Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril
Bibliographic record
Abstract
Importance: Consensus guidelines recommend the use of mineralocorticoid receptor antagonists (MRAs) for selected patients with symptomatic heart failure and reduced ejection fraction (HFrEF) to reduce morbidity and mortality; however, the use of MRAs in combination with other inhibitors of the renin-angiotensin-aldosterone system increases the risk of hyperkalemia. Objective: To determine whether the risk of hyperkalemia associated with use of MRAs for patients with HFrEF is reduced by sacubitril/valsartan in comparison with enalapril. Design, Setting, and Participants: The PARADIGM-HF (Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial randomly assigned 8399 patients with chronic HF, New York Heart Association class II to IV symptoms, and a left ventricular EF of 40% or less to treatment with enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily (previously known as LCZ696 [200 mg twice daily]) in addition to guideline-directed medical therapy. Use of MRAs was encouraged but left to the discretion of study investigators. Serum potassium level was measured at every study visit. The incidence of hyperkalemia (potassium level >5.5 mEq/L) and severe hyperkalemia (potassium level >6.0 mEq/L) among patients treated or not treated with an MRA at baseline and the risk of subsequent hyperkalemia for those newly treated with an MRA during study follow-up were defined in time-updated Cox proportional hazards models. Analyses were conducted between August 1 and October 15, 2016. Main Outcomes and Measures: Incident hyperkalemia and severe hyperkalemia. Results: In comparison with the 3728 patients (44.4% of enrolled participants [21.6% female]) not taking an MRA at baseline, the 4671 patients (55.6% [22.0% female]) taking an MRA tended to be younger, with a lower EF, lower systolic blood pressure, and more advanced HF symptoms. Among those taking an MRA at baseline, the overall rates of hyperkalemia were similar between treatment groups, but severe hyperkalemia was more common in patients randomly assigned to enalapril than to sacubitril/valsartan (3.1 vs 2.2 per 100 patient-years; HR, 1.37 [95% CI, 1.06-1.76]; P = .02). In analyses including patients who newly started taking MRAs during the PARADIGM-HF trial, severe hyperkalemia remained more common in those randomly assigned to enalapril than to those randomly assigned to sacubitril/valsartan (3.3 vs 2.3 per 100 patient-years; HR, 1.43 [95% CI, 1.13-1.81]; P = .003). Conclusions and Relevance: Among MRA-treated patients with symptomatic HFrEF, severe hyperkalemia is more likely during treatment with enalapril than with sacubitril/valsartan. These data suggest that neprilysin inhibition attenuates the risk of hyperkalemia when MRAs are combined with other inhibitors of the renin-angiotensin-aldosterone system in patients with HF. Trial Registration: clinicaltrials.gov Identifier: NCT01035255.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".