Imaging Benefits Without Demonstrated Clinical Improvement: Oral Anticoagulation Versus Antiplatelet Therapy After TAVR—A Systematic Review and Meta-Analysis of Randomized Trials

Efficacy and safety of pyruvate kinase activators in sickle cell disease: a systematic review and meta-analysis of randomised controlled trials Registration template: OSF Generalized Systematic Review Registration 1. Metadata Title: Efficacy and safety of pyruvate kinase activators in sickle cell disease: a systematic review and meta-analysis of randomised controlled trials Authors and affiliations: Aasim Ali, MBBS — Department of Neurology, Allied Hospital, Faisalabad, Pakistan (corresponding author). Funding: No external funding. Conflicts of interest: None declared. Language: English 2. Review methods Type of review: Systematic review with meta-analysis of randomised controlled trials (intervention review). Review stage at registration: Searches, screening, data extraction, risk-of-bias assessment and data synthesis completed; manuscript in preparation. Start date: 27 October 2026 Background: Sickle cell disease (SCD) causes chronic haemolytic anaemia, recurrent vaso-occlusive crises (VOCs), progressive organ damage and premature death. Sickle red cells have reduced pyruvate kinase activity, low ATP and raised 2,3-diphosphoglycerate (2,3-DPG), which promote haemoglobin S polymerisation, membrane damage and haemolysis. Oral pyruvate kinase (PK) activators, including mitapivat and etavopivat, increase red-cell ATP and lower 2,3-DPG. Placebo-controlled phase 2/3 trials (RISE UP for mitapivat; HIBISCUS for etavopivat) have reported improvements in haemoglobin, but their effects on VOCs differ. Previous evidence syntheses were narrative or pooled early-phase, mostly single-arm studies and did not include phase 3 randomised data. Primary research question: In patients aged 12 years or older with SCD, do oral PK activators, compared with placebo, increase the proportion of patients achieving a haemoglobin response and reduce the annualised rate of VOCs? Secondary research question: Do PK activators, compared with placebo, change the risk of serious adverse events in patients with SCD? Expectations / hypotheses: PK activators will increase haemoglobin response compared with placebo. The effect on VOC rate is uncertain given discordant phase 3 results. No increase in serious adverse events is expected. PICO Element Definition Population Patients aged ≥12 years with SCD of any genotype (HbSS, HbSC, HbSβ⁰/β⁺-thalassaemia or other sickle variants). Intervention Any oral pyruvate kinase (PKR) activator, including mitapivat (AG-348), etavopivat (FT-4202) and tebapivat (AG-946), at any dose. Comparator Placebo, with or without background standard care (e.g., hydroxyurea, L-glutamine, crizanlizumab). Outcomes Primary: haemoglobin response (increase ≥1 g/dL from baseline, as defined by each trial); annualised rate of VOCs / sickle cell pain crises (as defined and adjudicated by each trial). Secondary: serious adverse events. Study design Randomised controlled trials, including separately randomised phase 2 and phase 3 portions of seamless phase 2/3 trials. 3. Search strategy Databases: MEDLINE (via PubMed); Cochrane Central Register of Controlled Trials (CENTRAL, via the Cochrane Library). Trial registries: ClinicalTrials.gov. WHO ICTRP records are captured through CENTRAL. Grey literature: Sponsor press releases and company announcements (Agios Pharmaceuticals; Novo Nordisk) for results of eligible trials without a full published report. Conference abstracts (including ASH and EHA) are captured through CENTRAL. Date limits: From database inception to 27 October 2026. Language limits: None. Concepts combined: Sickle cell disease AND pyruvate kinase activators AND randomised controlled trials (trial filter applied in PubMed only). Query strings MEDLINE (PubMed) # Search string 1 "Anemia, Sickle Cell"[Mesh] 2 sickle*[tiab] OR drepanocyt*[tiab] OR HbSS[tiab] OR HbSC[tiab] OR "haemoglobin S"[tiab] OR "hemoglobin S"[tiab] OR "vaso-occlusive"[tiab] OR vasoocclusive[tiab] 3 #1 OR #2 4 mitapivat[nm] 5 mitapivat[tiab] OR "AG-348"[tiab] OR "AG 348"[tiab] OR AG348[tiab] OR Pyrukynd[tiab] OR etavopivat[tiab] OR "FT-4202"[tiab] OR "FT 4202"[tiab] OR FT4202[tiab] OR tebapivat[tiab] OR "AG-946"[tiab] OR AG946[tiab] 6 "Pyruvate Kinase"[Mesh] AND (activat*[tiab] OR agonist*[tiab]) 7 ("pyruvate kinase"[tiab] OR PKR[tiab] OR "PK-R"[tiab]) AND (activator*[tiab] OR activation[tiab] OR activating[tiab] OR agonist*[tiab]) 8 #4 OR #5 OR #6 OR #7 9 randomized controlled trial[pt] OR controlled clinical trial[pt] OR randomized[tiab] OR placebo[tiab] OR drug therapy[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab] 10 animals[mh] NOT humans[mh] 11 #9 NOT #10 12 #3 AND #8 AND #11 Cochrane CENTRAL (Search Manager) # Search string 1 [mh "Anemia, Sickle Cell"] 2 (sickle* OR drepanocyt* OR HbSS OR HbSC OR "haemoglobin S" OR "hemoglobin S" OR "vaso-occlusive" OR vasoocclusive):ti,ab,kw 3 #1 OR #2 4 [mh "Pyruvate Kinase"] 5 (mitapivat OR "AG-348" OR AG348 OR Pyrukynd OR etavopivat OR "FT-4202" OR FT4202 OR tebapivat OR "AG-946" OR AG946):ti,ab,kw 6 (("pyruvate kinase" OR PKR) NEAR/3 (activat* OR agonist*)):ti,ab,kw 7 #4 OR #5 OR #6 8 #3 AND #7 ClinicalTrials.gov Field Entry Condition or disease sickle cell disease Intervention / treatment mitapivat OR AG-348 OR etavopivat OR FT-4202 OR tebapivat OR AG-946 OR "pyruvate kinase activator" Study type Interventional Recruitment status All Search validation: The PubMed strategy was checked against known eligible reports (RISE UP phase 2 and phase 3 publications), both of which were retrieved. Other search strategies: Linking of multiple reports (journal articles, conference abstracts, registry records, errata) to each trial. Contacting authors: Not planned; sponsor-reported topline data are used where no full report exists. Search update: The search will be repeated before final submission if more than six months have elapsed, and when full results of the HIBISCUS phase 3 trial are published. 4. Screening Screening stages: (1) Removal of duplicates by matching PubMed identifiers and trial registry numbers; (2) title and abstract screening; (3) full-text or full-record eligibility assessment. Screened fields / masking: Title, abstract, publication type, registry fields. Reviewers are not masked to authors or journals. Inclusion criteria Randomised, placebo-controlled trial. Participants aged ≥12 years with SCD of any genotype. Intervention: oral pyruvate kinase activator, any dose. Reports at least one outcome of interest. Full-text article, conference abstract, trial registry results or sponsor-reported topline results. Exclusion criteria Non-randomised or open-label single-arm studies (including open-label extensions). Phase 1 dose-finding, pharmacokinetic or mechanistic studies without eligible outcomes. Healthy volunteers, children younger than 12 years, or other haemolytic anaemias (e.g., thalassaemia, pyruvate kinase deficiency). Ongoing trials without results. Reviews, editorials, comments, preclinical and laboratory studies. Screening reliability and reconciliation: Two reviewers screen all records independently at both stages; disagreements are resolved by discussion or, if needed, by a third author. Sample size: All eligible trials are included; no sampling. Reporting: Study selection is reported in a PRISMA 2020 flow diagram, with reasons for exclusion at the eligibility stage. 5. Data extraction Entities extracted: Trial name, registration number, phase, design, countries, sample size per arm, age, genotype, concomitant hydroxyurea use, drug, dose and frequency, treatment duration, outcome definitions and assessment time points; for each outcome, events and totals per arm (dichotomous) or annualised rates and rate ratios with 95% CIs (count outcomes); serious adverse events per arm; data source (publication, abstract, registry, press release). Extraction stages: Data are extracted from the most complete report for each trial, supplemented by linked reports. Extraction reliability and reconciliation: Two reviewers extract data independently; discrepancies are resolved by discussion or a third author. Multi-arm trials: From multi-arm phase 2 cohorts, only the dose carried forward into phase 3 (mitapivat 100 mg twice daily; etavopivat 400 mg once daily) and the placebo arm are included, to avoid double-counting the shared placebo group. Seamless phase 2/3 trials: Phase 2 and phase 3 portions randomised different participants and are analysed as separate studies. 6. Risk of bias and synthesis Risk-of-bias assessment: Revised Cochrane risk-of-bias tool for randomised trials (RoB 2), assessed for the primary outcomes across five domains (randomisation process, deviations from intended interventions, missing outcome data, outcome measurement, selection of the reported result) with an overall judgement of low risk, some concerns or high risk. Two reviewers assess independently. Results are displayed as a traffic-light plot (robvis). Effect measures: Risk ratio (RR) with 95% CI for haemoglobin response and serious adverse events; rate ratio with 95% CI for annualised VOC rate. Planned data transformations: Where a rate ratio is not reported, it is derived from arm-level annualised rates and their 95% CIs, with the standard error of the log rate ratio obtained by combining the arm-level standard errors. Where a relative reduction and its 95% CI are reported, the rate ratio is calculated as 1 minus the reduction. Handling of topline-only data: For trials reported only as topline results, haemoglobin response counts are back-calculated from reported percentages assuming the planned allocation ratio, and the standard error of the VOC rate ratio is derived conservatively from the reported relative reduction assuming a two-sided p value of 0.05. These values are flagged as estimated. Synthesis model: Generic inverse-variance meta-analysis on the log scale with a DerSimonian–Laird random-effects model. Heterogeneity is quantified with τ² and I². Two-sided p<0.05 is considered statistically signif