Original article A systematic review and meta-analysis of mortality in chronic Chagas cardiomyopathy versus other cardiomyopathies: higher risk or fiction?

INTRODUCTION

Chagas disease, caused by the parasite Trypanosoma cruzi, currently affects 6 to 8 million people, primarily in endemic areas in Latin America.¹ However, migration has turned Chagas disease into a worldwide public health issue, with nearly 300 000 cases estimated in the USA and 50 000 in Europe.¹ During the course of the disease, 30% of the patients will develop chronic Chagas cardiomyopathy (CCC), characterized by rapid heart failure (HF) progression and a high incidence of stroke and fatal ventricular arrhythmias.² Although the prognosis of HF patients ha significantly improved with the advent of neurohormonal blockade therapies during the last 4 decades, multiple studies indicate a persistent higher risk of adverse cardiovascular outcomes in the CCC population than in other cardiomyopathies (OC).³ Nonetheless, evidence supporting this association is mainly derived from individual original studies and reviews not focused on HF patients, leaving a substantial knowledge gap in this area.^4,5 Therefore, this study aimed to systematically assess the evidence comparing the mortality risk in CCC with that of OC.

METHODS

Data sources and search strategy

This study was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (table 1 of the supplementary data). We searched the PubMed/Medline (National Library of Medicine, United States) and EMBASE (Elsevier, Netherlands) databases from inception to October 3, 2023, to identify longitudinal studies comparing the incidence of mortality in adult ambulatory patients with CCC and OC. No language restrictions were applied. We used the following search terms: Chagas cardiomyopathy, Chagas disease, Trypanosoma cruzi, American trypanosomiasis, mortality, and outcomes, among others. The complete search strategy is described in the supplementary data.

Study selection and eligibility criteria

We included clinical trials and all observational studies (eg, cross-sectional, cohort, and case-control studies), except for case reports and case-series. We also excluded systematic reviews and meta-analyses. Studies that assessed adult patients with CCC and compared the mortality risk with those with OC were considered. The follow-up of included studies also had to be performed in an outpatient setting. We excluded studies in the pediatric population or animals.

Data screening and extraction

The selection process was carried out using Rayyan.⁶ Two independent reviewers screened the titles and abstracts, while considering the selection criteria. Any disagreements were resolved by a third reviewer. After this stage, full texts were reviewed to determine whether each study fulfilled the selection criteria. Relevant data from included studies was extracted using an Excel form. For studies reporting only medians and ranges (interquartile range, range, and maximum-minimum values), these values were converted into means and standard deviations using the method explained by Hozo, et al.⁷

Risk of bias assessment

The study quality was independently evaluated by 2 authors employing the Newcastle-Ottawa Scale. In instances where a consensus was elusive, a third author arbitrated to reach a resolution. The quality of each study was analyzed on a 10-point scale, stratified into “low risk of bias” for 9 to 10 points, “medium risk of bias” for 6 to 8 points, and “high risk of bias” for scores less than 6.

Data synthesis and analysis

The summary measures for continuous variables are reported as the mean ± standard deviation, while categorical variables are expressed as proportions. Participants were classified into 4 groups, initially: a) chronic Chagas cardiomyopathy (CCC); b) nonischemic cardiomyopathy (NICM), and c) ischemic cardiomyopathy (ICM). In addition, a fourth non-Chagas cardiomyopathy (non-CC) group was included for studies that did not characterize individuals in the comparator population (without Chagas cardiomyopathy) with respect to their etiology. Data synthesis was conducted by employing random effect models using the inverse variance method to estimate the pooled size effects, while the Paule-Mandel estimator was used to account for random error. In addition, the Hartung-Knapp adjustment was applied. Pooled unadjusted risk ratios (RR) were calculated from the mortality information reported, while adjusted hazard ratios (HR) were directly extracted from the multivariate models of the studies. Heterogeneity was assessed using the I² statistic. Value higher than 75% were considered to indicate high heterogeneity, those between 25% and 75% as moderate, and those less than 25% as low. Meta-regression analysis was performed in contrasts with more than 10 studies to assess variables that might explain heterogeneity in the observed associations. A meta-regression analysis was also performed in contrasts with more than 10 studies to assess variables that might explain the heterogeneity in the observed associations, while a sensitivity analysis comparing studies published before and after 2016 was performed to explore the potential influence of the use of the more recently introduced angiotensin receptor-neprilysin inhibitors. Finally, publication bias was assessed using funnel plots and Egger's test. If potential publication bias was identified, the trim-and-fill method was employed using the metafor package to calculate an adjusted effect size, accounting for the presence of this bias. Statistical significance was set at a P < .05. All analyses were conducted using R Statistical Software (v4.2.3; R Core Team 2023) and the meta and metafor packages.

RESULTS

Study and patient characteristics

Out of 2134 screened studies, 37 met the selection criteria and were included in the meta-analysis (figure 1 and table 1).^3,8–43 These studies were performed predominantly in Brazil (n = 32, 86.5%) and were primarily prospective cohorts (64.9%). A total of 17 949 patients (4258 with CCC and 13 691 with OC) were analyzed. CCC patients were younger (mean difference, −2.35 years; 95% confidence interval [95%CI], −4.05 to −.65 years; I², 93%) and less frequently male (odds ratio [OR], 0.74; 95%CI, 0.63-0.87; I², 40%) compared with patients with OC, with no significant differences in the proportion of patients in New York Heart Association class III-IV status (OR, 0.88; 95%CI, 0.70-1.09; I², 44.3%) or left ventricular ejection fraction (mean difference, 0.77%; 95%CI, −0.79% to 2.33%; I², 90%). The mean follow-up times in the assessed studies ranged from 100 days to 1970 days (median, 758 days). Finally, most of the studies (86.5%) were classified as having a low risk of bias (figure 2A,B).

Figure 1.

Central illustration. Flowchart of included studies.

Table 1.

General characteristics of the included studies and the evaluated population

First author	Year	Country/Region	Quality (NOS)	Study type	Total patients	Total CCC patients	Total OC patients	Median follow-up	Multivariate analysis of mortality*
Areosa CMN, et al.^8	2007	Brazil	5	Retrospective cohort study	330	94	236	1780	Yes
Ayub-Ferreira SM, et al.^9	2013	Brazil	7	Post-hoc trial analysis	342	55	287	1284	Yes
Barbosa AP, et al.^11	2011	Brazil	6	Prospective cohort study	352	246	106	851	Yes
Barbosa MPT, et al.^10	2013	Brazil	7	Retrospective cohort study	135	65	70	266	No
Bertolino ND, et al.^12	2010	Brazil	4	Retrospective cohort study	103	46	57	100	Yes
Bestetti RB, et al.^13	1997	Brazil	6	Prospective cohort study	125	75	50	NR	No
Bestetti RB, et al.^14	2013	Brazil	6	Prospective cohort study	374	244	130	1003	Yes
Bradfield J, et al.^15	2014	USA	6	Prospective cohort study	36	18	18	1970	No
Braga JCV, et al.^16	2008	Brazil	7	Prospective cohort study	191	89	102	365	Yes
Cardoso J, et al.^17	2010	Brazil	7	Prospective cohort study	110	33	77	760	No
Cerqueira-Silva T, et al.^18	2021	Brazil	7	Retrospective cohort study	404	210	194	1305	Yes
de Albuquerque DC, et al.^19	2023	Brazil	7	Prospective cohort study	3013	262	2751	346	No
De Campos Lopes CB, et al.^20	2006	Brazil	7	Prospective cohort study	458	98	360	730	Yes
de Melo RMV, et al.^21	2019	Brazil	6	Retrospective cohort study	108	52	56	478	Yes
Oliveira Jr MT, et al.^22	2005	Brazil	6	Prospective cohort study	126	56	70	NR	No
Dubner S, et al.^23	2005	Latin America	7	Prospective cohort study	507	201	306	213	Yes
Echeverría LE, et al.^24	2023	Colombia	7	Prospective cohort study	2514	86	2428	215	Yes
Femenía F, et al.^25	2012	Argentina	6	Retrospective cohort study	179	72	107	NR	No
Freitas HFG, et al.^26	2005	Brazil	8	Prospective cohort study	866	242	624	170	Yes
Freitas HFG, et al.^27	2009	Brazil	7	Retrospective cohort study	280	144	136	1043	Yes
Heringer-Walther S, et al.^28	2006	Brazil	7	Prospective cohort study	82	32	50	955	No
Issa VS, et al.^3	2009	Brazil	7	Post-hoc trial analysis	456	68	388	1326	No
Martinelli M, et al.^29	2017	Brazil	6	Prospective cohort study	426	115	311	365	Yes
Nadruz W, et al.^30	2018	Brazil	7	Prospective cohort study	944	159	785	730	No
Nakazone MA, et al.^31	2020	Brazil	7	Prospective cohort study	677	368	309	1459	Yes
Nunes MC, et al.^32	2010	Brazil	7	Prospective cohort study	287	224	63	1201	Yes
Nunes VL, et al.^33	2006	Brazil	4	Prospective cohort study	45	26	19	1825	No
Ochiai ME, et al.^34	2011	Brazil	6	Retrospective cohort study	350	92	258	523	Yes
Olivera MJ, et al.^35	2022	Colombia	6	Prospective cohort study	80	40	40	365	No
Passos LCS, et al.^36	2019	Brazil	6	Retrospective cohort study	54	13	41	456	No
Pereira FTM, et al.^37	2016	Brazil	8	Prospective cohort study	153	65	88	821	No
Rassi S, et al.^38	2005	Brazil	8	Prospective cohort study	204	57	147	1399	No
Shen L, et al.^39	2017	Latin America	7	Post-hoc trial analysis	2552	195	2357	973	Yes
Silva, et al.^40	2008	Brazil	5	Prospective cohort study	354	122	232	365	No
Traina MI, et al.^41	2015	USA	6	Prospective cohort study	135	25	110	1307	No
Vilas-Boas, LGC, et al.^42	2013	Brazil	7	Prospective cohort study	301	222	79	638	Yes
Ferreira SMA, et al.^43	2010	Brazil	5	Post-hoc trial analysis	296	47	249	758	Yes

CCC, chronic Chagas cardiomyopathy; NOS, Newcastle-Ottawa Scale; NR, not reported; OC, other cardiomyopathies.

*

Studies reporting adjusted effect measures derived from multivariate Cox proportional-hazards models assessing mortality as the dependent variable and CCC as an independent variable.

Figure 2.

Forest plots comparing mortality risk between CCC and heart failure of other etiologies. A: unadjusted RR for CCC vs NICM, ICM, and non-CC. B: adjusted HR derived from multivariable Cox proportional-hazards models for CCC vs NICM, ICM, and non-CC. 95%CI, 95% confidence interval; CCC, chronic Chagas cardiomyopathy; CM; cardiomyopathy; HR, hazard ratio; ICM, ischemic cardiomyopathy; LVEF, left ventricular ejection fraction; NICM, nonischemic cardiomyopathy; non-CC, nonchagasic cardiomyopathy; NOS, Newcastle-Ottawa Scale; RR, risk ratio. The bibliographic references cited in the figure correspond to: Issa et al.,³ Areosa et al.,⁸ Ayub-Ferreira et al.,⁹ Barbosa et al.,¹¹ Barbosa et al.,¹⁰ Bertolino et al.,¹² Bestetti et al.,¹³ Bestetti et al.,¹⁴ Bradfield et al.,¹⁵ Braga et al.,¹⁶ Cardoso et al.,¹⁷ Cerqueira-Silva et al.,¹⁸ de Albuquerque et al.,¹⁹ De Campos Lopes et al.,²⁰ de Melo et al.,²¹ Oliveira Jr et al.,²² Dubner et al.,²³ Echeverría et al.,²⁴ Femenía et al.,²⁵ Freitas et al.,²⁶ Freitas et al.,²⁷ Heringer-Walther et al.,²⁸ Martinelli et al.,²⁹ Nadruz et al.,³⁰ Nakazone et al.,³¹ Nunes et al.,³² Nunes et al.,³³ Ochiai et al.,³⁴ Olivera et al.,³⁵ Passos et al.,³⁶ Pereira et al.,³⁷ Rassi et al.,³⁸ Shen et al.,³⁹Silva et al.,⁴⁰Traina et al.,⁴¹Vilas-Boas et al.,⁴² Ferreira et al.⁴³

Mortality risk meta-analysis

In the unadjusted analyses, CCC patients had a significantly higher risk of mortality during follow-up compared with patients with NICM (RR, 1.44; 95%CI, 1.21-1.71; I², 65%; 12 studies), ICM (RR, 1.34; 95%CI; 1.11-1.63; I², 65%; 10 studies), and non-CC (RR, 1.42; 95%CI, 1.30-1.55; I², 37%; 22 studies) (figure 2A). Twenty studies provided adjusted effect measures for the risk of mortality, mainly including age, sex, New York Heart Association class, left ventricular ejection fraction, and HF medications as adjustment covariates. The meta-analysis of adjusted measures reported a significantly higher mortality risk in the CCC group compared with the NICM (HR, 2.04; 95%CI, 1.60-2.60; I², 47%; 8 studies) and the non-CC (HR 2.26; 95%CI, 1.65-3.10; I², 71%; 11 studies) groups, while no significant effect was observed when patients with CCC and ICM were compared (HR, 1.72; 95%CI, 0.80-3.66; I², 69%; 4 studies) (figure 2B). Of note, some studies reported information for more than one comparator group (ICM /NICM/non-CC), and consequently the total number of contrasts performed was higher than the number of articles included.

Meta-regression and publication bias

The results of meta-regression analysis revealed that none of the evaluated study characteristics (age, sex, New York Heart Association class, left ventricular ejection fraction, publication year, and follow-up time) was a significant source of heterogeneity (P > .05) (table 2 of the supplementary data). Moreover, a sensitivity analysis by publication year (before 2016 and after 2016) showed no significant differences in the effects between groups among the different contrasts (table 3 of the supplementary data). At the same time, Egger's test did not suggest publication bias in most of the performed analyses (P > .05), except for the unadjusted contrast between CCC and non-CC patients, which showed a potential bias toward reporting of larger effects (P = .024) (Figure 1 of the supplementary data). Nonetheless, after implementing the trim-and-fill method for this contrast, the adjusted estimates showed a consistently higher risk of mortality in the CCC group (RR, 1.39; 95%CI, 1.26-1.52; I², 44%) (Figure 2 of the supplementary data).

DISCUSSION

In the present meta-analysis, which evaluated more than 17 000 patients with HF, we observed that HF secondary to CCC was associated with a significantly higher mortality risk than HF arising from other causes. This result was evident in both unadjusted and adjusted models. Notably, we found a similar mortality risk in the meta-analysis of adjusted effects when comparing CCC and ICM. However, this finding was limited by a smaller number of studies (n = 4) compared with the other adjusted contrasts (CCC vs NICM [n = 8] and CCC vs non-CC [n = 10]). Overall, our findings confirm the previously reported trend in individual studies and provide valuable information on the estimates for each etiologic group and the magnitude of the mortality risk associated with the diagnosis of CCC in HF patients. Interestingly, we observed a lower prevalence of male sex in the CCC group compared with the OC group. Current evidence suggests that male sex is associated with greater progression from the indeterminate form of Chagas disease to CCC⁴⁴; however, there is also evidence suggesting that male sex is significantly associated with the development of OC, and the effect of this variable is potentially greater in other HF etiologies than in CCC.^45–48

CCC represents a rapidly progressive form of cardiac involvement with a unique pathophysiology, characterized by severe immune cell infiltration to the myocardium, leading to extensive myocardial remodeling, intense fibrotic involvement, and a dilated cardiomyopathy phenotype.⁴⁹ Moreover, transmural replacement of the myocardium by scar tissue is frequent in CCC and has been associated with the development of fatal arrhythmias, making sudden cardiac death the second cause of mortality in this population after worsening HF.⁵⁰ In addition, systemic embolisms are highly incident in CCC due to the high prevalence of structural abnormalities, such as ventricular aneurysms and atrial fibrillation, as well as the presence of coagulation disorders intrinsic to chronic Trypanosoma cruzi infection.^49,51 Finally, the neuroendocrine involvement observed during the course of the disease, marked by compromised adrenal and thymus gland function coupled with more pronounced parasympathetic denervation, may potentially explain the more severe clinical profile of this cardiomyopathy compared with other etiologies.^52,53 Despite these insights, targeted therapeutic solutions that take into account the intricate pathophysiology of CCC remain elusive. Equally, there have been no dedicated randomized controlled trials evaluating the benefit of neurohormonal blockade in this patient population. Consequently, it is unknown whether patients with CCC benefit similarly from these therapies or continue to be at increased risk of mortality and adverse cardiovascular outcomes despite receiving optimal HF treatment.^54,55 Therefore, the results of the PARACHUTE trial are eagerly anticipated, as they will compare sacubitril-valsartan with enalapril in patients with CCC, focusing on mortality risk and other cardiovascular outcomes. The results of this clinical trial may define the future of the pharmacological management of CCC and have the potential to set a new trend regarding mortality in this vulnerable population.⁵⁶

Limitations

Despite its comprehensiveness, our study has several limitations. First, the moderate to high heterogeneity among the included studies in some comparisons, including various populations, methodologies, and clinical settings, could have introduced potential biases. Although difficult to determine, the observed interstudy heterogeneity may be due to multiple factors. These factors include the year of study publication. Although the year of publication was not significantly associated with the impact of CCC diagnosis on mortality in the meta-regression analyses, the relatively low sensitivity of this approach does not allow us to rule out the presence of a significant effect. This is because the diagnostic and therapeutic approaches to HF varied significantly between the publication of the first included study (1997) and the last study (2023). Other important factors include the type and stage of cardiac involvement, since some studies did not clarify the etiologies of the comparator groups or whether the individuals included had a diagnosis of HF or were in earlier stages of cardiomyopathy, as well as the mean follow-up time, which, although not significant in the meta-regression analysis, could also have influenced the differences observed. Finally, although most of the studies were performed in Brazilian populations, 7 studies (19%) were conducted in other countries, mainly Colombia and the United States. Differences in the distribution of Trypanosoma cruzi discrete typing units and other variables could have also influenced the observed results.

Second, we identified a potential publication bias in the studies reporting unadjusted risks for CCC vs non-CC groups. However, a significant effect was still observed after we adjusted by this type of bias using a trim-and-fill method. Moreover, the potential confounders included in the multivariate-adjusted models varied significantly among studies, as different covariate selection approaches were used. Nevertheless, the absence of significant results in the meta-regression analyses supports the accuracy of our results. Furthermore, the absence of patient-level data restricted our ability to conduct more refined subgroup analyses or assess the influence of individual patient characteristics on outcomes.

Of note, patients with CCC represent a vulnerable population, with limited access to health services and, therefore, to HF medications and therapies that reduce mortality, such as neurohormonal blockade and implantable cardioverter-defibrillators, which may influence their survival. However, we were unable to include data on socioeconomic status, access to HF therapies, or adherence to these drugs in our analyses, representing an important limitation.

Finally, assessment of all-cause mortality allowed the inclusion of a larger number of studies, not discriminating between the different causes of mortality (HF, sudden cardiac death, stroke, among others).

CONCLUSIONS

This meta-analysis indicates that CCC patients have an almost 2-fold increase in mortality risk during follow-up compared with their counterparts with HF secondary to OC. This finding underscores the pressing need to increase awareness of CCC prognosis and encourage the performance of large RCTs evaluating the benefit of HF therapies in this special population. Furthermore, our results invite further investigation of the factors potentially associated with the worse prognosis observed in patients with CCC, potentially highlighting access to HF therapies, treatment adherence, and early diagnosis of cardiomyopathy. Such insights are critical for shaping effective public policies and focusing research initiatives to better address the challenges of CCC and enhance outcomes for this vulnerable patient group.

WHAT IS KNOWN ABOUT THE TOPIC?

• -

  CCC is characterized by a unique pathophysiology that differentiates it from other etiologies of HF, potentially limiting the benefit of conventional diagnostic and therapeutic approaches to HF.

• -

  CCC has been characterized by rapid progression and high mortality rate. Despite multiple studies highlighting worse clinical outcomes compared with other cardiomyopathies, there is lack of aggregated evidence analyzing whether diagnosis of CCC is associated with an increased risk of mortality.

WHAT DOES THIS STUDY ADD?

• -

  In this meta-analysis of 17 949 patients, those with CCC showed a consistently higher risk of mortality when compared with patients with other cardiomyopathies even after adjustment by relevant confounding covariates.

FUNDING

The present study did not require funding.

ETHICAL CONSIDERATIONS

The present work is exempt from approval by the institutional ethics committee because it corresponds to a systematic review of the literature and meta-analysis, which did not require patient recruitment or access to disaggregated information on individuals, since it was based on scientific publications freely available in the medical literature. Possible sex and gender biases have been taken into account in the preparation of this article.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tools were used for the design or preparation of this study.

AUTHORS’ CONTRIBUTIONS

S.A. Gómez-Ochoa participated in the study design, data collection, systematic review, study selection, methodology, statistical analysis, and manuscript review and editing. A.Y. Serrano-García oversaw the study design, data collection, systematic review, study selection, methodology, statistical analysis, and manuscript review and editing. A. Hurtado-Ortiz and A. Aceros were in charge of data collection, systematic review, study selection, and manuscript review. L.Z. Rojas and L.E. Echeverría oversaw the study design, study selection, and manuscript review and editing. All authors are responsible for reviewing the original manuscript and approving the final version.

CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest to disclose.