Cardiac Death

To enhance comparability, we followed the conceptual approach developed by Murray and Lopez in the GBD and currently applied by WHO; namely, to reassign deaths from GCs to causes in our cause list. This approach can be divided into three steps: identify GCs, identify the target causes where the deaths assigned to a GC should in principle be reassigned (based on pathophysiology or an assessment of certification practice); and choose the fraction of deaths assigned to a GC that should be reallocated to each target cause. In the work to date, the identification of target causes for a GC has been based on very general groupings, such as all injuries or all Group I diseases, and the allocation algorithm has largely been based on proportionate distribution within an age-sex group.
We expanded the approach taken in the literature. First, we carefully considered pathophysiology in identifying target causes for a GC. For example, for peritonitis, our targets include digestive diseases, such as intestinal obstruction; genitourinary diseases such as salpingitis and oophoritis; pregnancy, childbirth, and puerperium disease; conditions such as abortions; and some intentional and unintentional injuries. Details for some examples (exposure to unspecified factor X59, female genital organ malignant neoplasm, unspecified site C57.9, heart failure I50, peritonitis K65, septicemia A40, A41) are provided in Additional file 4 to give further illustration of this approach.
Second, we distinguished three methods for assigning GC deaths to a set of target underlying causes: proportionate redistribution within an age-sex group, statistical models, and expert judgment. We used a combination of all of these approaches depending on the four types of GCs. For causes with little information content, we used proportionate redistribution across target causes. In the case of heart failure, we developed a statistical model that helps identify the proportion of deaths for each target code within a given age-sex group. The algorithm eliminates all deaths with the code HF (ICD-10 I50) from the database. It identifies the fraction that should be extracted from HF and assigned to each of the target categories. To estimate the fractions allocated to each target code, we regressed by age, sex, and development status using all available ICD-10 mortality data the fraction of heart failure deaths from all deaths related to heart failure, including target causes.
Finally, for many GCs, we reviewed the published literature and engaged in consultation with GBD expert groups to develop an expert-based algorithm for assigning the fraction of deaths assigned to a GC within an age-sex group to be allocated to different target causes. A further criterion used in developing these expert algorithms was to compare the time trends in a cause by country across various revisions of the ICD. For example, the distribution of GCs to target codes for heart failure is a function of local epidemiology. Redistribution of GCs should in principle generate more plausible or continuous time trends commensurate with the underlying nature of a cause without observing the major discontinuities associated with a change in ICD.
The algorithms for reassigning each of the GCs have been developed in Stata. While conceptually simple, the allocation of each GC to target causes for each age-sex group is computationally intensive. We intend to make our software available to researchers or government agencies to enhance the comparability of their own data. We are currently producing a usable version of the program code for the general public. Once complete, the software will be publicly available on the Web site of the Institute for Health Metrics and Evaluation.

The primary study endpoint is the cardiac event rate, defined by a composite of a heart failure event (New York Heart Association class III or IV) or cardiac death. The secondary endpoints are: 1) change in LVEF and GLS at 6 and 12 months after initiation of HER2-targeted therapy compared to baseline; 2) incidence of asymptomatic LVEF decline, defined by a ≥ 10% absolute reduction from baseline to < 53%; 3) incidence of HER2-targeted treatment interruption, defined by a > 6 week delay between HER2-targeted treatment doses; and 4) feasibility, defined by the proportion of patients who complete the 6- and 12-month surveillance echocardiogram, per protocol. Patients who develop heart failure or asymptomatic LVEF decline will be referred for cardiology evaluation, and HER2-targeted therapy will be interrupted at the discretion of the treating physician.

Patients were followed prospectively after their initial visit, based on a standardized HVC follow-up program described previously^{4 (link)}. For the evaluation of outcome, events were defined as development of any criteria that indicated surgery or cardiac death related to MR. For the assessment of survival, the national mortality registry was queried and additional follow-up information was obtained from telephone interviews with the patients, their relatives, and their physicians.