Immunomodulatory treatment for lymphocytic myocarditis—a systematic review and meta-analysis

Immunomodulatory treatment for lymphocytic myocarditis—a systematic review and meta-analysis Deleterious inflammatory responses are seen to be the trigger of heart failure in myocarditis and therapies directed towards immunomodulation have been assumed to be beneficial. The objective of the present review was to systematically assess the effect of immunomodulation in lymphocytic myocarditis. Studies were included if diagnosis of lymphocytic myocarditis was based on EMB as well as on the exclusion of other etiologies of heart failure and if the patients had at least moderately decreased left ventricular ejection fraction (< 45%). All immunomodulatory treatments at any dose that target the cause of myocarditis leading to cardiomyopathy were included. Retrieval of PUBMED, SCOPUS, Cochrane Central Register of Controlled Trials, and LILACs from January 1950 to January 2016 revealed 444 abstracts of which nine studies with a total of 612 patients were included. As primary effectivity endpoint, a change in left ventricular ejection was chosen. No benefits of corticosteroids or intravenous immunoglobulin alone were reported. Immunoadsorption and subsequent IVIG substitution was associated with a greater improvement in left ventricular ejection fraction (LVEF) in one study. Single studies found a beneficial effect of interferon and statins on LVEF. We performed a meta-analysis for the combination of corticosteroids with immunosuppressants and found a non-significant increase of LVEF of + 13.06% favoring combined treatment (95%CI 1.71 to + 27.84%, p= 0.08). The current evidence does not support the routine use of immunosuppression in traditional lymphocytic myocarditis. Nevertheless, in histologically proven virus-negative myocarditis of high-risk patients, combined immunosuppression might be beneficial. Future research should focus on translation of these effects to clinical outcome. . . . Keywords Myocarditis Inflammatory cardiomyopathy Immunosuppression Immunomodulation Introduction Beside the infectious agent per se, the maladaptive immune- mediated responses against these agents are seen to be causa- Myocarditis is defined as an inflammatory disease of the myo- tive for the myocardial cell dysfunction and compromised con- cardium, histopathologically depicted by infiltration of mono- tractility [3, 5]. Outcome in myocarditis largely depends the nuclear cells to the heart muscle with the presence of development of malignant arrhythmias [8, 9], acute heart fail- myocellular necrosis [1, 2]. Clinical presentation is heteroge- ure [8], as well as the development of chronic active myocar- neous, ranging from subclinical disease with asymptomatic ditis and dilative cardiomyopathy (DCM) [10]. Determinants ECG changes to sudden cardiac death and acute deteriorating of progression from myocarditis to DCM remain unknown, but heart failure. The exclusion of other causes for heart failure and predominantly occur in patients with failure of viral clearance combination of symptoms, laboratory testing, ECG findings, leading to persistent inflammation or those that develop patho- and cardiac imaging leads to the diagnosis of myocarditis [3, genic cardiac autoantibodies directed against myocardial epi- 4]. Endomyocardial biopsy (EMB) has shown that viral infec- topes [11, 12]. To date, treatment of myocarditis largely focuses tions are the most important causes of myocarditis with up to on supportive care to prevent heart failure or concomitant ad- 38% of the samples being positive for viral genomes [5–7]. verse events; however, no approved curative therapy is avail- able. As deleterious inflammatory responses to viral infections provoke myocardial dysfunction in myocarditis, therapies di- * Alexander Niessner rected towards immunomodulation have been assumed to be alexander.niessner@meduniwien.ac.at beneficial. The scope of this review is these curative therapies with immunomodulatory effect in lymphocytic myocarditis. Department of Internal Medicine II, Medical University of Vienna, Due to the high incidence of spontaneous improvement in left Waehringer Guertel 18-20, 1090 Vienna, Austria 574 Heart Fail Rev (2018) 23:573–581 ventricular function and the responsiveness to conventional Study selection and data extraction heart failure treatment, only randomized trials with a properly defined control arm that truly evaluates efficiency of the treat- All published studies investigating curative immunomodula- ment were analyzed [3]. Owing to the rare incidence of myo- tory treatment to prevent the development of cardiomyopathy carditis with severely impaired left ventricular function, this as a sequel of myocarditis were identified. M.W. and P.S. systematic review will assess studies assessing the objective screened titles and/or abstracts for inclusion and in a second surrogate endpoint of echocardiographic measurement of left step, all potentially suitable manuscripts were reviewed for ventricular function. final eligibility. Duplicates were identified using the reference management software EndNote X6 (Thomson Reuters, NY, USA) and excluded. Additionally, the reference lists of the Methods included articles and reviews were examined for further rele- vant publications. Only randomized and controlled trials were The reported search strategy, study selection, data extraction, included. Full texts of all includable trials were obtained and and analysis were performed according to the PRISMA guide- two investigators (M.W. and A.N.) independently assessed lines for systematic reviews and meta-analysis [13]. study eligibility and extracted the data. The following details were recorded for each study: the first author, study design, Search strategy patient characteristics, inclusion criteria, interventions, out- come measurements, and funding. Two authors (M.W. and P.S.) systematically searched PUBMED, SCOPUS, Cochrane Central Register of Outcomes and measurements Controlled Trials, and LILACs for eligible trials from January 1950 to January 2016. To prevent potential publica- The primary efficacy outcome was LVEF measured by echo- tion bias, trial registries (www.who.int/trialsearch/Default. cardiography or scintigraphy. Secondary efficacy endpoints aspx, the WHO International Clinical Trials Registry were (i) New York Heart Association (NYHA) functional Platform, and www.clinicaltrials.gov) were screened for classification and (ii) viral clearance and resolution of the ongoing and completed trials. The search strategy was based inflammatory infiltrate in the myocardium. on the combination of disease, therapy, and study design using BAND^ and BOR.^ Study quality assessment Definitions and interventions Quality of included studies was assessed according to the Cochrane Handbook for Systematic Reviews of Studies were only eligible if participants were diagnosed with Interventions 5.1.0 [21]. Two investigators (M.W. and A.N.) traditional myocarditis. Diagnosis of myocarditis was based evaluated methodological quality of the studies independent- on EMB and the exclusion of other etiologies of heart failure ly. Studies with Binadequate^ methodology were excluded. [8]. Patients in the included trials had at least moderately de- Furthermore, blinding of those providing and receiving the creased left ventricular ejection fraction (LVEF) (< 45%). intervention (double blinding), description of losses to fol- Studies including patients with different etiologies of heart low-up, and the use of intention-to-treat analysis were docu- failure were included only if there was a separate analysis of mented. Disagreements were resolved by consensus. the results for patients with myocarditis. Studies investigating etiologies of the disease other than traditional lymphocytic Data analysis myocarditis (specific pathogens such as Borrelia burgdorferi and Trypanosoma cruzi, cardiac sarcoidosis) were excluded All results are summarized as mean difference for continuous [14–16]. variables or risk ratio for dichotomous variables and 95% Due to the multifactorial etiology of peripartum cardiomy- confidence interval (CI). Due to the heterogeneity of the dif- opathy (angiogenic imbalance [17], altered prolactin process- ferent treatments of myocarditis, an overall meta-analysis was ing [18], inflammatory cytokines [19], and myocarditis [20]) not feasible. Meta-analysis was performed for therapies with and difficulties to treat as per protocol given by the pregnancy, ≥ 3 studies assessing the effect on the primary surrogate end- patients with peripartum cardiomyopathy were not included point LVEF. A test for heterogeneity was used to decide into the clinical trials and could not be included in this whether a fixed effects model or a random effects model is analysis. adequate. Before entering into the meta-analysis, extracted All immunomodulatory treatments at any dose that target data is transformed from standard error of the mean (SEM) the cause of myocarditis leading to cardiomyopathy were or CI to standard deviation (SD). The potential for publication included. bias was assessed using a funnel plot. Statistical analysis was Heart Fail Rev (2018) 23:573–581 575 performed using the program Review Manager 5.0 (RevMan, 1). The main characteristics of the included studies are listed Copenhagen: The Nordic Cochrane Centre, The Cochrane in Table 1. Collaboration, 2008). Endomyocardial biopsy at baseline was performed in all studies as demanded per protocol. With the exception of one study that did not report the duration of symptoms (or duration of heart failure treatment), the duration at baseline was at least Results 3 months in all studies and was limited to 6 months to 2 years in seven studies. Study selection and characteristics Studies assessed immunomodulatory treatment with corti- costeroids only (n =2)[22, 23], a combination of immunosup- The database search on PUBMED, EMBASE, Cochrane pressants and corticosteroids (n =3) [24, 26, 29], intravenous Central Register of Controlled Trials, and LILAC retrieved immunoglobulin (IVIG) only (n =1) [30], a combination of 444 abstracts. Three hundred eighty-two abstracts were ex- immunoadsorption and IVIG (n =1) [27], statin (n =1) [28], cluded because of an inappropriate objective or study design. and anti-viral treatment with interferon or the interferon- From the remaining abstracts, 11 duplicates were excluded, 16 inducing agent thymomodulin (n =1) [25]. Two studies ap- abstracts were excluded because of inappropriate patient or plied a placebo treatment in the control group (Fig. 3). objective definition, and 12 abstracts were not available in English and were excluded. Overall, 23 full-text articles were retrieved. Fourteen articles were excluded because of inappro- Prednisone and immunosuppressive drugs priate study design or inadequate definition of myocarditis. Inter-readers agreement was high (kappa coefficient 0.99). Prednisone has been tested as monotherapy or in combination Nine controlled trials randomized 612 patients to immuno- with other immunosuppressants. Regarding monotherapy, modulatory therapy versus standard therapy ± placebo (Fig. two studies used prednisone over 3 months. Neither study Fig. 1 The flow diagram of study selection 576 Heart Fail Rev (2018) 23:573–581 Table 1 Characteristics of the included studies Study ID Design Intervention No. of Age Disease Duration NYHA Spec. inclusion Exclusion BX LV Placebo patients of symptom baseline criteria baseline Parillo Randomized, Prednisone No 102 43 (23–67) DCM < 2 years, NA None CAD, HTN, valvular Yes < 35% 1989 controlled mean 8 m CM, congenital CM [22] Latham Randomized, Prednisone No 52 41 ± 12 mean ± DCM < 2 years, II–IV None CAD, HTN, DMII, Yes < 40% 1989 controlled SD mean: secondary CM [23] 1.6–1.8 m Mason Randomized, Azathioprine or No 111 Int: 43 ± 14 MYO < 2 years; I–IV Myocardial CAD Yes < 45% 1995 controlled, cyclosporine + Cont: 41 ± 13 43–51% inflammation [24] open-label prednisone mean ± SD <1 m multicenter Miric 1996 Randomized, Interferon-α or No 38 10–54 range DCM or NA II–IV Myocardial CAD, valvular CM, Yes < 45 [25] controlled, thymomodulin MYO inflammation HTN, post-partum open label CM, congenital CM, giant-cell MYO Wojnicz Randomized, Azathioprine and Yes 84 Int: 41 (16–61) DCM > 6 m II–IV Increased HLA CAD, HTN, valvular Yes < 40% 2001 controlled, prednisone Cont: 39 expression CM/other CM [26] open-label (29–60) Mean (95% CI) Staudt Randomized, Immunoadsorption + No 25 Int: 50 ± 3 DCM < 6 m III–IV Myocardial Yes < 30% 2001 controlled IgG substitution Cont: 50 ± 3 inflammation [27] mean ± SEM Wojnicz Randomized, Atorvastatin No 74 39 ± 12 DCM > 6 m II–III HLA upregulation CAD Yes < 40% 2006 controlled, mean ± SD [28] open label, 2 center study Frustaci Randomized, Azathioprine and Yes 85 Int: 44.2 ± 15.8 DCM or >6 m II–IV Myocardial Less than 6 months onset Yes < 45% 2009 controlled, prednisone Cont: MYO inflammation of heart failure; CAD, [29] double 41.1 ± 15.1 sec. CMP, endocrine blinded, mean ± SD disease, significant multicenter CNI drug or alcohol abuse]; (iii) therapy with steroids within 6 months before the enrolment Kishimoto Randomized, IVIG No 41 19–76 range DCM or >6 m III–IV None DM II, thyroid disease, Yes < 40% 2014 controlled, MYO renal disease, (50%) [30] multicenter uncontrolled hypertension valvular heart disease, CAD Int intervention group, Cont control group, NA not available, CM cardiomyopathy, DCM dilated cardiomyopathy, NICM non-ischemic cardiomyopathy, CAD coronary artery disease, MI myocardial infarction, UA unstable angina, ACS acute coronary syndrome, MYO myocarditis, DM diabetes mellitus, HTN hypertension, m months Heart Fail Rev (2018) 23:573–581 577 found any significant differences of LVEF, NYHA functional ± 8% compared to a non-significant increase in the control class, inflammation of the myocardium, nor number of clinical group (n = 37) of 29 ± 7 to 30 ± 6%. Furthermore, the authors events over a follow-up period of 15 to 24 months [22, 23]. found a significant improvement of NYHA functional class in Parillo et al. reported a discrete improvement of the LVEF the treatment group compared to controls [28]. after 3 months in the prednisone group (n = 49) from 17.9 ± 1.0 to 22.2 ± 1.0 versus 17.1 ± 1.1 to 19.3 ± 1.4% in the con- Immunoglobulins and immunoadsorption trol group (n = 52), but this difference failed to reach statistical significance [22]. To date, one study has been conducted investigating IVIG Mason et al., Wojnicz et al., and Frustaci et al. investigated infusion alone in myocarditis. Kishimoto et al. treated patients the effect of a combined treatment with an immunosuppres- with myocarditis with 1–2 g/kg IVIG over 2 days and found a sant (cyclosporine or azathioprine) and prednisone for 3 to significant survival benefit after 60 days of follow-up. 6months[24, 26, 29]. Wojnicz et al. and Frustaci et al. found Interestingly, the IVIG-treated patients did not show an in- a significantly higher LVEF in the treatment group within the creased LVEF as compared to the conventionally treated con- observational periods. Wojnicz et al. reported in the immuno- trol group [30]. Staudt et al. evaluated the effect of suppression group (n = 41) an increase of LVEF from 23.8 ± immunoadsorption and subsequent IVIG substitution in pa- 8.6 to 35.9 ± 10.0% as compared to the control group (n =43) tients with myocarditis. In this trial, patients were randomized from 24.9 ± 7.3 to 27.2 ± 10.1% (p < 0.001). In line with this for IA therapy and subsequent IgG substitution at 1-month observation, Frustaci et al. found in the immunosuppression intervals until month 3. There was a 10 to 11% higher LVEF group (n = 43) an increase of LVEF from 26.5 ± 6.7 to 45.6 ± and a significantly better NYHA functional class in patients 9.6% as compared to a change from 27.7 ± 5.6 to 21.3 ± 5.3% treated with immunoadsorption compared to controls. (p < 0.001) in the control group (n =42). Furthermore, the authors demonstrated that CD3+ T cells de- This improvement was accompanied by an improvement creased significantly in the myocardium in patients treated of symptoms as depicted by a significant decrease in NYHA with immunoadsorption (from 5.7 ± 0.8 to 2.9 ± 0.5 cells/ functional class. In contrast to these data, Mason et al. found mm ,mean ± SEM, p < 0.01, compared to baseline and con- no significant differences in changes of the LVEF between trols) [27]. treatment and control groups at 28 and 52 weeks [24]. The pooled difference of the increase of LVEF between the com- Interferon and thymomodulin bined immunosuppression and control groups was higher in the combined immunosuppression groups (+ 13.06%) but Miric et al. separately investigated the effect of interferon-α or failed to reach statistical significance (95% CI − 1.71 to + thymic hormones in patients with dilated heart muscle disease 27.84%, p = 0.08; Figs. 2 and 3). Data was incorporated into and myocarditis. They found a significantly greater improve- a random effects model as the test for heterogeneity was sig- ment of the LVEF in both treatment groups of 3 to 4% com- nificant (p <0.001). pared to the control group. Moreover, NYHA functional class improved in 11 of 14 patients in the interferon group and in 8 Statins of 13 patients in the thymomodulin group in contrast to 5 of 13 patients in the control group. Regarding resolution of inflam- Within the predefined period, only one study has evaluated the mation, the authors reported that in 5 out of 5 patients that effect of statin treatment on EMB-proven myocarditis [28]. received interferon-α, in 4 out of 5 patients that received Wojnicz et al. used 40 mg atorvastatin per day and found a thymomodulin, and in 2 out of 5 patients receiving conven- significantly higher LVEF after 6 months in the treatment tional treatment myocarditis, inflammation had resolved in the group (n = 34) with a significant increase from 27 ± 7 to 34 follow-up biopsy [25]. Fig. 2 Forrest plot and meta-analysis for the effect of combined immu- SD and the mean difference (95% CI) of left ventricular ejection fraction nosuppression on ventricular ejection fraction. Results from the latest (%) between treatment groups was calculated with the Review Manager follow-up time point were used. Raw data were transformed to mean ± 578 Heart Fail Rev (2018) 23:573–581 Fig. 3 Forrest plot for the effect of all published immunomodulatory SD and the mean difference (95% CI) of left ventricular ejection fraction treatments on ventricular ejection fraction. Results from the latest (%) between treatment groups was calculated with the Review Manager. follow-up time point were used. Raw data were transformed to mean ± IA, immunoadsorption; IVIG, immunoglobulins Discussion endpoint. With three studies assessing the effect of combina- tion therapy with immunosuppressants and corticosteroids on To date, treatment of myocarditis and DCM largely focuses on LVEF, immunosuppression was identified as the most inves- supportive care with guideline-directed treatment of heart fail- tigated treatment strategy. Overall, the studies reported con- ure and arrhythmia [3]. Although modulation of the immune flicting results. Two of three studies found consistently better response in disease entities caused by maladaptive hyperim- LVEF and NYHA functional class over time in the treatment mune responses to infectious triggers has been considered group compared to the control group. Both studies revealing potentially beneficial, the limited availability of randomized beneficial effects used azathioprine as immunosuppressant, controlled trials testing this hypothesis reflects the immature whereas the failing study used either azathioprine or cyclo- state of this body of literature [31]. In the course of this sys- sporine [24, 26, 29]. Interestingly, the upregulation of HLA tematic review, we could identify nine trials that assessed the expression in the myocardium was found to be a useful crite- effect of immunomodulatory or immunosuppressive therapies rion to identify patients that might benefit from the combined on surrogate endpoints in patients with EMB-proven myocar- therapy [26]. The meta-analysis showed a non-significant ef- ditis (Fig. 3). We identified prednisone, immunosuppressive fect of combined immunosuppression with a pooled differ- combination therapy, interferone/thymomodulin, statins, ence of 13.06% for the increase of LVEF over the study period immunoadsorption, and IVIG as tested treatment approaches. (Fig. 2). Two studies found no benefit from corticosteroid Fours studies provided survival or event-free survival data treatment alone in patients with DCM or myocarditis [22, [23, 24, 26, 30]. Only one study [30] found a potential survival 23]. Common minor side effects such as increased weight benefit in their study group. Due to the fact that all of these were reported in patients treated with corticosteroids [22, studies investigated different treatment strategies (immuno- 26]. Immunoadsorption and subsequent IVIG substitution suppressive combination therapy, IVIG, statins, and predni- were associated with a significantly greater improvement in sone), a meta-analysis was not feasible. To assess a potential LVEF compared to the control group in one study [27]. pooled effect, we focused on changes in LVEF as a surrogate Additionally, this study found a significantly better NYHA Fig. 4 Funnel plot for the assessment of publication bias for studies investigating left ventricular ejection fraction (%) Heart Fail Rev (2018) 23:573–581 579 functional class and a significantly decreased CD3+ T cell Another obstacle restraining from routine use of immunosup- count in the myocardium in the treatment group [27]. In con- pressive therapy is the challenge to differentiate between trast to these findings, it has been observed that IVIG alone did virus-positive and virus-negative myocarditis. The clinical not significantly improve recovery of surrogate endpoints in practice of testing of viral antibody titers owes only a low the treatment group [30]. One study which assessed the effect specificity, as the cardiotropic viruses including of interferon or an interferon-inducing agent found a signifi- coxsackievirus and echovirus certainly dominate, but a myri- cantly higher LVEF in the treatment groups compared to con- ad of viruses can cause myocarditis. To rely on this approach trols after 6 months [25]. might result in a non-negligible proportion of false-virus- negative cases. The use of endomyocardial biopsy for the diagnosis of viral genomes in the myocardium might be ben- Conclusions eficial to distinguish between virus-positive and virus- negative myocarditis, but its sensitivity for this purpose has Overall, the observations of the analyzed studies point to- not been reported and remains a matter of speculation [35]. wards the benefit of immunomodulation and immunosuppres- Subsuming both clinical routine and the majority of the trials sion in myocarditis but the potentially beneficial effects are [23–25], [22, 26, 28] struggle to safely exclude viral infec- solely based on changes in surrogate endpoints. The results for tions. All results obtained from the performed meta-analysis combined immunosuppression are conflicting and the meta- must be interpreted with caution due to the significant clinical analysis could not show a statistically significant positive ef- heterogeneity between the included studies. In myocarditis, fect on LVEF. Statins, interferons, and immunoadsorption the evaluation of changes between the treatment group and a showed a positive effect on LVEF, but the relatively low evi- control group is of particular importance in this setting, as dence of only one study respectively does not permit a general spontaneous improvement in the majority of patients led to recommendation. When considering the ratio between risk/ an improvement in many cohorts regardless of the therapeutic cost and benefit, one may speculate that the following two agent. Randomization avoided confounding and selection bias therapeutic scenarios may be the most promising in the future: during enrolment in treatment groups. An insufficient descrip- (a) the use of immunoadsorption or combined immunosup- tion of the generation of the allocation sequence and/or con- pression, consuming large resources, in selected high-risk pa- cealment of the allocation impaired the quality of all studies. tients (e.g., by EMB) and (b) the use of statins, associated with The lack of double blinding was a major limitation in most only limited costs and few side effects, in a less strictly select- studies, particularly when assessing endpoints with consider- ed patient population with proven non-ischemic cardiomyop- able inter-observer variability such as LVEF measured by athy and only moderately reduced LVEF. In line with this echocardiography or when using the subjective reporting of functional status by patient. Selection bias may have occurred assumption, the highly lethal etiologies of myocarditis (acute necrotizing eosinophilic and giant cell myocarditis) are more as the majority of studies did not report loss to follow-up and/ commonly treated with immunosuppression. Although not or did not use an intention-to-treat analysis. Furthermore, the validated by robust randomized controlled data, this treatment inclusion of only biopsy-proven myocarditis per se may lead approach has shown promising results in case series and might to a selection bias as it favors the inclusion of more severe suggest the translation into traditional lymphocytic myocardi- cases of myocarditis and is poorly sensitive to detect those tis [16, 32–34]. patients with transient or focal myocardial inflammation. However, there are no prospective randomized trials that used clinical/radiologic criteria instead of biopsy criteria. No evi- Limitations dence was found for publication bias when searching for un- published studies or by the use of a funnel plot (Fig. 4). It must be emphasized that several issues impair the applica- bility of the results in general population. Firstly and most importantly, the included studies all showed difficulties to Implication for research obtain well-defined study populations. We observed that in studies that reported the numbers of screened patients, only Future research should focus on translation of the effects of 10% underwent endomyocardial biopsy (EMB) and only 5% statins and immunoadsorption on surrogate endpoints to clin- were finally enrolled. These numbers reflect the difficulty to ical outcome. Therefore, large multi-center trials are required identify patients with proven myocarditis. Especially in im- to ensure a sufficient number of endpoints in each treatment munosuppressive therapy regimens a proper patient selection group. Furthermore, future studies should try to confirm and valid EMB results are needed as it has been shown that promising results from single studies suggesting a beneficial particularly patients with evidence of inflammatory activation effect of thalidomide and interferon. Finally, it may be worth in the myocardium benefit from those treatments [26]. focusing on a specific treatment approach in patients with 580 Heart Fail Rev (2018) 23:573–581 Charron P, Elliott PM, European Society of Cardiology Working EMB-proven myocarditis. Regarding methodology, future Group on M, Pericardial D (2013) Current state of knowledge on RCTs should give better descriptions of allocation of treat- aetiology, diagnosis, management, and therapy of myocarditis: a ment, concealment of allocation, and the study flow and position statement of the European Society of Cardiology should furthermore use double blinding with placebo treat- Working Group on Myocardial and Pericardial Diseases. European Heart Journal 34 (33):2636-2648, 2648a-2648d. doi: ment in the control group. Additionally, as it is not a clinical https://doi.org/10.1093/eurheartj/eht210 practice to carry out EMB in all myocarditis patients, RCT’s 9. Klein RM, Vester EG, Brehm MU, Dees H, Picard F, Niederacher should also enroll patients with clinically suspected or better D, Beckmann MW, Strauer BE (2000) Inflammation of the myo- imaging-confirmed myocarditis. cardium as an arrhythmia trigger. Z Kardiol 89(Suppl 3):24–35 10. Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, Klingel K, Kandolf R, Sechtem U, Cooper LT, Bohm M (2012) Funding Information Open access funding provided by Medical Update on myocarditis. J Am Coll Cardiol 59(9):779–792. https:// University of Vienna. doi.org/10.1016/j.jacc.2011.09.074 11. 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Immunomodulatory treatment for lymphocytic myocarditis—a systematic review and meta-analysis

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Medicine & Public Health; Cardiology
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Abstract

Deleterious inflammatory responses are seen to be the trigger of heart failure in myocarditis and therapies directed towards immunomodulation have been assumed to be beneficial. The objective of the present review was to systematically assess the effect of immunomodulation in lymphocytic myocarditis. Studies were included if diagnosis of lymphocytic myocarditis was based on EMB as well as on the exclusion of other etiologies of heart failure and if the patients had at least moderately decreased left ventricular ejection fraction (< 45%). All immunomodulatory treatments at any dose that target the cause of myocarditis leading to cardiomyopathy were included. Retrieval of PUBMED, SCOPUS, Cochrane Central Register of Controlled Trials, and LILACs from January 1950 to January 2016 revealed 444 abstracts of which nine studies with a total of 612 patients were included. As primary effectivity endpoint, a change in left ventricular ejection was chosen. No benefits of corticosteroids or intravenous immunoglobulin alone were reported. Immunoadsorption and subsequent IVIG substitution was associated with a greater improvement in left ventricular ejection fraction (LVEF) in one study. Single studies found a beneficial effect of interferon and statins on LVEF. We performed a meta-analysis for the combination of corticosteroids with immunosuppressants and found a non-significant increase of LVEF of + 13.06% favoring combined treatment (95%CI 1.71 to + 27.84%, p= 0.08). The current evidence does not support the routine use of immunosuppression in traditional lymphocytic myocarditis. Nevertheless, in histologically proven virus-negative myocarditis of high-risk patients, combined immunosuppression might be beneficial. Future research should focus on translation of these effects to clinical outcome. . . . Keywords Myocarditis Inflammatory cardiomyopathy Immunosuppression Immunomodulation Introduction Beside the infectious agent per se, the maladaptive immune- mediated responses against these agents are seen to be causa- Myocarditis is defined as an inflammatory disease of the myo- tive for the myocardial cell dysfunction and compromised con- cardium, histopathologically depicted by infiltration of mono- tractility [3, 5]. Outcome in myocarditis largely depends the nuclear cells to the heart muscle with the presence of development of malignant arrhythmias [8, 9], acute heart fail- myocellular necrosis [1, 2]. Clinical presentation is heteroge- ure [8], as well as the development of chronic active myocar- neous, ranging from subclinical disease with asymptomatic ditis and dilative cardiomyopathy (DCM) [10]. Determinants ECG changes to sudden cardiac death and acute deteriorating of progression from myocarditis to DCM remain unknown, but heart failure. The exclusion of other causes for heart failure and predominantly occur in patients with failure of viral clearance combination of symptoms, laboratory testing, ECG findings, leading to persistent inflammation or those that develop patho- and cardiac imaging leads to the diagnosis of myocarditis [3, genic cardiac autoantibodies directed against myocardial epi- 4]. Endomyocardial biopsy (EMB) has shown that viral infec- topes [11, 12]. To date, treatment of myocarditis largely focuses tions are the most important causes of myocarditis with up to on supportive care to prevent heart failure or concomitant ad- 38% of the samples being positive for viral genomes [5–7]. verse events; however, no approved curative therapy is avail- able. As deleterious inflammatory responses to viral infections provoke myocardial dysfunction in myocarditis, therapies di- * Alexander Niessner rected towards immunomodulation have been assumed to be alexander.niessner@meduniwien.ac.at beneficial. The scope of this review is these curative therapies with immunomodulatory effect in lymphocytic myocarditis. Department of Internal Medicine II, Medical University of Vienna, Due to the high incidence of spontaneous improvement in left Waehringer Guertel 18-20, 1090 Vienna, Austria 574 Heart Fail Rev (2018) 23:573–581 ventricular function and the responsiveness to conventional Study selection and data extraction heart failure treatment, only randomized trials with a properly defined control arm that truly evaluates efficiency of the treat- All published studies investigating curative immunomodula- ment were analyzed [3]. Owing to the rare incidence of myo- tory treatment to prevent the development of cardiomyopathy carditis with severely impaired left ventricular function, this as a sequel of myocarditis were identified. M.W. and P.S. systematic review will assess studies assessing the objective screened titles and/or abstracts for inclusion and in a second surrogate endpoint of echocardiographic measurement of left step, all potentially suitable manuscripts were reviewed for ventricular function. final eligibility. Duplicates were identified using the reference management software EndNote X6 (Thomson Reuters, NY, USA) and excluded. Additionally, the reference lists of the Methods included articles and reviews were examined for further rele- vant publications. Only randomized and controlled trials were The reported search strategy, study selection, data extraction, included. Full texts of all includable trials were obtained and and analysis were performed according to the PRISMA guide- two investigators (M.W. and A.N.) independently assessed lines for systematic reviews and meta-analysis [13]. study eligibility and extracted the data. The following details were recorded for each study: the first author, study design, Search strategy patient characteristics, inclusion criteria, interventions, out- come measurements, and funding. Two authors (M.W. and P.S.) systematically searched PUBMED, SCOPUS, Cochrane Central Register of Outcomes and measurements Controlled Trials, and LILACs for eligible trials from January 1950 to January 2016. To prevent potential publica- The primary efficacy outcome was LVEF measured by echo- tion bias, trial registries (www.who.int/trialsearch/Default. cardiography or scintigraphy. Secondary efficacy endpoints aspx, the WHO International Clinical Trials Registry were (i) New York Heart Association (NYHA) functional Platform, and www.clinicaltrials.gov) were screened for classification and (ii) viral clearance and resolution of the ongoing and completed trials. The search strategy was based inflammatory infiltrate in the myocardium. on the combination of disease, therapy, and study design using BAND^ and BOR.^ Study quality assessment Definitions and interventions Quality of included studies was assessed according to the Cochrane Handbook for Systematic Reviews of Studies were only eligible if participants were diagnosed with Interventions 5.1.0 [21]. Two investigators (M.W. and A.N.) traditional myocarditis. Diagnosis of myocarditis was based evaluated methodological quality of the studies independent- on EMB and the exclusion of other etiologies of heart failure ly. Studies with Binadequate^ methodology were excluded. [8]. Patients in the included trials had at least moderately de- Furthermore, blinding of those providing and receiving the creased left ventricular ejection fraction (LVEF) (< 45%). intervention (double blinding), description of losses to fol- Studies including patients with different etiologies of heart low-up, and the use of intention-to-treat analysis were docu- failure were included only if there was a separate analysis of mented. Disagreements were resolved by consensus. the results for patients with myocarditis. Studies investigating etiologies of the disease other than traditional lymphocytic Data analysis myocarditis (specific pathogens such as Borrelia burgdorferi and Trypanosoma cruzi, cardiac sarcoidosis) were excluded All results are summarized as mean difference for continuous [14–16]. variables or risk ratio for dichotomous variables and 95% Due to the multifactorial etiology of peripartum cardiomy- confidence interval (CI). Due to the heterogeneity of the dif- opathy (angiogenic imbalance [17], altered prolactin process- ferent treatments of myocarditis, an overall meta-analysis was ing [18], inflammatory cytokines [19], and myocarditis [20]) not feasible. Meta-analysis was performed for therapies with and difficulties to treat as per protocol given by the pregnancy, ≥ 3 studies assessing the effect on the primary surrogate end- patients with peripartum cardiomyopathy were not included point LVEF. A test for heterogeneity was used to decide into the clinical trials and could not be included in this whether a fixed effects model or a random effects model is analysis. adequate. Before entering into the meta-analysis, extracted All immunomodulatory treatments at any dose that target data is transformed from standard error of the mean (SEM) the cause of myocarditis leading to cardiomyopathy were or CI to standard deviation (SD). The potential for publication included. bias was assessed using a funnel plot. Statistical analysis was Heart Fail Rev (2018) 23:573–581 575 performed using the program Review Manager 5.0 (RevMan, 1). The main characteristics of the included studies are listed Copenhagen: The Nordic Cochrane Centre, The Cochrane in Table 1. Collaboration, 2008). Endomyocardial biopsy at baseline was performed in all studies as demanded per protocol. With the exception of one study that did not report the duration of symptoms (or duration of heart failure treatment), the duration at baseline was at least Results 3 months in all studies and was limited to 6 months to 2 years in seven studies. Study selection and characteristics Studies assessed immunomodulatory treatment with corti- costeroids only (n =2)[22, 23], a combination of immunosup- The database search on PUBMED, EMBASE, Cochrane pressants and corticosteroids (n =3) [24, 26, 29], intravenous Central Register of Controlled Trials, and LILAC retrieved immunoglobulin (IVIG) only (n =1) [30], a combination of 444 abstracts. Three hundred eighty-two abstracts were ex- immunoadsorption and IVIG (n =1) [27], statin (n =1) [28], cluded because of an inappropriate objective or study design. and anti-viral treatment with interferon or the interferon- From the remaining abstracts, 11 duplicates were excluded, 16 inducing agent thymomodulin (n =1) [25]. Two studies ap- abstracts were excluded because of inappropriate patient or plied a placebo treatment in the control group (Fig. 3). objective definition, and 12 abstracts were not available in English and were excluded. Overall, 23 full-text articles were retrieved. Fourteen articles were excluded because of inappro- Prednisone and immunosuppressive drugs priate study design or inadequate definition of myocarditis. Inter-readers agreement was high (kappa coefficient 0.99). Prednisone has been tested as monotherapy or in combination Nine controlled trials randomized 612 patients to immuno- with other immunosuppressants. Regarding monotherapy, modulatory therapy versus standard therapy ± placebo (Fig. two studies used prednisone over 3 months. Neither study Fig. 1 The flow diagram of study selection 576 Heart Fail Rev (2018) 23:573–581 Table 1 Characteristics of the included studies Study ID Design Intervention No. of Age Disease Duration NYHA Spec. inclusion Exclusion BX LV Placebo patients of symptom baseline criteria baseline Parillo Randomized, Prednisone No 102 43 (23–67) DCM < 2 years, NA None CAD, HTN, valvular Yes < 35% 1989 controlled mean 8 m CM, congenital CM [22] Latham Randomized, Prednisone No 52 41 ± 12 mean ± DCM < 2 years, II–IV None CAD, HTN, DMII, Yes < 40% 1989 controlled SD mean: secondary CM [23] 1.6–1.8 m Mason Randomized, Azathioprine or No 111 Int: 43 ± 14 MYO < 2 years; I–IV Myocardial CAD Yes < 45% 1995 controlled, cyclosporine + Cont: 41 ± 13 43–51% inflammation [24] open-label prednisone mean ± SD <1 m multicenter Miric 1996 Randomized, Interferon-α or No 38 10–54 range DCM or NA II–IV Myocardial CAD, valvular CM, Yes < 45 [25] controlled, thymomodulin MYO inflammation HTN, post-partum open label CM, congenital CM, giant-cell MYO Wojnicz Randomized, Azathioprine and Yes 84 Int: 41 (16–61) DCM > 6 m II–IV Increased HLA CAD, HTN, valvular Yes < 40% 2001 controlled, prednisone Cont: 39 expression CM/other CM [26] open-label (29–60) Mean (95% CI) Staudt Randomized, Immunoadsorption + No 25 Int: 50 ± 3 DCM < 6 m III–IV Myocardial Yes < 30% 2001 controlled IgG substitution Cont: 50 ± 3 inflammation [27] mean ± SEM Wojnicz Randomized, Atorvastatin No 74 39 ± 12 DCM > 6 m II–III HLA upregulation CAD Yes < 40% 2006 controlled, mean ± SD [28] open label, 2 center study Frustaci Randomized, Azathioprine and Yes 85 Int: 44.2 ± 15.8 DCM or >6 m II–IV Myocardial Less than 6 months onset Yes < 45% 2009 controlled, prednisone Cont: MYO inflammation of heart failure; CAD, [29] double 41.1 ± 15.1 sec. CMP, endocrine blinded, mean ± SD disease, significant multicenter CNI drug or alcohol abuse]; (iii) therapy with steroids within 6 months before the enrolment Kishimoto Randomized, IVIG No 41 19–76 range DCM or >6 m III–IV None DM II, thyroid disease, Yes < 40% 2014 controlled, MYO renal disease, (50%) [30] multicenter uncontrolled hypertension valvular heart disease, CAD Int intervention group, Cont control group, NA not available, CM cardiomyopathy, DCM dilated cardiomyopathy, NICM non-ischemic cardiomyopathy, CAD coronary artery disease, MI myocardial infarction, UA unstable angina, ACS acute coronary syndrome, MYO myocarditis, DM diabetes mellitus, HTN hypertension, m months Heart Fail Rev (2018) 23:573–581 577 found any significant differences of LVEF, NYHA functional ± 8% compared to a non-significant increase in the control class, inflammation of the myocardium, nor number of clinical group (n = 37) of 29 ± 7 to 30 ± 6%. Furthermore, the authors events over a follow-up period of 15 to 24 months [22, 23]. found a significant improvement of NYHA functional class in Parillo et al. reported a discrete improvement of the LVEF the treatment group compared to controls [28]. after 3 months in the prednisone group (n = 49) from 17.9 ± 1.0 to 22.2 ± 1.0 versus 17.1 ± 1.1 to 19.3 ± 1.4% in the con- Immunoglobulins and immunoadsorption trol group (n = 52), but this difference failed to reach statistical significance [22]. To date, one study has been conducted investigating IVIG Mason et al., Wojnicz et al., and Frustaci et al. investigated infusion alone in myocarditis. Kishimoto et al. treated patients the effect of a combined treatment with an immunosuppres- with myocarditis with 1–2 g/kg IVIG over 2 days and found a sant (cyclosporine or azathioprine) and prednisone for 3 to significant survival benefit after 60 days of follow-up. 6months[24, 26, 29]. Wojnicz et al. and Frustaci et al. found Interestingly, the IVIG-treated patients did not show an in- a significantly higher LVEF in the treatment group within the creased LVEF as compared to the conventionally treated con- observational periods. Wojnicz et al. reported in the immuno- trol group [30]. Staudt et al. evaluated the effect of suppression group (n = 41) an increase of LVEF from 23.8 ± immunoadsorption and subsequent IVIG substitution in pa- 8.6 to 35.9 ± 10.0% as compared to the control group (n =43) tients with myocarditis. In this trial, patients were randomized from 24.9 ± 7.3 to 27.2 ± 10.1% (p < 0.001). In line with this for IA therapy and subsequent IgG substitution at 1-month observation, Frustaci et al. found in the immunosuppression intervals until month 3. There was a 10 to 11% higher LVEF group (n = 43) an increase of LVEF from 26.5 ± 6.7 to 45.6 ± and a significantly better NYHA functional class in patients 9.6% as compared to a change from 27.7 ± 5.6 to 21.3 ± 5.3% treated with immunoadsorption compared to controls. (p < 0.001) in the control group (n =42). Furthermore, the authors demonstrated that CD3+ T cells de- This improvement was accompanied by an improvement creased significantly in the myocardium in patients treated of symptoms as depicted by a significant decrease in NYHA with immunoadsorption (from 5.7 ± 0.8 to 2.9 ± 0.5 cells/ functional class. In contrast to these data, Mason et al. found mm ,mean ± SEM, p < 0.01, compared to baseline and con- no significant differences in changes of the LVEF between trols) [27]. treatment and control groups at 28 and 52 weeks [24]. The pooled difference of the increase of LVEF between the com- Interferon and thymomodulin bined immunosuppression and control groups was higher in the combined immunosuppression groups (+ 13.06%) but Miric et al. separately investigated the effect of interferon-α or failed to reach statistical significance (95% CI − 1.71 to + thymic hormones in patients with dilated heart muscle disease 27.84%, p = 0.08; Figs. 2 and 3). Data was incorporated into and myocarditis. They found a significantly greater improve- a random effects model as the test for heterogeneity was sig- ment of the LVEF in both treatment groups of 3 to 4% com- nificant (p <0.001). pared to the control group. Moreover, NYHA functional class improved in 11 of 14 patients in the interferon group and in 8 Statins of 13 patients in the thymomodulin group in contrast to 5 of 13 patients in the control group. Regarding resolution of inflam- Within the predefined period, only one study has evaluated the mation, the authors reported that in 5 out of 5 patients that effect of statin treatment on EMB-proven myocarditis [28]. received interferon-α, in 4 out of 5 patients that received Wojnicz et al. used 40 mg atorvastatin per day and found a thymomodulin, and in 2 out of 5 patients receiving conven- significantly higher LVEF after 6 months in the treatment tional treatment myocarditis, inflammation had resolved in the group (n = 34) with a significant increase from 27 ± 7 to 34 follow-up biopsy [25]. Fig. 2 Forrest plot and meta-analysis for the effect of combined immu- SD and the mean difference (95% CI) of left ventricular ejection fraction nosuppression on ventricular ejection fraction. Results from the latest (%) between treatment groups was calculated with the Review Manager follow-up time point were used. Raw data were transformed to mean ± 578 Heart Fail Rev (2018) 23:573–581 Fig. 3 Forrest plot for the effect of all published immunomodulatory SD and the mean difference (95% CI) of left ventricular ejection fraction treatments on ventricular ejection fraction. Results from the latest (%) between treatment groups was calculated with the Review Manager. follow-up time point were used. Raw data were transformed to mean ± IA, immunoadsorption; IVIG, immunoglobulins Discussion endpoint. With three studies assessing the effect of combina- tion therapy with immunosuppressants and corticosteroids on To date, treatment of myocarditis and DCM largely focuses on LVEF, immunosuppression was identified as the most inves- supportive care with guideline-directed treatment of heart fail- tigated treatment strategy. Overall, the studies reported con- ure and arrhythmia [3]. Although modulation of the immune flicting results. Two of three studies found consistently better response in disease entities caused by maladaptive hyperim- LVEF and NYHA functional class over time in the treatment mune responses to infectious triggers has been considered group compared to the control group. Both studies revealing potentially beneficial, the limited availability of randomized beneficial effects used azathioprine as immunosuppressant, controlled trials testing this hypothesis reflects the immature whereas the failing study used either azathioprine or cyclo- state of this body of literature [31]. In the course of this sys- sporine [24, 26, 29]. Interestingly, the upregulation of HLA tematic review, we could identify nine trials that assessed the expression in the myocardium was found to be a useful crite- effect of immunomodulatory or immunosuppressive therapies rion to identify patients that might benefit from the combined on surrogate endpoints in patients with EMB-proven myocar- therapy [26]. The meta-analysis showed a non-significant ef- ditis (Fig. 3). We identified prednisone, immunosuppressive fect of combined immunosuppression with a pooled differ- combination therapy, interferone/thymomodulin, statins, ence of 13.06% for the increase of LVEF over the study period immunoadsorption, and IVIG as tested treatment approaches. (Fig. 2). Two studies found no benefit from corticosteroid Fours studies provided survival or event-free survival data treatment alone in patients with DCM or myocarditis [22, [23, 24, 26, 30]. Only one study [30] found a potential survival 23]. Common minor side effects such as increased weight benefit in their study group. Due to the fact that all of these were reported in patients treated with corticosteroids [22, studies investigated different treatment strategies (immuno- 26]. Immunoadsorption and subsequent IVIG substitution suppressive combination therapy, IVIG, statins, and predni- were associated with a significantly greater improvement in sone), a meta-analysis was not feasible. To assess a potential LVEF compared to the control group in one study [27]. pooled effect, we focused on changes in LVEF as a surrogate Additionally, this study found a significantly better NYHA Fig. 4 Funnel plot for the assessment of publication bias for studies investigating left ventricular ejection fraction (%) Heart Fail Rev (2018) 23:573–581 579 functional class and a significantly decreased CD3+ T cell Another obstacle restraining from routine use of immunosup- count in the myocardium in the treatment group [27]. In con- pressive therapy is the challenge to differentiate between trast to these findings, it has been observed that IVIG alone did virus-positive and virus-negative myocarditis. The clinical not significantly improve recovery of surrogate endpoints in practice of testing of viral antibody titers owes only a low the treatment group [30]. One study which assessed the effect specificity, as the cardiotropic viruses including of interferon or an interferon-inducing agent found a signifi- coxsackievirus and echovirus certainly dominate, but a myri- cantly higher LVEF in the treatment groups compared to con- ad of viruses can cause myocarditis. To rely on this approach trols after 6 months [25]. might result in a non-negligible proportion of false-virus- negative cases. The use of endomyocardial biopsy for the diagnosis of viral genomes in the myocardium might be ben- Conclusions eficial to distinguish between virus-positive and virus- negative myocarditis, but its sensitivity for this purpose has Overall, the observations of the analyzed studies point to- not been reported and remains a matter of speculation [35]. wards the benefit of immunomodulation and immunosuppres- Subsuming both clinical routine and the majority of the trials sion in myocarditis but the potentially beneficial effects are [23–25], [22, 26, 28] struggle to safely exclude viral infec- solely based on changes in surrogate endpoints. The results for tions. All results obtained from the performed meta-analysis combined immunosuppression are conflicting and the meta- must be interpreted with caution due to the significant clinical analysis could not show a statistically significant positive ef- heterogeneity between the included studies. In myocarditis, fect on LVEF. Statins, interferons, and immunoadsorption the evaluation of changes between the treatment group and a showed a positive effect on LVEF, but the relatively low evi- control group is of particular importance in this setting, as dence of only one study respectively does not permit a general spontaneous improvement in the majority of patients led to recommendation. When considering the ratio between risk/ an improvement in many cohorts regardless of the therapeutic cost and benefit, one may speculate that the following two agent. Randomization avoided confounding and selection bias therapeutic scenarios may be the most promising in the future: during enrolment in treatment groups. An insufficient descrip- (a) the use of immunoadsorption or combined immunosup- tion of the generation of the allocation sequence and/or con- pression, consuming large resources, in selected high-risk pa- cealment of the allocation impaired the quality of all studies. tients (e.g., by EMB) and (b) the use of statins, associated with The lack of double blinding was a major limitation in most only limited costs and few side effects, in a less strictly select- studies, particularly when assessing endpoints with consider- ed patient population with proven non-ischemic cardiomyop- able inter-observer variability such as LVEF measured by athy and only moderately reduced LVEF. In line with this echocardiography or when using the subjective reporting of functional status by patient. Selection bias may have occurred assumption, the highly lethal etiologies of myocarditis (acute necrotizing eosinophilic and giant cell myocarditis) are more as the majority of studies did not report loss to follow-up and/ commonly treated with immunosuppression. Although not or did not use an intention-to-treat analysis. Furthermore, the validated by robust randomized controlled data, this treatment inclusion of only biopsy-proven myocarditis per se may lead approach has shown promising results in case series and might to a selection bias as it favors the inclusion of more severe suggest the translation into traditional lymphocytic myocardi- cases of myocarditis and is poorly sensitive to detect those tis [16, 32–34]. patients with transient or focal myocardial inflammation. However, there are no prospective randomized trials that used clinical/radiologic criteria instead of biopsy criteria. No evi- Limitations dence was found for publication bias when searching for un- published studies or by the use of a funnel plot (Fig. 4). It must be emphasized that several issues impair the applica- bility of the results in general population. Firstly and most importantly, the included studies all showed difficulties to Implication for research obtain well-defined study populations. We observed that in studies that reported the numbers of screened patients, only Future research should focus on translation of the effects of 10% underwent endomyocardial biopsy (EMB) and only 5% statins and immunoadsorption on surrogate endpoints to clin- were finally enrolled. These numbers reflect the difficulty to ical outcome. Therefore, large multi-center trials are required identify patients with proven myocarditis. Especially in im- to ensure a sufficient number of endpoints in each treatment munosuppressive therapy regimens a proper patient selection group. Furthermore, future studies should try to confirm and valid EMB results are needed as it has been shown that promising results from single studies suggesting a beneficial particularly patients with evidence of inflammatory activation effect of thalidomide and interferon. Finally, it may be worth in the myocardium benefit from those treatments [26]. focusing on a specific treatment approach in patients with 580 Heart Fail Rev (2018) 23:573–581 Charron P, Elliott PM, European Society of Cardiology Working EMB-proven myocarditis. Regarding methodology, future Group on M, Pericardial D (2013) Current state of knowledge on RCTs should give better descriptions of allocation of treat- aetiology, diagnosis, management, and therapy of myocarditis: a ment, concealment of allocation, and the study flow and position statement of the European Society of Cardiology should furthermore use double blinding with placebo treat- Working Group on Myocardial and Pericardial Diseases. European Heart Journal 34 (33):2636-2648, 2648a-2648d. doi: ment in the control group. Additionally, as it is not a clinical https://doi.org/10.1093/eurheartj/eht210 practice to carry out EMB in all myocarditis patients, RCT’s 9. Klein RM, Vester EG, Brehm MU, Dees H, Picard F, Niederacher should also enroll patients with clinically suspected or better D, Beckmann MW, Strauer BE (2000) Inflammation of the myo- imaging-confirmed myocarditis. cardium as an arrhythmia trigger. Z Kardiol 89(Suppl 3):24–35 10. Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, Klingel K, Kandolf R, Sechtem U, Cooper LT, Bohm M (2012) Funding Information Open access funding provided by Medical Update on myocarditis. J Am Coll Cardiol 59(9):779–792. https:// University of Vienna. doi.org/10.1016/j.jacc.2011.09.074 11. 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Heart Failure ReviewsSpringer Journals

Published: Jun 4, 2018

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