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Abstract
Introduction Systemic low-grade inflammation is a fundamental pathophysiological mechanism of heart failure with preserved left ventricular ejection fraction (HFpEF). The efficacy of anti-inflammatory therapy in HFpEF is largely understudied. The aim of the study is to assess the anti-inflammatory effect of colchicine in HFpEF by looking at inflammatory biomarkers: high-sensitivity C reactive protein (hsCRP) and soluble suppression of tumorigenicity 2 (sST2).
Methods and analysis This is a single-centre, prospective, randomised controlled, open-label, blinded-endpoint crossover clinical trial of stable but symptomatic patients with HFpEF. Patients will be randomised to either colchicine treatment 0.5 mg two times per day or usual care for 12 weeks followed by a 2-week washout period and crossover to 12 weeks of treatment with the alternate therapy. The primary objective is to investigate if administration of colchicine compared with usual care reduces inflammation in patients with HFpEF measured by primary endpoint sST2 and co-primary endpoint hsCRP at baseline and 12-week follow-up. Secondary objective is to determine if treatment with colchicine influences N-terminal pro-B-type natriuretic peptide levels, left ventricular diastolic function and remodelling, right ventricular systolic function and left atrial volumetric characteristics. We are aiming to enrol a total of 40 participants. This trial will answer the question if colchicine treatment reduces systemic low-grade inflammation and influences left ventricular diastolic function and remodelling with patients with HFpEF.
Ethics and dissemination Ethical approval was obtained from the Ethics Committee of Sechenov University (reference: 03-22).
Trial registration number NCT05637398.
- heart failure, diastolic
- biomarkers
- inflammation
Data availability statement
No data are available.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Systemic low-grade inflammation is a fundamental pathophysiological mechanism of heart failure with preserved left ventricular ejection fraction (HFpEF), while the efficacy of anti-inflammatory therapy in HFpEF is largely understudied.
WHAT THIS STUDY ADDS
This trial will answer the question if colchicine treatment reduces systemic low-grade inflammation and influences left ventricular diastolic function and remodelling in patients with HFpEF.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
The trial will provide data on colchicine effect in patients with HFpEF and will form the foundation for subsequent phase II and III studies.
Introduction
Heart failure with preserved left ventricular ejection fraction (HFpEF) is characterised by high morbidity and mortality worldwide. The pathophysiology of the syndrome is not fully understood. Systemic low-grade inflammation is one of the fundamental underlining mechanisms of cardiometabolic HFpEF involved in cardiomyocyte stiffening and myocardial fibrosis formation.1 2 Increased levels of inflammatory biomarkers including C reactive protein (CRP), interleukin (IL)-1 and IL-6, and soluble suppression of tumorigenicity 2 (sST2) have been associated with disease progression and adverse outcomes in patients with HFpEF.3–6 Among others, sST2 is acknowledged as a prognostic biomarker of heart failure (HF)7 8 and improves a risk stratification for death when added to N-terminal pro-B-type natriuretic peptide (NT-proBNP).9
Anti-inflammatory therapies in HFpEF are largely understudied. Data from post-hoc analysis of the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial showed a reduction in HF hospitalisation and mortality in patients with a history of myocardial infarction (MI) and elevated high-sensitivity CRP (hsCRP) treated with IL-1β inhibitor, canakinumab.10 However, in this study, patients with HF were not specifically investigated. To date, there are only two small studies in patients with HFpEF by Van Tassell et al in which inflammatory pathways were directly targeted with IL-1 inhibitor, anakinra. In both studies, significant reduction in hsCRP was demonstrated in the treatment arm, while the increase in peak oxygen consumption seen in the first pilot study11 was not confirmed in subsequent work with a bigger sample size.12 Further studies exploring the role of anti-inflammatory therapy in HFpEF are an unmet need. Just recently, the first large phase III trial of anti-inflammatory treatment in HFpEF has been registered. The HERMES (How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation) trial was designed to examine the effect of IL-6 inhibitor, ziltivekimab, on composite outcomes including cardiovascular death, HF hospitalisation or urgent HF visit (NCT05636176).
Colchicine is an anti-inflammatory agent which is currently in the spotlight in cardiology, since it has been demonstrated the drug is safe and effective in reducing cardiovascular events in patients with coronary artery disease (CAD).13 14 Colchicine interferes with several steps in the inflammatory process, including NLRP3 inflammasome suppression responsible for IL-1 and IL-6, and influences CRP production.15 Colchicine has never been studied in patients with HFpEF but was found to be safe in those with stable HF with reduced ejection fraction (HFrEF).16 We assumed that colchicine could have a place in the treatment of HFpEF as evidence for the role of inflammation in the disease pathophysiology is accumulating.
Our trial was designed to investigate if the treatment with colchicine (1) decreases systemic low-grade inflammation in HFpEF and reduces inflammation-related biomarker of HF sST2 and marker of systemic inflammation hsCRP, and (2) influences left ventricular diastolic function and remodelling.
Methods and analysis
Study overview
This trial is a single-centre, prospective, randomised controlled, open-label, blinded-endpoint crossover clinical trial conducted in the Cardiology Department of City Clinical Hospital named after S S Yudin. This trial will assess the effect of colchicine on inflammation-related biomarker of HF sST2 and hsCRP in patients with HFpEF. The study will be conducted in accordance with the principles stated in the Declaration of Helsinki and the International Conference on the Harmonization of Good Clinical Practice. All patients will provide written informed consent before being included. The study was registered on ClinicalTrials.gov (NCT05637398). A flow diagram of the study is depicted in figure 1.
Flow diagram of the study
Eligibility criteria
Men and women aged ≥40 years admitted to the City Clinical Hospital named after S S Yudin for other causes rather than acute HF decompensation with symptoms and signs of HF and left ventricular ejection fraction >50% are candidates for screening and will be enrolled at index hospitalisation or in outpatient settings. These patients undergo NT-proBNP and hsCRP measurements and will be enrolled if biomarkers are elevated; all inclusion criteria are met and none of the exclusion criteria are present. Major inclusion and exclusion criteria are listed in Box 1.
Inclusion and exclusion criteria of the trial
Inclusion criteria
≥40 years of age, male and female.
Left ventricular ejection fraction ≥50%.
Symptoms and signs of heart failure.
N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/mL at baseline (patients in atrial fibrillation at baseline NT-proBNP ≥600 pg/mL), left atrial volume index >34 mL/m2 or a left ventricular mass index ≥115 g/m2 for males and ≥95 g/m2 for females.
One of the following criteria: high-sensitivity C reactive protein levels >2 mg/L, body mass index ≥30 kg/m2 or type 2 diabetes mellitus.
Exclusion criteria
Established diagnosis of hypertrophic cardiomyopathy, cardiac amyloidosis or constrictive pericarditis.
Valvular heart disease.
Acute decompensation of heart failure in the last 1 month.
Acute myocardial infarction in the last 3 months, cardiac surgery or cerebrovascular accident within the recent 6 months.
Any active or chronic inflammatory diseases or infections.
Patients with other indications for colchicine therapy or history of colchicine intolerance.
Severe hepatic (alanine aminotransferase N3 upper limit of normal) or renal dysfunction (estimated glomerular filtration rate <45 mL/min/1.73 m2).
History of any malignancy or suffering from cancer.
Lack of informed consent.
Treatment protocol and follow-up
Randomisation and blinding
Eligible patients with HFpEF will be randomised in 1:1 ratio with either colchicine or usual care groups by an investigator. Randomisation will be performed by using a web-based randomisation system (REDCap). Blocked randomisation will be used to achieve balanced allocation and reduce the risk of bias. Given that no placebo will be used in the study, patients and the investigator will be unblinded. All other study members including the sonographer, laboratory specialist and statistician will be unaware of treatment allocation. Patients will be asked not to discuss any questions related to the study treatment with any study members except the investigator. The unblinded investigator is responsible for safety monitoring and collection of adverse events. Monitoring of adverse events will be focused on gastrointestinal manifestations, myalgias and cutaneous adverse events.
Drug intervention
The active treatment intervention consists of colchicine (Haupt Pharma Amareg) 1 mg per day. Deciding on the dosage regimen, we were guided by previous studies investigating the drug in patients with cardiovascular diseases (CVDs) as well as general recommendations for colchicine administration. Although the dosage regimen and treatment duration varied across the studies, the dose of 0.5–1.0 mg per day administrated for 3–24 months was found to be safe in patients with CAD, atrial fibrillation (AF) and HFrEF. The incidence of adverse events in the colchicine arm was largely comparable with those in the placebo arm across the studies.13–17 According to the general recommendations for colchicine use, the dosage of drug must be adjusted according to the patient’s weight increasing to 1 mg per day in those with body mass over 70 kg. Given that patients with HFpEF are generally overweight, the dosage of 1 mg daily was chosen for the study. The drug will be administered for 12 weeks by the investigator.
Follow-up and data collection
After randomisation, at baseline visit, blood samples will be collected for primary endpoint assessment and after centrifugation, the serum samples will be stored at −80°C. sST2 will be assessed with highly sensitive ELISA (BCA, USA). hsCRP will be assayed on Roche Diagnostics analysers. Transthoracic echocardiography (TTE) will be performed on Philips EPIQ 5 according to conventional protocol including left atrial volume index (LAVI), left ventricular mass index, relative wall thickness (RWT) and E/e’ calculation. Follow-up visits will be planned after 4 and 14 weeks for safety and clinical status assessment upon 4 weeks of colchicine treatment and at 12 and 25 weeks for endpoint collection. Each in-person study visit includes physical examination, review of medications, functional status and quality of life assessment with 6-minute walk test and Kansas City Cardiomyopathy Questionnaire, respectively; safety monitoring, blood sample collection and TTE. Telephone contact will be performed within 1 week of treatment by the investigator to assess the adverse events. Data will be collected at REDCap.
Study endpoints
The primary objective of the study is to investigate if administration of colchicine reduced inflammation in patients with HFpEF. Hence, the study primary endpoint is the change in sST2 levels from baseline to 12 weeks of colchicine treatment. Co-primary endpoint is the change in hsCRP levels. Study objectives and endpoints are listed in table 1. The secondary objective of the study was to evaluate if treatment with colchicine influences circulating biomarkers of haemodynamic stress (NT-proBNP). We will assess the change in NT-proBNP from baseline to 3 months of colchicine treatment. As a secondary objective, we will determine if treatment with colchicine influences left ventricular diastolic function and remodelling, right ventricular systolic function and left atrial volumetric characteristics. The changes in parameters of left ventricular diastolic function (E/e’), and remodelling (RWT), tricuspid annular plane systolic excursion and LAVI will be assessed. All echocardiographic examinations will be performed by one experienced sonographer to avoid the interobserver variability of echocardiography parameters.
Study objectives and related endpoints
The exploratory objective is to determine if treatment with colchicine changes other biomarkers of inflammation IL-6 and IL-1; biomarkers of fibrosis procollagen type I carboxy-terminal propeptide; carboxy-terminal telopeptide of collagen type-I and matrix metalloproteinase-1; and emerging biomarker of HFpEF, insulin-like growth factor-binding protein 7. Blood samples will be collected at baseline and after 3 months of treatment and stored at −80°C. Safety endpoints will be collected. Adverse events leading to study drug discontinuation will be recorded, as well as HF hospitalisation and all-cause mortality.
Statistical considerations
Sample size calculation
The trial is powered for the primary endpoint, which is the change in sST2 from baseline to 12 weeks of colchicine treatment. Based on the data from previous studies showing that the mean level of sST2 in HFpEF is 32 (23.7–55.7) ng/mL,5 6 18 consistent with the results from our patient cohort with HFpEF,19 and the data showing the better prognosis in those with sST2 less than 23 ng/mL, we have calculated that a total sample size of 36 patients is required to detect a 10 ng/mL difference in median of sST2, using a 30% absolute difference of SD of sST2 and margin 20% and considering a type I error rate of α=0.05 and a type II error rate of β=0.10 (statistical power=90%), allowing for a treatment discontinuation in up to 10% and assuring substantial power of 40 participants are required to undergo randomisation.
Statistical analysis
Analyses will use the intention-to-treat principle. The primary hypothesis is that treatment with colchicine reduces sST2 levels in patients with HFpEF by 10 ng/mL from baseline after 12 weeks of treatment with colchicine. The primary analysis will compare the difference in sST2 levels between intervention versus usual care over time using a linear mixed model. Secondary endpoints will be analysed using linear regression for continuous outcomes and logistic regression for binary outcomes comparing intervention versus control subjects while controlling for variables that are likely to be associated with outcomes. No adjustments will be made for multiple comparisons to allow for type 1 error in view of the exploratory nature of this proof-of-concept trial. Statistical tests will be performed using SPSS V.26.
Discussion
Disease-modifying therapies in patients with HFpEF are limited today by sodium-glucose transport protein 2 (SGLT2) inhibitors and a new search for therapeutic targets is an unmet need. Inflammation is acknowledged as a significant underlined mechanism of HFpEF which is largely understudied as a therapeutic target. The reduction of HF incidence and death in post-MI patients treated with anti-inflammatory agents has been reported.10 Currently, there are a limited number of studies on direct inhibition of anti-inflammatory pathways in HFpEF, which however demonstrated perspective in targeting this mechanism.11 12
Having shown an efficacy in reduction of cardiovascular events in patients with CAD, and in prevention of AF in those who underwent cardiothoracic surgery or cardiac intervention,13 14 17 colchicine has never been studied in patients with HFpEF. This drug interferes with several steps of the anti-inflammatory cascade including inhibitory effect on NALP3 inflammasome and cytokine release (IL-1, IL-6).15 Therefore, colchicine might hold great potential for clinical and prognostic benefits in HFpEF. In our study, we will investigate whether colchicine administration to patients with HFpEF reduces plasma level inflammatory biomarkers sST2 and hsCRP. If true, we assumed this might potentially be translated into clinically relevant outcomes.
sST2, a member of the IL-1 receptor family,20 has been recognised as a significant prognostic biomarker of HF. The associations between high sST2 levels and outcomes in HF have been repeatedly demonstrated and were remarkably strong in those with HFpEF.7 The biomarker substudy of the PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) clinical trial reported a reduction in sST2 levels in patients with HFpEF treated with sacubitril/valsartan.21 In anti-inflammatory studies conducted in patients with CVDs, changes of sST2 have never been previously assessed. Could we expect that colchicine will reduce sST2 levels in patients with HFpEF? Another question is if sST2 reduction can be translated into clinically important outcomes.
sST2 is produced by different human cells including fibroblasts, cardiomyocytes, alveolar epithelium, renal and endothelial cells in response to pro-inflammatory cytokine stimulation including tumour necrosis factor, IL-1α and IL-1β.22 23 Additionally, myocardial injury induces sST2 release by cardiac fibroblasts and cardiomyocytes.20 Endothelial production of sST2 by cardiac macro and micro vessels was found to be associated with diastolic load.20 Therefore, low-grade systemic inflammation and diastolic dysfunction, which accompany HFpEF, may cause sST2 release locally by cardiac cells. Given the broad mechanisms of colchicine action including NALP3 inflammasome inhibition, and IL-1 and IL-6 production, we can speculate colchicine may suppress sST2 production in patients with HFpEF preventing downstream maladaptive changes in the myocardium up on sST2 action.
sST2 antagonises the cardioprotective effects of IL-33/ST2L system which prevents myocardial fibrosis and cardiomyocyte hypertrophy.24 25 Higher sST2 levels are positively associated with infarct volume index in post-MI patients.26 Associations between sST2 plasma concentration and echocardiographic parameters of left ventricular remodelling and dysfunction were also demonstrated in post-MI patients26 and those with aortic stenosis,27 but not in individuals with HFpEF.18 28 Of note, in subjects with HFpEF, sST2 levels showed strong association with clinical signs and symptoms, burden of comorbidities, right ventricular disturbance, biomarkers of fibrosis and neurohormonal activation.18 20 Therefore, it is important to look at the sST2 changes along with hsCRP upon anti-inflammatory treatment with colchicine in patients with HFpEF, and their associations with cardiac chamber structure and function. In this regard, primary endpoints of the study will inform on inflammatory biomarkers’ response to colchicine treatment in HFpEF. Secondary outcomes will assess if the treatment with colchicine influences left ventricular diastolic function and remodelling, right ventricular systolic function and left atrial volumetric characteristics.
Limitations
Several limitations of the study should be noted. First, the study has a relatively small sample by necessity due to safety concerns as colchicine has never been studied in this patient population. Crossover design allows to increase the patient population and partly overcomes this limitation. Second, the optimal washout period for colchicine is unknown. Considering the data on colchicine half-life, which is 3–10 hours, we assumed that a minimum of 14 days of washout period would be enough to attenuate its effect on biomarkers of interest. Finally, considering the possible indirect anti-inflammatory effect of SGLT2 inhibitors, we acknowledge that this therapy may influence the results of the study. However, it is worth noting that no studies have been performed yet in which the effects of SGLT inhibitors on sST2 levels were investigated.
This trial will answer the question if colchicine treatment reduces systemic low-grade inflammation and influences left ventricular diastolic function and remodelling with patients with HFpEF.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was reviewed and approved by the Ethics Committee of Sechenov University (reference: 03-22). All patients gave written informed consent to participate in the study. The study was conducted according to the guidelines of the Declaration of Helsinki.
References
Footnotes
Twitter @AShchendrygina, @Cherkasova Natalia
Contributors ASh conceived and designed the trial. ASh and SR requested funding for the trial. NM, IK and ASu provided an input in the study design. ASh and NC drafted the first version of the manuscript. DG, VS, IK, NC, EM, DD, AK and JS contributed to patient inclusion, data collection and initial draft revision. All authors approved the final manuscript.
Funding This work was supported by an American College of Cardiology Clinical Trials Research Program award.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.