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Travel Medicine and Infectious Disease (2014) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis Juergen Ringwald a,*, Marina Lehmann b, Nicole Niemeyer a, Isabell Seifert a, Anne Daubmann c, Karl Wegscheider c, Annett Salzwedel d, Beate Luxembourg e,f, Reinhold Eckstein a, Heinz Voeller d,g a Department of Transfusion Medicine and Haemostaseology, University Hospital of Erlangen, D-91054 Erlangen, Germany b Medical Clinic 1, Department of Cardiology and Pneumology, Central Hospital of Fuerth, D-90766 Fuerth, Germany c Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany d Center of Rehabilitation Research, University of Potsdam, D-14469 Potsdam, Germany e Institute of Transfusion Medicine and Immunohaematology, Department of Molecular Haemostaseology, University Hospital Frankfurt, Red Cross Blood Donor Service Baden-Wuerttemberg e Hessen, D-60528 Frankfurt, Germany f Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, University Hospital Frankfurt, D-60590 Frankfurt, Germany g Rehabilitation Center Klinik am See, D-15562 Ruedersdorf, Germany
Received 16 December 2013; received in revised form 20 February 2014; accepted 25 February 2014
KEYWORDS Vitamin Kantagonists; Oral anticoagulation; Travel; Patient selfmanagement
Summary Background: Travel-related conditions have impact on the quality of oral anticoagulation therapy (OAT) with vitamin K-antagonists. No predictors for travel activity and for travel-associated haemorrhage or thromboembolic complications of patients on OAT are known. Methods: A standardised questionnaire was sent to 2500 patients on long-term OAT in Austria, Switzerland and Germany. 997 questionnaires were received (responder rate 39.9%). Ordinal or logistic regression models with travel activity before and after onset of OAT or travelassociated haemorrhages and thromboembolic complications as outcome measures were applied.
* Corresponding author. Department of Transfusion Medicine and Haemostaseology, University Hospital of Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany. Tel.: þ49 9131 85 42111; fax: þ49 9131 85 36973. E-mail address: [email protected] (J. Ringwald). http://dx.doi.org/10.1016/j.tmaid.2014.02.006 1477-8939/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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J. Ringwald et al. Results: 43.4% changed travel habits since onset of OAT with 24.9% and 18.5% reporting decreased or increased travel activity, respectively. Long-distance worldwide before OAT or having suffered from thromboembolic complications was associated with reduced travel activity. Increased travel activity was associated with more intensive travel experience, increased duration of OAT, higher education, or performing patient self-management (PSM). Travelassociated haemorrhages or thromboembolic complications were reported by 6.5% and 0.9% of the patients, respectively. Former thromboembolic complications, former bleedings and PSM were significant predictors of travel-associated complications. Conclusions: OAT also increases travel intensity. Specific medical advice prior travelling to prevent complications should be given especially to patients with former bleedings or thromboembolic complications and to those performing PSM. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Millions of patients worldwide are on long-term oral anticoagulation therapy (OAT) with vitamin K antagonists. To gain maximal efficacy, the variability of the international normalized ratio (INR) values must be low and the time in therapeutic range high [1]. Travel-related conditions, however, have impact on the quality of OAT with vitamin K antagonists for several reasons [2]. Among those, changes in diet or daily activities, climatic influences, infectious diseases (especially with diarrhea and vomiting) and possible drug interactions (e.g. antibiotics or malaria prophylaxis) are of major relevance. These influences could cause a higher variability of INR values increasing the risk for haemorrhages or thromboembolic complications with the need for professional medical treatment in the travel destination. Although vitamin K antagonists have been available more than 50 years, data about travel habits as well as travel-associated incidence of bleedings or thromboembolic complications under OAT with vitamin K antagonists are very rare. Aside one case report, Thulin presented data of Swedish patients with mechanical heart valves travelling predominantly around Sweden, countries nearby or to southern Europe and the Canary Islands. [3,4] Travel habits of patients on OAT seem to have changed with worldwide destinations in recent times. Additionally, a considerable number of patients perform patient self-management (PSM) or at least INR self-monitoring to get more freedom and independence. Therefore, updated scientific data on travel habits of patients on OAT and on the incidence of complications during travel are needed to enable physicians to give appropriate advice to these patients and to assess the patients’ individual risk for a distinct journey. The main purpose of this international study in German speaking countries was to identify predictors for more or less travel activity and for complication rates during journeys.
Materials and methods In cooperation with different clinical centers and patient organisations in Germany, Switzerland and Austria as well as the German atrial fibrillation network, a standardised questionnaire with 27 items was sent to 2500 patients between October 2009 and October 2010, who have been on
long-term OAT for at least two years. Exclusion criteria were transient OAT or severe underlying diseases (such as severe stroke, dementia) leading to a physical or mental disability to travel. Demographic data (age, sex, education, current profession, marital status), indication for OAT, INR target range and type of monitoring (PSM or control by physician), travel habits before/after the onset of OAT, especially frequency, duration and destination of journeys were recorded (Table 1). Thromboembolic complications and haemorrhagic episodes in the domestic environment and during travel were of special interest. In detail, we asked for the frequency, spontaneous or provoked manifestation and the site of haemorrhage or thromboembolic complications. As the patient answered the questionnaire without the assistance of a physician, we did not get detailed information about the clinical course of a haemorrhage such as fall of haemoglobin or the presence of a compartment syndrome. Therefore, the classification of haemorrhage in major or minor bleedings in accordance to the criteria of the International Society on Thrombosis and Haemostasis [5] was not reasonable. The study was approved primarily by the Institutional Ethics Committee of the University Erlangen-Nuremberg and in part by the local Ethics Committee of the participating clinical centers. Patients were informed about the goals of the study in a short accompanying letter and had to give their written informed consent to take part in the study.
Statistical analysis Descriptive analysis of the full dataset consisted of absolute and relative frequencies in categorical variables and the means standard deviations in continuous variables. The evaluated outcomes were travel activity (reduced, unchanged or increased after onset of OAT) and thromboembolic and haemorrhagic complications on travel (yes/no). For each outcome an ordinal (travel activity) or logistic (complications) regression model was fitted to the data with following potential predictors: demographic data, indication and duration of OAT, INR upper target range, type of monitoring (PSM or physician control), frequency and duration of journey before onset of OAT, destination of journey before (for travel activity) or after (for complications on travel) onset of OAT, complications on travel (only for travel
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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Oral anticoagulation and travel Table 1
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Summary of the travel-associated questions.
Travel habits Did you travel abroad before the onset of OAT? If yes, how often (per year), to which countries in or outside Europe and for how long (longer or shorter than 4 weeks)? Have you travelled abroad after the onset of OAT? If yes, how often (per year), to which countries in or outside Europe and for how long (longer or shorter than 4 weeks)? Complications at home Have you suffered from bleeding complications at home since the onset of the OAT? If yes, how often, which kind and what was done to stop the bleeding? Have you suffered from blood clotting events such as thrombosis or embolism since the onset of the OAT? If yes, how often per year and what kind? Complications during travel If you have been travelling since the onset of OAT, did you experience any problems such bleeding or clotting events during travel? If yes: - What kind of bleeding or clotting events? - Did you perform any kind of self-therapy? - Did you need professional medical treatment in the travel destination? If yes, what kind of therapy was applied? - In which countries and for how long have you been travelling on this particular journey with bleeding or clotting events? - Did you have to stop travelling prior than planned? - Do you still suffer from the consequences of the bleeding or clotting event during travel? - Will you be travelling abroad in the future again?
activity) and former haemorrhagic or thromboembolic complications. In a backward selection procedure variables were eliminated from the model, if they were not significant. The significance level was 0.05. The estimated odds ratios (ORs), 95% confidence intervals (95%-CIs) and p values are reported in forest plots. The statistical analyses were performed with SPSS version 19.0 (SPSS Inc., Chicago, IL).
Results We received 997 questionnaires resulting in a responder rate of 39.9%. Patient characteristics are shown in Table 2. The predominant INR target range was 2e3 (45.6%), followed by 2.5e3.5 (18.6%). However, patients reported more than 40 different INR target ranges.
Change of travel habits Seven hundred and seven patients gave detailed information about their travel habits: 307 (43.4%) changed travel habits since the onset of OAT with 176 (24.9%) reporting less travel activities (less frequent, shorter and/or only to destinations nearby with well-developed health care systems) and 131 (18.5%) indicating increased travel activities (more frequent, longer and/or farther to destinations with less-developed health care systems). Reasons for the change of travel habits were the underlying disease (34.1%), OAT (23.5%) or both (22.9%). Other reasons such as financial problems, increasing age, additional diseases, change in profession, and retirement were mentioned by 19.6% of the patients. In multivariate analysis, patients who travelled worldwide (including subtropical and tropical regions) or to
destinations far away from Europe (such as USA, New Zealand or Australia) before the onset of OAT revealed fewer travel activities since being treated with vitamin K antagonists (Fig. 1). The same was applicable for patients having had thromboembolic complications during OAT at home. In contrast, an increased travel activity after the onset of OAT was found for patients who had been travelling at least twice per year prior to OAT, or with increased duration of OAT, who performed PSM, or patients with a university degree.
Former haemorrhages and thromboembolic complications Two hundred and fifty-eight patients (25.9%) reported having had haemorrhages during OAT in their domestic environment, predominantly occurring spontaneously (45.3%). The incidence of bleeding in the context of injuries or operations was 30.6%. The majority of haemorrhages was epistaxis (46.1%) followed by skin haematomas (29.8%) and bleeding caused by injuries (25.2%). Gastrointestinal haemorrhage or haematuria was reported less often at 11.6% and 10.1%, respectively. Thromboembolic complications in the domestic environment during OAT were reported by 9.1% of the patients with 40.7%, 26.4% and 24.2% having suffered from deep venous thrombosis, pulmonary embolism and ischemic stroke, respectively.
Haemorrhages and thromboembolic complications while travelling Out of 810 patients travelling under OAT with vitamin K antagonists, 53 (6.5%) and 7 (0.9%) patients reported bleedings
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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J. Ringwald et al. Table 2
Baseline characteristics of 997 patients.
Sociodemographic parameters Age [years] Male gender Education College or university Secondary school Grammar school Marital status Married/living with a partner Professional status Retired Employed Self-employed Anticoagulation therapy Indication for OAT Heart valve prosthesis Atrial fibrillation Thrombophilia Others Duration of OAT [months] Vitamin K antagonist Phenprocoumona Acencoumarol Warfarin PSM Coagulometer Duration
62.0 12.9 (range 20e92) 63.9% 46.2% 30.4% 23.4% 78.3% 63.3% 23.3% 6.0%
33.9% 33.6% 28.9% 3.6% 102.4 75.8 90.9% 5.4% 3.4% 77.5% 92% using Coaguchek, 7% INRatio 64.7 48.4 months
OAT Z oral anticoagulation therapy. PSM Z patient selfmanagement. a Five patients with additional acetylsalicylic acid and one patient with additional acetylsalicylic acid and clopidogrel.
Fig. 1
or thromboembolic complications, respectively. Spontaneous epistaxis or skin haematomas were the predominant bleedings during travel. Five patients had gastrointestinal and six patients had urinary tract bleedings. Among seven patients with thromboembolic complications during travel, five patients reported that they suffered from deep venous thrombosis with or without pulmonary embolism. The other two patients indicated having had heart valve thrombus and transient ischemic attack. In the multivariate analysis, significant predictors for haemorrhages or thromboembolic complications while travelling were former thromboembolic complications (OR 2.77; 95%-CI 1.39e5.54, p Z 0.004), former bleedings (OR 3.52; 95%-CI 2.02e6.11, p < 0.001) and PSM (OR 3.60; 95%CI 1.26e10.28, p Z 0.017) (Fig. 2). A higher anticoagulation intensity (INR target value 3) was not a significant predictor.
Discussion Our study is the first to analyse travel habits and travelassociated complication rates in detail among a large cohort of patients orally anticoagulated with vitamin K antagonists in consideration of worldwide increasing travel activities and new options to control the anticoagulation intensity, namely PSM. Therefore it is not surprising that patients not only reduced but also increased their travel activities to a comparable degree. Only about 7% of all patients suffered from a complication, predominantly minor bleedings. Beside former haemorrhages or thromboembolic complications, surprisingly PSM was a significant predictor for travel-associated complications. More than 40% of the patients reported that OAT indeed has influenced their travel habits. Interestingly, the percentage of patients with unchanged travel habits under OAT (56.6%) was very similar to the rate of patients (55%) in the
Influence of different factors on travel activity before and after the onset of OAT.
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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Oral anticoagulation and travel
Fig. 2
5
Significant predictors of travel-associated complications.
cohort after heart valve replacement of Thulin in the 1980s [4]. Considering the above-mentioned travel-associated influences on OAT, it might be expected that OAT has mostly negative influences on the travel activity of patients. However, nearly every fifth patient (18.5%) reported increased travel activities after the onset of OAT, travelling more frequent, longer, farther, and/or even to destinations with less-developed health care systems. In the multivariate analysis, we found several independent predictors for either decreased or increased travel activities after the onset of OAT. Patients who had been travelling worldwide (including subtropical and tropical regions) or to destinations far away before the onset of OAT were significantly more likely to reduce travel activities after being on OAT. The same was applicable for patients who had suffered from haemorrhages or thromboembolic complications in their domestic environment. Increased travel activity, however, was associated with longer experience with OAT. Furthermore, patients, who travelled once per year before the onset of OAT, with a higher education (university degree) and patients performing PSM were also more likely to travel more intensively after the onset of OAT. Overall, these findings indicate that OAT with vitamin K antagonists does not deter well-educated patients from travelling, especially when performing PSM. Moreover, these patients had increased their travel activity after the onset of OAT. Our finding that approximately 93% of the travelling patients on OAT had never experienced any complication while travelling would probably be of high practical relevance for physicians giving travel medicine advice to patients under OAT. This rate had been 100% among the cohort of Thulin in the 1980s which might indicate at first glance that the situation might have been worsening during the last 30 years [4]. However, the results of the two studies are not comparable. More than 40% of our patients travelled worldwide including subtropical and tropical countries or at least to destinations with moderate climate but very far away from Europe such as USA, Australia or New Zealand. In contrast, patients interviewed by Thulin had been travelling predominantly around Sweden, countries nearby or at most to southern Europe and the Canary Islands. Travel duration, on the other hand, was quite similar as 23% in the former study and 25% of our travelling study population went on journeys lasting longer than four weeks. As PSM had not been introduced at the beginning of the 1980s, none of Thulin’s patients performed PSM. Surprisingly, PSM was a predictor for travel-associated
complications (OR 3.60). Therefore, according to our data PSM does not protect travellers under OAT against bleedings and thromboembolic complications. When comparing the incidence of non-travel-associated complications between patients performing PSM or being controlled by the physician, recently published large meta-analysis showed a significant reduction in thromboembolic complications among patients performing PSM but not for major haemorrhagic [6,7]. Butchart and co-workers found an association of an increased variability of INR with a higher complication rate associated with a reduced survival [8]. Although this was reported for patients under conventional anticoagulation therapy with vitamin K antagonists, we speculate that there could be a link to our results. Travelling patients on PSM being aware of the impact of travel conditions on their INR might perform more INR testing and consequently induce more and potentially unnecessary changes of the dosage of vitamin K or the vitamin K antagonist. The latter might lead to a higher variability of the INR value and consequently to a higher rate of complications. Patients having had bleedings or thromboembolic complications in a domestic environment are at higher risk for complications during travel (OR 3.52 and 2.77, respectively). Therefore, careful travel medicine advice should be especially given to patients on OAT who experienced bleedings or thromboembolic complications during OAT at home. The increased risk of clinical events might be associated with a higher probability for medical professional help during travel. Therefore, travelling to countries with a well-developed health care system and the availability of safe medical devices and blood products might be advisable for these patients. In our study, the level of the INR target value did not significantly influence the risk of complications during travel. This is in contrast to published data which had shown a positive correlation of bleeding complications and increasing therapeutic ranges of the INR [9e12]. A possible explanation could be the rather low number of complications during travel. Our study has some important limitations. First, the high rate of patients with PSM among our cohort might have caused some bias. Another limitation was that the answers of the patients could not have been validated by a physician to exclude any misunderstandings or to enable us to properly classify reported haemorrhages in minor or major bleedings as recommended by the International Society on Thrombosis
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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6 and Haemostasis [5]. Furthermore, the questionnaire may have been answered primarily by patients with an interest in travel. The rather low percentage of response (approximately 40%) might lead to a possible bias of patient selection. We did not ask for detailed socio-economic status of the patient which might also influence travel activity. The increased travel activity of patients with a university degree as well as the information of some patients that travelling was not possible anymore due to financial problems may underline this aspect. Finally, we cannot exclude a memory bias interfering in the patient report of travel activity and complications related to vitamin K antagonists. In conclusion, our data show that OAT influences travel habits. However, a substantial proportion had become more active. A high education level, performing PSM, travelling at least once per year before OAT, and the duration of OAT were independent variables for an increased travel activity after onset of OAT. Overall, the rather low complication rate indicates that travel seems to be safe for patients under OAT. Specific medical advice prior to travel to prevent complications should be given especially to patients with former bleedings and thromboembolic complications as well as to patients performing PSM. Among those, the choice of a travel destination with access to safe and appropriate treatment in case of complications for patients at increased risk is a major goal. Although more frequent INR testing might be reasonable for patients on PSM, they should be advised not to test too often leading to potentially unnecessary changes of the dosage of their vitamin K antagonists ending up in a higher variability of the INR and increased complication rate. Finally, the ability to easily check INR and manage the dosage of the vitamin K antagonist might increase the likeliness of patients on PSM to try out new or exotic food with unknown vitamin K content. Therefore, these patients should probably be advised not to take too many risks when traveling.
Funding The study was supported by a grant (10.000 V) of Roche Diagnostics, Mannheim, Germany. Except for sponsoring, Roche Diagnostics had no further influence on the study.
Conflict of interest The author JR received honoraria from Roche Diagnostics (Mannheim, Germany), Pfizer Pharma GmbH (Berlin, Germany), Bayer Vital (Leverkusen, Germany) and Boehringer (Ingelheim, Germany) outside the submitted work. The authors ML, NN, IS, AD, KW, AS, BL, RE and HV do not have any conflict of interest with respect to this article. None of the authors have any conflict of interest with regard to financial support of this study by of Roche Diagnostics.
Acknowledgements The authors thank the colleagues and the staff of all participating centers and associations: association for
J. Ringwald et al. patient self-management of anticoagulation (Heike Sichmann), atrial fibrillation network Muenster/Germany (Dr. Thomas Weiss, Ursula Thoene), working group of anticoagulated patients (Christian Schaefer), SwissINR (Dr. Angelika Bernardo), INR Austria (Ulrike Walchshofer), University Hospital of Frankfurt/Germany (Dr. Wolfgang Miesbach), University Hospital of Dresden/Germany (Dr. Jan Beyer-Westendorf), Training Centre for Patient Selfmanagement Marburg (Dr. Christa Meyszner), German Heart Centre Munich (Dr. Siegmund Braun), Strandklinik Boltenhagen (Dr. Juergen Bolte), Rehabilitation Center Klinik am See (Prof. Dr. med. Heinz Vo ¨ller, Karen Heyne) and MTBASA/Berlin (Katharina Weinkopf, Ulrike Hartwig and Ines Hartwig-Zaidan). Furthermore, we thank Prof. Dr. Martin Lohmann (Leuphana University, Department. of Business Psychology, Lueneburg, and North European Institute for Tourism Research, Kiel, Germany) for his valuable support and input during writing of the manuscript. Finally, we thank Mrs. Virginia Olsen (Seattle, USA) for checking the language style of the manuscript.
References [1] Oden A, Fahlen M. Oral anticoagulation and risk of death: a medical record linkage study. BMJ 2002;325:1073e5. [2] Ringwald J, Strobel J, Eckstein R. Travel and oral anticoagulation. J Travel Med 2009;16:276e83. [3] Truoung T, Armor BL. Successful management of anticoagulation therapy during international travel. Pharmacotherapy 2012;32:e45e9. [4] Thulin LI. International travel amongst patients on chronic anticoagulation therapy. Cor Vasa 1988;30:292e7. [5] Schulman S, Kearon C. Subcommittee on control of anticoagulation of the scientific and standardization committee of the international society on thrombosis and haeostasis. J Thromb Haemost 2005;3:692e4. [6] Heneghan C, Ward A, Perera R, , Self-Monitoring Trialist Collaboration, Bankhead C, Fuller A, et al. Self-monitoring or oral anticoagulation: systematic review and meta-analysis of individual patient data. Lancet 2012;379:322e34. [7] Bloomfield HE, Krause A, Greer N, Taylor BC, Mac Donald R, Rutks I, et al. Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes. Ann Intern Med 2011;154:472e82. [8] Butchart EG, Payne N, Li HH, Buchan K, Mandana K, Grunkemeier GL. Better anticoagulation control improves survival after valve replacement. J Thorac Cardiovasc Surg 2002;123:715e23. [9] Fihn StD, McDonnel M, Martin D. Risk factors for complications of chronic anticoagulation. Ann Intern Med 1993;118: 511e20. [10] Hylek EM, Chang YC, Skates SJ, Hughes RA, Singer DE. Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation. Arch Intern Med 2000;160: 1612e7. [11] Van der Meer F, Rosendaal F, Vandenbroucke J, Briet E. Bleeding complications in oral anticoagulant therapy. Arch Intern Med 1993;153:1557e62. [12] Van der Meer F, Rosendaal F, Vandenbroucke J, Briet E. Assessment of a bleeding risk index in two cohort of patients with oral anticoagulation. Thromb Haemost 1996;76:12e6.
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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Travel Medicine and Infectious Disease (2014) xx, 1e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis Juergen Ringwald a,*, Marina Lehmann b, Nicole Niemeyer a, Isabell Seifert a, Anne Daubmann c, Karl Wegscheider c, Annett Salzwedel d, Beate Luxembourg e,f, Reinhold Eckstein a, Heinz Voeller d,g a Department of Transfusion Medicine and Haemostaseology, University Hospital of Erlangen, D-91054 Erlangen, Germany b Medical Clinic 1, Department of Cardiology and Pneumology, Central Hospital of Fuerth, D-90766 Fuerth, Germany c Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany d Center of Rehabilitation Research, University of Potsdam, D-14469 Potsdam, Germany e Institute of Transfusion Medicine and Immunohaematology, Department of Molecular Haemostaseology, University Hospital Frankfurt, Red Cross Blood Donor Service Baden-Wuerttemberg e Hessen, D-60528 Frankfurt, Germany f Department of Internal Medicine, Division of Vascular Medicine and Haemostaseology, University Hospital Frankfurt, D-60590 Frankfurt, Germany g Rehabilitation Center Klinik am See, D-15562 Ruedersdorf, Germany
Received 16 December 2013; received in revised form 20 February 2014; accepted 25 February 2014
KEYWORDS Vitamin Kantagonists; Oral anticoagulation; Travel; Patient selfmanagement
Summary Background: Travel-related conditions have impact on the quality of oral anticoagulation therapy (OAT) with vitamin K-antagonists. No predictors for travel activity and for travel-associated haemorrhage or thromboembolic complications of patients on OAT are known. Methods: A standardised questionnaire was sent to 2500 patients on long-term OAT in Austria, Switzerland and Germany. 997 questionnaires were received (responder rate 39.9%). Ordinal or logistic regression models with travel activity before and after onset of OAT or travelassociated haemorrhages and thromboembolic complications as outcome measures were applied.
* Corresponding author. Department of Transfusion Medicine and Haemostaseology, University Hospital of Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany. Tel.: þ49 9131 85 42111; fax: þ49 9131 85 36973. E-mail address: [email protected] (J. Ringwald). http://dx.doi.org/10.1016/j.tmaid.2014.02.006 1477-8939/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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J. Ringwald et al. Results: 43.4% changed travel habits since onset of OAT with 24.9% and 18.5% reporting decreased or increased travel activity, respectively. Long-distance worldwide before OAT or having suffered from thromboembolic complications was associated with reduced travel activity. Increased travel activity was associated with more intensive travel experience, increased duration of OAT, higher education, or performing patient self-management (PSM). Travelassociated haemorrhages or thromboembolic complications were reported by 6.5% and 0.9% of the patients, respectively. Former thromboembolic complications, former bleedings and PSM were significant predictors of travel-associated complications. Conclusions: OAT also increases travel intensity. Specific medical advice prior travelling to prevent complications should be given especially to patients with former bleedings or thromboembolic complications and to those performing PSM. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Millions of patients worldwide are on long-term oral anticoagulation therapy (OAT) with vitamin K antagonists. To gain maximal efficacy, the variability of the international normalized ratio (INR) values must be low and the time in therapeutic range high [1]. Travel-related conditions, however, have impact on the quality of OAT with vitamin K antagonists for several reasons [2]. Among those, changes in diet or daily activities, climatic influences, infectious diseases (especially with diarrhea and vomiting) and possible drug interactions (e.g. antibiotics or malaria prophylaxis) are of major relevance. These influences could cause a higher variability of INR values increasing the risk for haemorrhages or thromboembolic complications with the need for professional medical treatment in the travel destination. Although vitamin K antagonists have been available more than 50 years, data about travel habits as well as travel-associated incidence of bleedings or thromboembolic complications under OAT with vitamin K antagonists are very rare. Aside one case report, Thulin presented data of Swedish patients with mechanical heart valves travelling predominantly around Sweden, countries nearby or to southern Europe and the Canary Islands. [3,4] Travel habits of patients on OAT seem to have changed with worldwide destinations in recent times. Additionally, a considerable number of patients perform patient self-management (PSM) or at least INR self-monitoring to get more freedom and independence. Therefore, updated scientific data on travel habits of patients on OAT and on the incidence of complications during travel are needed to enable physicians to give appropriate advice to these patients and to assess the patients’ individual risk for a distinct journey. The main purpose of this international study in German speaking countries was to identify predictors for more or less travel activity and for complication rates during journeys.
Materials and methods In cooperation with different clinical centers and patient organisations in Germany, Switzerland and Austria as well as the German atrial fibrillation network, a standardised questionnaire with 27 items was sent to 2500 patients between October 2009 and October 2010, who have been on
long-term OAT for at least two years. Exclusion criteria were transient OAT or severe underlying diseases (such as severe stroke, dementia) leading to a physical or mental disability to travel. Demographic data (age, sex, education, current profession, marital status), indication for OAT, INR target range and type of monitoring (PSM or control by physician), travel habits before/after the onset of OAT, especially frequency, duration and destination of journeys were recorded (Table 1). Thromboembolic complications and haemorrhagic episodes in the domestic environment and during travel were of special interest. In detail, we asked for the frequency, spontaneous or provoked manifestation and the site of haemorrhage or thromboembolic complications. As the patient answered the questionnaire without the assistance of a physician, we did not get detailed information about the clinical course of a haemorrhage such as fall of haemoglobin or the presence of a compartment syndrome. Therefore, the classification of haemorrhage in major or minor bleedings in accordance to the criteria of the International Society on Thrombosis and Haemostasis [5] was not reasonable. The study was approved primarily by the Institutional Ethics Committee of the University Erlangen-Nuremberg and in part by the local Ethics Committee of the participating clinical centers. Patients were informed about the goals of the study in a short accompanying letter and had to give their written informed consent to take part in the study.
Statistical analysis Descriptive analysis of the full dataset consisted of absolute and relative frequencies in categorical variables and the means standard deviations in continuous variables. The evaluated outcomes were travel activity (reduced, unchanged or increased after onset of OAT) and thromboembolic and haemorrhagic complications on travel (yes/no). For each outcome an ordinal (travel activity) or logistic (complications) regression model was fitted to the data with following potential predictors: demographic data, indication and duration of OAT, INR upper target range, type of monitoring (PSM or physician control), frequency and duration of journey before onset of OAT, destination of journey before (for travel activity) or after (for complications on travel) onset of OAT, complications on travel (only for travel
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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Oral anticoagulation and travel Table 1
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Summary of the travel-associated questions.
Travel habits Did you travel abroad before the onset of OAT? If yes, how often (per year), to which countries in or outside Europe and for how long (longer or shorter than 4 weeks)? Have you travelled abroad after the onset of OAT? If yes, how often (per year), to which countries in or outside Europe and for how long (longer or shorter than 4 weeks)? Complications at home Have you suffered from bleeding complications at home since the onset of the OAT? If yes, how often, which kind and what was done to stop the bleeding? Have you suffered from blood clotting events such as thrombosis or embolism since the onset of the OAT? If yes, how often per year and what kind? Complications during travel If you have been travelling since the onset of OAT, did you experience any problems such bleeding or clotting events during travel? If yes: - What kind of bleeding or clotting events? - Did you perform any kind of self-therapy? - Did you need professional medical treatment in the travel destination? If yes, what kind of therapy was applied? - In which countries and for how long have you been travelling on this particular journey with bleeding or clotting events? - Did you have to stop travelling prior than planned? - Do you still suffer from the consequences of the bleeding or clotting event during travel? - Will you be travelling abroad in the future again?
activity) and former haemorrhagic or thromboembolic complications. In a backward selection procedure variables were eliminated from the model, if they were not significant. The significance level was 0.05. The estimated odds ratios (ORs), 95% confidence intervals (95%-CIs) and p values are reported in forest plots. The statistical analyses were performed with SPSS version 19.0 (SPSS Inc., Chicago, IL).
Results We received 997 questionnaires resulting in a responder rate of 39.9%. Patient characteristics are shown in Table 2. The predominant INR target range was 2e3 (45.6%), followed by 2.5e3.5 (18.6%). However, patients reported more than 40 different INR target ranges.
Change of travel habits Seven hundred and seven patients gave detailed information about their travel habits: 307 (43.4%) changed travel habits since the onset of OAT with 176 (24.9%) reporting less travel activities (less frequent, shorter and/or only to destinations nearby with well-developed health care systems) and 131 (18.5%) indicating increased travel activities (more frequent, longer and/or farther to destinations with less-developed health care systems). Reasons for the change of travel habits were the underlying disease (34.1%), OAT (23.5%) or both (22.9%). Other reasons such as financial problems, increasing age, additional diseases, change in profession, and retirement were mentioned by 19.6% of the patients. In multivariate analysis, patients who travelled worldwide (including subtropical and tropical regions) or to
destinations far away from Europe (such as USA, New Zealand or Australia) before the onset of OAT revealed fewer travel activities since being treated with vitamin K antagonists (Fig. 1). The same was applicable for patients having had thromboembolic complications during OAT at home. In contrast, an increased travel activity after the onset of OAT was found for patients who had been travelling at least twice per year prior to OAT, or with increased duration of OAT, who performed PSM, or patients with a university degree.
Former haemorrhages and thromboembolic complications Two hundred and fifty-eight patients (25.9%) reported having had haemorrhages during OAT in their domestic environment, predominantly occurring spontaneously (45.3%). The incidence of bleeding in the context of injuries or operations was 30.6%. The majority of haemorrhages was epistaxis (46.1%) followed by skin haematomas (29.8%) and bleeding caused by injuries (25.2%). Gastrointestinal haemorrhage or haematuria was reported less often at 11.6% and 10.1%, respectively. Thromboembolic complications in the domestic environment during OAT were reported by 9.1% of the patients with 40.7%, 26.4% and 24.2% having suffered from deep venous thrombosis, pulmonary embolism and ischemic stroke, respectively.
Haemorrhages and thromboembolic complications while travelling Out of 810 patients travelling under OAT with vitamin K antagonists, 53 (6.5%) and 7 (0.9%) patients reported bleedings
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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J. Ringwald et al. Table 2
Baseline characteristics of 997 patients.
Sociodemographic parameters Age [years] Male gender Education College or university Secondary school Grammar school Marital status Married/living with a partner Professional status Retired Employed Self-employed Anticoagulation therapy Indication for OAT Heart valve prosthesis Atrial fibrillation Thrombophilia Others Duration of OAT [months] Vitamin K antagonist Phenprocoumona Acencoumarol Warfarin PSM Coagulometer Duration
62.0 12.9 (range 20e92) 63.9% 46.2% 30.4% 23.4% 78.3% 63.3% 23.3% 6.0%
33.9% 33.6% 28.9% 3.6% 102.4 75.8 90.9% 5.4% 3.4% 77.5% 92% using Coaguchek, 7% INRatio 64.7 48.4 months
OAT Z oral anticoagulation therapy. PSM Z patient selfmanagement. a Five patients with additional acetylsalicylic acid and one patient with additional acetylsalicylic acid and clopidogrel.
Fig. 1
or thromboembolic complications, respectively. Spontaneous epistaxis or skin haematomas were the predominant bleedings during travel. Five patients had gastrointestinal and six patients had urinary tract bleedings. Among seven patients with thromboembolic complications during travel, five patients reported that they suffered from deep venous thrombosis with or without pulmonary embolism. The other two patients indicated having had heart valve thrombus and transient ischemic attack. In the multivariate analysis, significant predictors for haemorrhages or thromboembolic complications while travelling were former thromboembolic complications (OR 2.77; 95%-CI 1.39e5.54, p Z 0.004), former bleedings (OR 3.52; 95%-CI 2.02e6.11, p < 0.001) and PSM (OR 3.60; 95%CI 1.26e10.28, p Z 0.017) (Fig. 2). A higher anticoagulation intensity (INR target value 3) was not a significant predictor.
Discussion Our study is the first to analyse travel habits and travelassociated complication rates in detail among a large cohort of patients orally anticoagulated with vitamin K antagonists in consideration of worldwide increasing travel activities and new options to control the anticoagulation intensity, namely PSM. Therefore it is not surprising that patients not only reduced but also increased their travel activities to a comparable degree. Only about 7% of all patients suffered from a complication, predominantly minor bleedings. Beside former haemorrhages or thromboembolic complications, surprisingly PSM was a significant predictor for travel-associated complications. More than 40% of the patients reported that OAT indeed has influenced their travel habits. Interestingly, the percentage of patients with unchanged travel habits under OAT (56.6%) was very similar to the rate of patients (55%) in the
Influence of different factors on travel activity before and after the onset of OAT.
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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Oral anticoagulation and travel
Fig. 2
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Significant predictors of travel-associated complications.
cohort after heart valve replacement of Thulin in the 1980s [4]. Considering the above-mentioned travel-associated influences on OAT, it might be expected that OAT has mostly negative influences on the travel activity of patients. However, nearly every fifth patient (18.5%) reported increased travel activities after the onset of OAT, travelling more frequent, longer, farther, and/or even to destinations with less-developed health care systems. In the multivariate analysis, we found several independent predictors for either decreased or increased travel activities after the onset of OAT. Patients who had been travelling worldwide (including subtropical and tropical regions) or to destinations far away before the onset of OAT were significantly more likely to reduce travel activities after being on OAT. The same was applicable for patients who had suffered from haemorrhages or thromboembolic complications in their domestic environment. Increased travel activity, however, was associated with longer experience with OAT. Furthermore, patients, who travelled once per year before the onset of OAT, with a higher education (university degree) and patients performing PSM were also more likely to travel more intensively after the onset of OAT. Overall, these findings indicate that OAT with vitamin K antagonists does not deter well-educated patients from travelling, especially when performing PSM. Moreover, these patients had increased their travel activity after the onset of OAT. Our finding that approximately 93% of the travelling patients on OAT had never experienced any complication while travelling would probably be of high practical relevance for physicians giving travel medicine advice to patients under OAT. This rate had been 100% among the cohort of Thulin in the 1980s which might indicate at first glance that the situation might have been worsening during the last 30 years [4]. However, the results of the two studies are not comparable. More than 40% of our patients travelled worldwide including subtropical and tropical countries or at least to destinations with moderate climate but very far away from Europe such as USA, Australia or New Zealand. In contrast, patients interviewed by Thulin had been travelling predominantly around Sweden, countries nearby or at most to southern Europe and the Canary Islands. Travel duration, on the other hand, was quite similar as 23% in the former study and 25% of our travelling study population went on journeys lasting longer than four weeks. As PSM had not been introduced at the beginning of the 1980s, none of Thulin’s patients performed PSM. Surprisingly, PSM was a predictor for travel-associated
complications (OR 3.60). Therefore, according to our data PSM does not protect travellers under OAT against bleedings and thromboembolic complications. When comparing the incidence of non-travel-associated complications between patients performing PSM or being controlled by the physician, recently published large meta-analysis showed a significant reduction in thromboembolic complications among patients performing PSM but not for major haemorrhagic [6,7]. Butchart and co-workers found an association of an increased variability of INR with a higher complication rate associated with a reduced survival [8]. Although this was reported for patients under conventional anticoagulation therapy with vitamin K antagonists, we speculate that there could be a link to our results. Travelling patients on PSM being aware of the impact of travel conditions on their INR might perform more INR testing and consequently induce more and potentially unnecessary changes of the dosage of vitamin K or the vitamin K antagonist. The latter might lead to a higher variability of the INR value and consequently to a higher rate of complications. Patients having had bleedings or thromboembolic complications in a domestic environment are at higher risk for complications during travel (OR 3.52 and 2.77, respectively). Therefore, careful travel medicine advice should be especially given to patients on OAT who experienced bleedings or thromboembolic complications during OAT at home. The increased risk of clinical events might be associated with a higher probability for medical professional help during travel. Therefore, travelling to countries with a well-developed health care system and the availability of safe medical devices and blood products might be advisable for these patients. In our study, the level of the INR target value did not significantly influence the risk of complications during travel. This is in contrast to published data which had shown a positive correlation of bleeding complications and increasing therapeutic ranges of the INR [9e12]. A possible explanation could be the rather low number of complications during travel. Our study has some important limitations. First, the high rate of patients with PSM among our cohort might have caused some bias. Another limitation was that the answers of the patients could not have been validated by a physician to exclude any misunderstandings or to enable us to properly classify reported haemorrhages in minor or major bleedings as recommended by the International Society on Thrombosis
Please cite this article in press as: Ringwald J, et al., Travel habits and complications in patients treated with vitamin K antagonists: A cross sectional analysis, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.02.006
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6 and Haemostasis [5]. Furthermore, the questionnaire may have been answered primarily by patients with an interest in travel. The rather low percentage of response (approximately 40%) might lead to a possible bias of patient selection. We did not ask for detailed socio-economic status of the patient which might also influence travel activity. The increased travel activity of patients with a university degree as well as the information of some patients that travelling was not possible anymore due to financial problems may underline this aspect. Finally, we cannot exclude a memory bias interfering in the patient report of travel activity and complications related to vitamin K antagonists. In conclusion, our data show that OAT influences travel habits. However, a substantial proportion had become more active. A high education level, performing PSM, travelling at least once per year before OAT, and the duration of OAT were independent variables for an increased travel activity after onset of OAT. Overall, the rather low complication rate indicates that travel seems to be safe for patients under OAT. Specific medical advice prior to travel to prevent complications should be given especially to patients with former bleedings and thromboembolic complications as well as to patients performing PSM. Among those, the choice of a travel destination with access to safe and appropriate treatment in case of complications for patients at increased risk is a major goal. Although more frequent INR testing might be reasonable for patients on PSM, they should be advised not to test too often leading to potentially unnecessary changes of the dosage of their vitamin K antagonists ending up in a higher variability of the INR and increased complication rate. Finally, the ability to easily check INR and manage the dosage of the vitamin K antagonist might increase the likeliness of patients on PSM to try out new or exotic food with unknown vitamin K content. Therefore, these patients should probably be advised not to take too many risks when traveling.
Funding The study was supported by a grant (10.000 V) of Roche Diagnostics, Mannheim, Germany. Except for sponsoring, Roche Diagnostics had no further influence on the study.
Conflict of interest The author JR received honoraria from Roche Diagnostics (Mannheim, Germany), Pfizer Pharma GmbH (Berlin, Germany), Bayer Vital (Leverkusen, Germany) and Boehringer (Ingelheim, Germany) outside the submitted work. The authors ML, NN, IS, AD, KW, AS, BL, RE and HV do not have any conflict of interest with respect to this article. None of the authors have any conflict of interest with regard to financial support of this study by of Roche Diagnostics.
Acknowledgements The authors thank the colleagues and the staff of all participating centers and associations: association for
J. Ringwald et al. patient self-management of anticoagulation (Heike Sichmann), atrial fibrillation network Muenster/Germany (Dr. Thomas Weiss, Ursula Thoene), working group of anticoagulated patients (Christian Schaefer), SwissINR (Dr. Angelika Bernardo), INR Austria (Ulrike Walchshofer), University Hospital of Frankfurt/Germany (Dr. Wolfgang Miesbach), University Hospital of Dresden/Germany (Dr. Jan Beyer-Westendorf), Training Centre for Patient Selfmanagement Marburg (Dr. Christa Meyszner), German Heart Centre Munich (Dr. Siegmund Braun), Strandklinik Boltenhagen (Dr. Juergen Bolte), Rehabilitation Center Klinik am See (Prof. Dr. med. Heinz Vo ¨ller, Karen Heyne) and MTBASA/Berlin (Katharina Weinkopf, Ulrike Hartwig and Ines Hartwig-Zaidan). Furthermore, we thank Prof. Dr. Martin Lohmann (Leuphana University, Department. of Business Psychology, Lueneburg, and North European Institute for Tourism Research, Kiel, Germany) for his valuable support and input during writing of the manuscript. Finally, we thank Mrs. Virginia Olsen (Seattle, USA) for checking the language style of the manuscript.
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