Impact of cannabidiol on myocardial recovery in patients with acute myocarditis: Rationale & design of the ARCHER trial.

AIMS: Acute myocarditis, although a rare disease, can be associated with sudden cardiac death or the need for transplantation in both children and young adults. To date, there is no definitive evidence to support the routine use of immunosuppressive therapy or treatment targeting inflammation in patients with myocarditis. Animal models of cardiovascular (CV), as well as neurological diseases, have demonstrated that cannabidiol has significant anti-inflammatory properties and may represent a promising therapy in acute myocarditis. This efficacy has been shown in a murine model of autoimmune myocarditis as well as in in vitro and in vivo models of heart failure (HF). METHODS AND RESULTS: We present the rationale and design of the ARCHER Trial, an international multicentre, double-blind, randomized, placebo-controlled, phase II study examining the safety and efficacy of a pharmaceutically produced cannabidiol formulation, in patients with mild to moderate acute myocarditis. Eligible patients are those with acute myocarditis, randomized within 10 days of the diagnostic cardiac MRI (CMR), which has met defined diagnostic criteria for myocarditis. Oral treatment (cannabidiol or placebo) is titrated from 2.5 mg/kg of body weight up to 10 mg/kg of body weight b.i.d. (or highest tolerated dose) and taken for 12 weeks in addition to standard of care therapy for HF. The primary endpoints are defined as changes in global longitudinal strain (GLS) and extra cellular volume (ECV), measured by CMR at 12 weeks. Assuming 80% power, a 5% alpha risk and 25% missing CMR follow-up data at Week 12, 100 patients are required to demonstrate the desired treatment effect of 18%. The change in left ventricular ejection fraction (LVEF) from baseline to Week 12 was selected as the secondary endpoint. Additional exploratory endpoints include changes in hs-troponin, NT-proBNP, markers of inflammation and endothelial function during the 12-week treatment period. The trial is ongoing but is now more than 50% recruited. As enrolment in the trial continues, no interim data are available for inclusion in this Design paper. CONCLUSIONS: The ongoing ARCHER Trial is an international, multicentre, double-blind, randomized, placebo-controlled phase II study, designed to determine the effect of a pharmaceutically produced cannabidiol formulation on CMR parameters in patients presenting with acute myocarditis. Enrolment of 100 patients is expected to conclude in Q3 2024. Study results will be available in early 2025.

Hemodynamic and neurochemical determinates of renal function in chronic heart failure.

Abnormal renal function is common in acute and chronic congestive heart failure (CHF) and is related to the severity of congestion. However, treatment of congestion often leads to worsening renal function. Our objective was to explore basal determinants of renal function and their response to hemodynamic interventions. Thirty-seven patients without CHF and 59 patients with chronic CHF (ejection fraction; 23 ± 8%) underwent right heart catheterization, measurements of glomerular filtration rate (GFR; inulin) and renal plasma flow (RPF; para-aminohippurate), and radiotracer estimates of renal sympathetic activity. A subset (26 without, 36 with CHF) underwent acute pharmacological intervention with dobutamine or nitroprusside. We explored the relationship between baseline and drug-induced hemodynamic changes and changes in renal function. In CHF, there was an inverse relationship among right atrial mean pressure (RAM) pressure, RPF, and GFR. By contrast, mean arterial pressure (MAP), cardiac index (CI), and measures of renal sympathetic activity were not significant predictors. In those with CHF there was also an inverse relationship among the drug-induced changes in RAM as well as pulmonary artery mean pressure and the change in GFR. Changes in MAP and CI did not predict the change in GFR in those with CHF. Baseline values and changes in RAM pressure did not correlate with GFR in those without CHF. In the CHF group there was a positive correlation between RAM pressure and renal sympathetic activity. There was also an inverse relationship among RAM pressure, GFR, and RPF in patients with chronic CHF. The observation that acute reductions in RAM pressure is associated with an increase in GFR in patients with CHF has important clinical implications.

Interpretation of subgroup results in clinical trial publications: insights from a survey of medical specialists in Ontario, Canada.

BACKGROUND: Clinicians routinely apply randomized trial evidence to their patients who meet study selection criteria. However, little is known about how clinicians interpret conflicting subgroup data. METHODS: We mailed a self-administered survey to all practicing cardiologists (n = 309) and 695 randomly chosen other specialists in Ontario, Canada. The survey presented 6 hypothetical trials where a subgroup result deviated from the overall result. We also elicited responses to some general statements about clinical evidence and subgroups. RESULTS: Completed surveys were received from 435 physicians (44%). Faced with overall benefit but no apparent treatment effect in a subgroup, almost 44% would exclude subgroup-type patients, notwithstanding the hazard of beta error. Given overall harm but significant benefit for a subgroup, responses were split approximately 60:40 between continuing conventional therapy for all and treating subgroup-type patients with the new drug. For an overall null result with a positive treatment-subgroup interaction term, 25% of respondents would continue conventional therapy, whereas 69% would adopt the new drug for subgroup-type patients. Physicians with an academic appointment, devoting more time to research, or with formal training in research methodology were more likely to ignore subgroups unless a treatment-subgroup interaction term was significant (P values ranging from .018 to <.0001). Asked if in general they paid special attention to individual subgroup results, respondents were again divided with 37.5% agreeing, 39.5% disagreeing, and the rest undecided. CONCLUSION: Clinicians disagree sharply in interpretation of clinical trials when the overall and subgroup results diverge. Clearer guidelines are needed for undertaking, reporting, and interpreting subgroup analyses.

Clinical prognosis, pre-existing conditions and the use of reperfusion therapy for patients with ST segment elevation acute myocardial infarction.

BACKGROUND: Some evidence-based therapies are underused in patients with a poor prognosis despite the fact that the survival gains would be highest among such patient subgroups. The extent to which this applies for acute, life-saving therapies is unknown. The impact of prognostic characteristics and pre-existing conditions on the use of reperfusion therapy among eligible patients with acute ST segment elevation myocardial infarction is examined. METHODS: Of 2829 acute myocardial infarction patients prospectively identified in 53 acute care hospitals across Ontario, 987 presented with ST segment elevation within 12 h of symptom onset and without any absolute contraindications to reperfusion therapy. The baseline prognosis for each patient was derived from a validated risk-adjustment model of 30-day mortality. Multiple logistical regression was used to examine the relationships among reperfusion therapy, prognosis and the number of pre-existing chronic conditions after adjusting for factors such as age, sex, time since symptom onset and socioeconomic status. RESULTS: Of the 987 appropriate candidates, 725 (73.5%) received reperfusion therapy (70.8% fibrinolysis, 2.6% primary angioplasty). The adjusted odds ratio of reperfusion therapy fell 4% with each 1% increase in baseline risk of death (adjusted OR 0.96, 95% CI 0.92 to 1.00, P=0.04) and fell 18% with each additional pre-existing condition (adjusted OR 0.82, 95% CI 0.76 to 0.90, P<0.001). The number rather than the type of pre-existing conditions inversely correlated with the use of reperfusion therapy. While the impact of baseline risk and pre-existing conditions was additive, pre-existing conditions exerted a greater impact on the nonuse of reperfusion therapy than did baseline risk. CONCLUSIONS: A treatment-risk paradox is demonstrable even within a cohort of lower risk patients with ST segment elevation myocardial infarction. These findings are consistent with the view that these clinical decisions are more likely to be attributable to concerns about patient frailty or side effects than to a misunderstanding of treatment benefits.

The relevance of subgroup-specific treatment effects: the Studies Of Left Ventricular Dysfunction (SOLVD) revisited.

BACKGROUND: The overall effect sizes estimated from randomized clinical trials may not apply similarly to all patients. Univariate subgroup analyses are often used to help determine the generalizability of a trial's results, but may themselves be misleading. We reanalyzed the Studies of Left Ventricular Dysfunction (SOLVD) to determine whether the treatment effect depended on the patients' baseline prognosis, defined on the basis of multiple clinical variables. METHODS: The SOLVD prevention (4228 patients) and the SOLVD treatment (2569 patients) trials were randomized, double-blind trials that studied the effect of enalapril in patients with reduced left-ventricular function or congestive heart failure. We combined both SOLVD populations and compared the results of a univariate analysis to a multivariate approach in which 3 patient subgroups were defined according to baseline risks for the combined end point of death or hospitalization for heart failure. RESULTS: Enalapril treatment resulted in 24% fewer events. The strongest predictors of an event were ejection fraction, New York Heart Association classification and age, antiplatelet agents, history of diabetes mellitus, treatment with digoxin or diuretics, and race. Only ejection fraction produced a significant treatment interaction (P =.004). Consistent with the original SOLVD reports, this interaction was also demonstrable when ejection fraction was scaled into tertiles and examined on its own (P =.012). However, there was no interaction present when patients were divided into tertiles of multifactorial baseline risk. CONCLUSIONS: We confirmed the treatment effect of enalapril, the impact of left-ventricular systolic function, and the negative prognostic importance of diabetes mellitus in this population. Although ejection fraction led to a subgroup-treatment interaction in the main SOLVD publications, a multifactorial approach to prognostic grouping abolished the interaction. These findings highlight the limitations of univariate subgroup analyses and illustrate that multivariate risk group analysis may be a complementary method for assessing the generalizability of the overall treatment effects observed in randomized trials.