Received: July 11, 2019
Accepted: July 13, 2019
Mediterr J Hematol Infect Dis 2019, 11(1): e2019056 DOI 10.4084/MJHID.2019.056
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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..
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
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. 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, in the USA 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, or are based on the local experiences of a few large HTC.[25,26]
|Table 1. Features of the ongoing multicenter perspective studies on aging patients with severe hemophilia A and B.|
Patterns of Drug Use in PWH
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 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 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 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%).
|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. 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.
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