Efficacy and Mechanism Evaluation (Aug 2024)
High-sensitivity cardiac troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent anthracycline cardiotoxicity: the Cardiac CARE RCT
Abstract
Background Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by rises in plasma cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. Methods In a multicentre prospective randomised open-label blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent plasma high-sensitivity cardiac troponin concentration monitoring and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Randomised controlled trial – patients at high risk of cardiotoxicity (plasma cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomised to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary end point was 6-month change in left ventricular ejection fraction. Prognostic cohort study – in low-risk non-randomised patients with plasma cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (± 2%). Results Between October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomised to cardioprotection (n = 29) or standard care (n = 28) had mean left ventricular ejection fractions of 65.7 ± 6.6% and 64.9 ± 5.9%, respectively, at 6 months. Twenty patients (68.9%) were adherent to cardioprotection therapy at 6 months. Adverse events were more commonly reported in the cardioprotection group, with 71.4% of patients having at least one adverse event compared with 12.7% non-randomised and 10.3% standard care patients. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean percentage-point difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was –0.4% (95% confidence interval –3.59 to 2.85%; p = 0.82). In low-risk non-randomised patients, baseline and 6-month left ventricular ejection fractions were 69.3 ± 5.7% and 66.4 ± 6.3%, respectively (estimated mean difference 2.9%, 95% confidence interval 1.45 to 4.28%; p = 0.92, not equivalent). The main secondary objective of demonstrating zero percentage-point change with equivalence of ± 2% was not met. Conclusions Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment plasma cardiac troponin I concentrations. Low-risk non-randomised patients had similar modest declines in left ventricular ejection fraction, suggesting that the clinical utility of routine cardiac troponin monitoring remains undefined. The modest short-term declines in left ventricular ejection fraction suggest that early cardioprotection therapy has a limited role in patients receiving anthracycline-based chemotherapy. Limitations Treatment effect might have been influenced by several patients stopping cardioprotection treatment within 2 months of randomisation. Across all groups, reduction in left ventricular ejection fraction was lower than expected and patients with high-risk cardiac troponin I concentrations did not exhibit a greater fall in left ventricular ejection fraction than low-risk patients. These factors, together with the trial being powered to detect a 5-percentage-point change in left ventricular ejection fraction, mean that a small treatment effect was not excluded. Future work Future work should aim to understand the transition from small changes in cardiac function, 6 months after completion of anthracycline chemotherapy, to the late development of heart failure in this population. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information. Plain language summary The improved survival for patients with cancer is in part down to chemotherapy drugs called anthracyclines. This medication can cause the unwanted side effect of heart muscle pump injury in a minority of patients. Cancer survivors have increased rates of heart problems, including heart muscle pump failure. Research questions The Cardiac CARE trial tested whether tablet medications called angiotensin receptor blockers and B-blockers, taken together (cardioprotection therapy), can prevent heart muscle injury related to chemotherapy. Doctors treat heart pump failure using these medications. We examined whether a blood test called high sensitivity cardiac troponin I can detect very slight heart muscle injury and predict future problems with heart pump failure. What we did In the trial, only patients with increased levels of the troponin blood test marker were treated with cardioprotection therapy. Breast and blood cancer patients receiving anthracycline treatment were approached to take part. After giving consent they had a detailed scan of their heart prior to starting and 6 months after completing anthracycline chemotherapy. Patients receiving anthracycline had blood taken routinely 2 or 3 days before each treatment. Cardiac troponin levels were measured in these blood samples, and patients with an increased level were allocated at random to treatment with cardioprotection therapy or to normal care. Research findings We found no evidence that cardioprotection therapy prevented decline in heart function in anthracycline-treated patients with elevated cardiac troponin levels. Patients with no increased troponin level had a similar decline in heart function. It was reassuring that the reduction in heart muscle function following anthracycline chemotherapy was small. We believe the results show that cardioprotection therapy is not effective and may not be required for most patients. Scientific summary Background Anthracycline chemotherapy has been shown to reduce the chances of cancer recurrence and death in individuals diagnosed with breast cancer and non-Hodgkin lymphoma. Anthracyclines can also cause damage to the heart muscle, potentially leading to left ventricular systolic dysfunction and cardiac failure. As cancer survival rates improve, there is growing concern about the long-term impact of chemotherapy-related cardiac toxicity. Previous studies have revealed that approximately 5% of patients treated with high doses of anthracycline experience cardiac failure, with the prevalence rising to 10% among those aged > 65 years. The progression from initial heart muscle injury during chemotherapy to the development of left ventricular systolic dysfunction and subsequent clinical heart failure remains poorly understood. Thankfully, the severity and incidence of cardiotoxicity have decreased with the implementation of modern chemotherapy protocols that use lower cumulative doses of anthracycline. To mitigate the risk of systolic dysfunction in patients receiving anthracyclines, recent clinical trials have investigated the use of medications commonly employed in heart failure treatment. A recent meta-analysis of 17 trials involving patients receiving anthracycline-based chemotherapy and randomised to neurohormonal blockade showed a mean 4-percentage-point higher left ventricular ejection fraction (LVEF) in the blockade group, along with a non-significant trend towards fewer clinical events. However, the studies in this meta-analysis have their limitations. First, therapy was prescribed to all patients, resulting in significant overtreatment as most patients do not develop cardiotoxicity. Second, the medications used targeted either the renin-angiotensin system or the sympathetic nervous system (B-adrenoreceptor blocker), even though the strongest evidence supports combined therapy with these medications for the treatment of left ventricular systolic dysfunction. With modern advancements in cancer care, lower rates of cardiotoxicity are being achieved. Consequently, future trials should focus on interventions for patients who are at the highest risk of developing cardiotoxicity. Addressing the limitations of previous studies, the Cardiac CARE trial (registered as EudraCT 2017-000896-99 and ISRCTN24439460) aimed to select patients who demonstrated the most evidence of anthracycline-induced myocardial injury and randomise them into a combination treatment of candesartan and carvedilol. Objectives The primary goals of the Cardiac CARE trial were twofold: first, to investigate whether high-sensitivity plasma cardiac troponin I (cTnI) monitoring can identify patients who are at risk of developing left ventricular systolic dysfunction after undergoing anthracycline chemotherapy, and, second, to determine if cTnI-guided treatment with candesartan and carvedilol can prevent the development of left systolic ventricular dysfunction. By achieving these objectives, Cardiac CARE trial findings would have immediate practical implications for clinical practice by testing a straightforward monitoring and intervention pathway that could easily be implemented within cancer treatment centres. The primary end point of the study was to measure the change in left ventricular ejection fraction using cardiac magnetic resonance imaging conducted 6 months after the final dose of anthracycline chemotherapy. The first secondary end point and main secondary objective were to establish the specificity of high-sensitivity cardiac troponin I (hs-cTnI) monitoring for cardiotoxicity by assessing the change in left ventricular ejection fraction in the low-risk non-randomised group. Additional secondary end points included evaluating hs-cTnI concentrations, conducting further cardiac magnetic resonance imaging measurements to assess the efficacy of candesartan and carvedilol treatment, and determining the specificity of hs-cTnI monitoring for cardiotoxicity. The study summarised clinically relevant thresholds for grading anthracycline cardiotoxicity based on treatment, but no formal statistical testing was performed due to inadequate power and the risk of testing multiple hypotheses simultaneously. Methods The study was conducted in accordance with the Declaration of Helsinki and received approval from the South East Scotland Research Ethics Committee (17/ES/0071). It followed a prospective, randomised, open-label, blinded end-point design. All patients received standard of care and underwent cardiac magnetic resonance imaging before and 6 months after completing anthracycline chemotherapy. Patients with high sensitivity plasma cTnI concentrations in the upper tertile during chemotherapy were randomly assigned in a 1 : 1 ratio to receive either standard of care alone or standard of care along with combined candesartan and carvedilol therapy. Patients aged ≥18 years who were starting anthracycline treatment for adjuvant or neo-adjuvant therapy of breast cancer or non-Hodgkin lymphoma were eligible to participate. To focus on the dose-dependent nature of anthracycline cardiotoxicity and considering the lower incidence observed in recent studies, only patients scheduled to receive a cumulative dose of at least 300 mg/m2 of epirubicin or 150 mg/m2 of doxorubicin over three, four or six cycles of treatment were approached. In comparison, the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) study included 60% of patients receiving low-dose anthracycline (cumulative epirubicin dose ≤ 240 mg/m2), and around 20% of them also received trastuzumab. Cardiac CARE excluded patients with HER2-positive disease scheduled for trastuzumab treatment. Although studying the outcomes of patients receiving anthracycline followed by trastuzumab is clinically relevant, it would require a larger study to account for the effects of two agents with interacting but distinct mechanisms of myocardial injury and potentially reversible changes in left ventricular ejection fraction occurring over an additional 15 months of trastuzumab administration. Plasma hs-cTnI concentrations were measured before and during chemotherapy to identify patients at high risk. The thresholds for randomisation were based on findings from a pilot study that identified patients with high sensitivity plasma cTnI concentrations in the upper tertile on completion of anthracycline chemotherapy. Patients were randomised using a web-based service to ensure allocation concealment and avoid bias. Randomisation was performed between the standard of care alone and the standard of care plus combined candesartan and carvedilol (cardioprotection) therapy groups. Patients assigned to the treatment intervention started with 8 mg of candesartan once daily, with dosage increases of at least 3 days to reach 16 mg and 32 mg once daily. Simultaneously, carvedilol was initiated at 6.25 mg twice daily and increased to 12.5 mg and 25 mg twice daily. The medications were dispensed on the day of randomisation and continued until patients completed the study or withdrew from participation. Adherence to medication was recorded through dose titration clinics and in patient diaries. Patients with plasma hs-cTnI concentrations below the randomisation threshold remained on standard of care alone. Health utility, measured with the EuroQol-5 Dimensions, five-level version (EQ-5D-5L) questionnaire, was assessed at chemotherapy cycle 1 by a research nurse and approximately every 9 weeks until the completion of the study (a total of five times). Sample size and statistical analysis The Cardiac CARE trial aimed to enrol at least 168 patients from various regional cancer centres in the UK. It was estimated that approximately one-third of the enrolled patients (n = 56) would develop high-sensitivity plasma cTnI concentrations that met the criteria for high risk based on the Cardiac CARE pilot study. We assumed that this threshold would select all patients at risk of experiencing a ≥ 5%-point reduction in left ventricular ejection fraction, which may be associated with long-term clinical outcomes. The randomisation was set at a 1 : 1 ratio between the treatment arm and standard care. Treatment allocation employed dynamic randomisation, with minimisation of group imbalances in prognostic factors, including age (≥ 65 or 300 mg/m2). To detect a difference of 5 percentage points between groups (standard deviation 5) with 90% power at a significance level of = 0.05, we needed to randomise 23 patients per group. Accounting for an estimated 17% missing data, the sample size requirement increased to 28 patients per group, resulting in a total randomised trial size of 56 patients. Since one-third of enrolled patients were expected to be randomised, the total enrolment needed to be at least 168 patients. To assess the specificity of the plasma hs-cTnI assay for left ventricular systolic dysfunction in non-randomised patients, we aimed to demonstrate that there was no change in left ventricular ejection fraction percentage (with equivalence limits of ± 2%). To achieve this, we needed complete paired magnetic resonance imaging scans from 68 non-randomised patients for a paired t-test with two-sided p-value of 0.05, 90% power, and a standard deviation of differences of 5%. Results Between 4 October 2017 and 30 June 2021, 175 patients were enrolled. Fifty-seven (32.6%) of patients were randomised. Twenty-nine were allocated to cardioprotection, with two patients in this group not completing the final follow-up magnetic resonance imaging (MRI) scan. Twenty-eight were allocated to standard care, with one patient not completing the final follow-up MRI scan. Within the remaining 118 non-randomised group, 21 patients did not complete the final follow-up magnetic resonance imaging scan. Twenty patients (68.9%) were adherent to cardioprotection treatment at 6 months. Two patients (6.9%) randomised to cardioprotection did not receive medication owing to illness at the time of randomisation. Adverse events were more common in cardioprotection than in the standard care groups (71.4% and 10.3%, respectively). Seven (24.1%) participants stopped both cardioprotection drugs within 2 months owing to symptoms. The mean (standard deviation) patient age in the non-randomised, cardioprotection and standard care groups was 52.1 (11.0) years, 54 (14.1) years and 53.5 (13.3) years, respectively. Mean mass (standard deviation) was higher in the standard care group (82.5 kg; 6.7 kg) than in the cardioprotection (70.7 kg; 16.5 kg) and non-randomised groups (76.6 kg; 6.5 kg); 71.2% of patients had received a diagnosis of breast cancer. Non-Hodgkin lymphoma patients were more frequently randomised than breast cancer patients, making up 43.9% of the randomised and 21.2% of the non-randomised groups. Cardiovascular risk markers and concomitant cardiovascular medication prescription were uncommon across all three groups. Hypertension and coronary disease were more common in the standard care group (14.3% and 7.1%, respectively) than in the non-randomised (8.5% and 3%) and cardioprotection groups (6.9% and 0%). The mean anthracycline dose was higher in the cardioprotection (469 mg/m2) and standard care groups (479 mg/m2) than in the non-randomised group (424 mg/m2). Radiotherapy was more commonly prescribed in the non-randomised group (71.2%) than in the cardioprotection (57.1%) and standard care groups (53.6%). Patients randomised to cardioprotection or standard care had a mean (standard deviation) LVEF 6 months after completion of anthracycline chemotherapy of 65.7% (6.6%) and 64.9% (5.9%), respectively. After adjustment, the estimated mean difference in 6-month LVEF between the cardioprotection and standard care groups was –0.4% points [95% confidence interval (CI) –3.6 to 2.8 points; p = 0.82]. We examined the per-protocol primary efficacy outcome between the randomised groups in a post hoc sensitivity analysis. When only 19 cardioprotection patients who were adherent to treatment were included, there was no change in the primary outcome. The estimated mean difference in the change in 6-month LVEF between the cardioprotection and standard care groups was –0.7 percentage points (95% CI –4.3 to 2.9 percentage points; p = 0.70). In non-randomised patients, the baseline and 6-month LVEF (standard deviation) were 69.3% (5.7%) and 66.4% (6.3%), respectively. The estimated mean difference was 2.9 percentage points (95% CI 1.45 to 4.28 percentage points; p = 0.92). The main secondary objective of demonstrating zero-percentage-point change with equivalence of ± 2% was not met. Secondary analysis identified a difference between cardioprotection and standard care groups in adjusted left ventricular end-diastolic volume indexed for body surface area of 6.0 ml/m2 (95% CI 0.6 to 11.4 ml/m2; p = 0.03). There was no difference between the groups in global longitudinal and circumferential strain, left ventricular mass or left atrial area. hs-cTnI concentrations were higher in the randomised groups. The adjusted change in hs-cTnI concentration from baseline to 2 months in the cardioprotection and standard care groups was 27.3 ng/l (7.4 ng/l) and 28.8 ng/l (8.8 ng/l) [estimated mean (standard error)]. The estimated mean difference was –1.6 ng/l (95% CI –17.6 to 14.4 ng/l; p = 0.85). No cardiovascular deaths or new atrial fibrillation were recorded during the trial. One patient in the standard care treatment group developed congestive cardiac failure. This patient received heart failure treatment including candesartan and their ejection fraction was seen to have recovered on the 6-month cardiac MRI scan. No patients met the criteria for asymptomatic cancer therapy-related cardiac dysfunction (CTRCD) of a 10-percentage-point LVEF fall and fall to an absolute LVEF below 50%. Similarly, the CTRCD criterion of > 15% fall in global longitudinal strain was uncommon across the groups. Chronic myocardial injury 2 months after completion of chemotherapy was not uncommon and was similar in the non-randomised (32.1%) and cardioprotection (35.7%) groups. The proportion with chronic myocardial injury was higher (60%) in the standard care treatment group. Any recording of high hs-cTnI concentration was confined to randomised groups. Conclusions We found no evidence of cardioprotection effect with combined candesartan and carvedilol. This combination was associated with side effects, and discontinuation of therapy was not uncommon. Our findings do not support the European Society Guidelines that give a class II recommendation to use of either an angiotensin blocker or B-blockers for high-risk anthracycline-treated patients. Furthermore, the small decline in LVEF at 6 months in all groups together with the low levels of other cardiotoxicity measures cast doubt over whether any form of broadly administered cardioprotection therapy is required for these patients. The recently published European Society of Cardio-Oncology Guidelines provide a class I recommendation for the use of cTn monitoring in anthracycline patients at high risk of cardiotoxicity. The Cardiac CARE trial findings raise doubt about whether this monitoring strategy is helpful when patients with both low- and high-risk hs-cTnI concentration profiles developed small reductions in left ventricular ejection fraction. Although the pathological link between cTn as a biomarker of anthracycline myocardial injury is clear, we found no evidence that elevated concentrations strongly predict cardiotoxicity, inform disease management or improve care when added to current treatment pathways. Further analysis of the data will establish the correlation between hs-cTnI concentrations and change in LVEF and global longitudinal strain. We will also examine whether there is a threshold hs-cTnI concentration below which patients do not develop a decline in LVEF. An LVEF decline of 4.3% at 6 months after chemotherapy may not have immediate clinical implications for an individual patient. Applied across a population, this magnitude of LVEF decline is likely to confer a generalised increased risk of future cardiac dysfunction and heart failure. Future research should be directed at understanding the factors determining the evolution of cardiac dysfunction with monitoring and longer-term follow-up studies. Trial registration This trial is registered as ISRCTN24439460 and EudraCT 2017-000896-99. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/48/20) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.
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