A Systematic Review of Direct Cardiovascular Event Costs: An International Perspective

Abstract

Introduction

There is a lack of comprehensive cost information for cardiovascular events since 2013.

Objective

A systematic review on the contemporary cost of cardiovascular events was therefore undertaken.

Methods

Methods complied with those recommended by the Cochrane Collaboration and the Centre for Reviews and Dissemination. Studies were unrestricted by language, were from 2013 to 23 December 2017, and included cost-of-illness data in adults with the following cardiovascular conditions: myocardial infarction (MI), stroke, transient ischaemic attack (TIA), heart failure (HF), unstable angina (UA), coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI), or peripheral artery disease (PAD). Seven electronic databases were searched, namely Embase (Ovid), MEDLINE (Ovid), MEDLINE In-Process Citations and Daily Update (Ovid), NHS Economic Evaluation Database (NHS EED), Health Technology Assessment (HTA) database, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed. The included studies reported data from a variety of years (sometimes prior to 2013), so costs were inflated and converted to $US, year 2018 values, for standardization.

Results

After de-duplication, 29,945 titles and abstracts and then 403 full papers were screened; 82 studies (88 papers) were extracted. Year 1 average cost ranges were as follows: MI ($11,970 in Sweden to $61,864 in the USA), stroke ($10,162 in Spain to $46,162 in the USA), TIA ($6049 in Sweden to $25,306 in the USA), HF ($4456 in China to $49,427 in the USA), UA ($11,237 in Sweden to $31,860 in the USA), PCI ($17,923 in Italy to $45,533 in the USA), CABG ($17,972 in the UK to $76,279 in the USA). One Swedish study reported PAD costs in a format convertible to $US, 2018 values, with a mean annual cost of $15,565.

Conclusions

There was considerable unexplained variation in contemporary costs for all major cardiovascular events. One emerging theme was that average costs in the USA were considerably higher than anywhere else.

FormalPara Key Points for Decision Makers
This review provides contemporary country- and event-specific cost estimates that can be used in support of technology appraisal.
The review identifies limitations associated with how costs are reported, particularly regarding transparency as to the cost categories included within calculations.
The review highlighted considerable international variation in cost estimates that cannot easily be explained.

Introduction

According to the World Health Organization, cardiovascular disease (CVD) is the number one cause of death globally, with more people dying annually from CVD than from any other cause [1]. In 2015, the direct medical costs of CVD totalled $US318 billion in the USA alone (year 2015 values) [2] and are estimated to reach €111 billion per year in the EU [3]. Cardiovascular events (CVEs) are the prime drivers of the clinical burden (mortality/morbidity) and financial burden (costs) of CVD. Many studies review the costs of major CVEs in the form of economic evaluations, but cost of illness (COI) per se has not been as widely explored in the recent literature [4]. Cost-effectiveness analyses (CEAs) have found lipid-lowering therapies to be an efficient use of resources largely due to the high costs of CVEs such as myocardial infarction (MI) and stroke, which such therapies help avoid [5]. In a previously published systematic review of CEA models, based on rates of atherosclerotic CVD (ASCVD) events, considerable variation was found in the sources of cost estimates used for CEA models. Its authors also observed underlying methodological weaknesses, particularly with respect to transparency of reporting [6]. In a recent publication, Nicholson et al. [4] presented the results of a systematic review undertaken on patient-level cost estimates of CVEs across multiple countries worldwide; however, this review, which was published in 2016, was based on evidence from before December 2012. This gap between publication and evidence base raises questions as to whether change in circumstances between 2012 and 2016 limit the relevance of any results [4]. Submissions to health technology agencies usually involve evidence reviews of the costs and benefits of different therapies often accompanied by bespoke economic models. With this in mind, systematic literature reviews are always helpful to update the existing COI literature with more recent cost estimates associated with selected CVEs. Accordingly, this review focused on total direct costs estimated from patient-level data of CVEs to identify the main cost drivers. In particular, the estimates of long-term costs and costs of subsequent events, which are an important input to decision-analytic models, were also examined. Indirect costs relating to patient and family burden were not considered as part of this review but undoubtedly form an important part of the true cost of CVEs. A recent systematic review demonstrated that not only does CVD impose burden in terms of morbidity, it also has considerable impact in terms of productivity loss. This review found that annual productivity, from all six countries studied (at year 2015 values), ranged from €1.4 billion (absenteeism) to €19.7 billion (premature mortality) [7, 8].

The aim of the present systematic literature review was to provide a global overview on the most up-to-date cost of select CVEs for use in health technology assessment (HTA) submissions, future economic models, and scientific publications based on studies from January 2013 onwards. The focus of this paper was costs that occurred in the acute sector defined as hospital-based treatment services, including inpatient, outpatient, and some primary care.

Methods

To reduce the risks of bias and error, this review adhered to a prespecified protocol and methods recommended by the Cochrane Collaboration [9] and the Centre for Reviews and Dissemination (York, UK), which are regarded as gold standard methodologies [10]. Study inclusion was not limited by language, but only studies with full reports, abstracts, or journal manuscripts in the public domain were eligible for inclusion in the review. The time period of inclusion was limited to a start year of 2013 given that a previous review [4] included studies up to the end of 2012, supporting the aim to provide contemporary estimates.

For the purposes of this review, patient-level cost information was reported on any of the following CVEs: MI, ischaemic and undefined stroke, transient ischaemic attack (TIA), heart failure (HF), unstable angina (UA), myocardial revascularisation procedures (as opposed to events) including percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG), and peripheral arterial disease (PAD), sometimes referred to as peripheral vascular disease (PVD).

Studies that were included were COI studies in adults (aged ≥ 18 years) with any of the following CVEs: MI, ischaemic stroke (and undefined stroke), TIA, HF, UA, PCI, CABG, and PAD. For convenience, throughout the report, PCI and CABG are referred to within the CVE classification, even though they are procedures used in the management of CVEs. Studies in mixed CVE populations were only included if costs relating to one of the specific CVEs of interest were reported separately. Budget-impact analyses, cost-effectiveness studies, and HTA submissions were excluded. Intervention-specific cost studies (e.g. CABG off-pump or on-pump) were also excluded, except those for PCI/CABG. Additional exclusion criteria were as follows: (1) population size < 100 patients, (2) partial costing studies that did not explicitly estimate the total cost of the event, (3) studies that did not report resource use separately from unit or total cost, and (4) studies that did not report timing. Comparison of cost estimates from different studies was possible when currency and pricing date were both reported, thereby enabling adjustment for both exchange rate conversion and the impact of in-country inflation. Studies failing to report currency and pricing date were excluded from this comparative analysis but were retained within the review on the basis that results may still be of interest to decision makers in specific countries, even though costs cannot be assessed in an international context. Systematic reviews and meta-analyses were retrieved as only background studies and reference checked for source estimates.

Extensive literature searches were performed using search strategies developed by an information specialist [full strategies are available in the electronic supplementary material (ESM)-1]. A total of seven electronic databases were searched from 2013 to 23 December 2017, including Embase (Ovid), MEDLINE (Ovid), MEDLINE In-Process Citations and Daily Update (Ovid), NHS Economic Evaluation Database (NHS EED), HTA database, Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed. This companion PubMed search was undertaken in tandem with MEDLINE via Ovid to detect the latest ‘ahead of print’ and ‘online first’ electronic content. Search strategies were developed individually for each database and the keywords adapted according to the configuration of each resource. Search strategies combined relevant search terms comprising indexed keywords [e.g. medical subject headings (MeSH)] and text terms appearing in the title and/or abstract of database records. Search terms were identified through discussion between the review team, by scanning background literature and key articles already known to the review team, and by browsing database thesauri. Supplementary searches were undertaken in conference abstracts, including European Atherosclerosis Society Congress, European Society of Cardiology Congress, American College of Cardiology meeting, American Heart Association Annual Scientific Sessions and International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Annual European Congress and Annual International Meeting. The reference lists of included studies and systematic reviews were checked for additional studies. Identified references were downloaded in Endnote software (Thomson Reuters, NY, USA) for further assessment and handling, and duplicate records were removed.

Studies were screened and selected per the inclusion/exclusion criteria, and data were extracted into a specifically developed spreadsheet in Excel (Microsoft Corporation, Redmond, WA, USA). Data were extracted on study characteristics (e.g. study aim, geographical relevance), study methods (e.g. source of data, patient populations, currency, and cost year), and cost outcome (e.g. CVE type and timing, sample size, cost of each event, and description of cost categories). The assessment of quality was based on the Downs and Black checklist [11] for observational studies. This checklist was adapted to best reflect the issues of interest to this review. The study selection process, data extraction, and quality assessments were performed independently by two reviewers. Any discrepancies between reviewers during screening, data extraction, or quality assessments were resolved through discussion or the intervention of a third reviewer.

All costs were inflated from the authors’ reported year to 2018. Inflation assumptions were taken either from national bank websites [12] or, where national bank data were difficult to access, from an open access web resource [13]. Costs were then standardised by applying exchange rate calculations (as of 20 September 2018) to $US based on values taken from another open access website [14]. Studies that did not report a price year for cost estimates were not included in the main analysis, but cost results for such studies are available in local currencies in appendix A in the ESM.

Results

Literature searches of electronic databases and other sources, including hand searching, retrieved a total of 29,945 titles and abstracts (after de-duplication). After screening, 403 references were selected for full-paper screening. After subsequent detailed review, 88 references were selected as meeting all of the inclusion criteria. Six included studies were reported in two separate references. This brought the total to 82 included studies (88 individual references) for data extraction. Figure 1 presents a summary of the searching, screening, and inclusion assessment process in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.

Fig. 1
figure1

Summary of study flow

Characteristics of Included Studies

Table 1 summarizes the characteristics of the 82 included studies. The studies encompassed 24 countries: Denmark [15, 16], France [17,18,19,20], Germany [21], Greece [22,23,24,25], Ireland [26], Italy [27,28,29,30,31], Netherlands [32, 33], Poland [34], Spain [35,36,37,38,39], Sweden [40,41,42,43,44,45], Turkey [46], UK [47,48,49,50], Nigeria [51], China [52,53,54,55,56,57,58,59,60], India [61, 62], Japan [63, 64], South Korea [65,66,67], Taiwan [68], Australia [69,70,71,72], Canada [73, 74], USA [75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94], Brazil [95, 96], Colombia [97], and Russia [98]. The two most-studied CVEs were stroke (32 studies) and HF (29 studies). No studies provided cost estimates for all events of interests, although three studies reported all except PAD [81, 82, 87].

Table 1 Summary of characteristics of included studies

Included studies varied considerably in terms of population. In the majority of cases (54/82 studies) it was not possible to determine the status of the population analysed in terms of their cardiovascular risk status prior to the CVE (i.e. whether they had no risk factors [primary prevention], known risk factors [high-risk primary prevention], or previous CVE [secondary prevention]). Additionally, the next most frequent population was a mix of all risk-populations (15/82 studies).

The majority of studies were cohort studies whereby patients with events were followed over time without a control group (51/82 studies). The next most frequent design was a case–control study (15/82 studies), with 60% (9/15 studies) being a nested case–control study in which a subset of controls within a cohort study were compared with those with incident CVEs. A cross-sectional design, where costs were assessed at a discrete point in time, was the next most frequent study type (12/82 studies). Three of the 82 studies did not fit any of these designs, using information generated alongside randomised controlled trials, and the remaining study was based on direct analysis of a claims database.

Perspective of analysis varied between studies, with 27 using a payer’s viewpoint (including all but one of the USA studies), 26 used a health service perspective (mainly European), and 15 used a societal view (again, mainly European), with 14 studies (mainly Asian) leaving the perspective undefined.

Another consideration was whether a top-down or a bottom-up approach was used in the COI study. Top-down costing is achieved by dividing total spend by the number of patients treated. Bottom-up costing uses disaggregated patient-level data to construct a cost profile. The top-down method was the only method employed in six studies [60, 66, 70, 74, 85, 92], with a further three studies employing both methods [17, 26, 73]. All other studies used bottom-up costing methods. Sample sizes were reported in five of the six top-down studies and were very large, with an average of 243,418 patients compared with an average of 51,820 patients for the 69/73 bottom-up studies that reported sample size. It is not appropriate to report sample size for mixed methods studies, since multiple samples were used to derive cost estimates.

The earliest cost year used in studies was 2004 [90], with the latest cost year being 2016 [66]; 17 did not report a price year for cost estimates [18, 19, 22, 29, 52, 54, 61, 63, 68, 70, 75, 77, 83, 88, 91, 95, 99] and were therefore omitted from standardised cost analysis (based on $US, year 2018 values).

Study Quality

Each individual study was assessed against six key parameters within the Downs and Black checklist [11]. The results are available in appendix A in the ESM. In overall terms, only four studies satisfied all of the quality criteria, three relating to HF [31, 38, 44] and one relating to stroke/TIA [68]. However, this stroke/TIA study [68] did not report a price year, which is an aspect not addressed by the Downs and Black checklist.

Cost Reporting

Data extraction of studies revealed considerable variation in the cost headings within studies. Consequently, we decided to harmonise definitions under broadly comparable headings. This harmonised assessment of costs focused on total, acute sector (hospital-based treatment services to include inpatient, outpatient, and some primary care), medication, and rehabilitation. Additionally, costs that authors attributed to the CVE that otherwise would not have been incurred (e.g. dedicated stroke rehabilitation) were extracted, where available, for each of those listed cost categories. These were termed CVD-specific costs in that they could relate to any of the individual CVEs in isolation or in combination). Cost components within these categories were sometimes missing and sometimes poorly reported, so information was provided as to how authors described individual cost components.

Where costs were reported over multiple years, losses to follow-up or deaths were accounted for in estimates of cost per patient. Some studies did not report results by patient but instead focused on costs per unit of activity or insured individuals [18, 20, 58, 66, 70, 79, 97]. Of these, two [18, 70] also failed to report year of cost estimates. These studies were also omitted from further analysis because they were clearly not comparable with cost-per-patient estimates. Therefore, 58 studies were included to provide comparable cost estimates (i.e. standardised to $US, year 2018 values) for direct care costs of people experiencing CVEs. Date of publication did not necessarily align with the year(s) to which activity was costed within individual studies. Study-specific price/cost years can be viewed in Table 1. Additionally, the results in the local currency at local prices and with standard deviations around mean values are available in appendix B in the ESM.

Costs of Cardiovascular Event (CVE) Type

The focus of this paper is acute sector care costs, which were reported in 39 of the included studies. Analysis of other cost headings such as total costs, and elements within those categories that researchers have attributed to CVD, are available on request. The most frequently reported category of care was a combination of inpatient, outpatient, and office visits (sometimes referred to as primary care). While it is important to note that the components of this care varied, it was useful to collate all such information under an umbrella heading labelled ‘acute sector care’ for this review. Crucially, this care heading excluded any longer-term treatment, rehabilitation, or formal home care. All such costs are summarised for all events and for all time periods in Tables 2, 3, 4, 5, 6, 7 and 8. Using this definition, variation in year 1 cost estimates were as follows:

Table 2 Costs of myocardial infarction: acute sector
Table 3 Costs of stroke: acute sector
Table 4 Costs of transient ischemic attack: acute sector
Table 5 Costs of heart failure: acute sector
Table 6 Costs of unstable angina: acute sector
Table 7 Costs of coronary artery bypass grafting: acute sector
Table 8 Costs of percutaneous coronary intervention: acute sector
  • MI costs (Table 2) varied from $11,970 in a study in Sweden in a secondary prevention population [41, 42] to $61,864 in a study in the USA in a diabetes population [92].

  • Stroke costs (Table 3) varied from $10,162 in a study in Spain in a non-defined prevention population [35, 36] to $46,162 in a study in the USA in a diabetes population [92]. Initial event in the study in Spain was a combination of ischaemic and other strokes (91% ischaemic stroke), whereas initial event was exclusively ischaemic stroke in the USA study. It is unlikely that population differences or inclusion of cost categories explain the variation in costs estimates.

  • TIA costs (Table 4) varied from $6049 in a study in Sweden in a secondary prevention population [41, 42] to $25,306 in a study in the USA in a mixed-risk population.

  • HF costs (Table 5) varied from $4456 in a study in China in a non-defined prevention population [60] to $49,427 in a study in the USA in a mixed-risk population [82].

  • UA costs (Table 6) varied from $11,237 in a study in Sweden in a high-risk primary prevention population [41, 42] to $31,860 in a study in the USA in a mixed-risk population [82].

  • CABG costs (Table 7) for 1 year were reported in two studies and were $17,972 in the UK in a mixed-risk population and $76,279 in the USA in a mixed-risk population [82].

  • PCI costs (Table 8) varied from $17,923 in a study in Italy in a secondary prevention population receiving dual antiplatelet therapy [100] to $45,533 in a study also in the USA in a mixed-risk population [82].

  • Only one study reported PAD costs in year 1. This was a study in Sweden reporting $15,565 for hospitalisations and outpatient care visits [45] (Table 9).

    Table 9 Costs of peripheral artery disease: acute sector

Seven studies (eight references) reported on the contribution of acute sector costs within total costs (including aspects of social care and/or rehabilitation) [15, 17, 21, 35, 36, 56, 64, 90]. All of these studies evaluated stroke and only one measured costs beyond 1 year, namely a Danish study that assessed costs in years 1, 2, and 3 following an index stroke event [15]. This study found that acute care costs represented 90% of total costs ($18,579/$20,568) in year 1; 49% of total costs ($3501/$7140) in year 2, and 9% of total costs ($345/$3898) in year 3. While no information of this type was presented for other CVEs, the profile for stroke was consistent with a condition requiring considerable continuing care and rehabilitation.

Seven studies (eight references) reported CVD-related cost elements within specific cost categories [41, 4245, 48,49,50, 84, 87]. There was little consistency in the time periods considered, but the most informative analysis came from a study in Sweden [41, 42] that looked at costs in years 1, 2, and 3 for ischaemic stroke, UA, and TIA. This was undertaken for both secondary prevention and high-risk primary prevention populations. For a secondary prevention population, in the case of ischaemic stroke, CVD-specific acute sector costs represented 92% of total acute sector costs ($12,616/$13,663) in year 1, 57% of total acute sector costs ($1587/$2803) in year 2, and 53% of total acute sector costs ($1526/$2879) in year 3. Further details are provided in appendix B in the ESM. In the case of UA, CVD-specific acute sector costs represented 90% of total acute sector costs ($10,422/$11,588) in year 1, 64% of total acute sector costs ($1869/$2921) in year 2, and 57% of total acute sector costs ($1495/$2601) in year 3. Further details are provided in appendix B in the ESM. In the case of TIA, CVD-specific acute sector costs represented 80% of total acute sector costs ($4848/$6049) in year 1, 64% of total acute sector costs ($2009/$3148) in year 2, and 32% of total acute sector costs ($646/$1994) in year 3. Similar findings were observed for high-risk populations. Further details are provided in appendix B in the ESM.

Relative Costs of CVE Type

The wide variability in methods between studies suggested a focus on within-study comparison of CVEs, specifically three studies that contained estimates for at least four events [41, 42, 82, 92]. This had the advantage that within-study definitions would be consistent across events as would underlying data sources. Figures 2, 3 and 4 show results for years 1, 2, and 3, respectively.

Fig. 2
figure2

Acute sector costs by CVE—year 1

Fig. 3
figure3

Acute sector costs by CVE—year 2

Fig. 4
figure4

Acute sector costs by CVE—year 3

TIA was associated with the lowest annual acute sector cost of CVEs assessed in the first year across three studies (ranging between $6049 for a secondary prevention population in Sweden [41] to $25,306 in a USA study in an all-risk population [82]). Acute sector costs of CABG were over 40% higher than the next most costly CVE (i.e. MI as reported in the only one of the three studies to look at CABG) [82]. Costs of other CVEs varied widely, with a Swedish study having notably lower costs than either of the USA studies. One study, in the USA, reported costs in years 1, 2, and 3 for HF, MI, stroke, TIA, UA, CABG, and PCI [82]. Costs in the first year were always higher than in subsequent years. In years 2 and 3, acute sector costs in HF in the USA study were the highest of any CVE, calculated as $27,247 in year 2 and $23,957 in year 3 (year 1 costs, $49,427). For other CVEs in this study, the mean costs for years 2 and 3, as reported in the same study, were broadly comparable across types. Years 2 and 3 costs for MI were $15,931 and $13,969, respectively (year 1 costs, $52,752); costs for stroke were $16,519 and $14,827, respectively (year 1 costs, $43,410); costs for TIA were $13,868 and $13,013, respectively (year 1 costs, $25,306); costs for UA were $15,488 and $15,312, respectively (year 1 costs, $31,860); costs for CABG were $12,791 and $12,059, respectively (year 1 costs, $76,279); and costs for PCI were $16,690 and $15,580, respectively (year 1 costs, $43,533). Figures 2, 3 and 4 show the costs by year for events mentioned.

One study in Sweden reported in a similar way for HF, MI, stroke, TIA, and UA but separately for secondary prevention and high-risk primary prevention groups [41]. In this study, as with the USA study, first-year costs were always higher than in subsequent years. Focusing here on the secondary prevention group (the larger of the two), acute sector costs in HF were, once again, the highest of any CVE beyond year 1, reported as $4791 in year 2 and $4141 in year 3 (year 1 costs, $11,308). For other CVEs, the mean costs for year 2 and year 3, as reported in the same study, were broadly comparable across types. Year 2 and 3 costs for MI were $3143 and $2945, respectively (year 1 costs, $11,970); costs for stroke were $2803 and $2879, respectively (year 1 costs, $13,663); costs for TIA were $3148 and $1994, respectively (year 1 costs, $6049); and costs for UA were $2921 and $2601, respectively (year 1 costs, $11,587).

Costs of CVE in Different Risk Groups

One aspect that was not well reported in studies was the risk grouping of patients in terms of whether they had previous CVE experience, presence of known risk factors (high risk), or neither CVE experience nor presence of risk factors. In 54 of the 82 studies, it was not possible to determine which group of patients was being reported; in a further 14 studies, the population was a mix of all risk categories. This left only a handful of studies where costs related to groups of patients defined by cardiovascular risk status. From these studies, it was difficult to provide a definitive judgement as to whether certain risk groups were always associated with higher or lower costs. In the case of UA, only two studies, one USA and one Swedish, made comparisons between risk groups, with costs generally higher in secondary prevention than in primary prevention but only slightly higher than in a high-risk primary prevention population [41, 42, 87]. Similar results were found for patients experiencing MI and HF, although one study did report a widening gap in costs of CVD-specific care for these events over time, with patients in a secondary prevention population having increasingly higher costs than those in the primary prevention group [81]. An additional finding was that patients with non-fatal MI had slightly higher mean 90-day costs when diabetes was a comorbidity [50]. These patterns were repeated for stroke, but an additional finding was that patients with atrial fibrillation (AF) appeared to have higher costs than those without AF, especially in terms of inpatient costs [26]. In the case of CABG, one study reported year 1 and year 2 acute sector costs as higher for a secondary prevention population than for a primary prevention population [80]. In the case of PCI, two studies each reported CVD-specific elements of acute sector costs as higher in a primary prevention than a secondary prevention population over the first 2 years [81, 87]. In speculating the reasons for this, it is possible that patients who have not experienced a previous CVE may be less likely to have ongoing management of CVD in place than those with previous event experience. This might explain the additional CVD-specific costs for primary prevention patients. Further details, including separation of CVD-specific elements, are available in appendix B in the ESM.

Discussion

This systematic literature review aimed to provide the most contemporary assessment of COI for eight CVEs, covering initial hospitalisation through to rehabilitation. Nine systematic reviews were identified that considered the cost of CVEs and were published in the last 4 years [4, 101,102,103,104,105,106,107,108]. Previous reviews either focused on a narrower set of events, a narrower set of countries, or both. Only one of the reviews [4] had a similar scope to this review (i.e. a global study of multiple CVEs). The current review is essentially an update to that study, which covered the years 2007–2012, whereas the present updated study covered the years 2013 through 23 December 2017. This review also included TIA and PAD as additional CVEs of interest not covered in the earlier review. The original review identified 114 studies and found that the average cost was $6466 for UA, $11,664 for acute MI, $11,686 for HF, $11,635 for acute ischaemic stroke, $37,611 for CABG, and $13,501 for PCI. This approach contrasts with that of the current study, in which an average across countries was not calculated because of underlying heterogeneity. However, a wide variation in cost estimates between countries was found in both reviews, with estimates for the USA being generally much higher than anywhere else.

A clear difference was observed according to geography, with CVE costs in the USA being considerably higher than in other parts of the world. On the whole, we found cost estimates to be considerably higher in the USA than in other parts of the world. Four scenarios (possibly acting in combination) may explain this. The first is that patients in the USA are in some way more ‘sick’ and hence more costly than in other countries. This is perhaps the least plausible reason, with no evidence to support it. A second possible reason might be that accounting practices in the USA are more comprehensive than in other parts of the world, where important costs may have been overlooked. There is little evidence to support this, since categories listed in US studies are similar to those in others, although we can perhaps only speculate on how overhead costs have been apportioned. A third explanation is that care is provided to a higher quality. The fourth explanation is that care in the USA is simply more expensive in terms of capital and labour inputs as well as profit taking. This seems the most likely of the four explanations, although we have no information as to whether additional costs are associated with better outcomes.

Within-study comparison of event costs was present in three studies reporting acute sector costs, one in Sweden and the other two in the USA. Results suggested that TIA was associated with the lowest annual costs, with CABG being much more expensive than other CVEs in the year of the event. In the longer term (years 2 and 3), HF was associated with the highest annual acute sector cost of any CVE. In broad terms, acute sector costs in year 2 were similar to those in year 3 for all CVEs.

Little information was available on the contribution of acute sector costs to overall costs. The most thorough examination was that by Jakobsen et al. [15] of Danish patients with ischaemic stroke, which suggested that the contribution of acute sector costs reduced from 90% of total costs in year 1 to 9% of total costs in year 3. Clearly, any economic study of stroke needs to address the long-term non-acute sector costs of care. Seven studies attempted to separate CVD-specific costs from other costs encountered by patients having experienced CVEs [41, 42, 45, 48,49,50, 84, 87]. The most thorough application of this method was in a Swedish study reporting costs of ischaemic stroke, UA, and TIA for secondary prevention and high-risk primary prevention groups [41, 42]. Differences between the risk-defined populations were minimal, particularly in year 1. Comparisons between events suggest that the proportional impact of CVD-specific acute sector care (on total acute sector costs) is less in all years for TIA than either stroke or UA and also appears to decline quicker over time.

In line with all other reviews, this review identified the limitations of lack of standardised reporting and scarcity of studies (in specific locations for specific events, e.g. anything other than stroke in Germany or PCI or CABG in UK). Cost components within categories were sometimes missing and sometimes poorly reported, and the wide variability in methods between studies made it difficult to compare event costs.

Several studies attempted to evaluate the costs of first, second, and third CVEs [81, 82, 87]. This is an important consideration when trying to build a COI profile for patients experiencing an initial event. One study that provided a profile of subsequent events found that 43% of cases had one or more new CVE and 19.8% had three or more new CVEs over a 2-year follow-up period, demonstrating this is an issue of considerable importance [87]. This study identified the proportions of patients having each specific subsequent CVE (e.g. 52.5% had HF as a subsequent event). However, the main issue not addressed in this approach is that the precise initial event for each subsequent event is unknown. It might be that second and subsequent CVEs are often the same event type as the first event, but no details were provided in the study [81]. It should be possible to generate analysis that looks at cost profiles for patients who experience each specific index event, taking into account the precise subsequent CVE experienced.

CVD-specific costs were sometimes reported either alongside or instead of total costs. Authors used three methods to attribute costs specifically to the CVE as opposed to those that might have been incurred without the CVE. The most popular method was use of a matched cohort of patients (who did not experience the event) to assess costs over and above what might have been experienced by patients with similar characteristics [41, 48, 81, 82, 87]. However, four studies [18, 45, 49, 88] used a different approach by examining costs experienced before and after the event. Perhaps the most sophisticated approach was deployed by Walker et al. [50], who used multisource electronic health records to match healthcare utilisation to CVD risk. From these data, activity was classified as either CVD related or coronary heart disease (CHD)-related using a combination of healthcare resource groupings (HRG) and International Classification of Diseases and Related Health Problems, Tenth Edition (ICD-10) codes. The authors acknowledged that such an approach involves limitations in that outpatient and primary care cannot yet be reliably assigned to these condition-specific classifications. As there are no studies comparing the three methods, it is not possible to comment on whether one technique has clear advantage over the others.

As mentioned in the introduction, time off work and premature death are associated with considerable indirect costs, and COI reviews and economic models based on a societal perspective should consider not only the direct costs but also the indirect costs pertaining to CVEs.

We make the following research recommendations:

  • Evaluate the costs of first, second, and third CVEs according to specific CVE history. Events often occur within a short period of time of one another, and further research is required to derive meaningful history profiling for the most prevalent (and resource-intensive) event sequences.

  • Apply the best methodological approach by comparing patients who experience CVEs with matched cohorts of patients without CVEs, to quantify marginal costs of CVEs.

  • Study the longer-term costs of CVEs (i.e. up to several years).

  • Use a bottom-up costing approach.

  • Explore the role that risk factors, such as diabetes, play in patient costs.

  • Improve reporting standards, particularly in terms of basic information, such as price year and definitions of cost categories.

Limitations

A potential weakness of this review is that not all cost categories reported within studies were analysed, but this was a practical consideration given that, after harmonisation, a total of 39 individual cost headings were retrieved during data extraction. One-third of these were truly unique in that they did not appear in more than one study. Longer-term costs for all CVEs were included within the study, rather than restricting to a follow-up period of 1 year following the initial event. However, very few studies reported longer-term costs; thus, analysis was often restricted to a few studies and a few years (notably years 1, 2, and 3). Indirect costs were not included in this review, restricting assessment of the overall cost burden for CVEs. An overall assessment would include both direct and indirect costs. Social care costs are an important element of longer-term care for patients with debilitating events, e.g. severe stroke. Some countries may include elements of social care costs within healthcare provision, whereas others may not. This can hinder any direct comparability between estimates of direct costs. Prices were also adjusted to $US, year 2018 values, but country-specific inflation indices were derived from multiple sources as no single reliable source was identified.

Conclusions

This systematic review presents the most recent cost estimates in a variety of geographical settings, across a number of CVEs, for different post-event durations, different cost categories, and for patients in different risk groups (to the extent possible). While costs remain relatively high in the USA, the wide variability in methods between studies made it difficult to compare event costs, and cost components within categories were sometimes missing or poorly reported. To enable cost comparisons in future studies, it is recommended that marginal/incremental costs (including long-term costs) be evaluated for each sequential CVE.

Data Availability

The data supporting the findings of this study are available within the article and its supplementary information files.

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Acknowledgements

The authors acknowledge the help of the following contributors who assisted with screening, data extraction, and/or quality assessment: Regina Leadley, Sonia Garcia Gonzalez-Moral, Frank O’Neill (formerly Amgen Inc.), and Anna Bychenkova (Amgen Inc.). Medical writing support was provided by Cathryn M. Carter (Amgen Inc.).

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Contributions

All of the listed authors conform to the requirements of the International Committee for Medical Journal Editors (ICMJE). SR, C-YW, SD, and NA designed the study, carried out the methodological framework, collected the data, reviewed the studies, and completed quality assessment. LS assisted in designing the study, developed and performed the original literature searches, and contributed to the writing and revision of the manuscript. SR, C-YW, and NA contributed to the writing, interpretation of the results, and revision of the manuscript. YQ, PR, JK, and KF participated in the study design, supervised the overall progress, and contributed to the interpretation of the results and revision of the manuscript. All authors read and approved the final manuscript. SR is the overall guarantor of this work.

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Correspondence to Steve Ryder.

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Funding

This study was funded by Amgen Inc. (Thousand Oaks, CA, USA).

Conflict of interest

Steve Ryder, Lisa Stirk, Nigel Armstrong, Ching-Yun Wei, and Sohan Deshpande are employees of Kleijnen Systematic Reviews (KSR) Ltd., an independent research company that was paid by Amgen Inc. to carry out this work. Jos Kleijnen is the owner of KSR Ltd. Pratik Rane and Yi Qian are employees and stock holders of Amgen Inc. Kathleen Fox serves as a consultant for Amgen Inc.

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This manuscript reports on secondary research and does not directly report research on human participants and/or animals.

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Informed consent and ethical approval were not required.

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Ryder, S., Fox, K., Rane, P. et al. A Systematic Review of Direct Cardiovascular Event Costs: An International Perspective. PharmacoEconomics 37, 895–919 (2019). https://doi.org/10.1007/s40273-019-00795-4

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