Aging with Hemophilia: The Challenge of Appropriate Drug Prescription

Pier Mannuccio Mannucci.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca’ Granda Maggiore Policlinico Hospital Foundation, Milan.

Correspondence to: P.M. Mannucci. Via Pace 9, 20122 Milano – Italy. Tel. +39 02 55035421; Fax +39 02 54100125. E-mail: piermannuccio.mannucci@policlinico.mi.it   

Published: September 1, 2019
Received: July 11, 2019
Accepted: July 13, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019056 DOI 10.4084/MJHID.2019.056

This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(
https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In high-income countries persons with severe hemophilia (PWH) A and B are aging, like their age-matched peers without hemophilia from the general population. Aging is associated not only with the comorbidities stemming from their inherited bleeding disorder (arthropathy, chronic viral infections such as hepatitis and AIDS) but also with the multiple chronic ailments associated with aging (cancer, cardiovascular disease, COPD). Multimorbidity is inevitably associated with polypharmacy, i.e., the chronic daily intake of at least five drugs, and with the related risk of severe adverse events associated with the use of inappropriate drugs and drug-drug interactions. Information on the pattern of drug prescription and usage by PWH is relatively scanty, but on the whole, the available data indicate that the rate of polypharmacy, as well as the risk of drug-drug interaction, is relatively low in PWH and better than that in their age peers without hemophilia followed by general practitioners. It is believed that this advantage results from the collaborative coordination on drug prescribing exerted, through their integration with practitioners and organ specialists, by specialized hemophilia treatment centers in the frame of comprehensive care programs. However, the available cross-sectional data were mainly obtained in relatively young PWH, so that there is a need to obtain more accurate data from the ongoing prospective studies that are being carried out in more and more progressively aging PWH..



Introduction

In the last few decades, western societies have experienced dramatic improvements in life expectancy owing to the increased availability of efficacious drugs and vaccines, specialized medical care, higher standards of living and lifestyles. Indeed, population aging is accelerating not only in high income countries but also worldwide, from 461 million people aged over 65 years in 2009 to an estimated 2 billions by 2050.[1] Even some cohorts of patients with rare diseases, who previously had a short life expectancy due to inadequate treatments, recently witnessed miraculous progress in management, so that their life expectancy has much increased. This is epitomized by patients with hemophilia (PWH), the most frequent inherited bleeding disorder.[2] Before the first significant progress in replacement therapy that took place in the early 1970s, PWH had a short life expectancy at birth (20-30 years), and many of them died young due to life-threatening bleeding episodes.[3-5] Those who survived did inevitably develop gross joint damage (arthropathy) with associated musculoskeletal handicaps and chronic pain as consequences of recurrent and poorly treated hemarthroses.[5] Moreover, throughout the 1980s the epidemic occurrence of bloodborne infections was registered in many PWH following the transmission of the human immunodeficiency virus (HIV) and the hepatitis B and C viruses (HBV, HCV) by plasma-derived coagulation factors employed for replacement therapy. These infections caused not only high peaks of mortality in the 1980s-1990s[3,4] but also chronic infectious diseases (hepatitis and AIDS) with long-term morbidity in those PWH who survived.[2,4,5] Today the management of PWH has markedly progressed due to the wider availability and safety of plasma-derived and recombinant coagulation factor products, highly active antiviral drugs that eradicate or stabilize chronic infectious diseases and, most importantly, for the wider establishment starting from the 1970s of hemophilia treatment centers (HTC) offering specialized comprehensive care.[2] A direct consequence of the improvement in the clinical management of PWH is a current life expectancy similar to that of males in the general population, at least in high-income countries, and the parallel attainment of older ages much more often than before.[3-5] A current challenge is the novel presence of an expanding cohort of older PWH who carry not only the co-morbidities related to the natural history of their bleeding disorder (arthropathy and viral disease) but also the multiple chronic ailments associated with aging: chronic obstructive pulmonary disease, cancer, neurodegenerative diseases such as Parkinson and dementia, and cardiovascular diseases as myocardial infarction, atrial fibrillation and stroke.[6-8] Accordingly, more and more PWH need, besides specific factor replacement and antiviral therapies, other medications.[8] While there are cross-sectional data and review articles[6-8] on the multiple chronic diseases affecting the aging PWH, information on associated polypharmacy and related consequences is rather scanty.[9-12] Thus, there is a need to better understand whether or not the aging PWH are optimally handled with multiple drugs for their multiple concomitant illnesses, in order to avoid the deterioration of their bleeding tendency and of the existing comorbidities, as well as the adverse events due to the intake of potentially inappropriate medications and drug-drug interactions.
With this background and gaps of knowledge on the relatively new challenge of aging with hemophilia, this article has as first goal to update the patterns of chronic diseases associated with aging other than the congenital bleeding disorder, with special emphasis on cardiovascular disease and related risk factors. A subsequent goal is to evaluate to which extent older PWH take multiple medications, in addition to those specifically prescribed for the prevention and treatment of their hemorrhages and viral infections. Finally, a goal is to evaluate the appropriateness of multiple medication prescription (polypharmacy) in these older patients, who are likely to be particularly vulnerable to drug-drug interactions and related adverse events: not only due to the baseline impairment of their hemostatic system but also to the often impaired function of organs as the liver and kidney, which play key roles in the kinetics and dynamics of commonly used drugs.


Patterns of Chronic Diseases in the Aging PWH

As a preamble, we offer definitions on the differences between comorbidity and multimorbidity. Comorbidity is the concomitant presence of one or more clinical conditions co-occurring in an individual as a consequence of a primary disease: in PWH typical comorbidities are arthropathy and chronic liver disease.[13] Multimorbidity is not only the coexistence but also the complex interactions of two or more chronic conditions, which have no overt relationship with the primary disease but make more challenging its management.[13]
Barring the comorbidities typical of hemophilia, have the main diseases prevalent in older people without hemophilia have the same prevalence in PWH? This question applies not only to such frequent cardiovascular diseases as coronary artery and cerebrovascular atherothrombotic disease, atrial fibrillation and heart failure but also to cancer, chronic kidney disease, degenerative arthritis and diabetes. Because aging with hemophilia is a relatively recent picture, data are relatively scanty and published reports mainly stem from cross-sectional observational studies or case series that obviously have inherent limitations in design and case selection.[9-12] In most of them, the age limit to define older PWH is as early as 40-50 years. Even though these patients would not be defined old according to the commonly used criteria, this early threshold is meaningful in PWH, because those who have currently reached at least this or older ages were born at a time when regular replacement therapy with coagulation factors, and particularly their prophylactic use, was far from being largely available. In addition, the majority of them became infected with HCV and HIV in the 1970s and 1980. Thus, owing to the inevitable effects of associated chronic comorbidities (liver and kidney disease) these patients are aging earlier and are more frail and vulnerable at relatively younger ages than their age peers without hemophilia.
The great majority of the published reports are quite concordant to indicate that older PWH have a lower prevalence of morbidity and mortality from atherothrombotic cardiovascular diseases than age-matched peers from the general population.[9-12] Lower morbidity and mortality are usually attributed to the protective effect on thrombus formation by the lifelong deficiency of coagulation factors, particularly cogent in older PWH poorly treated until recently, considering that in them there is no lower prevalence of atherosclerosis[14,15] nor of the general cardiovascular risk factors,[9,12,16,17] except for lower serum cholesterol.[10,17] An important CVD risk factor as hypertension has a higher prevalence than in the populations taken for comparison,[9,10,17,18] even though the underlying reasons are partially elusive.[19] Pertaining to such other ailments frequently associated with aging as diabetes, cancer [20,21] and osteoporosis, PWH are not spared from them but evidence of substantial differences in morbidity rates from the general population is scanty. Arthritis is a very common and precocious consequence of the hemophilic arthropathy and the related chronic pain is looming large in PWH. Atrial fibrillation, a disease typical of aging, is less frequent, perhaps because the investigated cohorts included very few patients above the age of 80, when this cardiac arrhythmia reaches the very high rates of 10% or more. On the whole, there is a need for prospective cohorts studies or registries to accrue more data on the incident burden of cardiovascular disease and other ailments typical of aging in PWH. Some of these cohort studies are indeed ongoing in the frame of a joint UK-Dutch effort,[17] in the USA[18] and in Italy[22,23] (Table 1), and the clinical picture of older PWH at enrolment is published.[17,18,22,23] The prospective follow-up of these cases and the acquisition of the corresponding data on incident events should help to develop guidelines on management, that are currently lacking, particularly for coronary artery disease and atrial fibrillation,[24] or are based on the local experiences of a few large HTC.[25,26]


Table 1 Table 1. Features of the ongoing multicenter perspective studies on aging patients with severe hemophilia A and B.

Patterns of Drug Use in PWH

Polypharmacy, defined as the chronic daily intake of 5 or more different medications,[27] is very frequent in older patients with multiple chronic diseases, being the consequence of the application to these patients of the findings of randomized clinical trials, which in turn are the basis of the guidelines for evidence-based medicine.[27,28] Thus, multiple diseases are often handled by adding to the same multimorbid individual all the drugs that are recommended by guidelines for every single disease.[29] The snag is that randomized clinical trials are based on the enrolment and inclusion of patients widely different from the multimorbid older patients treated in real-life situations: younger, with a single disease chosen as the target of the investigated drugs, and with general clinical features that minimize the risk of drug-related adverse events. This explains why polypharmacy rather than helping older people with multiple disease has become a disease itself, with consequences more ominous than those of the single diseases for which those drugs were prescribed:[29-31] higher mortality, more hospital admissions and re-hospitalizations, the cause of up to 30% of unexpected adverse events, a higher risk of drug-drug interactions, poor treatment adherence and frequent drug intake errors.[29-32]
With this knowledge on the noxious effects of polypharmacy in older people, the peculiar cohort of older PWH is likely, as mentioned above, to be particularly liable to the consequences of polypharmacy, owing to underlying comorbidities and related dysfunction of key organs such as the liver and kidney. Despite these concerns, until recently there have been few reports on the prescription pattern of drugs other than those specific for hemophilia in the aging persons with this disease. In their cross-sectional analysis of older PWH conducted in the frame of a multicenter cohort study promoted by the American Hemostasis and Thrombosis Network (ATHN) Sood et al[18] compared 200 patients with a mean age at enrolment of 61 years with age-matched controls selected from two large ongoing US population studies (ARIC and NHANES). Pertaining to the usage of medications for cardiovascular disease, aspirin was used much more seldom in PWH than in the comparison ARIC and NHANES cohorts, and a similarly spare prescription and usage rates applied to blood pressure lowering drugs, glucose-lowering drugs in diabetes and statins in patients with hyperlipidemia (Table 2). These findings indicate that there is a tendency to use with caution cardiovascular medications in PWH, contrasting with the frequent use of these drugs in age-matched peers without hemophilia. In the report of the ATHN cohort, there is no information on the concomitant use of more than one drug and thus on the frequency of polypharmacy, the usage rate being reported as split by each class of medications. The issue of polypharmacy was first tackled by a pilot study conducted in a single HTC[33] and then in the context of the baseline data of the prospective SPHERA cohort of aging PWH regularly followed up in Italy by 14 HTC.[22,23] In their monocentric and retrospective cross-sectional study Riva et al[33] chose to obtain data on medications, together with other clinical and laboratory variables, from 135 PWH (with a mean age of 47,7 years, 27.4% of them being older than 55 years). On the whole, the drugs more often taken, particularly by patients older than 55 years, were antihypertensives (particularly ACE inhibitors) and proton pump inhibitors, whereas the use of anti-inflammatory and analgesic drugs was rather spare. Regarding polypharmacy, the rate of patients with this feature was low, being somewhat higher in older PWH (27% vs 16%).[33]


Table 2 Table 2. Medication usage at enrolment in aging PWH compared with age-matched controls from the US-based ARIC and NHANES cohorts.

The limitations of this exploratory study were subsequently addressed by an analysis planned and carried out in the context of the SPHERA prospective cohort, which included 102 older PWH (mean age 64 years) and 204 age- and-residence-matched older people without hemophilia chosen randomly by the same general practitioners of the PWH.[23] In broad agreement with the results obtained in the pilot study, PWH took in average less drugs than their age peers without hemophilia attended by the same practitioners. Barring the very frequently used drugs for replacement therapy and those for HIV and HCV infections, PWH took more frequently non-steroidal anti-inflammatory drugs and proton pump inhibitors than their non-hemophilic age-peers, who in turn used more statins, antihypertensive and antithrombotic drugs. Importantly, the prevalence of potentially relevant and dangerous drug-drug interactions was lower in PWH than in controls, in spite of the fact that they were both followed by the same general practitioners in the routine care and that hemophilia-related comorbidities accrued more illness to the PWH group. This low rate of potential drug-drug interactions can be taken as a proxy of appropriateness of the chosen drugs, suggesting that the difference favoring PWH is related to the fact that they are regularly followed not only by their practitioners but also by the specialized HTC. These data emphasize an additional and hitherto unknown benefit of the comprehensive care implemented by HTC, that have obviously added to their routine a process of evaluation of the risks carried by some drugs, and thus implemented deprescribing in order to limit drug use in these frail and vulnerable patients. It remains to be seen whether this optimistic picture is generalizable, particularly when PWH will become older. Data on drug intake are being actually collected in the SPHERA cohort also at the 5- and 10 years of follow up, when patients will be older, more likely to increase drug intake and thus more susceptible to the adverse effects of polypharmacy.

Conclusions

This report shows that at least in high-income countries and in the specialized HTC there is awareness that PWH are aging, and that this obviously favorable event demands a change in the practice of the specialized care of these patients, until recently mainly concentrated on the problems of pediatric and adolescent patients. The advent of highly active anti-HIV drugs in the middle 1990s and of drugs able to eradicate HCV in the last decade have dramatically changed the clinical picture of the corresponding chronic infections, that are well controlled for HIV and very often cured in HCV-infected patients. Arthropathy is being ameliorated by the feasibility and related implementation in PWH of arthroplasties of the knee, ankle and hip, and by multidisciplinary rehabilitation programs that, involving physiotherapists, psychologists, occupational therapists and geriatricians, are becoming more and more tailored to the need of older PWH.[34] This basically optimistic picture on the clinical future of PWH demands that, as recommended by the Council of Europe,[35] the comprehensive hemophilia treatment team involves afresh in the management of older PWH also generalist physicians such as internists and geriatricians, more experienced than pediatricians and hematologists in the specific management of complex older patients.[34,36] In this context, it is also important that the likely increased usage of multiple drugs associated with further aging is dealt with in collaboration with pharmacists and clinical pharmacologists. To my knowledge, there is at the moment no centenarian with hemophilia, but the more and more successful aging of these patients makes this event no longer unrealistic!

References   

  1. GBD 2017 Mortality Collaborators. Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1684-735. https://doi.org/10.1016/S0140-6736(18)31891-9
  2. Mannucci PM. Miracle of haemophilia drugs: Personal views about a few main players. Haemophilia. 2018;24:557-62. https://doi.org/10.1111/hae.13519 PMid:29808952
  3. Plug I, Van Der Bom JG, Peters M, Mauser-Bunschoten EP, De Goede-Bolder A, Heijnen L, Smit C, Willemse J, Rosendaal FR. Mortality and causes of death in patients with hemophilia, 1992-2001: a prospective cohort study. J Thromb Haemost. 2006;4:510-6. https://doi.org/10.1111/j.1538-7836.2006.01808.x PMid:16460432
  4. Darby SC, Kan SW, Spooner RJ, Giangrande PL, Hill FG, Hay CR, Lee CA, Ludlam CA, Williams M. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood. 2007;110:815-25. https://doi.org/10.1182/blood-2006-10-050435 PMid:17446349
  5. Mazepa MA, Monahan PE, Baker JR, Riske BK, Soucie JM; US Hemophilia Treatment Center Network. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood. 2016;127:3073-81. https://doi.org/10.1182/blood-2015-10-675140 PMid:26983851 PMCid:PMC4911863
  6. Philipp C. The aging patient with hemophilia: complications, comorbidities, and management issues. Hematology Am Soc Hematol Educ Program. 2010;2010:191-6. https://doi.org/10.1182/asheducation-2010.1.191 PMid:21239793
  7. Angelini D, Konkle BA, Sood SL. Aging among persons with hemophilia: contemporary concerns. Semin Hematol. 2016;53:35-9. https://doi.org/10.1053/j.seminhematol.2015.10.004 PMid:26805905
  8. Mannucci PM, Iacobelli M. Progress in the contemporary management of hemophilia: The new issue of patient aging. Eur J Intern Med. 2017;43:16-21. https://doi.org/10.1016/j.ejim.2017.05.012 PMid:28532688
  9. Kulkarni R, Soucie JM, Evatt BL; Hemophilia Surveillance System Project Investigators. Prevalence and risk factors for heart disease among males with hemophilia. Am J Hematol. 2005;79:36-42. https://doi.org/10.1002/ajh.20339 PMid:15849761
  10. Siboni SM, Mannucci PM, Gringeri A, Franchini M, Tagliaferri A, Ferretti M, Tradati FC, Santagostino E, von Mackensen S; Italian Association of Haemophilia Centres (AICE). Health status and quality of life of elderly persons with severe hemophilia born before the advent of modern replacement therapy. J Thromb Haemost. 2009;7:780-6. https://doi.org/10.1111/j.1538-7836.2009.03318.x PMid:19220727
  11. Franchini M, Mannucci PM. Co-morbidities and quality of life in elderly persons with haemophilia. Br J Haematol. 2010;148:522-33. https://doi.org/10.1111/j.1365-2141.2009.08005.x PMid:19958358
  12. Fransen van de Putte DE, Fischer K, Pulles AE, Roosendaal G, Biesma DH, Schutgens RE, Mauser-Bunschoten EP. Non-fatal cardiovascular disease, malignancies, and other co-morbidity in adult haemophilia patients. Thromb Res. 2012;130:157-62. https://doi.org/10.1016/j.thromres.2011.12.012 PMid:22209337
  13. Ording AG, Sørensen HT. Concepts of comorbidities, multiple morbidities, complications, and their clinical epidemiologic analogs. Clin Epidemiol. 2013;5:199-203. https://doi.org/10.2147/CLEP.S45305 PMid:23861599 PMCid:PMC3704301
  14. Zwiers M, Lefrandt JD, Mulder DJ, Smit AJ, Gans RO, Vliegenthart R, Brands-Nijenhuis AV, Kluin-Nelemans JC, Meijer K. Coronary artery calcification score and carotid intima-media thickness in patients with hemophilia. J Thromb Haemost. 2012;10:23-9. https://doi.org/10.1111/j.1538-7836.2011.04514.x PMid:21951861
  15. Tuinenburg A, Rutten A, Kavousi M, Leebeek FW, Ypma PF, Laros-van Gorkom BA, Nijziel MR, Kamphuisen PW, Mauser-Bunschoten EP, Roosendaal G, Biesma DH, van der Lugt A, Hofman A, Witteman JC, Bots ML, Schutgens RE. Coronary artery calcification in hemophilia A: no evidence for a protective effect of factor VIII deficiency on atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:799-804. https://doi.org/10.1161/ATVBAHA.111.238162 PMid:22173226
  16. Biere-Rafi S, Baarslag MA, Peters M, Kruip MJ, Kraaijenhagen RA, Den Heijer M, Büller HR, Kamphuisen PW. Cardiovascular risk assessment in haemophilia patients. Thromb Haemost. 2011;105:274-8. https://doi.org/10.1160/TH10-07-0460 PMid:21136012
  17. Fransen van de Putte DE, Fischer K, Makris M, Tait RC, Chowdary P, Collins PW, Meijer K, Roosendaal G, Schutgens RE, Mauser-Bunschoten EP. Unfavourable cardiovascular disease risk profiles in a cohort of Dutch and British haemophilia patients. Thromb Haemost. 2013;109:16-23. https://doi.org/10.1160/TH12-05-0332 PMid:23138324
  18. Sood SL, Cheng D, Ragni M, Kessler CM, Quon D, Shapiro AD, Key NS, Manco-Johnson MJ, Cuker A, Kempton C, Wang TF, Eyster ME, Kuriakose P, von Drygalski A, Gill JC, Wheeler A, Kouides P, Escobar MA, Leissinger C, Galdzicka S, Corson M, Watson C, Konkle BA. A cross-sectional analysis of cardiovascular disease in the hemophilia population. Blood Adv. 2018;2:1325-33.
  19. Holme PA, Combescure C, Tait RC, Berntorp E, Rauchensteiner S, de Moerloose P; ADVANCE Working Group. Hypertension, haematuria and renal functioning in haemophilia - a cross-sectional study in Europe. Haemophilia. 2016;22:248-55. https://doi.org/10.1111/hae.12847 PMid:27880029
  20. Franchini M, Lippi G, Montagnana M, Targher G, Zaffanello M, Salvagno GL, Rivolta GF, Perna CD, Tagliaferri A. Hemophilia and cancer: a new challenge for hemophilia centers. Cancer Treat Rev. 2009;35:374-7. https://doi.org/10.1016/j.ctrv.2009.01.001 PMid:19195788
  21. Astermark J, Makris M, Mauser-Bunschoten E, Nemes L, D'oiron R, Oldenburg J, Ingerslev J; Malignancy in Haemophilia Workshop Group. Malignant disease in the haemophilic population: moving towards a management consensus? Haemophilia. 2012;18:664-71. https://doi.org/10.1111/j.1365-2516.2012.02846.x PMid:22630161
  22. Marchesini E, Oliovecchio E, Coppola A, Santagostino E, Radossi P, Castaman G, Valdrè L, Santoro C, Tagliaferri A, Ettorre C, Zanon E, Barillari G, Cantori I, Caimi TM, Sottilotta G, Iorio A, Mannucci PM. Comorbidities in persons with haemophilia aged 60 years or more compared with age-matched people from the general population. Haemophilia. 2018;24:e6-e10. https://doi.org/10.1111/hae.13379 PMid:29271531
  23. Mannucci PM, Nobili A, Marchesini E, Oliovecchio E, Cortesi L, Coppola A, Santagostino E, Radossi P, Castaman G, Valdrè L, Santoro C, Tagliaferri A, Ettorre C, Zanon E, Barillari G, Cantori I, Caimi TM, Sottilotta G, Peyvandi F, Iorio A. Rate and appropriateness of polypharmacy in older patients with hemophilia compared with age-matched controls. Haemophilia. 2018;24:726-32. https://doi.org/10.1111/hae.13595 PMid:30112863
  24. Staritz P, de Moerloose P, Schutgens R, Dolan G; ADVANCE Working Group. Applicability of the European Society of Cardiology guidelines on management of acute coronary syndromes to people with haemophilia - an assessment by the ADVANCE Working Group. Haemophilia. 2013;19:833-40. https://doi.org/10.1111/hae.12189 PMid:23710576
  25. Mannucci PM, Schutgens RE, Santagostino E, Mauser-Bunschoten EP. How I treat age-related morbidities in elderly persons with hemophilia. Blood. 2009;114:5256-63. https://doi.org/10.1182/blood-2009-07-215665 PMid:19837978
  26. Schutgens RE, Tuinenburg A, Roosendaal G, Guyomi SH, Mauser-Bunschoten EP. Treatment of ischaemic heart disease in haemophilia patients: an institutional guideline. Haemophilia. 2009;15:952-8. https://doi.org/10.1111/j.1365-2516.2009.02020.x PMid:19473421
  27. Hajjar ER, Cafiero AC, Hanlon JT. Polypharmacy in elderly patients. Am J Geriatr Pharmacother. 2007;5:345-51. https://doi.org/10.1016/j.amjopharm.2007.12.002 PMid:18179993
  28. Maher RL, Hanlon J, Hajjar ER. Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13:57-65. https://doi.org/10.1517/14740338.2013.827660 PMid:24073682 PMCid:PMC3864987
  29. Tinetti ME, Bogardus ST Jr, Agostini JV. Potential pitfalls of disease-specific guidelines for patients with multiple conditions. N Engl J Med. 2004;351:2870-4. https://doi.org/10.1056/NEJMsb042458 PMid:15625341
  30. Garfinkel D, Mangin D. Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy. Arch Intern Med. 2010;170:1648-54. https://doi.org/10.1001/archinternmed.2010.355 PMid:20937924
  31. Carroll C, Hassanin A. Polypharmacy in the elderly-when good drugs lead to bad outcomes: a teachable moment. JAMA Intern Med. 2017;177:871. https://doi.org/10.1001/jamainternmed.2017.0911 PMid:28437544
  32. Leelakanok N, Holcombe AL, Lund BC, Gu X, Schweizer ML. Association between polypharmacy and death: A systematic review and meta-analysis. J Am Pharm Assoc. 2017;57:729-38. https://doi.org/10.1016/j.japh.2017.06.002 PMid:28784299
  33. Riva S, Mancuso ME, Cortesi L, Nobili A, Santagostino E, Peyvandi F, Mannucci PM. Polypharmacy in older adults with severe haemophilia. Haemophilia. 2018;24:e1-e3. https://doi.org/10.1111/hae.13262 PMid:28544483
  34. Boccalandro E, Mancuso ME, Riva S, Pisaniello DM, Ronchetti F, Santagostino E, Peyvandi F, Solimeno LP, Mannucci PM, Pasta G. Ageing successfully with haemophilia: A multidisciplinary programme. Haemophilia. 2018;24:57-62. https://doi.org/10.1111/hae.13308 PMid:28780767
  35. Giangrande PLF, Peyvandi F, O'Mahony B, Behr-Gross ME, Hilger A, Schramm W, Mannucci PM. Kreuth IV: European consensus proposals for treatment of haemophilia with coagulation factor concentrates. Haemophilia. 2017;23:370-5. https://doi.org/10.1111/hae.13211 PMid:28401658
  36. Grumbach K. Chronic illness, comorbidities, and the need for medical generalism. Ann Fam Med. 2003;1:4-7. https://doi.org/10.1370/afm.47 PMid:15043173 PMCid:PMC1466552