Millions of individuals worldwide are on permanent or temporary oral anticoagulation treatment with vitamin K antagonists (VKAs). The effectiveness of VKAs has been established by clinical trials for several indications. Among these, the primary or secondary prevention of venous thromboembolism, the prevention of systemic embolism in patients with prosthetic heart valves, or atrial fibrillation are of highest relevance.1 Such travelers are at higher risk for bleeding episodes due to the anticoagulation and for thromboembolic events due to the underlying disease. This article reviews the most important issues to be considered to give adequate advice to travelers on oral anticoagulants.
Principles of Oral Anticoagulation and Therapy Control
Vitamin K is an essential cofactor for the production of functional clotting factors II, VII, IX, and X, as well as inhibitors such as protein C, S, and Z.2 If vitamin K is deficient or the effect of vitamin K is pharmaceutically blocked, the above-mentioned clotting factors cannot be activated, and the dependant clotting time is prolonged. The three available VKAs phenprocoumon, warfarin, and acenocoumarol exert their anticoagulant effect by reducing the regeneration of vitamin K from vitamin K epoxide in the vitamin K cycle.3 The main difference between the different VKAs is the different half-life with the 105 to 114 hours for phenprocoumon, 35 to 45 hours for warfarin, and 9 hours for acenocoumarol.
Several exogenous and endogenous factors influencing the metabolism of vitamin K and its antagonists (eg, nutrition, comedication, antibiotics) result in individual response to the treatment.
The International Normalized Ratio and Patient Self-Management
The small therapeutic range of the oral anticoagulant drugs and the potentially life-threatening effects of both underdosing and overdosing necessitate a close control of the actual intensity of anticoagulation using the international normalized ratio (INR).4 A major improvement toward an increased mobility of patients permanently treated with VKAs was the introduction of self-testing and self-dosing of the oral anticoagulation therapy about 20 years ago. Reliable and easy-to-handle point-of-care-devices for the INR determination such as CoaguCheck, INRatio2, or ProTime are available. Several studies have shown that patient self-management (PSM) results in improved adjustment of the anticoagulation therapy compared to the conventional regime with less frequent INR testing and dosage recommendations done by the physician.5,6 Patients performing self-testing but no self-dosing need to keep in contact with their physician or staff of the anticoagulation clinic. Nowadays, these patients can ask for dosage recommendation from nearly everywhere in the world.
Risks of Patients Under Therapy With Oral Anticoagulants
Patients with mechanical heart valve prosthesis who are anticoagulated more intensively with INR targets up to 4.5 show a yearly incidence of severe and even fatal bleeding episodes between 1.2% to 5.6% and 0.2% to 0.9%, respectively.7 For patients who are treated less intensively with an INR target between 2.0 and 3.0, the incidence of severe bleedings is approximately 0.3% per year.7 The risk for a bleeding episode is higher during the first 3 months of therapy with VKAs.8 Therefore, risky travel should be avoided during this period.
Compared to the above rates, the risk for thromboembolic events greatly varies between 0.2 and 8.1% per patient year and the management of the anticoagulation therapy.1,5
Oral Anticoagulation and Travel
Overall, there is only rare and no current scientific data about travel habits or travel-associated incidence of bleeding or thromboembolic episodes of patients under oral anticoagulation.9 The travel-associated influences on oral anticoagulation discussed in the following have one major consequence: intensified INR testing during travel to identify relevant changes at an early stage enabling to take adequate counteractive measures.
VKAs are prone to drug–drug interactions.10 This is mainly due to the high binding rate to plasma proteins and the metabolism via cytochrome P450 enzymes resulting in potentiation or inhibition of the anticoagulation effect.1 In general, the patient should be advised to control the INR more often after a new drug has been taken.
Antibiotics and Malaria Prophylaxis
Antibiotic drugs may enhance the anticoagulant effect of VKAs via drug–drug interactions and to a lesser extent through killing of the vitamin K–producing gut flora.10,11 The increase in the risk of bleeding depends on the kind of antibiotic administered and varies considerably.10 Of 62 different antibiotics taken in a large retrospective study, 10 were associated with a significantly increased bleeding risk. The relative risk was three to five for doxycycline, amoxicillin, amoxicillin/clavulanic acid, ciprofloxacin, cotrimoxazole, azithromycin, and pheneticillin; nine for tetracycline; and 43 (!) for cefradine and neomycin.
Doxycycline thus may not be the preferred antimalarial drug in patients on oral anticoagulation therapy. Mefloquine enhances the effect of VKAs due to its high plasma protein binding capacity.12 With regard to relevant interactions with VKA, no data are currently available for Malarone. As the binding rate to plasma proteins of one component of the drug, atovaquone, is very high (>99%), interactions with VKAs are likely. However, according to the product information of the manufacturer, no other drugs with a high-binding capacity to plasma proteins have been displaced by atovaquone in vitro, concluding that no relevant drug interactions via this mechanism could be expected. Although the exact mechanism of the interaction between proguanil and VKAs has not been studied, it is known that proguanil can enhance the anticoagulative effect of VKA. Beside the product information, we are aware of only one patient presenting with increased prothrombin ratio, bruising, and severe hematuria while being on proguanil and warfarin.13 Therefore, it seems to be advisable to start with any kind of chemoprophylaxis at least 1 week before departure. The fear of interactions between VKAs and antimalarial drugs should definitely not discourage patients under oral anticoagulation to take an adequate chemoprophylaxis.
Particularly, infections occurring in subtropical or tropical regions may lead to a procoagulant or hypocoagulant status, which is not always easily recognizable. Acute infections are associated with an increase of the activity of some clotting factors, especially fibrinogen and factor VIII. This may increase the thrombophilic risk and weaken the clinical effect of the anticoagulation therapy, although the INR may remain unaltered. In contrast, a diminished appetite during an infectious disease might lead to a reduced vitamin K uptake, thus enhancing the effect of VKAs. Some infectious diseases such as dengue fever may lead to a lowered platelet count increasing the risk of bleeding.14
Diarrhea and Vomiting
“Travelers’ diarrhea” sometimes associated with vomiting may result in a reduced uptake of vitamin K and the VKA resulting in unstable INR. Antibiotic treatment may further increase the problem.
Dengue Hemorrhagic Fever and Other Hemorrhagic Fevers
The risk for hemorrhagic fevers among travelers is low. Yellow fever is rare mainly due to the application of the vaccine.14 Other infectious agents are virtually restricted to rural or forest areas that are visited only by a small number of travellers.14 Dengue fever occurs more commonly particularly among long-term residents and frequent visitors to endemic areas.
Vaccinations in Patients on Treatment With VKAs
Patients receiving anticoagulant therapy have an increased risk for acquiring hepatitis B.15 Considering the very often underlying chronic diseases of patients on therapy with VKA, an optimal protection against infectious diseases is desirable. As stable liver function is an important issue for patients on treatment with VKA, vaccination against infectious liver disease is especially important. However, because of the risk of hematoma after intramuscular injections, these should be given only when clearly indicated in patients on anticoagulation therapy. Formerly, vaccines were all given subcutaneously until it was recognized that adjuvants induced an unacceptable rate of local reactions16 and that the intramuscular route was possibly associated with better immune response.17
Based upon the available product information, Table 1 gives an overview of injectable vaccines licensed and available in Germany and/or in the United States18,19 and shows which vaccines have central approval in the European Union or are approved via mutual recognition in at least two European countries.20,21 The vaccines listed in groups IV and V remain difficult to handle for patients with increased bleeding risk. If available, the use of alternative vaccines listed in groups I to III or orally or even intranasally applicable vaccines are preferred in patients on oral anticoagulation therapy. The determination of quantitative antibody titers to measure the immune response after subcutaneous vaccination is useful for some of the remaining vaccines listed in group IV.
|Preventable disease||Name of vaccine (examples)|
|Group I: Administered subcutaneously|
|Measles, mumps, rubella||M-M-R II**|
|Measles, mumps, rubella, varicella||Priorix-Tetra¶, ProQuad#,**|
|Meningococcal meningitis, A C||Meningococcal vaccine Mérieux|
|Meningococcal meningitis A, C, W135, and Y||Mencevax ACWY¶, Menomune**|
|Yellow fever||Stamaril, Yf-Vax**|
|Group II: Administration either intramuscular or (deeply) subcutaneously|
|Influenza||Many, see package insert|
|Measles||Measles vaccine Mérieux|
|Measles, mumps, rubella||MMR Triplovax, M-M-RvaxPro#, Priorix¶|
|Pneumococcal pneumonia||Pneumovax 23¶,**|
|Rubella||Rubella vaccine HDC Mérieux|
|Tetanus||Tetanus vaccine Mérieux|
|Tetanus, diphtheria||Td vaccine Mérieux|
|Typhoid fever||Typhim Vi*,**|
|Group III: Administration primarily intramuscular; no impaired immune response in subcutaneous application|
|Diphtheria||Diphtheria adsorbat vaccine Behring|
|Hepatitis A||HAVpur, Vaqta†,¶,**|
|Hepatitis A, typhoid fever||Viatim¶|
|Tetanus||Many, see package insert|
|Tetanus, diphtheria||Many, see package insert|
|Tetanus, diphtheria, poliomyelitis||Revaxis¶|
|Group IV: Administration primarily intramuscular; possible impaired immune response in subcutaneous application|
|Hepatitis A||Havrix 1440**|
|Hepatitis A, hepatitis B||Twinrix#,**|
|Hepatitis A, typhoid fever||Hepatyrix¶|
|Hepatitis B||Engerix-B Erwachsene¶,**, HBVAXPRO#, Fendrix#|
|Group V: Administration only intramuscular—subcutaneous alternative not mentioned or explicitly excluded|
|H5N1||Many, see package insert|
|Influenza||Many, see package insert|
|Meningococcal meningitis serogroup C||Meningitec¶, Menjugate Kit‡,¶, NeisVac-C§,¶|
|Meningococcal meningitis serogroup A, C, W135 and Y||Menactra**|
|Rabies||Many, see package insert|
|Tetanus||Various, see package insert|
|Tetanus, diphtheria||Various, see package insert|
|Tetanus, diphtheria, pertussis||Adacel**, Boostrix*,¶,**|
|Tetanus, diphtheria, pertussis, poliomyelitis||Boostrix Polio*,¶|
The need for intramuscular administration, however, remains for the vaccines listed in group V with no alternative. Risk and benefit must be balanced and caution steps should be taken to avoid the risk of hematoma. The use of a fine needle (≤23 gauge) and the application of firm pressure without rubbing to the injection site for at least 2 minutes are advised.15 Published data and anecdotal experience in large travel clinics on influenza and travel immunization in patients on oral anticoagulation (INR between 2 and 4.5) support this conclusion as no local complications were reported.22–25 The safety of administering influenza vaccine intramusculary in patients on oral anticoagulation with an INR up to 4 was demonstrated very recently.26 In this controlled clinical trial comparing the incidence of side effects after subcutaneous or intramuscular administration of influenza vaccine, no major side effect or hemorrhage was observed in any patient. Moreover, the appearance of local adverse reactions was significantly more frequent in the subcutaneous administration group.26 However, these results may not be generalized to other vaccines or to intramuscular injections with a higher volume or with needles of a greater gauge. As the incidence of a bleeding event is generally dependent on the intensity of the oral anticoagulation, the already low risk of bruising may be further minimized when performing the vaccination at a point in time when the INR of the patient is at the lower limit of the individual target range. The vast majority of patients on oral anticoagulation therapy have INR target ranges of 2.0 to 3.0 or 2.5 to 3.5. The indicated intramuscular vaccination should be performed exceptionally at INR values of approximately 2.0 or 2.5, respectively. Due to lack of scientific data, it is not possible to define an exact threshold INR value below which an intramuscular vaccination can be performed without increased risk of bruising. For the minority of patients with higher INR target ranges as mentioned above, it is rather difficult to give detailed recommendations. Reducing the INR to almost normal levels in these patients and bridging the anticoagulation with better manageable heparin while performing the necessary intramuscular vaccination may be one alternative approach. Whether this procedure is really necessary, however, remains unclear at present. Even more, as in some of the published data on influenza immunization, patients with INR values up to 4.5 were successfully vaccinated without hematoma forming.
In a prospective study, no bruising was detectable at the injection site, while clinically overt bleeding events, mainly mucocutaneous, were recorded in 11 of 104 patients. As INR remained stable in these patients, the authors hypothesized that these bleeding events might be secondary to transient platelet disorders caused by vaccination.22,27
The individual personal history of bleeding tendency and the comedication of the patient have to be considered. The bleeding risk is further increased in a patient a additionally on platelet inhibitors such as acetylsalicylic acid and/or ADP antagonists.
Finally, data on a possible effect of influenza immunization on the INR probably via a transiently depressing of hepatic cytochrome P450 activity are conflicting.28 Whereas the majority of authors did not find such an association,23,24,29–35 others reported a moderate increase36–38 or a slight decrease39,40 of INR. Thus, more closely monitoring of INR after influenza vaccination does not seem to be necessary.24 No significant association between the receipt of pneumococcal, tetanus, or hepatitis A vaccines and changes in INR was found in the only study investigating the effects of other vaccines on oral anticoagulation so far.29
Changes in diet habits are likely to occur on a journey. Patients may be faced with several exotic aliments with unknown vitamin K content, which could have an impact on the INR. Patients should be advised to be reluctant to try new and exotic food or dietary supplements on a journey. Substances such as “royal jelly,” the nourishment of the queen bee, might appear harmless but may have relevant interactions with VKAs.41 Dietary supplements may contain antibiotics, which might affect uptake of vitamin K. Increased drinking of alcoholic beverages could lead to an elevated INR.1
Travel-Associated Changes in Lifestyle
Change in Daily Activities
Lifestyle changes, such as increased or decreased activity, could influence the hormone balance and may have an impact on oral anticoagulation. Given the increased bleeding risks in patients under anticoagulation therapy, travelers should be advised not to try out new activities with a high risk for injuries.
High temperature in subtropical or tropical regions can result in an increased bleeding tendency due to vasodilatation independently from the INR. Some authors found lower INR values during spring and summer compared to autumn and winter.42,43 Several possible causes are discussed, such as seasonal differences in sensitivity to warfarin, a higher consumption of vegetables rich in vitamin K in summer, a higher consumption of alcoholic beverages in autumn, and a higher incidence of febrile infectious diseases in autumn and winter as well as a lower compliance in warfarin intake during the holiday season in summer.
Crossing time zones may also have an impact on the regular intake of VKAs. The VKAs with a long half-life, such as warfarin and especially phenprocoumon, seem to be more advantageous. No adjustment is needed as long as the travelers do not cross more than six times zones. For acenocoumarol with a significantly shorter half-life, the intake in constant intervals is important to avoid INR values outside the target range.
For journeys across more than six times zones and longer stays at the destination, several approaches are possible to adapt the intake of the drug to the new time zone. When traveling to the west (prolongation of the day), an additional quarter or half dose of the VKA should to be taken. Vice versa, when traveling to the east (shortening of the day), the first regular dose of the VKA should be reduced by 25% to 50%. An alternative approach is the stepwise adaptation of the daily time of drug intake to the new time. That means when traveling to the east or to the west, the intake of the VKA should be delayed or brought forward for 2 hours per day until the original daily time of drug intake is reached.
Staying at an altitude above 2,400 m is associated with a 2.7-fold increased risk for INR values falling below the target range.44 The causes (eg, effects of hypoxia to coagulation or drug metabolism) remain unclear.
INR Values and the Therapeutic Range
Experienced patients might have developed their own successful strategy to correct elevated or lowered INR values. It is important to keep calm as the absolute daily risk of bleeding even at excessive INR elevation is low.1 In case of INR values outside the therapeutic range, INR testing daily or at least every other day is recommended.
Elevated INR and Bleeding Risk During Travel—What To Do?
Omitting or reducing the daily dose of the VKAs is the first and most important measure. In addition, the dietary vitamin K intake may be increased. However, it is difficult to find familiar food rich in vitamin K content abroad. It is therefore advisable to include some vitamin K preparation in the travel kit. Modified from Ansell and colleagues,1 we developed recommendations for well-trained patients on how to manage elevated INR with or without bleeding symptoms on a journey (Table 2).
|INR value and clinical symptoms||Recommendation (In general more INR testing, once daily or at least every other day)|
|INR only minimally (up to 0.5) above the upper limit and no significant bleeding||No dose reduction. Wait and see.|
|INR <5.0 and no significant bleeding||Lower dose (5%–20% of weekly dose) or stop medication for oral anticoagulation for at least 1 d.|
|INR <5.0 and minimal bleeding||Lower dose (5%–20% of weekly dose) or stop medication for oral anticoagulation for 1 d, additionally 1 mg–2.5 mg vitamin K orally (alternatively eat food with a higher vitamin K content, if available). Should visit a medical center.|
|INR ≥5.0 but <9.0 and no significant bleeding||Stop medication for oral anticoagulation for at least 1 d, additionally 1 mg–2.5 mg vitamin K orally (alternatively eat food with high vitamin K content, if available). Should visit a medical center.|
|INR ≥5.0 but <9.0 and minimal bleeding||Stop medication for oral anticoagulation for at least 1 d, additionally 2.5 mg–5 mg vitamin K orally. Visit a medical center.|
|INR ≥9.0 and no significant bleeding||Hold VKA therapy, additionally 2.5 mg–5 mg vitamin K orally. Visit a medical center.|
|INR ≥9.0 and minimal bleeding||Hold VKA therapy, additionally 5 mg–10 mg vitamin K orally. Visit a medical center urgently.|
|Serious or even life-threatening bleeding at any elevation of INR||Hold VKA therapy, additionally 10 mg Vitamin K orally, Visit a medical center very urgently (Emergency!).|
Taking along specific clotting preparations (eg, preparations of the prothrombin complex) on a journey to exotic countries similar to patients with hemophilia A or B should not be considered for patients on oral anticoagulation. Beside logistic problems (adequate transport and storage conditions), such clotting preparations are only indicated in life-threatening bleedings or before urgent operations.45 Furthermore, the application of prothrombin complex preparation is associated with an increased thromboembolic risk caused by the underlying thrombophilic condition and by the drug itself. Especially for carriers of mechanical heart valve prosthesis, this could have a serious impact.
Lowering of the INR and Thromboembolic Risk During Travel—What To Do?
Increasing the dose of VKAs dependent on the decreased INR value in relation to the individual INR target range is the first step. However, especially for patients with a very high thromboembolic risk46 (Table 3), it should be clarified in advance how long an INR below the individual target could be accepted until additional measures might become necessary. According to data from patients with mechanical heart valve prosthesis, thromboembolic events occur mainly after 6 days or more during an uncontrolled interval.5 Therefore, an INR below the individual target should be corrected within 3 to 6 days. If the INR cannot be corrected within 3 days, an additional anticoagulation with heparin is recommended. Both kinds of heparin, low molecular weight heparin (LMWH) and unfractionated heparin (UFH), can be used in therapeutic dosage in principle.47 LMWH may be more appropriate. The dosage of the LMWH should be indicated to the patient prior to departure.
|Carriers of mechanical heart valve prosthesis, especially in mitral position|
|Deep vein thrombosis or pulmonary embolism within the last 4 wk|
|Arterial embolism within the last 4 wk|
|Atrial fibrillation with|
|severe cardial failure|
|thrombus in the left atrium|
|past ischemic event|
|dense spontaneous echoes|
Taking Along the INR Self-Testing Device
The safely packed INR self-testing kit should be accompanied by a multilingual or at least English custom declaration testifying the medical necessity and personal use of this kit and the associated equipment such as test strips and lancing devices. Most of the manufacturers of these devices provide custom declarations for free. A certificate is also needed for the LMWH including syringes and needles. As it can be difficult to get supplies even in industrialized countries, a sufficient amount of testing equipment considering the increased number of tests should be taken along. If traveling by air, it is of importance to inform the patient that all equipment and drugs should be carried in the hand luggage.
As far as the information available from the manufacturer, the x-ray at the airport does not harm the function of the devices. Further details of the available INR self-testing kit are summarized in Table 4. The test cuvettes for the ProTime should be stored at 2°C to 8°C to maintain a long shelf life. Therefore, beside the use of cooling bags for transportation, a reliably working refrigerator at the destination is needed, which might be difficult to find in many developing countries.
|Name of the device||CoaguChek XS||INRatio2||Protime Advantage|
|Manufacturer||Roche Diagnostics GmbH, Mannheim, Germany||Hemosense, San Jose, USA||ITC, Edison, USA|
|Size (cm × cm)||13.8 × 7.8||14.6 × 7.1||22.3 × 11.4|
|Weight without batteries (g)||127||180||750|
|Temperature for usage (°C)||18–32||10–35||15 - 30|
|Humidity for usage (%)||10–85||10–95||Not given|
|Power supply||Batteries 4 × 1.5 V AAA||Batteries 4 × 1.5 V AA||Net supply, rechargeable batteries|
|INR range||0.8–8.0||0.7–7.5||0.8 - 9.9|
|Test strips||Test strips||Test cuvettes|
|Size (cm × cm)||6.3 × 1||8.4 × 2.4||8.0 × 2.5|
|Needed sample volume (μL)||≥10||≥15||>27|
|Storage conditions/shelf life||Room temperature/12 mo||Room temperature/12 mo||2°C–8°C/12 mo Room temperature/30 d|
Traveling while being on oral anticoagulants is possible! Especially for well-trained and informed patients performing a sufficient PSM with a stable INR, there are primarily no contraindications even for journeys to exotic and risky regions. For the safety of the traveling patient, specific information about his mode of travel and the country of destination is necessary. The physician giving medical advice should mention and check the most important issues (see checklist in Table 5).
|Risk of underlying disease:|
|✓Is the patient fit for travel considering the underlying disease?|
|✓Is the journey unavoidable at present? (especially for patients under temporary anticoagulation)|
|Self-management of the patient:|
|✓Does the patient perform a sufficient PSM? If yes, when did he start with it?|
|✓Is the anticoagulation stable in the targeted INR range?|
|✓In case of instable INR: May a change to anticoagulation with LMWH be reasonable? How can the control of the platelet count be managed?|
|✓Can the patient manage problems with the INR-self-testing device?|
|Risk of complications:|
|✓Does the patient know what to do in case of INR-variations? Intake of vitamin K? Administration of heparin?|
|✓What to do in case of diarrhea and/or vomitus? Or other infectious diseases? (N.B.: Therapy with antibiotics?)|
|✓Any new activities planed during the journey? Risk of injury? Alcoholic beverages?|
|✓Is the patient well instructed on what to do in case of bleeding or clinical signs of thromboembolism?|
|Risk of destination:|
|✓What about the climatic risks?|
|✓Will the patient be traveling through different time zones?|
|✓Does the patient know about the alimentation risks during travel?|
|Infectious diseases and malaria|
|✓How is the infectious risk?|
|✓What kind of vaccinations are needed?|
|✓Which malaria prophylaxis is appropriate? (N.B: drug interaction)|
|Dengue and Hemorrhagic Fevers|
|✓What is the quality of medicine at the travel destination?|
|✓Are there any reliable medical centers that the patient could contact if necessary?|
|✓Multilingual or at least English customs declaration/certification for INR-self-testing device, equipment and medication?|
|✓Anticoagulation pass and, for carriers of mechanical heart valves, a leaflet with information to prevent endocarditis?|
|✓Information about the current health status of the patient (latest ECG, echocardiography)|
|✓Is the INR-self-testing device including test materials and drugs well-packed as hand luggage?|
|✓Are test strips or cuvettes in sufficient amount?|
|✓If applicable: Is thermo labile medication/equipment adequately stored?|
|✓Does the patient need to take Vitamin K preparation with him?|
|✓Does the patient have sufficient health insurance?|
Declaration of Interests
The authors state that they have no conflicts of interest.