Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies

Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a... Abstract Objectives Several chronic inflammatory diseases are associated with cardiovascular disease, but the risk in ANCA-associated vasculitis is poorly quantified. The aim of the present study was to review the evidence for an increased cardiovascular risk, including ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease, in patients with ANCA-associated vasculitis. Methods A comprehensive systematic review was conducted in accordance with guidelines of preferred reporting items for systematic reviews and meta-analyses. The databases PubMed, Embase.com and the Cochrane Library (Wiley) were searched for original observational studies comparing vasculitis patients with at least one control group. Summary estimates were derived with a random-effects model and reported as relative risks. Results One thousand three hundred and seventy-five studies were identified. Seven studies were included, comprising almost 14 000 ANCA-associated vasculitis patients vs general population controls in six studies and chronic kidney disease patients in one study. ANCA-associated vasculitis carried a relative risk of 1.65 (95% CI: 1.23, 2.22) for all cardiovascular events, 1.60 (95% CI: 1.39, 1.84) for ischaemic heart disease and 1.20 (95% CI: 0.98, 1.48) for cerebrovascular accidents. We did not find studies that addressed the risk for peripheral arterial disease separately. No heterogeneity was seen in the estimates. Conclusion This meta-analysis of observational studies supports an increase in cardiovascular risk in patients with ANCA-associated vasculitis of ∼65%, similar to that found in other chronic inflammatory diseases. Hence, there is a clear need for active cardiovascular risk management in patients with ANCA-associated vasculitis. vasculitis, ANCA, ANCA-associated vasculitis, cardiovascular disease, myocardial infarction, cerebrovascular accident, stroke, meta-analysis Rheumatology key messages Patients with ANCA-associated vasculitis have an increase in cardiovascular risk of 65%. There is a clear need for active cardiovascular risk management in patients with ANCA-associated vasculitis. Introduction ANCA-associated vasculitis (AAV) is a chronic inflammatory disease of the blood vessel wall. AAV can be subclassified into granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis [1]. Despite major progression in the development and optimization of immunosuppressive therapies, AAV patients remain at risk for complications of the disease and its therapy [2, 3]. A well-established long-term complication of many inflammatory diseases is premature atherosclerosis and cardiovascular events (CVE) [4–6]. A high incidence of cardiovascular events has also been reported in AAV [2, 7]; therefore, the most recent EULAR guideline for AAV recommends periodic assessment of cardiovascular risk in AAV patients [8]. However, the increased risk for CVE in AAV is poorly quantified. Our objective was to provide this quantification through a meta-analysis of observational studies. Methods A comprehensive systematic review was conducted in accordance with guidelines of preferred reporting items for systematic reviews and meta-analyses [9]. The review protocol was registered on 26 September 2016 in the International Prospective Register of Systematic Reviews database (registration number CRD42016047994). Eligibility criteria All articles that focused on CVE at all stages in AAV were identified. The following criteria were applied for the inclusion of articles: cohort or case–control studies with AAV patients; report of CVE, including ischaemic heart disease (IHD), cerebrovascular accident (CVA) and/or peripheral arterial disease (PAD); an estimate of the association between AAV status and outcome [i.e. relative risk (RR), odds ratio (OR), incidence rate ratio (IRR) or hazard ratio (HR)] and 95% CI or sufficient information to calculate them; and at least one comparison group. No language restrictions were applied. Articles published up to August 2016 were included. Search strategy The search strategy was developed in collaboration with an experienced librarian (R.H.J.O.). The databases PubMed (N.L.M.), Embase.com and the Cochrane Library (Wiley) were searched by two authors (R.H.J.O. and E.H.) from their inception to 30 August 2016. In brief, the keywords (ANCA-associated vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) were combined with each of the following: stroke, myocardial ischaemia and peripheral arterial disease. Search terms included indexed terms from Medical Subject Headings (MeSH) in PubMed, EMtree in EMBASE.com as well as free-text terms. The full list of search terms is provided in supplementary Table S1, available at Rheumatology Online. Two reviewers (E.L.P. and E.H.) independently screened the titles and abstracts of the search results and reviewed the full text of the articles that appeared to meet the inclusion criteria. The bibliographies of all included articles were hand searched for additional potentially eligible articles. Any discrepancy in the determination of study eligibility was resolved by discussion between three authors (E.L.P., T.H. and E.H.). Data collection process Data were collected through a standardized extraction sheet. One reviewer (E.H.) extracted and the second reviewer (T.H.) checked the data. Disagreements were discussed and resolved. For each study, the following data were collected: country, design of the study, patient characteristics (mean age, sex and diagnosis), follow-up duration, CVE, control group and inclusion period. Risks were quantified through the collection of the total number of events and RR, OR, IRR or HR as appropriate, with 95% CI. Quality assessment The quality of the included studies was assessed with the Newcastle–Ottawa Scale [10]. In this scale, studies are scored across three categories: selection of study groups (four questions), comparability of study groups (one question) and ascertainment of the outcome of interest (three questions). In all questions, a maximum of one star can be awarded, except for comparability of study groups, where a maximum of two stars can be awarded. The quality of the included studies was assessed by two investigators (T.H. and E.H.). Disagreements were resolved by consensus. Statistical analyses In the meta-analyses, the outcomes of interest were pooled RR for total CVE, IHD and CVA. IRR, HR and OR were assumed to be numerically the same as the RR. Forest plots and pooled estimates were derived with a random-effects model. Pooled estimates were calculated on the logarithm of the RR from the individual studies. The results were then transformed back to the RR scale. The heterogeneity among studies was tested with Cochran’s Q test. Significant heterogeneity was defined as a value of P < 0.10. The I2-statistic was used to quantify the heterogeneity. Data analysis was performed with Stata statistical software V.StataSE14 (stataCorp LLC, College Station, Texas, USA). Results A total of 1907 records were processed for a final selection of seven articles (Fig. 1). Most records were irrelevant, and of the 28 records retrieved for full-text assessment, four were conference abstracts. Excluded articles comprised 13 articles without a comparison group and two reporting only cardiovascular mortality. Two European studies compared observed event rates with reported expected event rates as calculated by Framingham Risk Scores. These articles were excluded after discussion owing to insufficient information in these articles as well as limited generalizability of the Framingham Risk Score in European countries [11–13]. Two abstracts were excluded because they overlapped with a full-text article. Data from the other two abstracts described the same unpublished cohort study. The authors of these abstracts were unable to provide the required event rates during the process of this review. The remaining seven cohort studies were included in the meta-analysis [14–20]. A list of the excluded articles is provided in supplementary Table S2, available at Rheumatology Online. Fig. 1 View largeDownload slide Flow chart of study selection Fig. 1 View largeDownload slide Flow chart of study selection Five out of the seven studies included only patients with granulomatosis with polyangiitis (Table 1) [15, 17–20]. The other two studies included all three subtypes, but did not provide separate estimates [14, 16]. Six of the seven studies used national registry databases from Canada, Denmark and Sweden [15, 17–20]. In three of these studies, the diagnoses were confirmed in medical files [16–18]. Six of the seven studies compared AAV patients with the general background population [15–20]; in the remaining study, the comparison was made with a chronic kidney disease cohort [14]. The included studies were of high quality, scoring 7–9 points out of 9 on the Newcastle–Ottawa Scale (Table 1). Four studies lacked a statement on the adequacy of follow-up [15, 16, 19, 20]. Two studies did not exclude patients with a history of cardiovascular events [16, 17], and one study did not draw the comparison cohort from the same source as the GPA cohort [14]. Table 1 Characteristics of included cohorts References  Country  inception cohort, y/n  Criteria for patient selection  Number of patients  Age, median (IQR), years  Male, %  Follow-up, years  Number of cardiovascular events in AAV  Cardiovascular outcome  Control group  Inclusion period  Quality score  Morgan et al. [14]  UK  y  CHCC AAV  65 GPA46 MPA2 EGPA113 ctrl  63 (52–70)  50  3  23  IHD, PAD, CVA  CKD patients  1995–2005  8  Aviña-Zubieta et al. [15]  Canada  y  ICD code ordiagnosis GPA on two visits and therapy  504 GPA5222 ctrl  57 (17)a  47  4  41  First MI or ischaemic CVA  General population  1996–2010  8  Englund et al. [16]  Sweden  y  ICD code or ANCA and clinical diagnosis  92 GPA83 MPA11 EGPA744 ctrl  65 (16)a  49  5  45  IHD, CVA  General population  1998–2010  7  Faurschou et al. [17]  Denmark  y  ICD code GPA and ACR criteria  293 GPA and general Danish population  59 (14–88)  53  8  63  IHD  General population  1973–99  8  Faurschou et al. [18]  Denmark  y  ICD code GPA and ACR criteria  180 GPA3420 ctrl  55 (41–61)  51  7  8  First CVA  General population  1993–2011  9  Zöller et al. [19]  Sweden  n  ICD codes GPA after hospitalization  1909 GPA and general Swedish population  N/A  N/A  N/A  4717  First CVA  General population  1987–2008  8  Zöller et al. [20]  Sweden  n  ICD codes GPA after hospitalization  12 670 GPA and general Swedish population  N/A  N/A  N/A  72  First IHD  General population  1964–2008  8  References  Country  inception cohort, y/n  Criteria for patient selection  Number of patients  Age, median (IQR), years  Male, %  Follow-up, years  Number of cardiovascular events in AAV  Cardiovascular outcome  Control group  Inclusion period  Quality score  Morgan et al. [14]  UK  y  CHCC AAV  65 GPA46 MPA2 EGPA113 ctrl  63 (52–70)  50  3  23  IHD, PAD, CVA  CKD patients  1995–2005  8  Aviña-Zubieta et al. [15]  Canada  y  ICD code ordiagnosis GPA on two visits and therapy  504 GPA5222 ctrl  57 (17)a  47  4  41  First MI or ischaemic CVA  General population  1996–2010  8  Englund et al. [16]  Sweden  y  ICD code or ANCA and clinical diagnosis  92 GPA83 MPA11 EGPA744 ctrl  65 (16)a  49  5  45  IHD, CVA  General population  1998–2010  7  Faurschou et al. [17]  Denmark  y  ICD code GPA and ACR criteria  293 GPA and general Danish population  59 (14–88)  53  8  63  IHD  General population  1973–99  8  Faurschou et al. [18]  Denmark  y  ICD code GPA and ACR criteria  180 GPA3420 ctrl  55 (41–61)  51  7  8  First CVA  General population  1993–2011  9  Zöller et al. [19]  Sweden  n  ICD codes GPA after hospitalization  1909 GPA and general Swedish population  N/A  N/A  N/A  4717  First CVA  General population  1987–2008  8  Zöller et al. [20]  Sweden  n  ICD codes GPA after hospitalization  12 670 GPA and general Swedish population  N/A  N/A  N/A  72  First IHD  General population  1964–2008  8  a Mean (s.d.). AAV: ANCA-associated vasculitis; CHCC: Chapel Hill Consensus Conference; CKD: chronic kidney disease; ctrl: controls; CVA: cerebrovascular accident; EGPA: eosinophilic granulomatosis with polyangiitis; GPA: granulomatosis with polyangiitis; ICD: International Classification for Diseases; IHD: ischaemic heart disease; MI: myocardial infarction; MPA: microscopic polyangiitis; N/A: not applicable; PAD: peripheral arterial disease; y/n: yes/no. Cardiovascular outcomes were variable in the seven included studies. Two studies reported estimates for total CVE including CVA and IHD. One study reported CVA, IHD and PAD together, but did not provide separate event rates [14–16]. In these three studies, 109 events were found in 803 AAV patients [14–16]. Of the seven included studies, four reported separate event rates for IHD, of which two articles reported IHD only. A total of 4834 ischaemic heart events were found in 13 653 AAV patients [15–17, 20]. Another four articles reported CVA, of which two articles reported CVAs only. In three studies, CVAs included both ischaemic and haemorrhagic CVAs [16, 18, 19]. In one study CVAs included ischaemic events only [15]. Overall, 112 CVAs were found in 2779 AAV patients [15, 16, 18, 19]. Two studies by a Danish group contained data from cohorts with partly overlapping populations. The separate studies reported different outcomes and were therefore analysed separately only [17, 18]. The same applied to two studies from Swedish national registry cohorts. The cohorts partly overlapped and were therefore analysed for the separate outcomes only [19, 20]. Three studies assessed the RR for total CVE comprising IHD and CVA (in one study also PAD), among AAV patients and 6079 controls. The pooled RR for total CVE is 1.65 (95% CI: 1.23–2.22; Fig. 2). Four studies assessed the RR for IHD among AAV patients vs 5966 controls and the general Danish population in one study and the general Swedish population in another study. The pooled RR for IHD in AAV is 1.60 (95% CI: 1.39–1.84; Fig. 3). Four studies assessed the RR for CVA among AAV patients vs 9386 controls and the general Swedish population in one study. The pooled RR for CVA in AAV is 1.20 (0.98–1.48; Fig. 4). No heterogeneity was seen in the above estimates. The exact number of patients in the Swedish and Danish background population cohorts was not reported. Fig. 2 View largeDownload slide Meta-analysis on the relative risk for cardiovascular events in ANCA-associated vasculitis Cardiovascular events comprising ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease. Fig. 2 View largeDownload slide Meta-analysis on the relative risk for cardiovascular events in ANCA-associated vasculitis Cardiovascular events comprising ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease. Fig. 3 View largeDownload slide Meta-analysis on the relative risk for ischaemic heart disease in ANCA-associated vasculitis Fig. 3 View largeDownload slide Meta-analysis on the relative risk for ischaemic heart disease in ANCA-associated vasculitis Fig. 4 View largeDownload slide Meta-analysis on the relative risk for cerebrovascular accidents in ANCA-associated vasculitis Fig. 4 View largeDownload slide Meta-analysis on the relative risk for cerebrovascular accidents in ANCA-associated vasculitis Discussion In this first meta-analysis on the topic, we show that patients with AAV have an increase in cardiovascular risk of 65%. Most of this risk stems from an increase in IHD, with only a trend for CVA, and very limited data on PAD. The increased risk was consistent, with no evidence of heterogeneity. Several pathophysiological mechanisms might account for the increased risk for cardiovascular events in AAV, including active vasculitis, atherosclerosis, a hypercoagulable state and/or haemorrhage. Little is known on the role of active vasculitis in the excess of CVE in AAV. In a recent study by McGeoch et al. [21], coronary artery disease considered secondary to GPA was found in 2 of 517 GPA patients (0.004%) at any point during their illness, suggesting that active vasculitis plays a limited role in the excess of IHD. CVAs attributable to AAV can be caused by cerebral vasculitis, which is a rare but serious complication [22]. Faurschou et al. [18] reported that 83% of strokes in the AAV group occurred during treatment for newly diagnosed or relapsing GPA or within 2 months of immunosuppressive therapy for active vasculitis. Furthermore, in the analyses by Zöller et al. [19, 20] the event rates for IHD, ischaemic and haemorrhagic CVAs were highest early after diagnosis. These findings suggest that active vasculitis is, at least in part, an explanation for the increased risk for strokes. Inflammation is widely known to play a key role in all stages of atherosclerosis [23]. Indeed, a high burden of atherosclerosis and an increased cardiovascular risk have been reported in other inflammatory diseases [5, 6, 19, 20, 24]. Evidence for (accelerated) atherosclerosis in AAV was observed in multiple studies: two found endothelial dysfunction [25, 26]; another reported increased arterial stiffness, as measured by pulse wave velocity [27]; and several studies found increased intima–media thickness in AAV patients [28, 29]. Besides chronic inflammation, many of the anti-inflammatory drugs in vasculitis, and specifically glucocorticoids, have metabolic side-effects (such as hyperglycaemia, hypertension and central obesity) that may predispose to atherosclerosis and cardiovascular events [30, 31]. However, this relationship is complex because predisposing effects may be counteracted by the positive anti-inflammatory effects. Another potential pathway is impaired physical activity caused by chronic damage and fatigue [32]. It is likely that other pathways also contribute. For instance, recent studies have provided evidence for a hypercoagulable state in patients with AAV, which might contribute to the cardiovascular risk [33, 34]. In line with this, Faurschou et al. [18] also reported a markedly increased risk of pulmonary embolism and deep venous thrombosis in patients with AAV. Finally, many AAV patients have chronic kidney disease, a well-known risk factor for cardiovascular disease [35, 36]. Only one of the included studies controlled for kidney function. In this study, by Morgan et al. [14], a chronic kidney disease population was used as a control group. Given that this study reported the highest RR for CVE, kidney impairment per se is most probably not the only explanation for the increased cardiovascular risk in AAV. Most of the included studies did not provide enough clinical information, such as traditional cardiovascular risk factors, kidney function and/or vasculitis activity, to determine the potential contribution of each pathway. Two recent studies found that age, myeloperoxidase ANCA status, hypertension and BMI predict cardiovascular events in AAV patients [7, 37]. More studies are required to map cardiovascular risk profiles in AAV patients and stratify cardiovascular risk by patient and disease characteristics. This could shed new light on the above-mentioned pathophysiological pathways and may contribute to future preventive therapies. One recent study, published after our literature search, retrospectively compared cardiovascular risk in AAV patients with that in patients with arterial hypertension and found a higher burden of cardiovascular disease in AAV patients (P = 0.01) [38]. This was the first study to provide a meta-analysis of the risk for CVE in AAV. In the absence of statistical heterogeneity, the meta-analysis increased the power and precision of the estimate. Although quantitative heterogeneity was absent, the included studies had qualitative heterogeneity in the form of a variety of inclusion criteria and different control groups. Inception and non-inception cohorts were included, and some studies reported first CVE after diagnosis, whereas others reported first ever events. Furthermore, some studies defined IHD as myocardial infarction only, whereas others used a more extensive definition, including angina pectoris and chronic coronary heart disease. Owing to the limited number of studies, we were unable to perform sensitivity analyses in these subgroups, so the absence of statistical heterogeneity should be interpreted with caution. A sensitivity analysis with patients with GPA only was not performed because of the low number of studies with all types of AAV and their limited weight in the meta-analyses. Furthermore, owing to the limited number of studies we were unable to perform an evaluation of publication bias. Most of the included studies were based on national registry databases, which provide a large amount of information but might have inaccuracies. Aviña-Zubieta et al. [15] reported that in previous studies 89% of patients who were registered as having GPA were confirmed to meet the ACR criteria [39]. The included studies did not provide information on the number of AAV patients who were not incorporated in the national registries, so the sensitivity and specificity of the registration systems is unknown. In summary, this is the first meta-analysis to focus on the RR for CVE in AAV. Overall, the risk for CVE was found to be increased by 65%. Our results underline the recently published EULAR guideline, in which active monitoring and treatment of traditional cardiovascular risk factors is recommended as part of the standard care for AAV patients [8]. This will include cessation of smoking, control of weight and encouragement to engage in physical activity. Furthermore, traditional treatment of cardiovascular risk factors, such as hypertension and hypercholesterolaemia, should actively be performed. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. 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Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies

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Abstract

Abstract Objectives Several chronic inflammatory diseases are associated with cardiovascular disease, but the risk in ANCA-associated vasculitis is poorly quantified. The aim of the present study was to review the evidence for an increased cardiovascular risk, including ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease, in patients with ANCA-associated vasculitis. Methods A comprehensive systematic review was conducted in accordance with guidelines of preferred reporting items for systematic reviews and meta-analyses. The databases PubMed, Embase.com and the Cochrane Library (Wiley) were searched for original observational studies comparing vasculitis patients with at least one control group. Summary estimates were derived with a random-effects model and reported as relative risks. Results One thousand three hundred and seventy-five studies were identified. Seven studies were included, comprising almost 14 000 ANCA-associated vasculitis patients vs general population controls in six studies and chronic kidney disease patients in one study. ANCA-associated vasculitis carried a relative risk of 1.65 (95% CI: 1.23, 2.22) for all cardiovascular events, 1.60 (95% CI: 1.39, 1.84) for ischaemic heart disease and 1.20 (95% CI: 0.98, 1.48) for cerebrovascular accidents. We did not find studies that addressed the risk for peripheral arterial disease separately. No heterogeneity was seen in the estimates. Conclusion This meta-analysis of observational studies supports an increase in cardiovascular risk in patients with ANCA-associated vasculitis of ∼65%, similar to that found in other chronic inflammatory diseases. Hence, there is a clear need for active cardiovascular risk management in patients with ANCA-associated vasculitis. vasculitis, ANCA, ANCA-associated vasculitis, cardiovascular disease, myocardial infarction, cerebrovascular accident, stroke, meta-analysis Rheumatology key messages Patients with ANCA-associated vasculitis have an increase in cardiovascular risk of 65%. There is a clear need for active cardiovascular risk management in patients with ANCA-associated vasculitis. Introduction ANCA-associated vasculitis (AAV) is a chronic inflammatory disease of the blood vessel wall. AAV can be subclassified into granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis [1]. Despite major progression in the development and optimization of immunosuppressive therapies, AAV patients remain at risk for complications of the disease and its therapy [2, 3]. A well-established long-term complication of many inflammatory diseases is premature atherosclerosis and cardiovascular events (CVE) [4–6]. A high incidence of cardiovascular events has also been reported in AAV [2, 7]; therefore, the most recent EULAR guideline for AAV recommends periodic assessment of cardiovascular risk in AAV patients [8]. However, the increased risk for CVE in AAV is poorly quantified. Our objective was to provide this quantification through a meta-analysis of observational studies. Methods A comprehensive systematic review was conducted in accordance with guidelines of preferred reporting items for systematic reviews and meta-analyses [9]. The review protocol was registered on 26 September 2016 in the International Prospective Register of Systematic Reviews database (registration number CRD42016047994). Eligibility criteria All articles that focused on CVE at all stages in AAV were identified. The following criteria were applied for the inclusion of articles: cohort or case–control studies with AAV patients; report of CVE, including ischaemic heart disease (IHD), cerebrovascular accident (CVA) and/or peripheral arterial disease (PAD); an estimate of the association between AAV status and outcome [i.e. relative risk (RR), odds ratio (OR), incidence rate ratio (IRR) or hazard ratio (HR)] and 95% CI or sufficient information to calculate them; and at least one comparison group. No language restrictions were applied. Articles published up to August 2016 were included. Search strategy The search strategy was developed in collaboration with an experienced librarian (R.H.J.O.). The databases PubMed (N.L.M.), Embase.com and the Cochrane Library (Wiley) were searched by two authors (R.H.J.O. and E.H.) from their inception to 30 August 2016. In brief, the keywords (ANCA-associated vasculitis, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) were combined with each of the following: stroke, myocardial ischaemia and peripheral arterial disease. Search terms included indexed terms from Medical Subject Headings (MeSH) in PubMed, EMtree in EMBASE.com as well as free-text terms. The full list of search terms is provided in supplementary Table S1, available at Rheumatology Online. Two reviewers (E.L.P. and E.H.) independently screened the titles and abstracts of the search results and reviewed the full text of the articles that appeared to meet the inclusion criteria. The bibliographies of all included articles were hand searched for additional potentially eligible articles. Any discrepancy in the determination of study eligibility was resolved by discussion between three authors (E.L.P., T.H. and E.H.). Data collection process Data were collected through a standardized extraction sheet. One reviewer (E.H.) extracted and the second reviewer (T.H.) checked the data. Disagreements were discussed and resolved. For each study, the following data were collected: country, design of the study, patient characteristics (mean age, sex and diagnosis), follow-up duration, CVE, control group and inclusion period. Risks were quantified through the collection of the total number of events and RR, OR, IRR or HR as appropriate, with 95% CI. Quality assessment The quality of the included studies was assessed with the Newcastle–Ottawa Scale [10]. In this scale, studies are scored across three categories: selection of study groups (four questions), comparability of study groups (one question) and ascertainment of the outcome of interest (three questions). In all questions, a maximum of one star can be awarded, except for comparability of study groups, where a maximum of two stars can be awarded. The quality of the included studies was assessed by two investigators (T.H. and E.H.). Disagreements were resolved by consensus. Statistical analyses In the meta-analyses, the outcomes of interest were pooled RR for total CVE, IHD and CVA. IRR, HR and OR were assumed to be numerically the same as the RR. Forest plots and pooled estimates were derived with a random-effects model. Pooled estimates were calculated on the logarithm of the RR from the individual studies. The results were then transformed back to the RR scale. The heterogeneity among studies was tested with Cochran’s Q test. Significant heterogeneity was defined as a value of P < 0.10. The I2-statistic was used to quantify the heterogeneity. Data analysis was performed with Stata statistical software V.StataSE14 (stataCorp LLC, College Station, Texas, USA). Results A total of 1907 records were processed for a final selection of seven articles (Fig. 1). Most records were irrelevant, and of the 28 records retrieved for full-text assessment, four were conference abstracts. Excluded articles comprised 13 articles without a comparison group and two reporting only cardiovascular mortality. Two European studies compared observed event rates with reported expected event rates as calculated by Framingham Risk Scores. These articles were excluded after discussion owing to insufficient information in these articles as well as limited generalizability of the Framingham Risk Score in European countries [11–13]. Two abstracts were excluded because they overlapped with a full-text article. Data from the other two abstracts described the same unpublished cohort study. The authors of these abstracts were unable to provide the required event rates during the process of this review. The remaining seven cohort studies were included in the meta-analysis [14–20]. A list of the excluded articles is provided in supplementary Table S2, available at Rheumatology Online. Fig. 1 View largeDownload slide Flow chart of study selection Fig. 1 View largeDownload slide Flow chart of study selection Five out of the seven studies included only patients with granulomatosis with polyangiitis (Table 1) [15, 17–20]. The other two studies included all three subtypes, but did not provide separate estimates [14, 16]. Six of the seven studies used national registry databases from Canada, Denmark and Sweden [15, 17–20]. In three of these studies, the diagnoses were confirmed in medical files [16–18]. Six of the seven studies compared AAV patients with the general background population [15–20]; in the remaining study, the comparison was made with a chronic kidney disease cohort [14]. The included studies were of high quality, scoring 7–9 points out of 9 on the Newcastle–Ottawa Scale (Table 1). Four studies lacked a statement on the adequacy of follow-up [15, 16, 19, 20]. Two studies did not exclude patients with a history of cardiovascular events [16, 17], and one study did not draw the comparison cohort from the same source as the GPA cohort [14]. Table 1 Characteristics of included cohorts References  Country  inception cohort, y/n  Criteria for patient selection  Number of patients  Age, median (IQR), years  Male, %  Follow-up, years  Number of cardiovascular events in AAV  Cardiovascular outcome  Control group  Inclusion period  Quality score  Morgan et al. [14]  UK  y  CHCC AAV  65 GPA46 MPA2 EGPA113 ctrl  63 (52–70)  50  3  23  IHD, PAD, CVA  CKD patients  1995–2005  8  Aviña-Zubieta et al. [15]  Canada  y  ICD code ordiagnosis GPA on two visits and therapy  504 GPA5222 ctrl  57 (17)a  47  4  41  First MI or ischaemic CVA  General population  1996–2010  8  Englund et al. [16]  Sweden  y  ICD code or ANCA and clinical diagnosis  92 GPA83 MPA11 EGPA744 ctrl  65 (16)a  49  5  45  IHD, CVA  General population  1998–2010  7  Faurschou et al. [17]  Denmark  y  ICD code GPA and ACR criteria  293 GPA and general Danish population  59 (14–88)  53  8  63  IHD  General population  1973–99  8  Faurschou et al. [18]  Denmark  y  ICD code GPA and ACR criteria  180 GPA3420 ctrl  55 (41–61)  51  7  8  First CVA  General population  1993–2011  9  Zöller et al. [19]  Sweden  n  ICD codes GPA after hospitalization  1909 GPA and general Swedish population  N/A  N/A  N/A  4717  First CVA  General population  1987–2008  8  Zöller et al. [20]  Sweden  n  ICD codes GPA after hospitalization  12 670 GPA and general Swedish population  N/A  N/A  N/A  72  First IHD  General population  1964–2008  8  References  Country  inception cohort, y/n  Criteria for patient selection  Number of patients  Age, median (IQR), years  Male, %  Follow-up, years  Number of cardiovascular events in AAV  Cardiovascular outcome  Control group  Inclusion period  Quality score  Morgan et al. [14]  UK  y  CHCC AAV  65 GPA46 MPA2 EGPA113 ctrl  63 (52–70)  50  3  23  IHD, PAD, CVA  CKD patients  1995–2005  8  Aviña-Zubieta et al. [15]  Canada  y  ICD code ordiagnosis GPA on two visits and therapy  504 GPA5222 ctrl  57 (17)a  47  4  41  First MI or ischaemic CVA  General population  1996–2010  8  Englund et al. [16]  Sweden  y  ICD code or ANCA and clinical diagnosis  92 GPA83 MPA11 EGPA744 ctrl  65 (16)a  49  5  45  IHD, CVA  General population  1998–2010  7  Faurschou et al. [17]  Denmark  y  ICD code GPA and ACR criteria  293 GPA and general Danish population  59 (14–88)  53  8  63  IHD  General population  1973–99  8  Faurschou et al. [18]  Denmark  y  ICD code GPA and ACR criteria  180 GPA3420 ctrl  55 (41–61)  51  7  8  First CVA  General population  1993–2011  9  Zöller et al. [19]  Sweden  n  ICD codes GPA after hospitalization  1909 GPA and general Swedish population  N/A  N/A  N/A  4717  First CVA  General population  1987–2008  8  Zöller et al. [20]  Sweden  n  ICD codes GPA after hospitalization  12 670 GPA and general Swedish population  N/A  N/A  N/A  72  First IHD  General population  1964–2008  8  a Mean (s.d.). AAV: ANCA-associated vasculitis; CHCC: Chapel Hill Consensus Conference; CKD: chronic kidney disease; ctrl: controls; CVA: cerebrovascular accident; EGPA: eosinophilic granulomatosis with polyangiitis; GPA: granulomatosis with polyangiitis; ICD: International Classification for Diseases; IHD: ischaemic heart disease; MI: myocardial infarction; MPA: microscopic polyangiitis; N/A: not applicable; PAD: peripheral arterial disease; y/n: yes/no. Cardiovascular outcomes were variable in the seven included studies. Two studies reported estimates for total CVE including CVA and IHD. One study reported CVA, IHD and PAD together, but did not provide separate event rates [14–16]. In these three studies, 109 events were found in 803 AAV patients [14–16]. Of the seven included studies, four reported separate event rates for IHD, of which two articles reported IHD only. A total of 4834 ischaemic heart events were found in 13 653 AAV patients [15–17, 20]. Another four articles reported CVA, of which two articles reported CVAs only. In three studies, CVAs included both ischaemic and haemorrhagic CVAs [16, 18, 19]. In one study CVAs included ischaemic events only [15]. Overall, 112 CVAs were found in 2779 AAV patients [15, 16, 18, 19]. Two studies by a Danish group contained data from cohorts with partly overlapping populations. The separate studies reported different outcomes and were therefore analysed separately only [17, 18]. The same applied to two studies from Swedish national registry cohorts. The cohorts partly overlapped and were therefore analysed for the separate outcomes only [19, 20]. Three studies assessed the RR for total CVE comprising IHD and CVA (in one study also PAD), among AAV patients and 6079 controls. The pooled RR for total CVE is 1.65 (95% CI: 1.23–2.22; Fig. 2). Four studies assessed the RR for IHD among AAV patients vs 5966 controls and the general Danish population in one study and the general Swedish population in another study. The pooled RR for IHD in AAV is 1.60 (95% CI: 1.39–1.84; Fig. 3). Four studies assessed the RR for CVA among AAV patients vs 9386 controls and the general Swedish population in one study. The pooled RR for CVA in AAV is 1.20 (0.98–1.48; Fig. 4). No heterogeneity was seen in the above estimates. The exact number of patients in the Swedish and Danish background population cohorts was not reported. Fig. 2 View largeDownload slide Meta-analysis on the relative risk for cardiovascular events in ANCA-associated vasculitis Cardiovascular events comprising ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease. Fig. 2 View largeDownload slide Meta-analysis on the relative risk for cardiovascular events in ANCA-associated vasculitis Cardiovascular events comprising ischaemic heart disease, cerebrovascular accidents and peripheral arterial disease. Fig. 3 View largeDownload slide Meta-analysis on the relative risk for ischaemic heart disease in ANCA-associated vasculitis Fig. 3 View largeDownload slide Meta-analysis on the relative risk for ischaemic heart disease in ANCA-associated vasculitis Fig. 4 View largeDownload slide Meta-analysis on the relative risk for cerebrovascular accidents in ANCA-associated vasculitis Fig. 4 View largeDownload slide Meta-analysis on the relative risk for cerebrovascular accidents in ANCA-associated vasculitis Discussion In this first meta-analysis on the topic, we show that patients with AAV have an increase in cardiovascular risk of 65%. Most of this risk stems from an increase in IHD, with only a trend for CVA, and very limited data on PAD. The increased risk was consistent, with no evidence of heterogeneity. Several pathophysiological mechanisms might account for the increased risk for cardiovascular events in AAV, including active vasculitis, atherosclerosis, a hypercoagulable state and/or haemorrhage. Little is known on the role of active vasculitis in the excess of CVE in AAV. In a recent study by McGeoch et al. [21], coronary artery disease considered secondary to GPA was found in 2 of 517 GPA patients (0.004%) at any point during their illness, suggesting that active vasculitis plays a limited role in the excess of IHD. CVAs attributable to AAV can be caused by cerebral vasculitis, which is a rare but serious complication [22]. Faurschou et al. [18] reported that 83% of strokes in the AAV group occurred during treatment for newly diagnosed or relapsing GPA or within 2 months of immunosuppressive therapy for active vasculitis. Furthermore, in the analyses by Zöller et al. [19, 20] the event rates for IHD, ischaemic and haemorrhagic CVAs were highest early after diagnosis. These findings suggest that active vasculitis is, at least in part, an explanation for the increased risk for strokes. Inflammation is widely known to play a key role in all stages of atherosclerosis [23]. Indeed, a high burden of atherosclerosis and an increased cardiovascular risk have been reported in other inflammatory diseases [5, 6, 19, 20, 24]. Evidence for (accelerated) atherosclerosis in AAV was observed in multiple studies: two found endothelial dysfunction [25, 26]; another reported increased arterial stiffness, as measured by pulse wave velocity [27]; and several studies found increased intima–media thickness in AAV patients [28, 29]. Besides chronic inflammation, many of the anti-inflammatory drugs in vasculitis, and specifically glucocorticoids, have metabolic side-effects (such as hyperglycaemia, hypertension and central obesity) that may predispose to atherosclerosis and cardiovascular events [30, 31]. However, this relationship is complex because predisposing effects may be counteracted by the positive anti-inflammatory effects. Another potential pathway is impaired physical activity caused by chronic damage and fatigue [32]. It is likely that other pathways also contribute. For instance, recent studies have provided evidence for a hypercoagulable state in patients with AAV, which might contribute to the cardiovascular risk [33, 34]. In line with this, Faurschou et al. [18] also reported a markedly increased risk of pulmonary embolism and deep venous thrombosis in patients with AAV. Finally, many AAV patients have chronic kidney disease, a well-known risk factor for cardiovascular disease [35, 36]. Only one of the included studies controlled for kidney function. In this study, by Morgan et al. [14], a chronic kidney disease population was used as a control group. Given that this study reported the highest RR for CVE, kidney impairment per se is most probably not the only explanation for the increased cardiovascular risk in AAV. Most of the included studies did not provide enough clinical information, such as traditional cardiovascular risk factors, kidney function and/or vasculitis activity, to determine the potential contribution of each pathway. Two recent studies found that age, myeloperoxidase ANCA status, hypertension and BMI predict cardiovascular events in AAV patients [7, 37]. More studies are required to map cardiovascular risk profiles in AAV patients and stratify cardiovascular risk by patient and disease characteristics. This could shed new light on the above-mentioned pathophysiological pathways and may contribute to future preventive therapies. One recent study, published after our literature search, retrospectively compared cardiovascular risk in AAV patients with that in patients with arterial hypertension and found a higher burden of cardiovascular disease in AAV patients (P = 0.01) [38]. This was the first study to provide a meta-analysis of the risk for CVE in AAV. In the absence of statistical heterogeneity, the meta-analysis increased the power and precision of the estimate. Although quantitative heterogeneity was absent, the included studies had qualitative heterogeneity in the form of a variety of inclusion criteria and different control groups. Inception and non-inception cohorts were included, and some studies reported first CVE after diagnosis, whereas others reported first ever events. Furthermore, some studies defined IHD as myocardial infarction only, whereas others used a more extensive definition, including angina pectoris and chronic coronary heart disease. Owing to the limited number of studies, we were unable to perform sensitivity analyses in these subgroups, so the absence of statistical heterogeneity should be interpreted with caution. A sensitivity analysis with patients with GPA only was not performed because of the low number of studies with all types of AAV and their limited weight in the meta-analyses. Furthermore, owing to the limited number of studies we were unable to perform an evaluation of publication bias. Most of the included studies were based on national registry databases, which provide a large amount of information but might have inaccuracies. Aviña-Zubieta et al. [15] reported that in previous studies 89% of patients who were registered as having GPA were confirmed to meet the ACR criteria [39]. The included studies did not provide information on the number of AAV patients who were not incorporated in the national registries, so the sensitivity and specificity of the registration systems is unknown. In summary, this is the first meta-analysis to focus on the RR for CVE in AAV. Overall, the risk for CVE was found to be increased by 65%. Our results underline the recently published EULAR guideline, in which active monitoring and treatment of traditional cardiovascular risk factors is recommended as part of the standard care for AAV patients [8]. This will include cessation of smoking, control of weight and encouragement to engage in physical activity. Furthermore, traditional treatment of cardiovascular risk factors, such as hypertension and hypercholesterolaemia, should actively be performed. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. Supplementary data Supplementary data are available at Rheumatology online. 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RheumatologyOxford University Press

Published: Mar 1, 2018

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