Compliance to Iron Chelation Therapy with Desferrioxamine Androulla Eleftheriou, PhD TIF Scientific Co-ordinator
Thalassaemia International Federation Publications
About the author Dr. Androulla Eleftheriou obtained her graduate and postgraduate degrees from London University, in the fields of Microbiology and Virology. She has been awarded a number of scholarships by the World Health Organisation and Fullbright Commission, and has held an honorary research post at University College Medical School, UK. Her postdoctoral fellowship was completed at the Centres for Disease Control in Atlanta, GA, USA. Dr. Eleftheriou has been the head of the Virus Reference Centre of the Cyprus Ministry of Health since 1990 and was closely involved in its establishment. She has organised and actively participated in numerous national and international workshops, conferences and projects. She currently serves as a WHO Consultant on issues related to her field of expertise. Dr. Eleftheriou’s main interest and research work has been in the area of viral infections in thalassaemia major. Through her research in this area, she has had a great deal of personal contact with physicians and research scientists involved in this area, as well as with patients with thalassaemia in countries across the world. Since 1993, Dr. Eleftheriou has collaborated on a voluntary basis with the Thalassaemia International Federation. TIF realised the tremendous need of medical information books, and most importantly, providing medical personnel with opportunities for continuing education in thalassaemia through the organisation of educational workshops. In 1997, a new post, TIF Scientific Co-ordinator, was created to address this need, and it was unanimously proposed that Dr. Eleftheriou be appointed. She accepted wholeheartedly and has held this post since that time fulfilling her duties independently of her official government post Through her work with TIF, Dr. Eleftheriou has carried out numerous projects of both local and international scope in close cooperation with physicians and thalassaemia associations worldwide. She has completed several publications in collaboration with WHO and other bodies on a wide range of scientific topics related to the prevention and mainly clinical management of thalassaemia major. Dr. Eleftheriou is Chief Editor of TIF News and performs a key role in the organisation of TIF workshops on Clinical Management of Thalassaemia and Compliance to desferrioxamine. The great success of the latter has led to the materialisation of this publication.
3
Contributors Alan Cohen, MD Professor of Pediatrics, University of Pennsylvania School of Medicine, USA Antonio Piga, MD Professor, Dipartimento di Scienze Pediatriche e dell’Adolescenza, Universita degli Studi di Torino, Italy John Porter, MD Professor, Department of Haematology, University College London, UK Emma Prescott, RN Charge Sister, Haematology Department, The Whittington Hospital, London, UK George Constantinou Board Member, Thalassaemia International Federation, London, UK Loizos Pericleous TIF Secretary, Thalassaemia International Federation, Nicosia, Cyprus Margaret Santamas, MSc Research Associate, Thalassaemia International Federation, Nicosia, Cyprus
5
Contents Preface
9
Introduction
11
Clinical Management of Thalassaemia
14
The Importance of Iron Chelation Therapy
17
What is Compliance?
23
Barriers and Aids to Compliance / Adherence
25
The Importance of a Dedicated Thalassaemia Centre
38
References
49
Figure 1: Primary global distribution of ‚-thalassaemia
11
Figure 2: Therapeutic index
16
Figure 3: Survival by birth cohort at different ages in patients with transfusion-dependent thalassaemia
21
Figure 4: Causes of death reported in patients with thalassaemia born between 1960 and 1984, in order of frequency
21
Figure 5: Survival as a function of compliance to iron chelation therapy in patients with thalassaemia major
22
Figure 6: Compliance index
23
Figure 7: Examples of infusion devices
26
Figure 8: Preferred needle types
26
Figure 9: Rotation of infusion sites
28
Table 1:
Psychological issues affecting compliance
45
Table 2:
Physician guidelines for improving compliance
46
Table 3:
Summary of issues affecting compliance and possible solutions
47
7
Preface With the dramatic developments that have occurred in the past two decades in the clinical management of thalassaemia major, particularly in the Western World, impressive improvement has been observed in the survival rate among patients with thalassaemia major in these countries. However, the disease-free and complication-free survival reflecting better quality of life has yet to be achieved. Poor compliance to iron chelation therapy with desferrioxamine is one of the main reasons for this. This book is intended to address this important problem and to propose possible means of maximising compliance to desferrioxamine regimens. Although the problem was identified some time ago, no co-ordinated effort was been undertaken until recently. TIF has focused its attention on this issue as part of an ongoing effort to improve the survival and quality of life of patients with thalassaemia across the world. George Constantinou, a thalassaemic and Board Member of TIF, spearheaded a determined and persistent struggle to introduce this problem as one of TIF’s priorities for global action. His expert advice, comments, and suggestions based on of his personal experience have been invaluable throughout the planning, development and execution of this project. The unwavering support and interest of TIF Board of Directors in this project has motivated and facilitated the rapid organisation of workshops and gathering of essential material for this book. To date, TIF has organised three collaborative workshops on compliance to desferrioxamine therapy. The first of these took place during the International Conference on Thalassaemia and the haemoglobinopathies in Bangkok–Thailand in June 1999. This year, two additional regional workshops have been conducted with great success in Amman–Jordan and Tehran–Iran. These workshops provided the basis for and the bulk of information contained in this book and have greatly assisted us, particularly through the group discussion sessions, in identifying as many factors as possible which may contribute to lapses in adherence to desferrioxamine therapy. In a cooperative
9
effort including physicians, nurses, patients, parents, and government officials a variety of potential ways of addressing the diverse facets of this problem have been identified. TIF greatly appreciated the contribution of all those who participated in the three workshops particularly the devoted support of Prof. Antonio Piga and Prof. John Porter whose close involvement in every aspect of these workshops was instrumental to their success. TIF is also grateful to Novartis Pharma AG (Basel and regional offices) for their generous support in the organisation of these workshops, and for the contribution of their Scientific Department, represented by Dr Christopher Adams. This book represents the first year of TIF’s investigation into compliance and associated problems. We recognise that there is still much to be done before a solution is achieved and we hope that through the publication and distribution of this book patients, parents, physicians and governments will become sensitised to the magnitude and seriousness of the problem and the tremendous need for present action to address this issue. As we await further scientific developments which will bring a more tolerable means of chelation and eventually a cure for thalassaemia, it is important to make the most of the best treatment currently available. As Dr. Evgenia Georganda, a well-known psychologist and thalassaemic, stressed, "do not allow thalassaemia to dominate your life. Your life is too important for that."
Panos Englezos TIF Chairman
10
Introduction Overview of thalassaemia Thalassaemia was first described by Cooley and Lee in 1925 in several Italian children, as characterised by severe anaemia with splenic and liver enlargement, discoloration of the skin, and bone changes. The term "thalassaemia" was not used until seven years later when Whipple and Bradford published a paper describing the pathophysiology of the disease. The term "thalassaemia" (literally: anaemia of the sea) came into use to note the association of this disease with the Mediterranean region. At that time, most diagnosed cases of the disease were in families originating from countries bordering the Mediterranean Sea, particularly Greece and Italy. Even as early as the 1930s, there were case reports indicating that thalassaemia occurred in Asians as well, yet it was not until the publication by Munich (1954) that thalassaemia was no longer considered exclusively a Mediterranean affliction, but was accepted as occurring in high frequency in Asia and Southeast Asia as well [Herr, Choy et al. 1998].
Diagnosis and primary global distribution By the early 1980s it had been shown definitively that the different forms of ·- and ‚-thalassaemia are the commonest monogenic diseases in humans and occur at a high frequency throughout the Mediterranean region, the Middle East, parts of the Indian Sub-continent, and Southeast Asia – an area commonly referred to as "the thalassaemia belt." Figure 1: Primary global distribution of ‚-thalassaemia
11
Once it became possible to analyse ·- and ‚-thalassaemia at the DNA level, a remarkable picture of the global distribution of their underlying mutations emerged. Thalassaemia syndromes were the first diseases to be diagnosed prenatally by recombinant DNA technology, and a better understanding of their pathophysiology has led to considerable improvement in their clinical management.
Thalassaemia in developing countries Over the last 30 years, research in the richer Western countries where thalassaemia constituted a selectively rare disease has shown that a great deal can be achieved towards the control and management of thalassaemia by screening, genetic counselling, prenatal diagnosis, and improvement in symptomatic treatment. Nevertheless, it appears that the thalassaemias are likely to pose an increasing global health problem through a massive increase in the number of patients with different forms of thalassaemia in many developing countries during the first decades of the new millenium. The World Health Organization’s target of "Health for All" specifically includes ‚-thalassaemia as one of the inherited haemoglobinopathies responsible for a large amount of chronic illness throughout the world. While rates of neonatal and childhood mortality overall are declining as a result of hygiene improvement, nutrition, and control of infections, children with serious genetic diseases are increasingly likely to survive the first years of life. Throughout the Middle East, the Indian subcontinent and South East Asia, thousands of children are born annually with thalassaemia, many of whom will live long enough to require extensive treatment. It is of immense importance therefore, that the WHO, the World Bank, and other international agencies extend these serious concerns to candidate governments and provide support and expertise to establish more adequate surveys of the frequency of the disease and to advise them on setting up centres for its control and management.
12
Health burden in immigrant populations [Angastiniotis, Modell 1998] Migration during the twentieth century has introduced thalassaemia and other haemoglobinopathies into areas of Northern Europe and North America where the indigenous population had been relatively free from these disorders. As a result, these countries are now facing a series of problems in addressing the health problems that arise in immigrant populations. Although these countries have the means to provide adequate control, they face serious problems in reaching immigrant groups, which may be scattered throughout the host country. Such problems are mainly related to socio-economic status, birth-rates, language, and cultural and religious differences. Data from such countries (e.g. UK, Germany) strongly suggest underutilisation of available health services. Identification of the problems these minorities face should lead to improvement. Monitoring of the national effort through state registries of patients and of prenatal diagnoses, coupled with basic indicators such as number of carriers / carrier rate, pregnant carriers per year, annual at risk pregnancies, and affected births per year will help to focus attention on areas of improvement.
13
Clinical Management of Thalassaemia Prior to the 1970s, the prognosis of patients with thalassaemia was very poor. Death was expected to occur before puberty due to the pathophysiology of the disease. In severe untreated ‚-thalassaemia, erythropoiesis is dramatically accelerated, more than 95% of which may be ineffective due to the toxic effects of excess ·-globin chains which interfere with most stages of erythroid maturation. This severe ineffective erythropoiesis results in significant erythroid marrow expansion, the cause of the characteristic deformities of the skull and face, and marrow hyperplasia leads inevitably to increased iron absorption and its deposition in body tissues. Although initiation of blood transfusion therapy significantly increases life expectancy by controlling anaemia and its sequelae, this treatment also leads to progressive deposition of iron in the tissues, posing significant risk of severe cardiac, endocrinological, and hepatic complications, which are fatal if not prevented. Thus, iron overload, whether through increased iron absorption caused by erythropoietic activity or as a result of transfusional iron loading, constitutes the most important complication in ‚-thalassaemia and the major focus of clinical management. In the past 20 years, the treatment of thalassaemia major has improved tremendously in countries with access to adequate and safe blood and iron chelation therapy with desferrioxamine.
Standard iron chelation therapy with desferrioxamine The combination of blood transfusion and iron chelation is now the reference treatment for thalassaemia major. Blood transfusion is necessary to maintain a level of haemoglobin high enough to supply an adequate supply of oxygen to the tissues and to suppress the production of (defective) red cells [Porter 1999]. Supertransfusion regimens evolved between 1979 and 1981, shifting the goal from simply correcting symptomatic anaemia to systematically maintaining a minimum haemoglobin level above 12g/dl. While beneficial in combating anaemia, supertransfusion regimens increased the degree of iron
14
overload and its consequences. Therefore, current recommendations favour transfusion regimens maintaining a pre-transfusion haemoglobin level of 9-10.5 g/dl [Cappellinial 2000]. In addition, the early detection of iron-related complications is actively pursued, and their aggressive treatment has become standard practice. Desferrioxamine was discovered in 1960 and was introduced in 1962 as an intramuscular injection for iron chelation [Sephton-Smith 1962]. By the 1970s, it was clear that desferrioxamine given through this route decreased liver iron concentration and the risk of hepatic fibrosis in thalassaemia major [Barry et al 1974]. Propper, Schwin et al, in 1976, published data on the evaluation of continuous subcutaneous infusion which was later shown to maintain negative iron balance if 8-10 hour infusion time was used [Pippard 1978]. Evidence for improved survival in patients treated with desferrioxamine began to emerge in the 1980s [Modell 1982] and in the late 1980s and early 1990s, the full impact of desferrioxamine on survival was clearly documented [Zurlo 1989; Brittenham 1994]. The probability of survival free from cardiac disease has been shown to increase to 91%, provided that at least two-thirds of serum ferritin values remain below 2,500 Ìg/L [Olivieri et al 1994]. Recently, hepatic iron levels were shown to correlate well with the risk of clinical disease. Maintenance of hepatic iron concentration below 15 mg/g (dry weight) has been associated with decreased risk of severe cardiac disease and death [Olivieri 1999]. Iron chelation treatment should be started when serum ferritin levels reach about 1000 Ìg/L, which usually occurs after the first 10-20 transfusions (near 3 years of age). Desferrioxamine is infused via a thin needle inserted subcutaneously and connected by an infusion line to a portable pump. The infusion continues for 8-10 hours and is given 5-7 times per week at a mean daily dose of 20-50 mg/kg body weight. Urinary iron excretion of 0.5 mg/kg/day is generally indicative of negative iron balance. The dose of desferrioxamine should be adjusted according to body iron stores and age. Dose adjustment can be made with reference to the serum ferritin level using the therapeutic index [Porter 1989], as shown on the next page:
15
Figure 2: Therapeutic Index
Therapeutic index = mean daily dose (mg/kg)* ferritin (Ìg/L)
The aim is to keep the index < 0.025 at all times Using this index will assist in reducing the risk of toxicity associated with excess chelation. A scheme for adjusting the dose of desferrioxamine according to serum ferritin levels and clinical condition can be found in Excerpta Haematologica 1 (1999), "Current strategies and perspectives in thalassaemia treatment," by Dr. John Porter, published by Novartis Pharma AG.
*mean daily dose = actual dose received on each occasion x doses per week 7
16
The Importance of Iron Chelation Therapy In patients with thalassaemia major who are not receiving iron chelation therapy, the accumulation of iron will progress steadily and when about 20 g of iron have been deposited, severe clinical manifestations of iron loading may be anticipated. The most important complications of iron overload are cardiac, hepatic and endocrinological disorders.
Cardiac complications Pathologic findings include dilated thickened ventricular walls with particularly heavy iron deposits in the ventricles, epicardium, and papillary muscles. These cellular deposits induce increased membrane lipid peroxidation in the sarcolemma, resulting in impaired mitochondrial inner-membrane respiratory chain activity [Hershko, Koniju et al 1999]. Advanced cardiac siderosis results in heart failure and life-threatening arrhythmia. Myocardial siderosis is considered the single most important cause of mortality in inadequately treated patients. Fortunately, end-stage iron-induced cardiomyopathy is becoming less frequent as chelation is widely and continuously applied. Older patients dying from this complex have almost always been either non-compliant to desferrioxamine regimens or unable to comply. In patients receiving transfusion but not chelation therapy, symptomatic cardiac disease has been reported within 10 years of the start of transfusion [Olivieri 1999]. The strongest direct evidence supporting the beneficial effect of desferrioxamine in haemosiderotic heart disease is the reversal of established myocardiopathy in some advanced cases. Continuous 24-hour ambulatory intravenous infusion of desferrioxamine through central venous ports using standard portable infusion devices is a very effective method for the rapid reversal of established haemosiderotic heart disease. Moreover, this method of chelation has been associated with greater compliance, allowing uninterrupted delivery of 6-12 g of desferrioxamine per day and thus the effective depletion of very large
17
iron stores [Hershko, Koniju et al 1999]. It should be emphasized that such large doses should only be used for short periods of time to get over crisis stage of cardiac involvement. Prevention of iron-induced cardiac disease is the most important beneficial effect of desferrioxamine therapy and the greatest improvement in survival rates (Figures 3-5) is attributable to decreased cardiac mortality. Diagnostic tools to detect early cardiac dysfunction have not been routinely applied nor are they significantly predictive of subsequent cardiac events. However, investigators have reported that it may be possible to demonstrate early myocardial dysfunction in asymptomatic patients using MUGA scan or dobutamine stress echocardiography [Hershko, Koniju et al 1999]. At present, the most powerful and most commonly used predictive information for these patients includes transfusion records, serum ferritin measurements, and compliance to chelation regimens [Jessup, Manno 1998].
Endocrine complications Endocrine problems caused by iron accumulation in the endocrine glands, or indirectly through the hypothalamic / pituitary axis are common. Stunted growth, delayed puberty, hypothyroidism, hypoparathyroidism, and diabetes mellitus are well-recognised complications of transfusional iron loading. Significantly, diabetes and hypothyroidism generally manifest only after most endocrine cells have been destroyed and replaced by fibrosis. Such complications are rarely reversible. With the establishment of optimal chelation therapy with desferrioxamine in the past 20-30 years, patients with thalassaemia now achieve relatively normal growth. In most cases, these patients also obtain full sexual development, resulting in improved prognosis for fertility, and quality of life without these complications of iron overload. For example, the proportion of patients who spontaneously develop secondary sexual characteristics has gradually risen, although this improvement is more marked in females (70%) than males (40%). Insulin-dependent diabetes now affects only about 6% of patients
18
with thalassaemia major under optimal treatment regimens. This complication is much more likely in poorly chelated patients, although other factors such as family history and acute or chronic hepatitis may contribute.
Hepatic complications Iron-induced liver disease is another common cause of increased morbidity and mortality in these patients. Collagen formation and portal fibrosis have been reported within two years of initiation of transfusions, and if not prevented by effective iron chelation, this may lead to cirrhosis in the first decade of life. Iron per se may be responsible for the progression to cirrhosis in many cases, and as is also true with cardiac problems, its incidence is age-related. Some investigations have shown that the risk of fibrosis in these patients is augmented at body iron loads corresponding to hepatic iron content of >7 mg/g dry weight [Olivieri 1999]. The co-existence of chronic hepatitis B or C, the incidence of which ranges from 9% to 70% of patients with thalassaemia major in various geographic areas, aggravates iron-induced liver disease and is indicative of the complexity of this problem. Some investigators have thus proposed that the goal of iron chelation therapy should be to maintain hepatic iron content at approximately 3.2-7.0 mg/g dry weight of liver. Ferritin levels corresponding to these hepatic iron levels have not been clearly defined [Olivieri 1994].
Infections Hepatitis: A large number of investigations in recent years have focused on the role of iron in the severity and/or progression of chronic viral hepatitis (B or C) and on its effect on the response to antiviral treatment, particularly with ·-recombinant interferon [Bonkovsky and Bauer 1997]. Studies in patients with thalassaemia major, as well as in non-thalassaemic patients, have demonstrated the direct relationship of hepatic iron content to the severity of infection or liver histological activity, and its inverse association with the outcome of interferon therapy [Clemente 1994; De Virgillis 1981; Di Marco 1997]. In one study, reestablishment of iron chelation therapy
19
in patients with thalassaemia major infected with hepatitis C significantly improved hepatopathy and increased the rate of sustained response to antiviral treatment [Clemente 1998].
Such results demonstrate the importance of compliance to effective regular iron chelation regimens in achieving low hepatic iron levels. Chronic viral hepatitis, particularly hepatitis C, constitutes one of the most important causes of severe liver disease in patients with thalassaemia major and is the main reason for liver transplant. Iron loading not only exacerbates the damage caused by hepatitis, but also renders the treatment of this infection significantly less effective. By contrast, optimal iron chelation may significantly improve the prognosis in terms of progression, as well as the treatment outcome of chronic viral hepatitis. HIV: There is growing evidence of the role of iron in enhancing progression of HIV infection. Iron chelators have been used in studies of HIV infection in non-thalassaemics to investigate their possible role in delaying such progression [Delanghe 1998; De Monye 1999; Costagliola 1994; Boelart 1999; Salmon-Ceron 1995; Jacobs 1995]. It has been demonstrated that the progression to AIDS is delayed in those HIV-infected patients with thalassaemia major who adhere faithfully to chelation regimens using >40 mg/kg body weight/day of desferrioxamine and also maintain serum ferritin levels below 1935 Ìg/L [Salhi 1998; Costaglia 1994]. The effects of iron on chronic viral infections have been attributed to its direct role in viral replication and the rate of mutation, specifically in impairing significant host immune mechanisms, and non-specifically through hydroxyl-radical-related damage of important cellular components. It is appreciated that still other mechanisms not yet defined, and others less clearly understood, may also be involved, and results from such studies will shed more light in this area in the near future. Other infections: A number of other organisms become particularly virulent in the presence of iron overload. Moreover, there is some evidence for defects of neutrophil and monocyte function in thalassaemia. These patients may be more prone to severe clinical mani-
20
festations of infections caused by such microorganisms. Some studies in a non-iron-loaded environment have demonstrated the ability of desferrioxamine to hasten recovery from malaria, presumably by inhibiting parasitic growth. Desferrioxamine has also been shown to inhibit the proliferation in vitro and in vivo of other intracellular parasites such as Leishmania dovani, Trypanosoma cruzii, Pneumocystis carinii and Legionella pneumophilia. Iron chelators may open new horizons and channels for exploring the possibility of controlling infection by means of selective intracellular iron deprivation. In thalassaemia major, with its varying degrees of iron overload, adherence to standard iron chelation regimens becomes particularly important and may to a great extent prevent progression of infections caused by such pathogens.
Survival and compliance to chelation therapy The study on survival and disease complications in thalassaemia major by Borgna-Pignatti et al is the largest one to date, including 1,146 patients born with thalassaemia major from June 1, 1960 to December 31, 1987. Results are shown in Figure 3. [Annals of the New York Academy of Sciences 1998; June 30: 227-23]
Figure 3: Survival by birth cohort at different ages in patients with transfusion-dependent thalassaemia. Age (years)
1970-1974
1975-1979
1980-1984
10 15 20 25
98% 95% 89% 82%
98% (96-99) 97% (94-98) 96% (93-98)
99% (95-100) 98% (93-100)
(96-99) (92-97) (85-92) (77-86)
These results confirm the tremendous improvements in survival, with modern therapy making thalassaemia no longer a rapidly fatal disease. The majority of patients receiving optimal therapy now reach adulthood and are able to enjoy employment, marriage and a family. Nevertheless, even in patients with access to optimal therapy, the prevalence of complications is still high.
21
Figure 4: Causes of death reported in patients with thalassaemia born between 1960 and 1984, in order of frequency [adapted from Borgna-Pignatti 1998] Cause of death
Number
%
Cardiac causes Infections Liver disease Tumors Endocrine complications Thrombosis Unknown Anaemia Other causes
171 28 15 7 6 3 3 2 5
71% 12% 6% 3% 3% 1% 1% 1% 2%
The current emphasis in thalassaemia research is on containing, in as much as is possible, the complications of the disease that lead to a poor quality of life in these patients. However, even in countries where the standard recommended treatment is both available and affordable, there is overwhelming evidence that poor compliance to treatment is relatively common. This constitutes the most important threat for the occurrence of complications leading to increased morbidity and mortality in these patients. Figure 5: Survival as a function of compliance to iron chelation therapy in patients with thalassaemia major
22
What is Compliance? Compliance can be defined as the extent to which a patient’s behaviour coincides with the doctor’s prescription. In the case of thalassaemia, this is more specifically defined as the extent to which the patient adheres to the number of days per week, number of hours per day, and number of grams of desferrioxamine per infusion prescribed by the physician. Among the many factors associated with poor compliance, one important factor which is consistently cited is lack of knowledge about the disease and its outcome in the absence of treatment. Patients may be misled by the fact that poor adherence to iron chelation therapy generally has no immediate or overly negative consequences and, on the contrary, in many cases missing a dose may result in lessening of drug-related side effects such as pain. This temporary effect may lead patients to feel assured that missing doses is relatively harmless. Thus ñ reducing the frequency of doses and ñ failing to follow administration guidelines are the most commonly observed types of non-adherence in these patients. As discussed above, long-term compliance with chelation therapy has a significant effect on prognosis and must therefore be encouraged in every way possible. However, there is no perfect way to measure compliance, which makes verification problematic. One suggested approach is the use of a compliance index [Cohen, Cappellini et al 1999]: Figure 6: Compliance Index
Compliance index =
no. of days of treatment / year no. of days for which treatment is prescribed
23
The use of such an index implies that records are kept of the amount of treatment actually being used. One approach to collecting such data is to give the patient a calendar on which each infusion of desferrioxamine is noted down at the time given. Another possibility is to keep a record of empty vials returned to the provider of desferrioxamine at the time the new prescription is filled. Assuming an accurate record is kept, compliance can then be expressed as the compliance index, using the formula above. This information can be useful in keeping track of fluctuations in compliance over a period of time, which may be helpful in identifying particular events or situations that contribute to decreases in compliance.
24
Barriers and Aids to Compliance / Adherence Practical aspects of chelation therapy Chelation therapy is difficult and burdensome. The practical details of this treatment and the instruments with which the medication is administered are cumbersome and uncomfortable. The process itself is time-consuming, and must be repeated on a daily basis for the duration of the patient’s life. Moreover, the benefits of chelation therapy accumulate over the long-term so that neither the positive effects of adhering to therapy nor the negative effects of failure to adhere are readily apparent to the patient. In contrast, foregoing the treatment may provide short-term comfort and relief. This combination leaves the temptation towards reduced compliance with desferrioxamine therapy very strong [Politis 1998; Yamashita 1998]. It is essential that patients not only understand, but also come to accept the importance of adherence to chelation therapy in maintaining a good quality of life. Unless they really believe in the benefits of treatment, some lapses in compliance are almost inevitable.
Infusion device As described above, for chelation with desferrioxamine to be optimally effective, it must be delivered subcutaneously over a period of 8-12 hours daily. This requires the use of an infusion device to administer the medication at a steady rate throughout this period. The majority of these devices are battery-operated portable infusion pumps, which have a number of disadvantages, particularly for active young people: Restriction in activities: Although portable, the infusion device can place a certain amount of restriction on a patient’s activities. If used during the daytime, it is not always possible to participate in sports or other energetic activities at school or at work, because of the danger of damaging or dislodging the pump. Alternatively, the pump could be used during the night. However, many patients complain of not sleeping properly because of discomfort or noise generated by the infusion device.
25
Size of device: Infusion devices vary greatly in size and weight. Older models of pumps may be fairly large and heavy, and can be difficult to carry and cause conspicuous bulges under clothing. They may be uncomfortable or require adjustment in position as the patient moves and changes activities during the day. Newer pumps are considerably smaller and lighter. Balloon-style infusion devices are small enough to be concealed inside a sleeve, allowing greater freedom for the patient both in terms of movement and activities and in matters of discretion and confidentiality. Figure 7: Examples of infusion devices
Technical defects: Most pumps are fairly reliable. Nevertheless, like all mechanical and electrical devices they are subject to breakdown from time to time. This may be as simple as a dead battery, or a complex problem requiring the pump to be sent to the manufacturer for repair. Noise: This varies greatly depending on the model of pump used. Some patients with thalassaemia find this a sound that they can get used to and "tune out," while others find the sound of the pump irritating or embarrassing, particularly during the night or in situations where ambient noise is very low. Patients may feel that using the pump at work is not appropriate due to the noise it produces [cited during Jordan workshop].
Needle and infusion line Figure 8: Preferred needle types
26
Not a simple pinprick, the needle remains under the skin of the patient for the entire duration of the infusion. If the needle is not comfortably inserted, this can cause pain. Irritation at the site of infusion and local reactions can further aggravate discomfort. Needle type: It is important to explore different types of needles to find the one which is easiest for the patient to use, with the least possible discomfort. Many patients find the butterfly needle, which is inserted at a 45-degree angle below the skin, to be quite easy to use. Others may prefer a short pin-type needle which is inserted straight downwards into the skin and secured by a tape surrounding the needle. Infusion line: Although not often cited as a problem, some patients have reported relief from local reactions with the use of a filtered infusion line [Paravati 2000].
Availability of products Access to a variety of infusion devices and needles is limited in many countries due to funding allocation policies for medical care of thalassaemia by governments and insurers. Education of decision-making officials in these agencies is essential to ensure that these instruments are not viewed as an isolated expense. The cost of improved iron-chelation treatment should be weighed against the cost of treatment for complications of iron overload, which will inevitably develop with poor compliance. Although certain products may initially appear more costly, the long-term benefits of increased compliance through the use of these products will more than make up the difference in initial expenses.
Adverse / unwanted effects of desferrioxamine use [Porter 1999; Cappellini 2000] Most of the serious toxic effects associated with desferrioxamine therapy have been observed in patients using relatively high doses of desferrioxamine (>50 mg/kg/day) in the presence of only modest body iron burdens. Such effects include audiovisual disturbances, sensorimotor neurotoxicity, changes in renal function and pulmonary toxic-
27
ity. In young children, growth can be affected. However, desferrioxamine toxicity can be prevented by regular monitoring of body iron levels, with dose adjustment as appropriate, according to the therapeutic index (see Fig. 2). At standard recommended doses, adverse effects are generally reversible and can be managed as below. Local reactions: These can range from minor redness and itching, to bruises, pain, rashes and lumps. There are a number of possible factors which can affect the frequency and severity of these reactions: ñ Infusion strength – The recommended dilution of desferrioxamine is 10% (i.e. 5 ml of water for each 500 mg of drug). Local reactions are more common if the infusion exceeds this strength. Reducing the infusion strength by diluting the drug in a larger amount of water can be helpful. This may require the use of a larger syringe. ñ Infusion duration – Increasing the duration of infusion reduces the amount of drug passing through the skin at a given moment. This can help to prevent local reactions. ñ Infusion site – Certain parts of the body may be more sensitive to local reactions than others. This applies to sites recently used for infusion, and it is therefore best policy to rotate infusion sites as much as possible. Avoiding parts of the body where local reactions have been more common may help to reduce discomfort. Figure 9: Rotation of infusion sites
ñ Hydrocortisone – This can be applied to the site of local reactions as a topical cream after reactions have occurred and may help to
28
relieve the symptoms. In cases of severe reactions or reactions at several infusion sites, adding 5 mg of hydrocortisone to the infusion may help to prevent such reactions. ñ Topical anaesthetic – such as Emla® (generic name) cream can be applied approximately two hours before the infusion to help desensitise the infusion site and reduce pain. ñ Alternative route of infusion – Patients with high body iron burdens who reject infusion by the subcutaneous route or who suffer severe persistent local reactions may benefit from the use of a surgically implanted venous access port (e.g. Port-a-cath). This route of infusion is more often recommended for patients with very high iron burdens, as it allows for continuous infusion of desferrioxamine. Generalised reactions: These include fever and muscle aches, and on rare occasions anaphylactic reactions. Patients experiencing such reactions may be desensitised following published procedures [Miller 1981] and generally resume desferrioxamine treatment without further events. Infections: The most common of these is Yersinia species, particulalry Y. enterocolitica, a siderophore which can multiply rapidly in the presence of desferrioxamine. Patients who experience a high fever, diarrhoea and/or abdominal pain should discontinue desferrioxamine and see their physician immediately for evaluation and treatment of the infection. Desferrioxamine can be safely resumed once the full course of treatment has been given and symptoms of the infection have completely resolved.
Time considerations Preparation: Preparation of each day’s infusion takes approximately half an hour to reconstitute the drug, load the syringe and prime the pump, insert the needle and start the infusion. This time-consuming regimen is one of the most often cited reasons for non-compliance. The time required for preparation may be significantly reduced by usage of Desferal (desferrioxamine) 2g vials. Premixed infusions or pre-filled balloons (see "Infusion device" above) significantly reduce
29
the amount of time required to set up the infusion, and many patients have found these to be an aid in maintaining compliance. Regimens of continuous i.v. desferrioxamine infusion in which the infusion site is changed weekly by medical personnel eliminate the need for daily preparation of the infusion and can help to improve compliance. Such regimens require care of the infusion site and a weekly visit to the clinic, however, which should also be considered in evaluating the time factor. Infusion duration: Once initiated, the infusion must continue uninterrupted for 8-12 hours. One commonly cited reason for non-adherence is being "busy with other activities" which are incompatible with the use of the infusion device (see above). Many patients have found that it is more convenient to use the pump during the night, while others prefer to complete their infusion during the daytime. Adjusting the time of day of the infusion to suit the patient’s schedule and activities is very important. The use of a more "discreet" infusion device may be helpful, particularly for those patients who prefer to chelate in the daytime.
Psychological burden of chelation therapy In addition to the physical manifestations of chronic illness, both the disease and its treatment place an additional psychological burden on the patient and his/her family. Experience with chronic diseases such as diabetes, renal failure, tuberculosis and hypertension indicate that adherence to treatment averages 40-60% [Ball 1999]. Factors consistently associated with poor adherence in patients with chronic diseases include: ñ ñ ñ ñ ñ ñ ñ
Lack of knowledge about the disease Lack of awareness of the reasons for medication Anxiety about taking medication Concern or fear about side effects Health beliefs Complexity of regimen Poor doctor-patient relationships
All of these factors indicate that one of the primary goals of psycho-
30
logical support must be to ensure that patients are given all of the information they need about their disease, the recommended treatment (as well as other treatment options, if appropriate) and the reasoning behind the prescription of each medication they are to use. Patients must be given ample opportunity to ask questions and express concerns regarding their treatment, and should be given thorough and honest responses. Ultimately, patients will be responsible for their own adherence to therapy or failure to comply. In as much as possible, the treating physician should help them to retain a sense of control from the onset. In addition to the factors noted above, certain aspects of thalassaemia, and particularly of sub-cutaneous iron chelation therapy with desferrioxamine, are associated with particular psychological responses and concerns. Acceptance of the need for therapy: Knowledge about the reasons for iron chelation and the dangers of iron overload does not necessarily imply acceptance of this information [Yamashita 1998]. The first shock of diagnosis may leave parents feeling guilty and confused. These feelings can take a long time to overcome, and can be transferred to the young patient who may develop negative feelings as well. As patients reach the age where they begin to take over their own care, they may not yet have developed the maturity required to maintain a course of therapy whose effects are only visible in the long term. Since they see no immediate results from failure to adhere to treatment for a day or two, patients may feel that daily compliance is not really necessary. This is a factor of acceptance that the long-term consequences of iron overload will eventually affect them. Daily regimen: The daily need for repetition of this painful and timeconsuming regimen is a constant reminder to thalassaemics that they have a chronic disease. They may remove the pump or skip doses of desferrioxamine as a reprieve from feelings of "difference" and "illness" or just to live one day without having to think about thalassaemia. This can be ameliorated to an extent by attitudes in which patients view the treatment as a part of their lifestyle, keeping the focus on the other aspects of their life that good compliance makes better.
31
Limitations on activities: As discussed above, use of the infusion device may restrict patients’ participation in certain types of activities [Ratip and Modell 1996]. They may not sleep well at night due to noise or discomfort caused by the pump. They may feel "left out of the fun" others in their peer group engage in [Lightfoot 1999]. Intimate contact may not seem possible while using the pump. Experienced over a long period, these limitations on basic needs can lead to negative emotional reactions [Politis 1998]. Patients may forego treatment in order to enjoy pleasures they feel are denied to them. Adjustment in the chelation schedule or the use of an alternative infusion device may reduce these feelings of being "tied to the pump." Aggression: Insertion of the needle for the infusion punctures the skin and leaves a foreign object embedded in the patient. This can be painful, but even if not, implies an act of violence – however small or well-intended – which is inflicted on the patient on a daily basis. Moreover, this act of aggression is generally either self-directed or inflicted by the patient’s loved ones, and can lead to negative feelings and worsening of relationships within the family as the patient feels tortured rather than nurtured by those s/he cares most about [Cappellini 2000]. To counteract this reaction, it may be helpful for the patient to insert the needle, freeing the loved ones to provide unmitigated comfort. Body image damage: Chelation requires the patient to be punctured with a sharp needle on a daily basis. This may be painful, particularly on skin which may already be sore from bruises or local reactions such as lumps, rashes and itching. In addition, the daily puncture may cause the patient to feel less confident about his/her appearance. Patients may feel that they are "full of holes" or they may repeatedly choose the same sites for needle insertion in order to minimize the area of "damaged" skin. The latter can increase pain at the site of infusion as the area is not given a chance to heal before being "violated" again. Both the needle damage and the pain are likely to contribute to negative feelings and attitudes. Family relationships: It is important for the patient to be treated the same as all other members of the family. Under optimal therapy, patients with thalassaemia are able to engage in the same activities
32
as other children their age. They should have their equal role in household chores as well as family fun. They should have an equal degree of privacy and an equal degree of responsibility. From a young age (as early as 6 or 7) patients should begin to take over their own chelation therapy. This will help to balance family relationships so that feelings of being smothered, pampered or tortured because of the treatment can be avoided. Focus on illness: Patients and their families, partially because of the realities of treatment for thalassaemia, may find themselves focusing almost entirely on the disease and the various means of treating and coping with thalassaemia. While this may have its positive side in keeping them well informed about developments in clinical management, it can also have a negative side if the treatment becomes the most important aspect of the patient’s life. Patients may wonder "If this is all there is to life, why keep it up?" It is important that treatment be kept in perspective, as a means to improve patients’ quality of life so that they can get on with other, far more interesting, activities.
Social Concerns Community support: The community where the patient lives can have a tremendous supportive effect on the patient, or the exact opposite. In areas where thalassaemia awareness programmes have achieved a measure of success, members of the community are likely to have a greater understanding of the disease. Such communities will probably house established thalassaemia support associations and may very well organise regular activities within the community to promote awareness and encourage better treatment. Patients who are active members of such an organisation generally show better compliance and are better integrated into society. In these communities, patients’ perceived need to conceal evidence of the illness may also be greatly reduced. In other regions, particularly where thalassaemia is less prevalent, patients may feel isolated. There may not be any other thalassaemics living near them. Members of the community may not be aware of the disease and may react with surprise or negativity if they learn of
33
the patient’s thalassaemic status. In such a community, issues of confidentiality become much more important. Education: In countries where thalassaemia is relatively common (e.g. Cyprus, Italy), it has become standard practice to include a lesson on thalassaemia as part of the school curriculum. Children thus grow up with an understanding of the disease, which is helpful in generating community support, particularly during the critical adolescent years, when patients are particularly susceptible to peer group influence [Lightfoot 1999; Ratip and Modell 1996]. Relationships: The presence of the pump and the need for daily medication can make patients feel self-conscious around peers. This can have a negative influence on compliance if patients feel the need to remove the pump to "prove" to peers that they are "normal." In addition, patients may feel uncomfortable with intimate contact because of the pump and may avoid using the device while pursuing a relationship with the opposite sex [Vullo 1998]. Greater awareness about thalassaemia, for example through the educational programme described above, can help to counteract these reactions. In communities where there is a greater prevalence of thalassaemics, provision of a community centre or organised activities which allow thalassaemics to meet each other and exchange ideas, problems and solutions can be an important means of support. Such interaction gives patients an outlet to express feelings of frustration, anger and stress to people who understand from experience. Thus, these feelings can be dealt with before reaching harmful levels. Relationships as motivating factors: Being in love, starting a family and providing for them all give the patient a focus outside him/herself and entirely separate from thalassaemia, which provide a selfperpetuating reason to live and to actively pursue good health. Patients who plan a pregnancy may be more meticulous with treatment and more determined in adherence, in the knowledge that lowering iron levels beforehand will make the pregnancy safer and easier for both mother and baby. After the birth of the baby, compliance may be increased as the importance of maintaining good health and quality of life is now given the direct focus of keeping well to bring up the child.
34
Higher education and employment: Continuing to higher education, and/or professional development in a career are progressive acts which place an emphasis on long-term activities. As is true with building a family, by making an investment in his/her future professional life, the patient develops a reason for maintaining good health and a focus of attention which is separate from and unrelated to thalassaemia. This can also be a powerful motivating factor in improving compliance. Figures of respect: It is not uncommon for a patient to be told repeatedly by a physician about the need for adherence and the dangers of iron overload but to actually accept this information only after hearing it from an outside source. In particular, the opinions of other thalassaemics who "have been there" can be strongly motivating. The attitude of a prominent community figure (In some communities this could be a religious leader, in others perhaps a pop musician or film star.) can be seen as an endorsement of a particular behaviour or attitude. If these people can be encouraged to support thalassaemia and to stress the importance of optimal treatment it can have an extremely positive effect on compliance.
The medical community As has become clear from the above discussion, compliance is a multifaceted problem, the solution to which requires close interaction between the patient, the family and the medical community. In the words of TIF Board Member George Constantinou, "If this were a problem the doctors could solve on their own, it would have been dealt with long ago. But it isn’t." By the same token, it is not a problem that can be resolved purely by the patients either. Compliance is not merely a matter of will; practical aspects of the treatment make 100% adherence extremely difficult to maintain in the long term [Cappellini 2000; Yamashita 1998]. It takes concerted efforts on the parts of all concerned, and active investigation of possible solutions to find, on an individual basis, the pattern of therapy that best suits the needs of each patient. Physician-patient relationship: The quality of the physician-patient relationship may ultimately have the greatest impact on compliance.
35
The wide range of factors which may interfere with compliance, as described above, can vary from patient to patient, and across time periods for the same patient. It is important that the physician be familiar with the possible barriers to compliance and be flexible in trying to find solutions to these problems. Conversation with the patient must be fluid and two-sided: listening as well as recommending. Like other chronic patients, thalassaemics are generally well informed about their disease and about current research and developments in the field. Honesty is the best practice; suppression of negative medical information to "protect" the patient severely undermines a patient’s trust. Patients need to feel that the physician is accessible, and physicians should make themselves available to patients so that they will feel free to seek support in times of crisis. The office visit: Office visits should be scheduled to interfere as little as possible with other aspects of the patient’s life (e.g. school, work, family time) [Lightfoot 1999]. During the visit, not only should all the necessary medical examinations and interventions take place, but there should also be sufficient time allotted for the patient and physician to discuss the success or failure of the prescribed regimen since the time of the previous visit. Ideally, this should be a free discussion, where the patient can present the problems without accusation and the physician can offer suggestions without judgment. In reality, it is difficult to deal with many of the barriers to compliance discussed above unemotionally. Physicians should make every effort to comprehend the concrete causes behind the patient’s emotional responses and attempt to find practicable ways of dealing with the underlying source of the problem. "Anti-solutions:" Compliance is an emotionally charged topic. There is a tendency to tacitly encourage non-compliance in an effort to lessen the physical and psychological demands of chelation therapy [Cappellini 2000]. This should be discouraged. "Solutions" which decrease the efficacy of the therapy such as reducing the dose or the frequency of infusions are counter-productive as they give the message that the treatment is not really essential. The same is true for condoning "breaks" from therapy. When faced with such requests, it is important that the physician discuss them thoroughly with the patient to determine the underlying reason for the request. Then a solution can be found which deals with the root cause.
36
Relationship with nurses: This relationship can be at least as important for patients as interaction with the primary treating physician. Patients generally have more frequent contact with nurses, and often spend more time with them, particularly during regular transfusions. In addition to being more accessible, nurses may be seen as more sympathetic to problems with iron chelation therapy, since they are not directly responsible for prescribing it. Patients may more readily discuss problems they face in compliance with their nurses rather than directly with the physician. The nurse is therefore in the position to serve as a bridge between the patient and the physician, supporting their relationship and providing valuable information which may not come to light during the office visit. The nurse can fulfil an essential function in educating young patients and families about the treatment, while stressing that with proper therapy the child can grow, develop and live a normal life. Provided that the transfusion unit offers an appropriate setting, the thalassaemia nurse is in a unique position to arrange and supervise a support group for parents and thalassaemics. This opportunity to exchange information helps to ease tensions and concerns about the treatment and develop an atmosphere of familiarity and routine in chelation therapy [Yamashita 1998]. Patients can then view the treatment as a part of their lives and the lives of people they know, rather than a suffering imposed on them alone. For these reasons, it is very important that the nurse be kept involved in the patient’s treatment as much as possible, and that s/he be clearly informed about the details of chelation therapy, the reasons it is prescribed, expected results, and potential adverse effects. Nurse networking is also important in providing an opportunity for nurses working different shifts to compare observations and, on a larger scale, for nurses at different centres or in other countries to exchange information and share experiences and to learn from each other’s knowledge.
37
The Importance of a Dedicated Thalassaemia Centre The importance of a dedicated thalassaemia centre cannot be stressed strongly enough. These patients can be given an optimal prognosis when receiving regular care from specialist thalassaemiologists as part of a team of specialists covering all aspects of thalassaemia care and complications: Haematology, Endocrinology, Cardiology, Hepatology, Virology, Immunology and Psychology [Cappellini 2000; Vullo 2998; Ratip and Modell 1996]. Such specialist care can only be effectively given in a separate dedicated facility for patients with haemoglobinopathies. There are a number of important reasons that such a facility is absolutely necessary:
Continuity of care Thalassaemia is a chronic disease which can present a varying clinical picture from visit to visit. Physicians who are familiar with the longterm therapy of the patient can individualise treatment, avoiding the possibility of over or under-treatment of clinical change. With regular interaction, patients and physicians build up a relationship of mutual trust and can communicate more openly about problems faced with the treatment, mutually negotiating solutions. This need for continuity of care extends to nurses and other thalassaemia centre staff as well. Characteristically, in countries where such units have been long established it is not uncommon for patients to refer to the thalassaemia clinic as "our centre." The clinic staff can become like a second family, familiar with the patient’s needs and habits and able to react quickly and appropriately to provide support and guidance as needed. In this type of treatment setting, compliance is maximised as patients know very well who to turn to for solutions.
Separation from acute-care facilities Thalassaemia therapy is distinct from the treatment of acute illness in that the emphasis is on maintaining health rather than "getting bet-
38
ter and getting out". This type of maintenance treatment requires a different attitude on the part of both medical staff and patients. Ironically, it is often taking the focus away from the disease itself which proves most effective in maintaining compliance. It is also very important to separate these patients from acute cases so as to avoid unnecessary exposure to nosocomial infections.
Family and peer interaction The lifestyle aspects of this blood disorder need to be stressed. Because it is a genetic disorder, the family is involved not only in a support function, but also as potential carriers of the thalassaemia trait. There may be thalassaemic family members of varying ages, even across generations. It is extremely important that treatment be offered which utilises and enhances the potential for familial support – especially during the years when a patient is reaching adulthood and beginning to take over personal responsibility for his/her own care. At this stage, the positive influences of thalassaemics who have successfully made the transition to adulthood can be of invaluable benefit in ensuring that the patient retains hope for the future and maintains adherence to chelation therapy.
Transition from paediatric to adult care Classic adolescent rebellion can be an added problem for patients with thalassaemia which is often exacerbated by the organisational structure of traditional hospitals. In such a setting, the age at which patients are expected to change from paediatric to adult medical care, with a new primary treating physician, is also the age at which patients are likely to have the greatest psychosocial barriers to chelation therapy. This painful and time-consuming treatment is difficult to maintain even with a highly positive attitude and strong personal and medical support. Disruption of services during this delicate period could be catastrophic for the health of these patients. In a dedicated facility, the patient has a personal physician / haematologist who will see him/her throughout life from diagnosis to adulthood and into old age. Recognising the onset of adolescence, the
39
physician is in a position to help the patient through the transition to adulthood, as the young adult begins to take over his/her own care. In settings where patients must make the transition from paediatric care to adult haematological care, this should be done gradually and smoothly, with an intervening period where the paediatrician and the haematologist see the patient together [Ratip and Modell 1996]. In addition to allowing easier transfer of patient information and current regimens, this also provides the opportunity for the patient to develop a relationship as described above with the haematologist before interaction with the familiar paediatrician is withdrawn. Elements of successful transition programmes include the availability of a multidisciplinary team, appropriate integration of the patient into the decision making process, assistance for the patient’s family so that they can properly support the child, and increased staff training to effectively bridge the gap between paediatric and adult medicine [Weissman 1998]. Thalassaemics who are given proper regular continuous care from familiar medical practitioners throughout their lifetimes enjoy good health and a good quality of life, and they generally maintain better compliance. These patients have significantly fewer complications and are fully productive members of society, missing only an average of 10 – 12 days per year of school or work for routine care and monitoring. Patients whose care is not maintained steadily, or who are moved from clinic to clinic, or practitioner to practitioner have a much higher incidence of complications and of non-compliance, leading to significantly increased costs and notably reduced ability of the patient to live productively in society. Tables 1-3 at the end of this book provide a summary of issues affecting compliance, the physician’s role and possible solutions for patients of different ages. Through investigation of these issues as they affect each patient individually, the physician, the patient and the family can negotiate the best possible solution for improving compliance within the framework of the local medical system and products available.
40
Conclusions Responses by patients with thalassaemia to their two required therapies, blood transfusion and iron chelation, are often diametrically opposed. Almost all patients comply diligently to blood transfusion therapy, as this treatment provides immediate verification of its efficacy in a sense of greater well being. On the other hand, nearly all patients have had lapses in their adherence to iron chelation therapy at some time, as the efficacy of this treatment is not readily apparent, but the treatment can have a great impact on both the patient’s physical sense and his/her social condition. Beyond any doubt, the use of desferrioxamine in iron chelation therapy has brought about dramatic improvement in the survival of patients with thalassaemia. However, a number of factors related to practical and psychological aspects of treatment make this therapy very difficult to accept and more importantly to maintain consistently throughout the patient’s lifetime. Attacking the problem of compliance requires a comprehension of the patient’s cultural milieu, how they understand the disease and its management, what it means to their personal lives and how it impacts their everyday activities. Most of the problems associated with desferrioxamine treatment have been recognised long ago and are very familiar to patients and clinicians alike. With the organisation of workshops focused on compliance issues over the past year, however, even more problems have been identified. Encouragingly, these workshops were also extremely beneficial in pinpointing actions and attitudes which contribute to a solution. It is hoped that the suggestions presented in this book will greatly assist in the campaign for improvement. Nevertheless, efforts need to continue, reaching every corner of the earth where thalassaemia exists. The rigorous requirements of life-long use of portable pumps, and the high cost of chelation therapy are serious obstacles to its universal application, especially when the majority of patients with thalassaemia major are born in developing countries with very limited funding for the treatment of this disease. These limits extend not only to the purchase of expensive infusion devices but also to the provi-
41
sion of the drug itself. In this area, TIF and WHO still have a lot of work ahead. In view of these considerations, there is a great need for the development of alternative, orally effective chelating agents. In addition, the application of modern approaches such as the use of modulators of haemoglobin synthesis to decrease the need for transfusion need to be explored more thoroughly, as options for reducing the need for chelation. These and other solutions can help maintain the highest level of health in our thalassaemics during the interim as we continue research into a final cure for this disease.
42
TIF’s Plans for Establishment of Clinical Management Programmes and Improvement of Compliance to Desferrioxamine For countries with available "optimal" clinical management, TIF will continue to work closely with national thalassaemia associations to distribute information and to sensitise government officials to take action on the issue of compliance to desferrioxamine treatment. Through collaboration with manufacturers of thalassaemia-related products TIF will strive to improve the quality of delivery systems and needles. Although the fruits of such efforts will already bring about significant relief, further efforts will be made specifically directed towards reducing the psychological and social burdens of this disease. Additionally, in those developing countries where iron chelation with desferrioxamine has already been implemented as an essential part of the clinical management of patients with thalassaemia major (e.g. Iran, Jordan), and where the availability of desferrioxamine is therefore not the key problem, TIF will have to work hard and collaborate closely with national associations, the WHO, and physicians involved in thalassaemia to increase the awareness of government officials and health policy makers at the Ministry of Health level of the equal importance of the need for appropriate delivery systems to administer desferrioxamine and to ensure: ñ The purchase of infusion devices and needles, and where basic equipment is available ñ The improvement in quality of infusion devices and needles (see above) Furthermore, relief of pain and reduction of psychological and social burdens are also extremely important towards improving compliance in all communities and medical centres throughout each country. Continuing education of the government health policy makers
43
regarding technical improvements and new scientific developments is essential, in conjunction with reinforcement of prevention and clinical management programmes in these countries. Organised delegation visits, national and international workshops, distribution of educational materials, and frequent correspondence with national thalassaemia associations, Ministries of Health, and the World Health Organisation are among the means TIF already makes use of in its campaign to improve clinical management and compliance. TIF will continue the struggle to support our thalassaemics in these countries until thalassaemia is an established health priority in every country worldwide, with the highest degree possible of prevention, clinical management and compliance. Lastly countries in which clinical management of thalassaemia is not available are, unfortunately, often countries where the problem is severe. These countries need basic surveys to identify the magnitude of the problem, followed by the establishment of prevention programmes to cover all estimated needs and both aspects of prevention (screening and prenatal diagnosis). Concurrently, comprehensive programmes for clinical management must be put into effect. Regrettably, efforts to establish such programmes are often hampered by financial and cultural constraints. TIF is continually striving to sensitise international health organizations, the UN, the World Bank and others to the need for greater involvement in this area. Establishment and provision of continuous support to promote strong national thalassaemia associations is TIF’s main tool for achieving these goals. The direct relationship between the existence of a strong national association and a country’s success in establishing good prevention and clinical management programmes for thalassaemia has been shown again and again. TIF collaborates closely with WHO, governmental health authorities and national thalassaemia associations to put pressure on pharmaceutical companies to improve infusion devices and to continue their intense research into new sage and effective products with a more tolerable mode of delivery. Through all its activities, TIF’s ultimate goal is to promote the complete social and professional integration of thalassaemics into society and to provide motivation for them to believe in a positive future.
44
Table 1: Psychological issues affecting compliance
Psychological factor Age of patient
Possible strategy
Acceptance of iron chelation treatment
ñ Good physician/ patient relationship ñ Patient education ñ Peer patient support
Child Adolescent
Daily regimen is a constant reminder of disease
Child➔Adult
ñ Good support ñ Focus on treatment as part of lifestyle making other activities possible through better health
Damage to body image
Child➔Adult
ñ Better quality needles and filtered infusion lines ñ Sympathetic physician ñ Prompt treatment of local reactions
Physical presence of pump
Adolescent➔ Adult
ñ Use of smaller, more discreet pumps & chelation schedule to suit patient’s lifestyle
Physician collusion with patient
Child➔Adult
ñ Physician education: reasons behind non-adherence should be addressed directly
Iron chelation has no immediate effect
Adolescent➔ Adult
ñ Strong physician/patient relationship with support of nurse(s) ñ Awareness & discussion of the dangers of iron overload ñ Focus on long-term effects
Negative emotional state
Child➔Adult
ñ Good physician/patient/ family relationships ñ Peer and community support ñ Strategies to relieve stress
45
Table 2: Physician guidelines for improving compliance ❖ Treat each patient as an individual, not as a set of symptoms
Situation
Inappropriate approach
Better approach
Physician is faced with parents who feel guilty and under pressure
ñ Prescribe Desferal incorrectly (i.e. too little and/or too late)
ñ Ensure that the parents understand when and why iron chelation needs to begin and what the expected benefits of treatment are
Physician is faced ñ Tell the patient to with an adolescent “try harder next month” or young adult showing poor ñ Threaten the patient compliance with consequences of non-compliance
ñ Find out why the patient is not complying and look for solutions to the specific cause ñ Describe the potential future life of a patient who adheres to treatment and one who does not ñ Motivate the patient with the prospect of marriage/ family/education/career and other long-term goals if s/he maintains good health
Physician is faced ñ Offer hope of new with a patient who treatments still under finds iron chelation development or in increasingly painful planned research and tiresome
ñ Beware of offering false hope (adherence can drop if patients believe an easier new treatment is imminent) ñ Pay attention to the site of infusions and explore options to reduce local reactions (e.g. topical anaesthetic, hydrocortisone) ñ Consider ways to adjust the treatment to the patient’s lifestyle ñ Keep informed about new developments in treatment
See also Chapter 10 of TIF Guidelines for the Clinical Management of Thalassaemia for further recommendations
46
Table 3: Summary of factors affecting compliance and possible solutions
ISSUES AFFECTING COMPLIANCE Infancy ñ Illness and therapy are kept secret due to stigma attached to genetic blood disease ñ Reluctance to accept situation, fear of treatment ñ Start of chelation therapy
Adolescence ñ Physician seen as authority figure leading to rebellion ñ Physician viewed as judgemental rather than supportive ñ Feelings of isolation from peer group – desire to "belong" ñ Feelings of difference from other family members ñ Inability to fully participate in peer group activities ñ Feelings of awkwardness about using the pump in public Adulthood ñ Complacency derived from surviving to adulthood ñ Frustration with ongoing difficult treatment regimen
All ages ñ Pain due to delivery method and local reactions ñ Physician/nurse collusion with counter-productive approaches to relief ñ Time considerations ñ Negative feelings and reactions ñ Lack of community support
POSSIBLE SOLUTIONS
ñ Parent education: accurate and detailed information about the disease and prognosis improves motivation to comply ñ Support groups with nurses and parents of older thalassaemic children ñ Early start of chelation establishes the lifestyle more easily, and gives better clinical picture which helps motivate continued adherence
ñ Establishment of good physician /patient relationship before adolescence – listening to patient’s concerns (also non-medical) ñ Family membership in a thalassaemia association / support group ñ Assignment of regular family duties and responsibilities, inclusion in decisions ñ Use of more discreet infusion device ñ Encouragement to engage in personal development – planning for future and involvement in long-term activities
ñ Increased physician vigilance and reminders about the importance of chelation ñ Availability of more convenient methods of preparation and delivery of the drug ñ Strong family support and responsibility
ñ Use of topical anaesthetics, better needles, hydrocortisone or filtered infusion lines ñ Physician and nurse continuing education: important to keep up on new developments ñ Flexible scheduling for transfusions, chelation at times to suit the patient’s other activities (work, school, etc) ñ Patient support groups, family support ñ A dedicated thalassaemia center ñ Educational programmes on thalassaemia ñ Support from "figures of respect"
47
References Angastiniotis M and Modell B. "Global Epidemiology of Haemoglobin Disorders." Annals of the New York Academy of Sciences 1998; 850:251-269 Ball CS. "Patterns of adherence – not just to medication." The AIDS Reader 1999; 9:514-518 Barry M, Flynn DM, et al. "Long-term chelation therapy in thalassaemia: effect on liver iron concentration, liver histology and clinical progress." British Medical Journal 1974; 2:16-20 Boelart JR, Sperber K, et al. "Is there a place for chloroquine in treatment of HIV infection?" World Congress on Iron Metabolism: BIOIRON 1999, Sorrento-Naples, Italy Bonkovsky LH, Banner BF, et al. "Iron and Chronic Viral Hepatitis." Hepatology 1997; 759-768 Brittenham GM, Griffith PM et al. "Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassaemia major." New England Journal of Medicine 1994; 331(9):567-573 Cappellini N, Cohen A, Eleftheriou A, Piga A, Porter J (Eds). Guidelines for the Clinical Management of Thalassaemia. Thalassaemia International Federation 2000 Clemente MG, Congla M, et al. "Effect of iron overload on the response to recombinant interferon alpha treatment in transfusion-dependent patients with thalassaemia major and chronic hepatitis C." Journal of Pediatrics 1994; 123-128 Clemente MG, Baltoi R, et al. "·-interferon treatment in thalassaemia major patients with chronic hepatitis C and liver iron overload." Journal of Hepatology 1998; 28:191-200
Costagliola D, DeMontalembert M, et al. "Dose of desferrioxamine and evolution of HIV-1 infection in thalassaemic patients." British Journal of Haematology 1994; 87:849-52 Delanghe JD. "HIV infection and iron load." AIDS 1998; 12:1027 DeMarco O, LoIacono P, et al. "Long-term efficacy of ·-interferon in ‚-thalassaemia with chronic hepatitis C." Blood 1997; 90:2207-2212
49
DeMonyé C, Karchov DS, Boelart JR, Gordent VR, " Bone marrow macrophage iron grade and survival of HIV-seropositive patients." AIDS 1999 Feb 25; 13(3):375380 DeVirgillis S, Cornucchia G, et al. "Chronic liver disease in transfusion-dependent thalassaemia: liver iron quantitation." Acta Haematologica 1981; 65:32-29 DeVirgillis S, Fiorelli G, et al. "Chronic liver disease in transfusion-dependent thalassaemia." Journal of Clinical Pathology 1980; 33:949-53 Heer N, Choy J et al. "The Social Impact of Migration on Disease: Cooley’s Anemia, Thalassaemia and New Asian Immigrants." Annals of the New York Academy of Sciences 1998; 850:509-511 Hershko C, Koniju AM, et al. "Therapeutic potential of iron chelating drugs." Hematologia 1999; 3:67-71 Jacobs DP. "Randomization to iron supplementation of patients with advanced human immunodeficiency virus disease." Journal of Infectious Diseases 1995; 173:1044-1045 Jessup M, Mauno CS. "Diagnosis and Management of Iron-induced Heart Disease in Cooley’s Anemia." Annals of the New York Academy of Sciences 1998; 850:242250 Lightfoot J, Wright S, Sloper P. "Supoprting pupils in mainstream schools with an illness or disability: young people’s views." Child: Care, Health and Development 1999; 25(4):267-238 Miller KB, Rosenwasser LJ et al. "Rapid desensitization for desferrioxamine anaphylactic reaction." The Lancet 1981; (i):1059 (letter) Modell D, Letsky EA et al. "Survival and desferrioxamine in thalassaemia major." British Medical Journal of Clinical Resident Education 1982; 284:1081-1084 Olivieri NF. "The ‚-thalassaemias." New England Journal of Medicine 1999; 341:99-109 Olivieri NF, Nathan DG, et al. "Survival in medically treated patients with homozygous beta-thalassaemia." New England Journal of Medicine 1994; 331(9):574-578 Paravati C. "Compliance evaluation programme of micro-filtered infusion lines for delivery of iron chelating drugs to thalassaemia/sickle cell patients." TIF News 2000; 29:17 Pippard MJ, Callender ST et al. "Intensive iron chelation with desferrioxamine in
50
iron loading anaemias." Clinical Science and Molecular Medicine 1978; 54:99-106 Politis C. "The psychosocial impact of chronic illness." Annals of the New York Academy of Sciences 1998; 850:349-354 Porter JB. Current strategies and perspectives in thalassaemia treatment. Novartis Pharma Verlag, Excerpta Haematologica 1 1999 Porter JB, Jaswon MS, et al. "Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage." British Journal of Haematology 1989; 73:403-409 Propper RD, Shuriu SB, et al. "Reassessment of the use of desferrioxamine in iron overload." New England Journal of Medicine 1976; 294:1421-1423 Ratip S and Modell B. "Psychological and Sociological Aspects of the Thalassaemias." Seminars in Haematology 1996; 33(1):53-65 Salhi Y, Costagliola D et al. "Serum ferritin, desferrioxamine, and evolution of HIV1 infection in thalassaemic patients." Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1998; 18:473-478 Salmon-Cèron D, Fontbonne A, et al. "Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of pneumocystis carinii pneumonia." Journal of Infectious Diseases 1995; 172:656664 Sephton-Smith R. "Iron excretion in thalassaemia major after administration of chelating agents." British Medical Journal 1962; ii: 1577-1580 Weissman L, Treadwell M, Foote D, Heer N, Vichinsky EP. "Approaches to working with adult thalassaemia patients in pediatric settings." Annals of the New York Academy of Sciences 1998; 850:516-517 Vullo C, Zani B, DiPalma A. "Psycho-social integration of adolescents with transfusion dependent thalassaemia: The Ferrara experience." TIF News 1998; 23:32-3 Yamashita RC, Foote D, Weissman L. "Patient cultures: Thalassaemia service delivery and patient compliance." Annals of the New York Academy of Sciences 1998; 850:521-522 Zurlo MG, DeStafano P et al. "Survival and causes of death in thalassaemia major." The Lancet 1989; 2:27-30
51
TIF Board Members Mr Panos Englezos TIF Chairman 80 Arch. Makarios III Avenue (P.O. Box 1824), 1513 Nicosia - Cyprus Email:
[email protected] Mrs Shobha Tuli TIF President D-110 Panchsheel Enclave New Delhi – 110017, India Email:
[email protected] Mr. Constantinos Anastasiou TIF Secretary P.O. Box 28660, 2081 Nicosia, Cyprus Email:
[email protected] Mr. Riyad Elbard TIF Treasurer Thalassaemia Foundation of Canada 807-35 Empress Avenue Toronto, ON M2N 6T3, Canada Email:
[email protected] Email:
[email protected] Mr. Robert Ficarra TIF Board Member c/o Manrob Sales Corporation 108 West 39th Street, Suite 1001 10th Floor, NY 10018, U.S.A. Email:
[email protected] Email:
[email protected]
Ms Martina Fanari Vice President Thalassaemics India Fondazione Italiana "Leonardo Giambrone" per la Guarigione dalla Thalassemia, Via Livorno 30/b Sassari Sardinia, Italy Email:
[email protected] Mrs Katrina Demetriou TIF Board Member 19 The Broadway, Southgate Circus, London N14 6PH, UK Email :
[email protected] Website : www.ukts.org Ms Merulla Steagall TIF Assistant Treasurer ABRASTA Rua Pamplona, 518 – 5o andar CEP 01405-000 Sao Paolo – SP – Brazil Email:
[email protected] /
[email protected] Website: www.abrasta.org.br Mr. Odysseas Platis TIF Board Member POSMA: 11 Makedonias Street, 4 Tasker Road, Belsize Park, 10433 Athens - Greece Email:
[email protected]
Ms Dawn Adler TIF Board Member C/o Beltran , 4447 Cowell 47 Davis, CA 95616 U.S.A. Email:
[email protected] Mrs Fatemeh Hashemi TIF Board Member Charity Foundation for Special Diseases P.O. Box 15815-3333, Tehran - Iran Email:
[email protected] Mr, George Constantinou TIF Board Member 20 Corringham Road, London NW11 7BT, U.K. Email:
[email protected]
53
TIF Scientific Advisory Panel Dr. Androulla Eleftheriou TIF Scientific Coordinator Director, Virus Reference Laboratory Ministry of Health Thalassaemia Center Nicosia, Cyprus Phone: 357-2-493-600 357-2-319-129 Fax: 357-2-314-552 Email:
[email protected] Prof Bernadette Modell Honorary Advisor Emeritus Dept of Primary Care and Population Sciences Archway Resource Center, 2nd Floor Holbborn Union Building Whittington Hospital, Highgate Hill London N19 5NF, United Kingdom Phone: 44-207-288-5733 Fax: 44-207-281-8004 Email:
[email protected] Dr. Alan Cohen Haematology Division Children’s Hospital of Pennsylvania 34th Street and Civic Centre Boulevard Philadelphia, PA 19104-4399, USA Phone: 1-215-590-3437 / 590-3438 Fax: 1-215-590-3525 / 590-3992 E-mail:
[email protected] Dr. C. Th. Smit Sibinga BloedbankNoor Nederland Locatie Groningen P.O. Box 1191 9701 BD Groningen, The Netherlands Phone: 31-50-369-5555 Fax: 31-50-369-5556 Email:
[email protected] Dr. Vincenzo De Sanctis Divisione Pediatrica Azienda Ospedaliera-Archispedale S. Anna Corso Giovecca, 2034100 Ferrara, Italy Phone: 390-532-236-934 Phone : 31-50-369-5555 Fax: 390-532-247-107 Email:
[email protected]
54
Dr. George Stamatoyannopoulos University of Washington School of Medicine and Medical Genetics Box 357720, Room K253 Seattle, WA 98195-7720, USA Phone: 1-206-543-3526 E-mail:
[email protected] Dr. J. Dusheiko Prof. of Medicine & Honorary Consultant Royal Free Hospital The Royal Free Hampsted NHS Trust University College London Hospitals The Royal Free Hampsted NHS Trust Pond Street London NW3 2QG, United Kingdom Phone: 44-207-472-6169 Fax: 44-207-472-6184 Dr. Malcolm Walker Consultant Cardiology /Hatter Institute Cecil Fleming House University College London Hospitals Grafton Way London WC1E 6AU, United Kingdom Phone: 44-207-380-9756 Fax: 44-207-388-5095 Email:
[email protected] Prof. Renzo Galanello Ospedale Regionale Microcitemie Via Jenner (sn) 09121 Cagliari, Italy Phone: 390-706-095-508 Fax: 390-706-095-509 Email:
[email protected] Dr. Beatrice Wonke The Whittington Hospital St. Mary's Wing, Dept. of Haematology Highgate Hill London N19 5NF, United Kingdom Phone: 44-207-288-5144 / 288-5034 Fax: 44-207-288-3485
Thalassaemia International Federation (TIF) The Thalassaemia International Federation (TIF) was established in 1987 to improve awareness of thalassaemia and quality of life for thalassaemics. TIF is a Non Governmental Organization, in official relations with WHO since 1995. Currently TIF comprises Members - both thalassaemia associations and individuals from eighty-one (81) different countries, and this number is increasing rapidly.
The goals of TIF are to: ñ Motivate and support National Thalassaemia Associations. ñ Unite Associations from around the world in a co-ordinated struggle against thalassaemia. ñ Encourage governments and official national bodies to implement prevention and public education programmes regarding thalassaemia. ñ Promote and assist thalassaemia research; improve treatment protocols and support projects leading to a final cure for thalassaemia. ñ Promote collaboration with the World Health Organisation and other international health bodies. ñ Promote education, employment and integration of thalassaemics into society. In conjunction with its objective to promote thalassaemia research, TIF is involved in many different projects short term and ongoing in a wide range of areas. One of TIF's main objectives is the dissemination of standardised information on all issues related to thalassaemia. To this end, TIF publishes a variety of informational booklets, many of which are available in several languages. This book is only one of the many informational materials published and distributed by TIF. In addition to our published educational materials, TIF sponsors three main types of educational events, each intended for a specific section of the community concerned with thalassaemia: 1. Bi-annual International Thalassaemia Conferences 2. Annual International Workshops on Laboratory Aspects (May) 3. Annual International Course on Clinical Management of Thalassaemia (November) More information about TIF publications and workshops can be obtained by contacting TIF Headquarters. TIF's involvement in the international community of thalassaemics and those who support them extends in a variety of directions. TIF is there when you need us for: ñ Links with medical centres, commercial sources, support groups and other concerned parties. ñ Delegation visits by patients, scientists and TIF Board Members to local associations in various countries. ñ Participation in and organisation of scientific, educational and motivational events related to thalassaemia, particularly celebration of International Thalassaemia Day - May 8th. ñ Information related to specific aspects of thalassaemia, clinical management or complications. ñ Objective assessment of clinical trials by panels of scientific experts.
55
56
57
58
59
