Data Monitoring Experience in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure: Potentially High-Risk Treatment in High-Risk Patients

The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) was a double-blind, randomized, placebo-controlled trial in 3,991 patients with New York Heart Class II–IV heart failure and LVEF ≤0.40. The two primary objectives were to determine the effect of metoprolol CR/XL on all-cause mortality and on the combined endpoint of all-cause mortality or all-cause hospitalizations (time to first event). There was a two-week placebo run-in period. after which patients were randomized to either metoprolol CR/XL at a dose of 12.5 mg (NYHA III–IV) or 25mg (NYHA II) once daily or matching placebo. The randomized treatment was titrated up to 200 mg once daily or to the highest tolerated dose over an eight-week titration phase. The trial was designed to follow patients for a total mean follow-up of 2.4 years. The Data and Safety Monitoring Board (DSMB) had two tasks. The first was to review all reported Serious Adverse Events (SAEs) on a monthly basis and produce a short report to the sponsor aimed for regulatory agencies. This was done because the sponsor had received a waiver for expedited reporting of SAEs from regulatory agencies including the U.S. Food and Drug Administration (FDA). The second was to perform three pre-specified interim analyses of total mortality. After the second interim analysis, at the point of observing one-half of the targeted number of deaths, the trial was stopped early by the International Steering Committee on recommendation of the DSMB (mean follow-up time 1 year). Final results showed that all-cause mortality was lower in the metoprolol CR/XL group compared to the placebo group (145 deaths, corresponding to 7.2% per patient-year of follow-up for the metoprolol CR/XL group versus 217 deaths, 11.0% per patient-year of follow-up for the placebo group, p = 0.0062 adjusted for interim analyses, p = 0.00009 nominal). The second primary endpoint of all-cause mortality combined with all-cause hospitalizations was also lower for the metoprolol CR/XL group (641 events) compared to placebo (767 events), p = 0.00012 nominal. The procedures developed by the DSMB to implement the required intense safety follow-up will be described.