Long-Term Safety of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in CKD: A Systematic Review and Meta-Analysis of Randomized Trials
Bibliographic record
Abstract
Background: Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors are an oral treatment for anemia of chronic kidney disease (CKD). We assessed long-term safety of HIF prolyl hydroxylase inhibitors in CKD. Methods: In this systematic review and meta-analysis, MEDLINE, Embase and Cochrane databases were searched to March 2023. Randomized trials comparing HIF prolyl hydroxylase inhibitors with an erythropoiesis-stimulating agent (ESA) or placebo with ≥48 weeks of follow-up were eligible. Major adverse cardiovascular events (MACE), individual components of composite cardiovascular endpoints, thrombotic events, and non-cardiovascular adverse events were evaluated. We conducted analyses separately in people with CKD treated with dialysis and those not treated with dialysis (PROSPERO registration CRD42021278011). Results: Twenty-five trials involving 26,478 participants proved eligible. Of these, 13 trials were conducted in 13,230 participants with dialysis-dependent CKD, and 12 trials involved 13,248 participants with CKD not requiring dialysis. There was no evidence that HIF prolyl hydroxylase inhibitors and ESA had different effects on MACE in people with dialysis-dependent CKD (relative risk [RR] 0.99, 95% CI 0.92 to 1.08) and non-dialysis CKD (RR 1.08, 95% CI 0.95 to 1.22). Similarly, there was no evidence that HIF prolyl hydroxylase inhibitors and placebo had different effects on MACE (RR 1.10, 95% CI 0.96 to 1.27) in people with non-dialysis CKD. The lack of difference between HIF prolyl hydroxylase inhibitors and ESA or placebo was observed for individual components of MACE, and for cardiovascular death. The safety of HIF prolyl hydroxylase inhibitors for other outcomes was similar to ESA in dialysis-dependent CKD. In non-dialysis CKD, dialysis access thrombosis, infections, hyperkalemia and seizures occurred more frequently in the HIF prolyl hydroxylase inhibitor group than the placebo group. In non-dialysis CKD, esophageal or gastric erosion was more frequent with HIF prolyl hydroxylase inhibitors than ESA. Conclusions: The long-term effects of HIF prolyl hydroxylase inhibitors were similar to ESA in dialysis-dependent CKD. However, HIF prolyl hydroxylase inhibitors increased the incidence of some adverse outcomes in non-dialysis CKD.
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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 | 0.018 | 0.040 |
| Meta-epidemiology (narrow) | 0.003 | 0.002 |
| Meta-epidemiology (broad) | 0.021 | 0.033 |
| Bibliometrics | 0.005 | 0.006 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".