ISMAAP Conference 2009

From October 1-3, 2009, the 5th International Patient & Physician Conference on Anticoagulant Therapy took place in Brussels, Belgium. The event was organized by the International Self-Monitoring Association for oral Anticoagulated Patients (ISMAAP) and the International Self-Monitoring Association for oral Anticoagulation (ISMAA).

On Friday October 2, the plenary lectures, which brought together medical experts and patient organizations, cast new light on some of the hot topics of life with anticoagulation therapy.

Invited speakers: Jack Ansell, MD, New York/USA; Rebecca Beyth, MD, Gainsville/Florida/USA; David Garcia, MD, Albuquerque/USA; Chris Gardiner, PhD, London/UK; Scott Kaatz, MD, Detroit/USA; Heinrich Körtke, MD, Bad Oeynhausen/Germany; Hermann Krüttner, MD, Salzburg/Austria; Marcel Levi, MD, Amsterdam/the Netherlands; Hannelore Rott, MD, Duisburg/Germany; Heinz Völler, MD, Rüdersdorf/Germany.

The plenary sessions were opened by Rebecca J. Beyth, MD, MSc, Associate Professor, University of Florida at Gainesville. She pointed out that anticoagulants are effective in the prevention and management of many thrombo-embolic disorders, which are in general more common in older patients.

Ms. Beyth stated, however, that: “the increased use of anticoagulants in older patients raises concerns about an increased risk of anticoagulant-related bleeding. These concerns may lead clinicians to be less willing to prescribe anticoagulant therapy to older patients who might benefit most from treatment.”

The odds ratio for major bleeding is 3 for patients > 75 years old, compared to those < 65 years of age. “We need to continue to develop better strategies and tools to minimize this risk” said Beyth, and also stated the importance of patient education in teaching basic concepts of safe, effective anticoagulation, discussing the importance of regular INR monitoring, and counseling on the use of other medication and alcohol.

Provider education, on the other hand, should create increased awareness of co-morbidities that may influence the risk of bleeding and the willingness to avoid or limit the use of interacting medication. “There is a need to develop innovative strategies for improving adherence, and to make best use of anticoagulant management models such as dedicated services and clinics, patient self-testing and self-monitoring, as well as computer-assisted dosing” said Beyth. “The essential stratification required to identify those at highest bleeding risk should rely less on subjective impressions, while including assessments of other domains such as functional and cognitive status. Furthermore, the risk needs to be reassessed over time.”

One important statistic: The anticoagulant response to warfarin increases with age. While the average Warfarin daily dose in patients younger than 50 was 6.1 mg/day, it was only 3.5 mg/day in patients older than 80. (James AH et al. J Clin Path 1992;45:701-706).

Report by Thomas Klein, MD, MSc (Nov. 2009)

Trials including older patients on anticoagulation therapy are not that common. “Studies have the tendency to exclude older patients”, commented Scott S. Kaatz, DO, MSc, FACP, Clinical Associate Professor of Medicine, Director Anticoagulation Clinics, Henry Ford Hospital, Detroit, in his talk entitled “INR self-management in the elderly”. He knows of only one trial which specifically enrolled elderly patients managing their own INR, and there are no trials on this subject comparing groups of older patients to younger ones.

Kaatz also poses a fundamental question: “Who should be regarded as elderly? Does it start with 65? Or 75? We must also take into account that our life expectancy will rise during the next decades.”Report by Thomas Klein, MD, MSc (Nov. 2009)

Many female patients with severe forms of thrombophilia (a hypercoagulable state due to hereditary and acquired factors) are today on long-term oral anticoagulation with warfarin or, in Germany, with phenprocoumon. “Advisory information for women of childbearing age is necessary,” said Hannelore Rott, MD, MVZ-Lab, Duisburg, Germany. “Two months’ time is the optimal interval between last use of Vitamin-K-Antagonists and conception”.The use of low molecular weight heparins (LMWH) makes a safe pregnancy possible even in patients with severe thrombophilia. International guidelines endorse the use of LMWH for both treatment and prophylaxis in pregnancy. The advantages of LMWH over unfractionated heparins include a reduced bleeding risk, a longer half life, a higher bioavailability, a minimal risk of heparin-induced thrombocytopenia, a much lower risk of osteoporosis, and no need for monitoring except in patients with renal insufficiency. Rott stated: “Usually, a spontaneous delivery is possible under medication with LMWH because the bleeding risk is not higher in pregnant women on prophylaxis with LMWH in comparison to women without LMWH prophylaxis. It’s important to discontinue LMWH injection for regional anaesthesia during labor for 12–24 hours depending on the dose of LMWH.” Post-partum, the prophylaxis with low molecular heparin is continued during the time of breast-feeding, or can be changed to warfarin, which is not secreted in the breast milk.“According to our experience, it is early enough to stop anticoagulation before the 6th week of gestation to prevent warfarin-embryopathia”, said Rott, “If a patient becomes pregnant under oral anticoagulation, stop warfarin immediately and administer a high dose of oral vitamin K (10 mg/day) for a week, and immediately switch to low molecular weight heparin, which does not cross the placenta.”

Report by Thomas Klein, MD, MSc (Nov. 2009)

The next speaker, Heinrich Koertke, MD, Bad Oeynhausen (Germany), focused on the topic of pregnant women with mechanical heart valves and lifelong anticoagulation. “Is there a contra-indication for pregancy in women with mechanical heart valves? If there is the wish to have a baby, this complex question should be openly discussed between the gynecologist and the cardiologist. Patient INR self-management is a crucial part in these discussions,” said Koertke. 

Based on the findings from international studies, which partly differ from international guidelines, Koertke suggests the following procedure in the case of pregnancy: After the exclusion of warfarin resistance, an INR value within the range of 1.2 to 2.1 (target: 2.0) in aortic valve replacement and 2.0 to 2.5 (target: 2.3) in the case of a mitral or double valve replacement should be achieved using low-dose warfarin therapy. These INR target ranges were found in the ESCAT III study, where the Institute for Applied Telemedicine (IFAT) in Bad Oeynhausen introduced a telemedical approach for INR patient management using CoaguChek® XS point-of-care systems, mobile transmitters and electronic patient records. 

“Vitale et al were able to prove that 33 pregnancies under continuous warfarin treatment below 5 mg resulted in the birth of 33 healthy children, without complications for the mothers and the children”, stated Koertke. “We have managed several patients who received this kind of care: We only stopped the warfarin therapy and offered heparin 14 days prior to childbirth. We should bear in mind that the administration of heparins, conventional as well as unfractionated, also needs tight control during pregnancy.”

Report by Thomas Klein, MD, MSc (Nov. 2009)

In his second talk of the day, Scott Kaatz elaborated on the multiple modalities available to manage patients who are anticoagulated with Vitamin K antagonists, such as patient education, patient self-testing and patient self-management. Kaatz examined how these different systems affect the patient’s quality of life.

“There has been much scientific emphasis on clinical outcomes of thrombo-embolic and hemorrhagic complications. In contrast the direct impact on patients’ quality of life has been less well investigated,” said Kaatz.

Kaatz had no doubt that the most accurate way to measure the effect of different management modalities on patients’ quality of life is through randomized clinical trials. However, clear answers are prevented by the low availability of studies, especially for the comparison between usual care and anticoagulation management service, as well as multiple evaluation tools and global quality-of-life questionnaires, which may not be precise enough. However, given these limitations, one questionnaire, specifically designed to evaluate the effects of patient self-testing or management on quality of life has been used in several trials and has shown consistent improvement in patients’ well being.

“As compared to usual anticoagulation monitoring, patients enrolled in anticoagulation management service have a perception of improvement in their care. Patients empowered to perform patient self testing or management have further gains in their quality of life,” concluded Kaatz.

Report by Thomas Klein, MD, MSc (Nov. 2009)

After the break, there was a light-hearted dialog on stage between Albert O. Meyer, Berne, Switzerland, representing the patient’s view, and Hermann Krüttner, MD, Grossgmein, Austria, representing the doctor’s view: The two addressed daily real-life questions, such as the best option if the INR is out of range, if a biopsy is planned, or where test strips are not available, as in some remote regions of the world. In the end, Krüttner’s conclusion was that patient self-management and sound education on both sides, the patient’s as well as the physician’s, is the key to a successful handling of anticoagulation therapy.

Report by Thomas Klein, MD, MSc (Nov. 2009)

There is only rare, and no current, scientific data on travel habits or travel-associated incidence of bleeding or thrombo-embolic episodes”, pointed out Heinz Völler, MD, of Rüdersdorf, Germany, in his talk. “The major consequence for the patient should be intensified INR testing while traveling to identify relevant changes at an early stage, enabling the taking of adequate counteractive measures.”Changes in INR can be caused by drug-drug interactions, e.g. for tetracycline the bleeding risk is ninefold. “But patients should definitely not be discouraged from taking an adequate antibiotic and malaria prophylaxis or having the required vaccinations,” said Völler. Formerly, vaccinations in patients on treatment with VKAs were all given subcutaneously until it was recognized that adjuvants induced an unacceptable rate of local reactions and that the intramuscular route was possibly associated with a better immune response.Infectious diseases lead to a procoagulant or hypocoagulant status, and are associated with an increase in the activity of some clotting factors, especially fibrinogen and factor VIII. This means an increase of thrombophilic risk, although the INR may remain unaltered. Völler strongly suggests an optimal protection against infectious diseases such as hepatitis.In addition, changes in lifestyle can change the INR, including several exotic foods and increased consumption of alcohol. Climatic influences also play a role: High temperature increases the bleeding tendency due to vasodilatation. High altitude (>2500m) means a 2.7-fold increased risk for lower INR values.“If traveling by air, the self-testing device, all equipment and all drugs should be carried in the hand luggage” Völler advised those patients present. “X-ray at the airport does not harm the functioning of the device, and it’s important not to forget: a reliably working refrigerator is required at the destination.”

Report by Thomas Klein, MD, MSc (Nov. 2009)

“A particularly frustrating aspect of anticoagulation therapy is the management of dosing when an invasive procedure is required”, said Jack Ansell, MD, Chairman Department of Medicine, Lenox Hill Hospital, New York.

A decision to use or not to use an alternative short-acting anticoagulant (called “bridging therapy”) in the peri-operative period is based on the perceived risk of thrombosis if the anticoagulant is stopped, or the risk of bleeding from an alternative short-acting anticoagulant. The number of variables is so great that it is not surprising that large, randomized, controlled trials, from which one could assess various alternative therapeutic interventions, have not been performed. “The bridging therapy is easy to do, but it is hard to know when it should be done,“ Ansell emphasized, before describing different approaches to performing a risk assessment.

The traditional management of peri-operative anticoagulation involves a brief pre- and post-operative infusion of unfractionated heparin, when an alternative is needed after oral anticoagulants are discontinued several days before the procedure. “Such a therapy requires an in-patient admission, and is costly, labor intensive, inconvenient, and carries potential risk,” said Ansell. “Low molecular weight heparin (LMWH) offers a simpler alternative, because subcutaneous, unmonitored therapy can be delivered at home.”

Finally, the physician managing the patient’s oral anticoagulation must arrive at an agreement with the physician performing the procedure. For some surgeons or interventionalists, the fear of bleeding if anticoagulation is continued during a procedure may outweigh the concern about thrombo-embolism if anticoagulation is discontinued. “Thus, even when the literature indicates that oral anticoagulation can be continued, the process may be one of negotiation and compromise with the physician performing the procedure,” said Ansell.

Report by Thomas Klein, MD, MSc (Nov. 2009)

“Vitamin K antagonists are effective in the prevention and treatment of a variety of arterial and venous thrombotic disorders, but are associated with an increased risk of serious bleeding complications”, stated Marcel Levi, MD, Academic Medical Center, University of Amsterdam, the Netherlands, opening his talk.

Based on well-documented studies of patients using vitamin K antagonists, the incidence of major bleeding is 0.5%/year and the incidence of intracranial bleeding is 0.2%/year. “However, in real-life practice this incidence may be even higher,” Levi suspects. Risk factors for bleeding are the intensity of anticoagulation, the management strategy to keep the INR in the desired range, and patient characteristics. In the case of serious or even life-threatening bleeding in a patient who uses anticoagulant agents or when a patient on anticoagulants needs to undergo an urgent invasive procedure, anticoagulant treatment can be reversed by various specific strategies.

“In the case of very serious or life-threatening bleeding, immediate correction of the INR is mandatory and can be achieved by the administration of vitamin K-dependent coagulation factors,” said Levi. “Theoretically, these factors are present in fresh frozen plasma: however, the amount of plasma that is required to correct the INR is very large, carries the risk of fluid overload, and will probably take hours to administer. Therefore, prothrombin complex concentrates (PCCs), containing all vitamin K-dependent coagulation factors, are more useful.”

Report by Thomas Klein, MD, MSc (Nov. 2009)

Chris Gardiner, PhD, Department of Haematology, University College London Hospitals, London, United Kingdom, described the design and the results of the study “Self monitoring of oral anticoagulation: Does it work outside trial conditions?” (Journal of Clinical Pathology, February 2008, Volume: 62 (2): 168-71. Less than 1% of the estimated one million patients receiving oral anticoagulation therapy (OAT) in the UK monitor their own PT/INR. Patient self-monitoring (PSM) of OAT is known to improve anticoagulant control, but poor uptake and high dropout rates in UK studies have prompted suggestions that PSM is suitable for only a minority of patients. In this study 318 consecutive patients referred, for the first time, to an anticoagulation clinic were assessed for eligibility using established criteria. Patients electing for PSM attended training and, following successful assessment, performed a capillary blood INR every two weeks or more frequently if directed to do so by the anticoagulation clinic. The aim was to determine whether PSM is a viable alternative to regular hospital anticoagulant clinic attendance, if offered to the patient from the start of treatment. “23% of all patients receiving oral anticoagulation were suitable, willing and able to self-test,” Gardiner said, summarizing the results. “The uptake is improved if offered at the start of treatment, particularly among younger patients.”Two more findings: Most patients were happy to remain on self-testing rather than proceeding to self-management, and the quality of anticoagulant control achieved through PST may be superior to that of the routine specialist anticoagulant clinic.“The situation in the UK is like this: Test strips are available on prescription from the National Health Service, but some general practitioners and primary care trusts are reluctant to prescribe strips, because they are still sceptical about self-monitoring,” said Gardiner. “They think that self-monitoring is suitable for only a minority of patients. But hospitals cannot cope with the increasing numbers of patients requiringanticoagulation.”

Report by Thomas Klein, MD, MSc (Nov. 2009)

“Over the next 10 years, patients who require anticoagulation will have more and, we hope, better therapeutic options,” said David Garcia, MD, Albuquerque, USA. He then examined the current situation with novel anticoagulant medication in the late stages of development and the potential benefits of genetic testing.

Concerning Pharmacogenetics, there is clear evidence that two genetic polymorphisms exist that have a large impact on the required warfarin dose. Potential benefits from genetic testing could therefore be a more accurate initial dosing, fewer blood draws and doctor visits, and less frequent dose adjustments. Less bleedings, less thrombo-embolism and fewer hospitalizations are also expectations for pharmacogenetic testing.

“However, many questions remain”, said Garcia. “Is routine pharmacogenetic testing affordable, and is the turnaround time rapid enough? Will PG testing reduce the need for frequent PT measurement during initiation of VKA?”

To Garcia, although the science of pharmacogenetics has substantially improved, the understanding of the inter-individual dose variability seen with VKA, the hypothesis that genotyping can improve patient-important outcomes, remains unproven. The evidence from four small RCTs he regards as inconclusive at best, models with genotyping and clinical risk factors explain about 50% of dose variability. “Ongoing trials will give much more accurate information” said Garcia. “Current estimates suggest that pharmacogenomic testing is not cost effective, since early INR response may provide much of the information obtained by genotyping.”

On the therapeutic side, the future has room for improvement too. Garcia stated: “The current vitamin K antagonists (VKA) have many limitations, which prevent them from being perfect anticoagulants. They show a narrow therapeutic index and drug/diet interaction, and therefore require frequent monitoring. Their long half-life and slow onset of action complicate the management of bleeding patients and patients with high INR.”

So it is not surprising that there is a high level of interest in novel anticoagulants such as the Thrombin-targeting dabigatran or the factor Xa-targeting rivaroxaban and apixaban. “From a public health perspective, it is hoped that one or more of the agents in development will increase the number of at-risk patients who receive optimal antithrombotic therapy. Currently, many patients who stand to benefit from anticoagulant treatment do not receive it because of the burdens associated with long-term vitamin K antagonists. New drugs are expected to be a step forward, not only because the need for frequent monitoring and dose adjustment could disappear, but also because peri-operative “bridging therapy” using parenteral agents may well become unnecessary.

“ADVANCE–2 and RE-LY suggest that we may find doses of these novel agents where efficacy will be preserved at the same time that bleeding risk is reduced”, said Garcia.

However, even with all the promising properties of the novel agents, some topics remain open for Garcia, like the situation in patients with renal insufficiency or mechanical heart valves, cost issues, the possibility of assessing the anticoagulant effects in laboratories, and therapy reversal strategies in emergency situations.

“Forecasting the death of vitamin K antagonists may be premature”, said Garcia, “Innovations such as patient-self testing, computerized dose adjustment, and specialized anticoagulant management teams, continue to make VKAs more effective and safer than ever.”

Report by Thomas Klein, MD, MSc (Nov. 2009)