Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Patients with heart failure may experience a nearly two-fold increase in mortality risk during the next year after an outpatient intensification of diuretic therapy.

Evidence Rating Level: 2 (Good)

Hospitalizations are associated with increased mortality risk after discharge in patients with decompensated heart failure, with intensifying diuretic therapy being one of the main interventions given during hospitalization. However, as demonstrated in the PARADIGM-HF trial [Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) With angiotensin-converting enzyme inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure], this intervention alone increased mortality risk in a clinical trial setting, in the absence of hospitalizations. With higher doses of loop diuretics associated with higher mortality risk, reoccurences of fluid retention treatment without hospitalization may be a frequently overlooked but important marker for heart failure progression.In this retrospective cohort study, out of 192 706 patients from the Danish National Register with incident HF diagnosed between 2001 to 2016 and who received ACEI/ARB and BB within 120 days, 74 990 patients were included (median 71yo, 36% women, 51% with ischemic heart disease, 34% AF). These patients were followed for 5 years, or until death, migration, or the end of 2017. To calculate absolute 1-year mortality risk, patients who experienced an intensification event (defined by jumps in dosage according to the DOSE trial protocol*) and those hospitalized for HF were risk set matched with two controls from the study population, who did not experience these signs of worsening. The intensification and hospitalization groups had comparable demographics, with those receiving intensification being slightly older (median age 72 vs 70yo), more frequently living in a nursing home (6 vs 4%), and less likely to be treated with an MRA (31 vs 43%). Patients experiencing an intensification event had an absolute 1-year mortality risk of 18.0% (n= 2910, HR 1.75 after first event, p<0.001) while HF hospitalization patients had 22.6% (n= 2741, HR 2.28 after first event, p<0.01), compared to 9.8% from the matched controls (n=2437, 95% CI, 9.5-10.1%). While intensification events were associated with a cumulative 8.8% incidence of HF hospitalization (95% CI, 8.0-9.6%), there remains an association between these events with a significant increase in hospitalization-free mortality. Subgroup analyses did note that among patients first diagnosed as outpatients, those younger than 70 years old and those with COPD experienced no significant difference in mortality risk subsequent intensification events and hospitalizations. These results apply to a select population of HF patients (ex. the frailest patients who did not survive 120 days past diagnosis were excluded), and there was no data on intensification events that occurred during hospitalizations, or on clinical signs and laboratory results that could have allowed for further stratified analyses. Nevertheless, these findings support reevaluating patients who experience intensification events, in addition to patients hospitalized for worsening HF, for therapeutic optimization.

*intensification event: a) newly prescribed loop diuretics of a minimum 80mg/d furosemide equivalent, b) doubled dosage of initial dose equivalent to a minimum 160mg/d of furosemide, or c) newly prescribed thiazide added to ≥160 mg/d furosemide

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