Haemophilia care is complex, often requiring health management beyond the prevention and treatment of bleeding. Ad hoc trained haematologists and nurses have the knowledge and experience to address a wide range of haemophilia-specific needs [1,2]. Musculoskeletal experts, such as physical therapists, can help manage recovery from bleeding into joints and prevent chronic joint damage. Psychosocial support can be delivered by social workers and psychologists, as persons with haemophilia (PWH) often experience social stigma, vocational challenges and decreased quality of life [3]. Infectious disease specialists and gastroenterologists have been required to manage viral infections, such as HIV and hepatitis C.

As a result, care for PWH is often multidisciplinary and specialized. This model of care can be defined as ‘integrated care’, and is the most largely represented of the four principle care models for PWH available for adoption in the Western world. The integrated care model is usually delivered by Comprehensive Care Centers (‘comprehensive care’ is used as an alternative definition for integrated care), which provide all components of care (including supervision of home-based treatment) via coordinated and geographically co-located multidisciplinary teams. Comprehensive Care Centers coordinate care, secure and administer funding, provide technical assistance, organize professional education and training, and engage in data collection and analysis.

There are three alternative models of care. In a specialist-based care model, a haematologist, who may or may not have specialized training in haemophilia, provides care in a non-specialized centre, such as a hospital or medical office. Care delivered by a non-specialist in a non-specialist setting takes the form of a family physician delivering care in their practice, or an emergency room physician delivering care in an emergency room setting. The ‘no care’ model, with a complete absence of dedicated care, does not appear to be operating in the Western world, but exists in other areas of the world where PWH do not have access to care due to profound resource constraints [4,5].

While the integrated care model has been strongly supported by physician and patient organizations since its introduction in the United Kingdom in the late 1940s [6–9] and increased uptake in the 1960s and 1970s, and is currently widely accepted as the ‘de facto’ standard of care, there have been no attempts to systematically assess the evidence comparing the different care models for PWH. The aim of this paper is to report the results of a systematic review of the literature to assess the impact of haemophilia care models on patient-important outcomes.

This systematic review was performed according to methods in the Cochrane Collaboration Handbook [10] and reported according to the PRISMA statement [11], and was used to provide the evidence base for a guideline addressing the choice of care models for the management of haemophilia [12].

The literature search identified 6789 non-duplicate records. After title and abstract screening, 197 articles were assessed for eligibility with full-text review, and subsequently, 172 articles were excluded. Seven additional articles eligible for inclusion were retrieved during the process. As a result, 27 unique non-randomized studies (which were reported in 32 published articles) were included. A PRISMA diagram of the selection flow is provided in Fig. 1. Eight studies were comparative and 19 studies were single-arm non-comparative studies.

Characteristics of the included comparative and non-comparative studies are described in Table 1 and Appendix S2 respectively. The risk of bias of the comparative studies assessed using the ACROBAT-NRSI tool is presented in Table 2. We present a summary of the results from comparative studies in Table 3, and present the data from the non-comparative studies in Appendix S3. We reported the results with a study estimate or narrative, and did not perform a formal meta-analysis due to heterogeneity in the study designs and outcome definitions.

We found low- to very low-quality evidence that integrated care reduces mortality, emergency room and walk-in clinic visits, hospitalizations (and length of stay), missed days of school and work, and increases knowledge seeking. The evidence for the effects of integrated care on functional status, measured by joint damage or joint disease was less clear, and the analysis is likely confounded by disease severity. This means that the true effects of integrated care may be substantially different from what we found (i.e. overestimated or under-estimated). We also did not find evidence to compare the effects of integrated care to other models for quality of life, educational attainment and patient adherence.

This systematic review has two clear strengths: its rigorous methodology and its comprehensive scope. Our systematic search of electronic databases was supplemented with snowballing and broad expert consultation (useful strategies when addressing a rare disease). We did not restrict by study design and therefore believe that we have captured the current available evidence for care models in PWH. We used best-in-class tools to assess risk of bias and evaluate the quality of the body of evidence to interpret and present the current best evidence. Despite the comprehensive search, we found few comparative studies yielding a limited body of evidence, but allowing us to suggest several considerations for future research.

Limitations of the current body of evidence clearly indicate targets for improvement. The conduct of randomized controlled trials in health care services and different care models is possible but very challenging, as evident from systematic reviews of randomized controlled trials of health care models in other chronic conditions, such as asthma and chronic obstructive pulmonary disease [50–53]. The challenges would be even greater in haemophilia, where the rarity of disease, the long-term nature of the most patient-important outcomes (e.g. mortality or joint disease), and the widespread adoption of the integrated care model as standard of care would make a randomized trial almost impossible to perform. However, even where integrated care models are already in place, non-randomized studies comparing PWH attending integrated or non-integrated care are still feasible.

First, future attempts to more clearly define integrated and non-integrated care groups could be made. We found three studies by Soucie et al. [18,38,46] and another by Monahan et al. [28] that included large populations of PWH and compared the risk of many important patient outcomes between different uses of HTC and integrated care. Use and attendance at HTC were however, defined differently across these studies. Soucie et al. [18,38] defined their integrated and non-integrated care arms as patients attending HTC and non-HTC respectively. In contrast, the other studies did not define integrated and non-integrated care arms, and thus we reanalyzed their data to provide comparisons. Soucie et al. [46] and Monahan et al. [28] compared the frequency of HTC visits rather than HTC and non-HTC arms. To reanalyzed this data, we defined integrated care as equivalent to frequent HTC use (one or more visits per year) and non-integrated care as equivalent to infrequent HTC use (less than one visit per year) or first time visits. These were, admittedly, indirect measures of integrated and non-integrated care. Stemming from the literature we reviewed, integrated care would include supervision of the PWH by a coordinated and centralized multidisciplinary team. The integrated care model would include some or all of the following: provide home-based treatment, coordinated care and technical assistance; secure and administer funding; organize professional education and training; and engage in data collection and analysis. Therefore, in future studies, it will be important to provide details on which components and functions the specific integrated care model under study entails. The non-integrated care group would be further defined as the specialist-based care model that centres on a haematologist, who may or may not have specialized training in haemophilia, providing care in a non-specialized centre, such as a hospital or medical office; care delivered by a non-specialist in a non-specialist setting with a family physician delivering care in their practice, or an emergency room physician delivering care in a hospital; or the ‘no care’ model, in which there is a complete absence of care. Of course, integrated care models with different compositions or function could also be used as comparators.

Second, we found that the selected outcomes, and how they were defined and measured were very heterogeneous across studies, which essentially prevented us from pooling data across studies. Few to no studies reported on some of our set of outcomes, which were identified as important by key stakeholders [12]. Additionally, reported outcomes were measured differently from study to study. For example, missed days of school or work was measured continuously in days in some studies, but dichotomized as the number of people who had greater or less than a threshold value of missed days in others. In future research, we suggest that data should be collected and analyzed for standardized measures of missed days from work or school, length of in-patient stay, quality of life, joint damage and other functional outcomes, educational attainment, patient adherence, and patient knowledge. Reference to standardized international definitions can be of value [54].

Third, we had hypothesized that integrated care may have different effects in different populations with haemophilia, but we were unable to incorporate subgroup analyses into this review. There were a paucity of data from the studies to group by disease severity, age (in particular paediatric and geriatric groups), inhibitor status, ethnicity, comorbidities and access to care (i.e. insurance status). We found one large study showing that effects on joint damage or disease may be related to severity of haemophilia, but were unable to explore this further in other studies. In the future, studies addressing these principle subgroups would allow for analyses to determine the benefits or harms of integrated care models in specific populations.

To the best of our knowledge, this is the first systematic review to assess the impact of models of care delivery on important outcomes for patients with haemophilia. From its results, it is clear that care models in the management of haemophilia is a research topic that has been relatively neglected in the past, which is likely amplified by the rare disease setting. While the paucity of supportive evidence has not had a negative impact on the provision of integrated care, it should be noted that, at least in the US, approximately two-thirds of the haemophilia population receive care from an HTC [18], a figure that is certainly much lower in developing countries. Should further research reinforce integrated care as an important component of haemophilia management on patient-important outcomes, there may be important implications for future research to address and overcome barriers to HTC utilization, including the allocation of resources to areas that need this care. On the other hand, if further research changes the current favourable effects of integrated care, then it may be worth considering providing less costly and resource-intensive care models to specific patient populations, perhaps starting with those with low disease burden. Coordinated, well-funded, large-scale research initiatives to better understand the effect of care models in the management of haemophilia are worth being pursued and are urgently needed. On this note, this review provides a starting point and many suggestions for future research on integrated health care models in PWH.