The Effectiveness and Efficiency of Disease Management Programs for Patients with Chronic Diseases

Objective: Disease management (DM) approach is increasingly advocated as a means of improving effectiveness and efficiency of healthcare for chronic diseases. To evaluate the evidence on effectiveness and efficiency of DM, evidence synthesis was carried out. Methods: To locate eligible meta-analyses and systematic reviews, we searched Medline, EMBASE, the Cochrane Library, SCI-EXPANDED, SSCI, A&HCI, DARE, HTA and NHS EED from 1995 to 2010. Two reviewers independently extracted data and assessed a study quality. Results: Twenty-eight meta-analyses and systematic reviews were included for synthesizing evidence. The proportion of articles which observed improvement with a reasonable amount of evidence was the highest at process (69%), followed by health services (63%), QOL (57%), health outcomes (51%), satisfaction (50%), costs (38%) and so on. As to mortality, statistically significant results were observed only in coronary heart disease. Important components in DM, such as a multidisciplinary approach, were identified. Conclusion: The evidence synthesized shows considerable evidence in the effectiveness and efficiency of DM programs in process, health services, QOL and so on. The question is no longer whether DM programs work, but rather which type or component of DM programs works best and efficiently in the context of each healthcare system or country.


Introduction
The growing burden of chronic diseases, such as coronary heart disease, diabetes mellitus, depression, asthma, cancer, and so on, has contributed to increasing healthcare costs in the past decades all over the world (WHO, 2005;Adeyl et al., 2007). The management of healthcare for persons with chronic diseases has advanced substantially in recent decades, yet these issues remain deficient. To improve systematically the quality and efficiency of healthcare for chronic diseases are critical problems for healthcare decision-making .
Numerous studies have been carried out to evaluate the impact of DM programs. However, the quality of these studies has varied very widely and the effectiveness of DM programs has remained undetermined (Walker et al., 2002;Linden et al., 2005). Moreover, recent large randomized trials of Medicare-coordinated care demonstration for DM under a fee-for-service context in the US failed to demonstrate effectiveness or cost reduction (Peikes et al., 2009). Those results have evoked a lot of controversies on the value of DM programs in the US (Ayanian, 2009) and have led to a focus on alternative approaches such as medical home (Rosental, 2008), care coordination (Boult et al., 2010), and transitional care (Naylor et al., 2004). However, while firm evidence on effectiveness and /or efficiency for these approaches is still lacking, recent analyses of the method of Medicare demonstration projects suggested that well-targeted DM efforts can be cost-effective (Brown, 2009). Therefore, to examine and summarize the existing evidence on effectiveness and efficiency of diverse DM programs, as well as DM's applicability to a healthcare system is extremely valuable to the formulation of future healthcare decision making and the exploration of possibilities for new approaches. The author has examined these issues before (Velasoc-Garrido et al., 2003), and indicated that most of the DM programs evaluated have been shown to improve the management of diseases, although there is insufficient evidence on mortality reduction, as the final outcome, and cost-effectiveness. Since then, numerous meta-analyses and systematic reviews of DM in several disease areas have been expanded and accumulated rapidly. This article critically evaluates and synthesizes the evidence on effectiveness and efficiency of DM programs from meta-analyses and/or systematic reviews available.

Methods
Since there is no consensus about the definition of disease management, we have done a systematic literature search for evidence from meta-analyses and/or systematic reviews relative to the effectiveness and efficiency of DM programs for chronic diseases, by using a broad definition of disease management with several key components (Hunter et al., 1997;Epstein et al., 1997;Ellrodt et al., 1997), as is mentioned before. The inclusion criteria for relevant articles were as follows: a reference to the definition of disease management, inclusion of more than one component of disease management programs, satisfaction for minimum requirement for meta-analyses or systematic reviews (e.g., explicit question and search strategy), and outcomes measures (e.g., patient outcomes or costs). As an exception, articles relative to the Chronic Care Model (Bodenheimer et al., 2002) were included, even if they did not refer to disease management. Articles with only specific and single intervention (e.g., self-management, case management, etc), or no outcome measure, and narrative reviews were excluded.
To identify articles as meta-analyses and/or systematic reviews of DM programs, we conducted systematic literature searches in several databases between January 1995 and May 2010. The former report confirmed that there was no relevant article before 1995. Firstly, as a preliminary search, we conducted a search in Medline with the following key words: 'disease management' and, 'meta-analysis' or 'systematic review'. Ninety-three articles were identified as meta-analyses or systematic reviews. Their contents were examined to construct a further literature search strategy and 8 key outcome items for data extraction: mortality, health outcomes, process, quality of life (QOL), satisfaction, knowledge or life-style change, health services, and costs.
Based on this result, the following databases were searched: Medline, EMBASE, SCI-EXPANDED, SSCI, A&HCI, Cochrane Library (Cochran Reviews, DARE, HTA, NHS EED). We constructed a search strategy by using combinations of the following keywords: "disease management or disease management programs", "comprehensive multidisciplinary program", "case management or case management program", "care management or care management program", "chronic disease", "meta-analysis", and "systematic review".
A preliminary review was done to decide key outcome items, which were relevant for evaluating disease management programs. The following 8 items were identified: mortality, health outcomes (e.g., morbidity, disability and function), process (e.g., compliance or adherence to guidelines), quality of life, satisfaction, knowledge or life-style, health services (e.g., hospitalization or admission), and costs. Data on 8 key outcome items were extracted by two researchers, independently. Discrepancies were resolved by consensus development between them.
The quality of meta-analyses and systematic reviews were explicitly assessed according to the guide developed by the Evidence-Based Medicine Working Group (Oxman et al., 2002). Two items (i.e., validity and contents of results) and their 7 sub-items among three items in this guide were used to assess the quality of these analyses and reviews. The item related to applicability was excluded, since this item mainly depended on the context of each user. The proportion of sub-items satisfied by each paper was more than 70%, although the sub-item for precision of results was not applicable to qualitative reviews.
The data obtained were analyzed and presented according to the following items: the definition and components of DM, the effectiveness and efficiency of DM programs, the features of interventions in DM programs and economics of DM programs. This study was carried out between June 2010 and April 2011. Table 1 shows the definitions of DM programs cited among all 28 articles evaluated. Although there was something similar among them, there existed no common definition of DM, and a considerable variation was observed, strictly speaking. While seven articles had their own definitions (Gohler et al., 2006;Whellan et al., 2005;Phillips et al., 2005;Maciejewski et al., 2009;Nori et al., 2002, Neumeyer-Gromen et al., 2004Badamgarav et al., 2003a), four articles (Gonseth et al., 2004;Niesink et al., 2007;Weingarten et al., 2002;Ofman et al., 2004) adopted the definition of Weingarten (2002) and four articles (Lemmens et al., 2009;Steuten et al., 2009;2007;Krause, 2005) adopted that of the Disease Management Association America (2003). Three articles (Jerant et al., 2005;Ara, 2004;Knight et al., 2005) referred to the same definition of Epstein (Epstein et al., 1996). Also, three articles (Yu et al., 2006;Peytremann-Bridevaux et al., 2008;Badamgarav et al., 2003b) adopted that of Ellrodt (1997) and two articles (McAlister et al., 2001b;Sin et al., 2003) that of Hunter (1997). One specific definition of the chronic care model was mentioned in three articles (Adams et al., 2007;Steuten et al., 2009;Tsai et al., 2005). This definition did not use the expression of DM, but what it specified could be classified as DM in a broad sense. On the other hand, there was no explicit statement about the definition in three articles (Roccaforte et al., 2005;McAlister et al., 2001a;Taylor et al., 2005).

Definition and Components of Disease Management
Despite the diversity of the definition of DM, several key components were mentioned in the definitions of DM as follows: systematic, comprehensive, population-based, multi-components, coordinated healthcare, specific disease entity, continuous quality improvement, multidisciplinary, practice guidelines, patient and/or provider education, and so on ( Table 1). As is shown in Table 2, in each article, several key words were used for searching relevant articles for meta-analyses or systematic reviews on DM as follows: disease management, case management, comprehensive health care, health service research, multidisciplinary care, guidelines, home care services, patient care planning, primary care nursing, and so on.

Effectiveness and Efficiency of DM Programs
a. Overall Studies Table 2 shows the characteristics of DM programs, main results and conclusions among articles (i.e., 20 meta-analyses and 8 qualitative systematic reviews). Table 3 shows the summary of important outcomes in DM programs. Details of improvement in each article and in each item are shown in Table 2.
If improvement with limited evidence (indicated by △? for qualitative review) was included, this proportion increased, and ranged from 100% (satisfaction) to 20% (mortality). In particular, the proportion in satisfaction, QOL, health services, and knowledge or life-style increased respectively to 100%, 81%, 81% and 70%. On the other hand, if improvement was limited only to results with statistically significance by meta-analysis (○symbol), the proportion decreased and ranged from 50% (health outcome) to 10% (knowledge or life-style).
The proportion of articles which observed improvement with considerable evidence was the highest for process (100%, 3/3) and health outcomes (100%, 2/2), followed by knowledge or life-style (67%, 2/3). Those in QOL, satisfaction, health services and costs were 0%. Mortality was not evaluated. If improvement with limited evidence was included, the proportion in knowledge or life-style, QOL, satisfaction and health services increased to 100%.

Features of Interventions in DM Programs
While the types of interventions in DM programs were summarized in Tables 2, the results related to specific interventions by meta-analyses and qualitative reviews are shown in Table 4. The proportion of articles which examined effect or impact of specific interventions in DM programs was 43% (12/28).
Multidisciplinary team approaches (Gohler et al., 2006;Roccaforte et al., 2005;McAlister et al., 2001a) were the most frequently indicated intervention which were related to health outcomes (e.g., mortality or morbidity) and health services utilization (e.g., hospitalization). Also, multi-component programs (Lemmens et al., 2009;Adams et al., 2007;Tsai et al., 2005) were mostly shown or suggested to be effective in QOL, health services, and other items, in both usual DM and CCM programs.
On the other hand, while disease severity as a target of DM programs played an important role (Krause, 2005), high quality of studies (Roccaforte et al., 2005) and long term interventions (Roccaforte et al., 2005;Taylor et al., 2005;Badamgarav et al., 2003b) were important factors for evaluating effectiveness.

Economics
The economic evaluation of DM programs was reported in 16 articles (Tables 3 and 4). The proportion of articles with considerable evidence, indicating some form of favorable effects, was 38% (6/16). If articles with limited evidence were included, the proportion increased to 50% (8/16).

Study Design and Quality of Studies Reviewed
The main types of study design of studies reviewed among the articles were randomized controlled trials (RCTs), controlled trials (CTs), cohort studies and before-after studies ( Table 1). As is shown in Table 1, the proportion of articles, which included only RCTs (or experimental studies) and RCTs or CTs (or quasi-experimental studies) were 43% and 64%, respectively. The former proportion varied from 100% to 19%. Table 4 shows information on the results of reviewing the quality of studies included in each article. The proportion of articles evaluating quality of studies was 61% (17/28). While the Jadad score (1996) was used in about one third of quality evaluations (Phillips et al., 2005;Gonseth et al., 2004;Peytremann-Bridevaux et al., 2008;Taylor et al., 2005;Taais et al., 2005;Ofman et al., 2004), other criteria such as the HTA Disease Management (Steuten et al., 2004), the Cochrane Collaboration Handbook (2006) and the evidence-based Guide to Community Preventive Services-method (Briss et al., 2000) were also used. The proportion of studies with high or good quality, according to the criteria used, varied widely form 20% to 80%.

Discussion
The synthesis of meta-analyses and systematic reviews on DM programs showed considerable evidence of their effectiveness on outcomes from healthcare outcomes, health process and health services, to knowledge, satisfaction, QOL and costs (Tables 2-4). Even if only meta-analyses were examined, similar results were obtained. However, as to mortality, evidence is very limited and inconclusive. Two recent meta-analyses (Gohler et al., 2006;Roccaforte et al., 2005) showed statistically significant mortality reduction. These results were mostly shared among subgroups of target diseases, such as CHD, COPD, diabetes and depression. The evidence of DM programs for rheumatoid arthritis is very limited.
An earlier synthesis report about DM programs (Velasoc-Garrido et al., 2003), based on only four systematic reviews available at that time, was unable to draw definitive conclusions about diverse outcomes of DM programs. Incorporating meta-analyses and systematic reviews over the past seven years, this synthesis could analyze the evidence on effectiveness and efficiency more deeply and comprehensively. However, the results of this study should be carefully examined for application to healthcare decision making.
First, DM programs vary widely in their structure, and are hard to describe with a single definition, since they usually contain many components. In this analysis, there existed no common definition of DM, and a considerable variation was observed (Tables 1 and 2). Also, diverse key words for searching literature on DM were differently mixed and used (Table 2). These different definitions and search strategies may lead to the inclusion of different studies and yield different results. While these results depend on the specific operational definition of DM, the effects of DM programs among different articles seem to be relatively similar (Table 3). However, there is an urgent need to develop a consensus on the more systematic or common concept and classification of DM programs, to allow for more reliable and valid analyses and comparisons.
Second, it is difficult to confirm the relative effectiveness and efficiency of the types, components or interventions of DM programs. In this synthesis, each article adopted its own components or interventions of DM programs (Tables 2 and 3 These articles compared different components or their combinations, arbitrarily rather than systematically or comprehensively. The analysis of components indicated the statistically significant impact of the following components or interventions: multidisciplinary team interventions, clinical follow-up by a specialist, home visit or telephone follow-up, discharge planning and post-discharge follow-up, delivery system design, self-management, decision support, and so on (Tables 2-4).
This evidence obtained is closely related to the six components that appear to influence of effectiveness of DM after detailed analyses of Medicare demonstration projects after their failure (Brown, 2009). Also, new developments for chronic disease care, such as medical home (Rosenthal, 2008), care coordination (Boult et al., 2010) and transitional care (Naylor et al., 2004) shared a lot of components with DM programs in these articles reviewed, although the emphasis on components and their structure are very different among these approaches and DM programs. On the other hand, as to each component adopted by existing DM programs, there is evidence based on systematic reviews in self-management (Chodosh et al., 2005;Warsi et al., 2004;Blaiss, 2004, Monninkhof et al., 2003, care management (Windham et al., 2003), case management (Norris et al., 2002;Ferguson et al., 1998), multidisciplinary care (Philbin, 1999;McAlister et al., 2004) and integrated care (Owens et al., 2005).
Although these findings give an insight into the effective components of DM programs, the evaluation of components or interventions, as well as their combinations, is still in its infancy. It is not possible to draw conclusions about essential components or their ideal combinations for DM programs. A future challenge is the need to develop and implement more systematic and comprehensive analyses on components of DM programs.
Third, careful examination about the types of study design and their quality is the basis of evaluation of DM programs. In evaluating effectiveness of healthcare, RCT is recognized as a gold standard of a hierarchy of strength of evidence (Guyatt et al., 2002). The main types of study design for evaluating DM programs in this synthesis were randomized controlled trials (RCTs) and controlled trials (CTs), which comprised 43% to 64% of studies evaluating DM programs among the articles reviewed. The proportion of studies with high and good quality varied from 20% to 80%.
These figures are not satisfactory to assure the validity of studies evaluated by the articles. However, they should be cautiously interpreted. The assessment of complex multi-component interventions and diverse measures of outcomes are methodological challenges unique to organizational or community interventions like DM programs. Although well-conducted RCTs provide the most reliable evidence, these are not always feasible for interventions in this situation. Also, RCTs may increase the internal validity, while decreasing the external validity. Corresponding to this challenge, the guide for allowing non-randomized controlled trials or observational studies is proposed by the Cochrane Effective Practice and Organization of Care Review Group (EPOC) (Cochrane Effective Practice and Organization of Care Review Group) and the Task Force on Community Preventive Services (Briss et al., 2000). Moreover, from the perspective of recent argument on comparative effectiveness study, practical trials or advanced observational studies would be more suitable for evaluation of DM programs (Dreyer et al., 2010).
The additional important issue related to study design is the unclear status of comparators. The studies in the reviews included in the articles used mostly compare DM programs with usual care. However, the organization and provision of usual care differs across and within healthcare systems. Therefore, precise components and interventions of usual care should be described and evaluated simultaneously. In evaluating DM programs, application of these criteria and consideration of comparators would increase feasibility and flexibility of evaluation and enable the evaluation to reflect the comprehensive view of effectiveness and efficiency of DM programs.
Forth, the most controversial outcomes in DM programs are mortality and cost-effectiveness. In this analysis, although the effectiveness of DM programs has been shown on health outcomes, process and services, only two meta-analyses demonstrated statistically significant mortality reduction in coronary heart diseases (Gohler et al., 2006;Roccaforte et al., 2005). In COPD, four meta-analyses failed to demonstrate significant decrease in mortality, although relative risks of mortality were less than 1 (Peytremann-Bridevaux et al., 2008;Adams et al., 2007;Taylor et al., 2005;Sin et al., 2003). There may be several explanations. Most analyses did not have a large enough sample size to detect a mortality reduction. Also, the follow-up period of the studies was relatively short. The average follow-up of most studies is less than 12 months. A large study population with long-term follow-up would be needed to evaluate actual impact of DM programs on mortality.
The number of meta-analyses and systematic reviews of economic evaluation of DM programs are relatively limited (Tables 3-4). The proportion of articles with favorable effects in costs or cost-effectiveness was 38% in this analysis. However, there were few articles which evaluated formally and comprehensively economic results. Economic evaluation is defined as the comparative analysis of alternative courses of action in terms of both their costs and consequences (Drummond et al., 2005). Since most studies of economic evaluation on DM programs focused only on costs, they are classified as partial evaluation (e.g., cost analysis), rather than full economic evaluation (e.g., cost-effective and cost-benefit analysis) (Drummond et al., 2005). Furthermore, where costs were examined, undefined or very limited cost items, such as medical care costs, were evaluated in the articles. The implementation of DM programs requires substantial investments in development of a program, and additional human or organizational costs for implementing it (Kesteloot, 1999). A recent review (Goetzel et al., 2005) on return on investment (ROI) of DM programs reported a positive ROI in congestive heart failure and multiple diseases, but the range and detail of costs and benefits was unclear and limited under a financial point of view. Therefore, the cost savings or cost-effectiveness of DM programs still remained undetermined, and formal full economic evaluations are needed.
Finally, the generalizability and transferability of the findings in this synthesis has not been examined for applying them within and across countries. While DM programs have continued to evolve and mature over time and places, with failure and success, they have diffused from the US to other countries such as the UK (Departement of Health, 2002;Mason et al., 1999), Germany (Busse, 2004;Boseken, 2003), the Netherlands (Vrijhoef et al., 2001), Canada (Tsasis et al., 2008) and developing countries (WHO, 2002). In fact, many studies evaluating DM programs have been already carried out in other countries. For example, in a comprehensive systematic review (Roccaforte et al., 2005;Gonseth et al., 2004;Weingarten et al., 2002), while about a half of the studies came from the US, the other half came from the UK, the Netherlands, Sweden, Australia, Canada, Finland, Argentina, New Zealand, Italy, Israel, and so on. Therefore, much effort should be made towards examining generalizability or transferability of evidence about DM programs, according to the characteristics and context of the healthcare system in each country.
In summary, there is considerable evidence on the effectiveness and efficiency of DM programs, and several components or interventions in DM programs were suggested to be effective. However, further research is needed to examine which type or component of DM programs works best and efficiently. Also, new emerging approaches for care coordination of chronic diseases should be integrated or added to the DM approach.

Tsai 2005
The CCM is a primary care-based framework aimed at improving the care of patients with chronic illness. The model integrates a number of elements into a plausible package designed to foster more productive interactions between prepared, proactive teams and well-informed motivated patients. DM with specialist nurse-led HF clinics would be a promising strategy or effective alternative whose benefit may be optimized by programs with a homogeneous structure and components that are delivered with consistency.

Gonseth 2004
Diseases: HF Interventions: types of DM programs with home visits, out-patient visits to a clinic, patient longer follow-up Outcomes: hospital readmission for HF or other cardiovascular causes, all-cause readmission, readmission and mortality Readmission in RCTs for HF or CVD : RR=0.70 (CI 0.62~0.79), for all-cause: RR=0.88 (0.79~0.97) Combined event of readmission or death: RR=0.82 (0.72~0.94) The magnitude of DM program benefits reported by non-randomized studies was more than double that reported by randomized studies.
DM programs are effective at reducing re-admissions among elderly patients with HF. Their effectiveness is close to that observed in clinical trials evaluating drugs for HF. However, the relative effectiveness of types of healthcare delivery within the DM program is not known. Significant effects (follow-up more than 3 months): hospital readmission 53% (10/19), mortality 3% (3/13), combined event 62% (8/13), QOL 50% (4/8), cost reduction 88% (7/8) Suggested factors for effective DM program (not statistically significant): case management, multi-disciplinary team, counseling by allied health, optimized medical therapy, exercise counseling, home visit This study defines precisely the characteristics of the care team and the organization content and delivery method of the DM program which are crucial to enhance the discharge outcomes of older people with HF..

Jerant 2005
Diseases: HF Interventions: HFDM incorporating telemedicine, 4 types of interventions Outcomes: hospitalization, emergency visit, mortality, QOL, costs Hospitalizations and emergency visits: significant reduction Mortality, costs and QOL: varied among fewer studies which examined them There was no significant improvement in any outcomes among less severe disease and /or in health systems with preexisting proactive approach.
HFDM programs incorporating telemedicine can reduce acute care utilization by severely affected patients, but their impact on other outcomes is unproven. Less symptomatic patients and those cared for in well-organized health systems do not appear to benefit from HFDM.

Ara 2004
Diseases: cardiovascular disease (congestive heart failure, hypertension, hyperlipidemia and/or coronary artery disease) Interventions: multiple health care professionals, patient and physician education, intensive drug therapy, lifestyle modification, close patient monitoring Outcomes: not specified A variety of interventions demonstrate some effectiveness in improving to the 3 disease states. While all 5 studies for CHF appeared to be successful, 3 studies among 9 studies of hypertension and 6 studies of heperlipidemia-CAD were unsuccessful. A few studies employed a fully experimental design and posed significant limitations.
A number of cardiovascular DM strategies reported promising results. Many of the multidisciplinary CH DM programs were more complex than were those for hypertension and hyperlipidemia-CAD, due to the nature and severity of the disease.

COPD and asthma
Meta-analysis

Niesink 2008
Diseases: COPD Interventions: multidisciplinary care team, clinical pathway, case management, self-management or patient education Statistically significant improvement: QOL 50% (5/10) Clinically relevant improvement: QOL 70% (7/10) in intervention groups, 40% (4/10) in control groups All chronic DM projects for people with COPD involving primary care improve quality of life. In most of the studies, aspects of chronic DM were applied to a limited extent. Quality of RCTs was not optimal.

Meta-analysis
Göhler 2006 Multidisciplinary team and personal post-discharge contact were more effective and suggested as factors explaining heterogeneity in re-hospitalization between studies. --

Roccaforte 2005
High quality studies and multidisciplinary programs appeared to be more consistently associated with a beneficial effect on mortality and health failure related re-hospitalization rates.
The quality of each study was evaluated according to component approach, examining randomization, blinding and so on. Thirty percent of studies were decided to be of high quality.

Whellan 2005
Interventions using clinic follow up by specialist, home visit, or telephone follow up significantly decreased all-cause hospitalization.
-Although most of studies reported a cost for providing the intervention, it only reflected estimates of direct personal expenses. Indirect expenses were not included.

Phillips 2005
Interventions with hospital discharge planning were more effective in readmission rate.
In assessing methodological quality, the Jadad score for each study was calculated. The median Jadad score was 3.5. Sixty-seven percent of studies were of high quality.
Only three programs reported complete data for the cost of care (initial hospital care, intervention costs, out patient care, and charges for readmissions). The potential savings was observed, but not significant.

Gonseth 2004 -
The study quality was assessed by the Jadad scale for randomized controlled trial. Only 11 of 27 trials attained a core of 3 on the scale. Among 27 non-randomized trials, no study adjusted for confounding factors.
Thirteen studies assessed the cost of DM programs. Only several studies considered intervention costs besides healthcare costs.

McAlister 2001b
-- Only three trials described the costs of interventions. Two reported cost savings, but none performed formal cost-effectiveness analysis.

McAlister 2001a
Multidisciplinary team providing specialized follow-up reduced the risk of hospitalization.
-Only one trial reported cost saving. There is no detailed cost description.

Yu 2006
Characteristics of effective DM programs were analyzed by case-control like analysis. The difference was observed in several items including counseling in hospital by allied health and exercise counseling, but none of them were statistically significant.
-Seven of eight effective programs were indicated to be cost saving.
However, there is no information on costs, except cost per case.

Jerant 2005 -
The quality of studies was assessed according to the User's Guide to Medical Literature. Only eight of 33 trials were judged to be of acceptable.
Reduction of acute care costs and medical care charges were mentioned based on systematic reviews. There is no detailed information on costs.
Ara 2004 -- One study indicated cost-effectiveness based on blood pressure reduction. The other three studies mentioned expenditure per capita, medical care costs and cost of anti-hypertensive therapy, but there was no detailed information on costs.

Lemmens 2009
Triple interventions (patient-related, professional-directed and organizational interventions) including case management showed significant difference in quality of life, although double interventions did not. Double interventions including a pharmacist showed significant difference in quality of life, although triple interventions did not. However, a qualitative comparison suggested more significant effects of triple rather double interventions.
Study quality was assessed with the Health Technology Assessment, Disease Management instrument (0 to 100 points). Studies of inferior quality (below 50 points) were excluded. Forty-two percent of studies were evaluated as good quality. -

Peytremann -Bridevaux
2008 - The quality of trials was assessed using 3 different instruments (Jadad score, qualitative categories by Cochrane Collaboration. and Health Technology Assessment, Disease Management instrument). The mean Jadad score was 2.4. Studies with high quality in other scales were less than half. -

Adams 2007
The relative risk of emergency visits and hospitalizations were significantly low for multi-component studies.
The US Preventive Task Force criteria were used. Only one study was evaluated as good and four studies were as fair among 20 RCTs.
Among 4 trials reporting costs, three demonstrated a range of 34% to 70% reduction in health care costs in the intervention groups, predominantly because of reduced hospitalizations.

Talyor 2005 -
The Delphi list and the Jadad criteria were used. Most of 9 trials had potential methodological limitations. -

Sin 2003 -
The scoring system was not used to evaluate the quality of the trials. The authors restricted the analysis to trials with randomization, placebo-control, blind ascertainment of end point, and so on. -

Qualitative review
Maciejewski

-
The quality of study was examined in terms of study design, intervention description, and statistical adjustment.
The studies' quality was poor in these respects. -

-
The methodological quality of the articles was evaluated with the Health Technology Assessment, Disease Management instrument (0 to 100 points). The overall mean score was 67.6. Forty-seven percent of studies were of good quality.
Three studies, presenting cost data, showed difference observed (e.g., prescription costs, hospitalization related costs). However, none of them reported significant changes in total costs.

Niesink 2008 -
The 11 criteria were used to assess methodological quality. The average score was 5.8. The proportion of studies with high score (i.e., more than six) was 60%. -

-
The methodological quality of the articles was evaluated with the Health Technology Assessment, Disease Management instrument (0 to 100 points). The overall mean score was 60.0. Only three studies showed good quality.
In one study, significant decrease in annual total costs was reported. However, using total costs as a single primary outcome measure poses a threat to the validity of outcome.

Noris 2001 -
Studies met the minimum quality standard of the evidence-based Guide to Community Preventive Services, method.
One study showed no difference in average cost between intervention and control groups after 2 years. The other cost-benefit study showed incremental benefit cost ratio of 1.86. Both studies were classified as good.

Neumeyer-Gromen 2004 -
The validity assessment of each study was conducted on the basis of the Cochrane Collaboration Handbook. Except for three studies with quality of A/B, B and B/C, all other studies were those of best quality (A).
Based on 6 cost-effectiveness/cost-utility analysis, overall cost-utility ratios ranged between $9,051 and $49, 500 per quality adjusted life year. The studies were evaluated by NHS EED economists as mostly valid and reliable.

Badamgarav 2003b --
All three programs measured total health services cost associated with treatment and indicated that program participants incurred higher costs. But the effect was not statistically significant.

Badamgarav 2003a
Based on the number of units of interventions, the studies offering equal or less than 6 units of interventions were associated with higher effect, although estimates did not reach statistical significance. --

Meta-analysis
Tsai 2005 Four elements of the CCM (delivery system design, self-management support, decision support, and clinical information system) were associated with better outcomes and processes.
In assessing methodological quality, the Jadad score for each study was calculated. Among 93 RCTs, only 32% scored 3, and none scored higher than 3. However, double blinding is rarely possible in studies of organizational interventions. -

Krause 2005
Statistically significant difference of effect size was observed by DM interventions (e.g., team-managed) and disease severity, but the former was not found after the latter was taken into consideration.
-As direct economic measures, 4 items (i.e., medical cost, hospital admissions or readmissions, physician office or clinic visit, and emergency department visits) were used. The individual effect size values were averaged and included as one construct.

Weingarten 2002
Education, feedback and reminder for provider, as well as education, reminder and financial incentives, were all associated with improvement in provider adherence to guidelines and/or patient disease control.

Qualitative review
Ofman 2004 -The quality of clinical trials was assessed using criteria described by Jadad.
Utilization and cost-related outcomes showed benefit in relatively few studies.
DM: disease management, DMAA: Disease Management Association of America, CCM: chronic care model, RCT: randomized controlled trial, CT: controlled trial, HF: heart failure, COPD: chronic obstructive pulmonary disease