advantages of PSM were demonstrated in 5 reviews. In 2 reviews (7, 18), the reported advantage was not significant. On the other hand, 4 reviews (7, 14, 17, 18) failed to demonstrate a statistically significant positive effect for PST alone compared with standard therapy. Only the review of Xu in 2012 (15), which exclusively included patients with mechanical heart valve replacements, also found a statistically significant advantage for PST.
Thromboembolic events—Analyses for thromboembolic events were reported in 7 reviews, while 1 paper (16) presented a combined meta-analysis of severe complications (thromboembolic and hemorrhagic events) only. All of the 7 meta-analyses for thromboembolic events and the one for severe complications demonstrated a statistically significant positive effect in favor of PST/PSM with relative risk reductions between 41% and 50% (calculated from the data in Table 3 (Figure 2). Statistical heterogeneity ranged from I2 = 0% to 53%.
Major bleeding—A definition of major bleeding was provided in 6 reviews. Results regarding major hemorrhages were reported in 7 reviews. None of the meta-analyses showed a statistically significant advantage or disadvantage for PST/PSM compared with standard therapy, in the presence of no or very low statistical heterogeneity (Table 3, Figure 2).
In the context of subgroup analyses, 6 reviews (7, 14, 15, 17–19) reported separate results for PSM compared with standard therapy, but none of these reviews showed any statistically significant group difference. Results for PST alone were presented in 5 reviews (7, 14, 15, 17, 18). These were mixed. A statistically significant advantage over standard therapy was found in 2 reviews (14, 17), while the other 3 reviews showed no statistically significant difference.
Quality of life—In 5 reviews information about patient satisfaction or quality of life (QoL) was reported (13, 14, 17–19). Because different instruments were used in the various RCTs, none of these trials provided a quantitative summary. All 5 reviews reported data on perceived treatment quality, which in 3 RCTs were collected using a questionnaire developed by Sawicki (3). Here the comparison revealed a significant advantage of PSM over standard care for 4 or all 5 categories of the questionnaire. With PST, a significant difference was only demonstrated in the “self-efficacy” category. Several other patient satisfaction instruments also indicated advantages for PST/PSM.
QoL was assessed using a variety of instruments (EuroQoL/EQ-5D, SF-36, SEIQoL, and a questionnaire specifically designed for patients on anticoagulation) and the corresponding results were only incompletely published. As far as reported, the differences between the groups were generally not significant. The available data did not allow to draw definite conclusions about the impact of PST/PSM on quality of life.
Anticoagulation control—In the reviews, data on anticoagulation control were reported as INR measurements in the target range or as the percentage of time in the target range. Pooled data of the time in the target range were reported in 4 reviews (13, 17–19) and ranged between 56% and 66% in the control groups, while for PST/PSM comparatively better results were found, ranging from 64% to 73%. However, most of these reviews do not provide information about the statistical significance of these differences. Regarding the percentage of INR values in the target range, only 1 review reported pooled results (13); the percentages were 59% for the control group and 71% for PST/PSM. The weighted difference between the two groups was not statistically significant.
Detailed information about QoL and anticoagulation control findings is available in the full report of the Federation of Austrian Social Insurance Institutions (HVB) (12).
Altogether 8 high-quality systematic reviews concerned with patient self-testing or self-management (PST/ PSM) versus standard care were identified. All systematic reviews consistently showed a reduction in thromboembolic events with PST/PSM; in the majority of reviews significantly lower mortality rates were also reported. The incidence of major bleeding events remained unchanged in all reviews. A significant advantage for PST/PSM with regard to treatment satisfaction was observed in most reviews and also found in a study among patients older than 60 years (6). When the various strategies for the assumption of responsibility by patients are considered separately, PSM appears to be the superior strategy.
Likewise, the authors of the 2010 Cochrane Review (14) on PST/PSM with oral anticoagulation, which was included in this review, arrive at the conclusion that patients can with the help of PST/PSM improve the quality of therapy compared with standard care. For both the number of deaths (relative risk: 0.64 [0.46–0.89]) and the number of thromboembolic events (relative risk: 0.50 [0.36–0.69]) a statistically significant reduction was achieved without any additional harm (Table 3). In addition, the Cochrane Review showed that for about half of all patients long-term therapy with PST or PSM is a viable option. This was confirmed by the SPOG 60 + study (20) especially for elderly patients. It goes without saying that, for example, elderly bedridden patients and patients with dementia or major visual impairment who have nobody to take over the care are excluded from self-management.
At present, no studies are available that directly compare therapy with coumarin derivatives under PST or PSM with the new antithrombotic agents (currently approved: dabigatran, rivaroxaban, apixaban). Thus, the difference between the two therapies can only be estimated by comparing the effects of each of the therapeutic options with standard treatment (physician-managed coumarin therapy). In addition, further considerations regarding their use under real-life conditions are to be taken into account as well. Inasmuch as significant advantages have been observed in the studies evaluating the new antithrombotic agents (21–23) to date, the estimated annual numbers needed to treat (NNTs) were above 200 for all-cause mortality, at least 130 for thromboembolic events such as stroke and myocardial infarction, and above 100 for major bleeding. However, many studies did not find significant differences for these endpoints. In contrast, for PST/PSM, especially if PSM is evaluated alone, annual NNTs for all-cause mortality and thromboembolic events of under 100 can be assumed.
Heneghan (2012) calculated the NNTs on the basis of individual patient data and described positive effects of PST and PSM on thromboembolic events, with an NNT of 78 after 1 year and an NNT of 27 for a period of 5 years (7).
A limitation of this review may be that the systematic research undertaken was limited to only 1 electronic database. However, since a validated filter was used, it can be assumed that the most important papers were identified. These include recent publications in peer-reviewed journals, a Cochrane Review and health technology assessment (HTA) reports, most of which used the same RCTs as evidence basis and arrived at essentially similar results when evaluating the efficacy of PST/PSM. This was an interesting observation since at the start of our research we had expected major differences between the reviews with regards to the included RCTs and, consequently, their results. The selected method of using secondary literature as the basis for the evaluation allows to save the steps on the primary literature level already undertaken by the authors of high-quality reviews, without compromising on the robustness of the result of our research while avoiding redundant analyses. However, this robustness advantage postulated by us also has the aspect of a limitation as it is to be expected that reviews based on the same studies will arrive at similar results.
Finally, it should be noted that there is a general need for care optimization in the area of anticoagulation management. The paper of Saal (2009) shows that, for example, in Germany significant safety gaps exist among physicians, especially regarding documentation, patient information, awareness of side effects, and drug interactions (24). This situation will not change with the prescription of the new antithrombotic agents, which, because of their mechanism of action, naturally have a comparable side effect profile, in particular with regard to the risk of bleeding events. This was documented in the study evaluating dabigatran in patients with mechanical heart valves which was terminated early (25). In addition, costs should be taken into consideration. Even when the annual costs associated with self-management (test sticks and a coumarin-type anticoagulant) are added up, the new antithrombotic agents are still about EUR 1000 more expensive on an annual basis (26). Nevertheless, the number of new prescriptions, e.g. of rivaroxaban, rose to a 2-digit million figure within just a few months (27). The use of such new blockbuster drugs adds a further enormous burden on the German health system, especially since the majority of patients with a long-term indication for anticoagulation can be adequately treated with conventional coumarin therapy (28). Even though not all health insurance providers reimburse the costs of the devices as a rule, these costs are in most cases covered if conclusive reasons are given (Table 4). Therefore, a large health services research study (PICANT) has recently been initiated (29) in Germany with the aim of improving the care of patients with a long-term indication for anticoagulant medication and of reducing the incidence of anticoagulation-associated complications, by using a best practice approach.
Altogether it was shown that adult patients with a long-term indication for oral anticoagulation benefit from patient self-management compared with standard therapy with physician-managed anticoagulation. However, for patient self-testing alone this was not confirmed.
We would like to thank Ms. Antonia Zengerer for her support with collecting and checking the data.
Conflict of interest statement
At the Institute of General Practice, Goethe University Frankfurt, the BMBF-sponsored study (FKZ: 01GY1145) on “Primary Care Management for Optimized Antithrombotic Treatment (PICANT)” has been conducted since March 2012. The HEALTH Institute of JOANNEUM RESEARCH Forschungs-GmbH prepared a health economic analysis regarding the self-management of oral anticoagulation for ROCHE Diagnostics in 2011.
The full report of this manuscript was prepared by the authors for the Federation of Austrian Social Insurance Institutions (HVB) and is available on its homepage under www.hauptverband.at/mediaDB/953046_Bericht_Selbstmanagement_orale_Antikoagulation.pdf
Manuscript received on 21. June 2013; revised version accepted on
16 October 2013.
Translated from the original German by Ralf Thoene, MD.
Prof. Dr. med. Andrea Siebenhofer-Kroitzsch
Institut für Allgemeinmedizin
Goethe-Universität Frankfurt am Main
60590 Frankfurt am Main, Germany
@For eReferences please refer to:
EBM Review Center, Medical University of Graz: Univ.-Prof. Dr. med. Siebenhofer, Dr. med. Jeitler,
PD Dr. med. Horvath, Mag. rer. nat. Semlitsch
Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz: Dr. med. Jeitler
Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz:
PD Dr. med. Horvath
Institute of Biomedicine and Health Sciences (HEALTH), JOANNEUM RESEARCH Forschungsgesellschaft mbh, Graz: DI Dr. techn. Habacher, Schmidt MSc, Mag. rer. nat. Semlitsch
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