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Norethisterone stops implant-related prolonged bleeding
Oral norethisterone acetate was more effective than placebo for stopping prolonged bleeding in etonogestrel implant users, but bleeding often returned soon after stopping pills.
*Randomized, blinded, placebo-controlled trial; Level 1b (OCEBM).

Citation

Andrade MCRA, Yamaguti EMM, de Nadai MN, et al. Norethisterone for prolonged uterine bleeding associated with etonogestrel implant (IMPLANET): a randomized controlled trial. American Journal of Obstetrics & Gynecology. 2026;234(1):101–115. doi:10.1016/j.ajog.2025.08.029

Background

Prolonged bleeding is a common reason people stop the etonogestrel contraceptive implant. Extra progestogen pills are often used, but evidence has been limited.

Patients

Adults aged 18–40 in Brazil using an etonogestrel implant ≥40 days, with ≥7 consecutive days of bleeding and no other identified cause.

Intervention

Norethisterone acetate 10 mg by mouth daily until 2 bleeding-free days or up to 30 days; repeatable for new episodes.

Control

Matching placebo using the same instructions.

Outcome

Bleeding stopped within 7 pills (primary); additional bleeding outcomes and safety.

Follow-up Period

Up to 210 days.

Results

Outcome Norethisterone acetate Placebo Absolute difference
Bleeding stopped within 7 pills (primary) 86.7% (39/45) 48.9% (22/45) +37.8%; NNT 3
Bleeding stopped within 14 pills 91.1% (41/45) 64.4% (29/45) +26.7%; NNT 4
Treatment failure (bleeding continued after 30 days of pills) 2.2% (1/45) 17.8% (8/45) -15.6%; NNT 7
Days of pills until bleeding stopped (median) 3 days 5 days 2 days faster
Bleeding-free days in first 30 days (median) 21 days 13 days +8 days
Time to bleeding return after stopping pills (median) 5 days 10.5 days 5.5 days sooner
NNT = number needed to treat.
Primary outcome used a modified intention-to-treat approach; several time-based outcomes used a per-protocol approach.

Limitations

Brazil-only sample; many dropouts after day 30; placebo tablets lacked drug imprint; longer-term bleeding outcomes were harder to interpret.

Funding

Organon Investigator-Initiated Studies Program; industry funding may bias results.

Clinical Application

For bothersome prolonged bleeding with the etonogestrel implant, consider short-course norethisterone acetate to stop bleeding, while counseling that recurrence is common within days.

Top Journal Rankings - March 2026

1913 abstracts scored across 7 criteria. Click any article to expand criterion scores.
1. 8.8
SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis.
Overall: A large, high-quality meta-analysis of randomized trials shows consistent, clinically meaningful reductions in CKD progression and kidney failure across eGFR and albuminuria strata, highly relevant to outpatient prescribing, though harms and practical barriers are not described in the abstract.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
CKD, diabetes, and heart failure are common in primary care, and the question (benefit across eGFR/albuminuria strata, including stage 4 CKD and minimal albuminuria) directly informs prescribing decisions generalists make.
Validity, Bias Control & Precision 9.5
Meta-analysis restricted to large randomized, double-blind, placebo-controlled trials with ≥6 months follow-up; very large pooled sample (70,361) with tight confidence intervals for key outcomes, supporting precise estimates.
Patient-Oriented Outcomes 8.5
Primary outcome includes kidney failure and death due to kidney failure (patient-important), though it is a composite that also includes ≥50% eGFR reduction; kidney failure alone is also reported.
Magnitude of Net Benefit 8.5
Shows substantial relative risk reduction for CKD progression (HR 0.62) and kidney failure (HR 0.66) with consistent benefit across eGFR/UACR subgroups; however, the abstract provides no harms, discontinuation, or burden data, limiting net-benefit certainty.
Implementability & Practicality 8.0
SGLT2 inhibitors are widely available oral medications already used in outpatient care; the abstract does not detail monitoring, contraindications, cost, or access barriers, which prevents a higher score.
Practice-Changing Potential 9.0
By addressing uncertainty in stage 4 CKD and low/absent albuminuria with robust trial-level evidence, the findings are likely to broaden clinician comfort and guideline-concordant use across a wider CKD spectrum.
2. 8.5
Effects of Sodium Glucose Cotransporter 2 Inhibitors by Diabetes Status and Level of Albuminuria: A Meta-Analysis.
Overall: Large RCT-based meta-analysis with patient-important outcomes shows consistent reductions in kidney progression, hospitalization, and AKI across diabetes and albuminuria strata, with generally precise estimates; incomplete reporting of some potential harms and real-world prescribing friction modestly limit immediate uptake.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.5
Chronic kidney disease and SGLT2 inhibitor prescribing are common outpatient decisions; findings apply across diabetes status and albuminuria strata that primary care clinicians routinely encounter, though some patients are co-managed with nephrology.
Validity, Bias Control & Precision 9.5
Inverse-variance meta-analysis of 8 randomized placebo-controlled trials with a very large sample (n=58,816) and generally tight confidence intervals supports strong internal validity and precise estimates.
Patient-Oriented Outcomes 9.0
Reports clinically meaningful outcomes including kidney disease progression, acute kidney injury, hospitalization, and death rather than relying mainly on surrogate markers.
Magnitude of Net Benefit 8.0
Shows consistent absolute reductions in kidney progression and hospitalization and reduced AKI; mortality benefit is clearer in diabetes and less certain without diabetes (CI includes no effect). Abstract provides limited detail on non-serious or class-specific adverse effects, tempering certainty about net benefit.
Implementability & Practicality 7.5
SGLT2 inhibitors are widely used and feasible to prescribe outpatient, but real-world use can involve cost/coverage barriers and requires routine monitoring and patient counseling.
Practice-Changing Potential 8.5
By demonstrating benefits across diabetes status and UACR levels with absolute event rates, the findings could reasonably broaden or strengthen routine use in CKD and influence guideline/clinical thresholds.
3. 8.4
An mHealth (Mobile Health) Intervention for Smoking Cessation in People With Tuberculosis: A Cluster Randomized Clinical Trial.
Overall: This large multicenter cluster RCT reports a substantial improvement in biochemically verified smoking abstinence and a lower mortality signal with a low-burden text-message intervention, making the findings both credible and highly implementable, albeit most directly applicable to TB-care settings.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 7.0
Addresses smoking cessation (a common primary-care priority) but is delivered in TB clinics in Bangladesh/Pakistan with eligibility restricted to patients with recent drug-sensitive pulmonary TB who smoke and have phone access, which may limit direct generalizability to broader primary-care populations.
Validity, Bias Control & Precision 8.5
Multicenter cluster randomized clinical trial with a large sample (n=1080), good retention (91%), and biochemical verification for the primary endpoint; some typical cluster-trial limitations (e.g., lack of blinding and limited detail on allocation/concealment) remain, but effect estimates are reasonably precise.
Patient-Oriented Outcomes 8.5
Primary outcome is continuous smoking abstinence verified biochemically, and secondary outcomes include death and TB treatment outcomes, which are directly patient-important rather than purely surrogate markers.
Magnitude of Net Benefit 9.5
Shows a large absolute increase in verified abstinence at 6 months (41.7% vs 15.3%) and lower mortality (3.5% vs 7.5%), with a low-burden intervention (texts) and no reported signals of meaningful harm in the abstract.
Implementability & Practicality 9.0
Text-messaging support is simple and scalable where mobile access exists, requires minimal clinician time, and fits into routine outpatient TB treatment workflows.
Practice-Changing Potential 8.0
Given the strong abstinence effect and feasible delivery, the intervention could plausibly change tobacco-cessation support within TB programs, though its immediate impact on general primary-care practice may be more limited by the TB-specific context.
4. 8.4
Online Unsupervised Tai Chi Intervention for Knee Pain and Function in People With Knee Osteoarthritis: The RETREAT Randomized Clinical Trial.
Overall: A well-conducted community RCT shows an easily deployable, low-risk online tai chi program improves patient-important knee OA pain and function over 12 weeks with clinically meaningful responder differences and no serious harms, making it highly applicable and potentially practice-influencing for primary care.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Knee osteoarthritis pain and function are very common primary-care problems, and an online exercise option fits typical outpatient management and counseling.
Validity, Bias Control & Precision 8.0
Randomized superiority trial with high completion (96%) and reported effect estimates with 95% CIs; however, the sample size is modest (n=178) and follow-up is short (12 weeks).
Patient-Oriented Outcomes 8.0
Primary outcomes are pain during walking and functional difficulty (WOMAC), which are directly patient-important; quality of life and global improvement were also assessed as secondary outcomes.
Magnitude of Net Benefit 7.5
Between-group improvements were clinically meaningful for many patients (MCID responders 73% vs 47% for pain; RD 0.3), with no serious adverse events reported, but benefits are demonstrated only over 12 weeks and require ongoing participation effort.
Implementability & Practicality 9.5
Unsupervised, video-based, free-to-access web intervention with optional app support is highly scalable and low-resource compared with supervised programs.
Practice-Changing Potential 8.5
Provides randomized evidence for an accessible, guideline-consistent nonpharmacologic option that could realistically be recommended broadly when in-person tai chi is unavailable.
5. 8.3
A Lay Health Worker-Led Symptom Intervention and Acute Care Use in Older Adults With Cancer: A Randomized Clinical Trial.
Overall: This multisite randomized trial in older Medicare Advantage patients with cancer reports large, statistically precise reductions in ED visits and hospitalizations and lower costs with a lay health worker–led telephone symptom monitoring and escalation pathway; outcomes are strongly patient-oriented and the intervention appears scalable, though it is rooted in oncology clinic workflows and the abstract does not detail potential harms or resource constraints.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 7.5
Targets older adults with cancer and aims to reduce ED visits/hospitalizations—highly relevant to outpatient longitudinal care, though the setting is oncology clinics and the workflow is anchored in specialty cancer care rather than typical general primary-care clinics.
Validity, Bias Control & Precision 8.5
Multisite randomized clinical trial with prespecified outcomes and 12-month follow-up. Sample size (n=416) and reported adjusted effect estimates with reasonably tight 95% CIs support credible and fairly precise findings, although blinding is not described.
Patient-Oriented Outcomes 9.0
Primary and secondary outcomes (ED use, hospitalizations, costs, hospice-related end-of-life care measures, facility deaths) are directly patient- and system-important rather than surrogate physiologic markers.
Magnitude of Net Benefit 8.5
Large absolute and relative reductions in acute care use (e.g., ED visits 30.5% vs 47.7%; hospitalizations 18.5% vs 39.8%) plus lower costs. Harms and patient burden are not reported, but the intervention is telephone-based and appears low-burden as described.
Implementability & Practicality 8.0
Telephone-based symptom assessments led by lay health workers with escalation to advanced practice practitioners suggests scalability, but it still requires staffing, training, and a structured escalation pathway; generalizability beyond Medicare Advantage/oncology networks is not fully established in the abstract.
Practice-Changing Potential 8.5
If reproducible, the sizable reductions in ED visits/hospitalizations and end-of-life acute care could meaningfully change how clinics monitor and respond to symptoms in older adults with cancer, using a relatively simple workforce model.
6. 8.2
Norethisterone for prolonged uterine bleeding associated with etonogestrel implant (IMPLANET): a randomized controlled trial.
Overall: A blinded multicenter RCT shows a large, patient-relevant short-term benefit of norethisterone acetate for stopping implant-associated prolonged bleeding, with practical outpatient use, but limited durability due to recurrence and a modest sample size.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.5
Addresses a common outpatient/primary-care and reproductive health problem (prolonged bleeding with contraceptive implant) with a clear treatment decision point applicable to routine counseling and management.
Validity, Bias Control & Precision 8.0
Multicenter randomized, blinded, placebo-controlled trial with prespecified outcomes and adjusted analysis; sample is modest (90 in modified ITT) but effect estimates include CIs and show clear separation.
Patient-Oriented Outcomes 8.5
Bleeding cessation, bleeding-free days, recurrence timing, and discontinuation are directly patient-experienced outcomes rather than lab surrogates.
Magnitude of Net Benefit 8.5
Large absolute improvement in early bleeding cessation (86.7% vs 48.9%; adjusted risk difference 35.6%) and fewer treatment failures, with only short-course oral therapy; recurrence occurred sooner, tempering longer-term net benefit.
Implementability & Practicality 8.5
Oral norethisterone acetate is straightforward to prescribe and time-limited, with patient self-monitoring; requires prior evaluation to exclude secondary causes but otherwise fits typical outpatient workflows.
Practice-Changing Potential 7.5
Provides high-quality evidence for a practice stated to lack evidence previously and shows a clinically meaningful short-term effect, though limited by modest size and the finding that it does not prevent recurrence.
7. 8.2
Age-Adjusted D-Dimer Cutoff Levels to Rule Out Deep Vein Thrombosis.
Overall: A large prospective multicenter management study shows age-adjusted D-dimer thresholds can safely increase rule-out rates for suspected DVT with patient-important follow-up outcomes, and the approach is easy to implement.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 7.0
Evaluates a common outpatient diagnostic problem (suspected DVT) using tools generalists use (Wells score, D-dimer), though the population was emergency-department outpatients rather than primary-care clinics.
Validity, Bias Control & Precision 8.5
Large multicenter prospective management outcome design with standardized strategy and 3-month follow-up; effect estimates include confidence intervals, though it is not a randomized comparison of strategies.
Patient-Oriented Outcomes 9.0
Primary outcome was adjudicated symptomatic venous thromboembolic events during follow-up—directly patient-important rather than surrogate-only.
Magnitude of Net Benefit 7.5
Using the age-adjusted threshold increased the proportion of negative D-dimers (notably in patients ≥75 years) with 0% observed failures in the key subgroup (upper 95% CI 2.3%), suggesting meaningful reduction in imaging/workup with no detected safety signal in this dataset.
Implementability & Practicality 9.0
Age-adjusted D-dimer calculation and Wells-based pathways are simple and scalable, relying on widely available tests and routine clinical assessment.
Practice-Changing Potential 8.0
Provides prospective validation for DVT (not just PE), supporting broader adoption of age-adjusted cutoffs to safely reduce downstream ultrasound use, especially in older adults.
8. 8.2
Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials.
Overall: A large, high-quality IPD meta-analysis of double-blind RCTs strongly refutes most statin label-attributed adverse effects while identifying a few small absolute excesses (mainly liver test abnormalities), making the results highly actionable for routine primary-care prescribing and counseling.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.5
Statins are among the most commonly prescribed primary-care medications, and clarifying true adverse effects directly informs everyday counseling, shared decision-making, and adherence discussions.
Validity, Bias Control & Precision 9.0
Individual participant data meta-analysis restricted to large (≥1000), long (≥2 years), double-blind randomized trials with placebo or intensity comparators, large overall sample (n=123,940), and reported RRs with 95% CIs plus false discovery rate control.
Patient-Oriented Outcomes 6.5
Many assessed outcomes are symptoms/conditions relevant to patients (eg, cognitive impairment, depression, neuropathy), but several key signals are laboratory abnormalities (liver tests, urinary composition), which are more intermediate than directly patient-important.
Magnitude of Net Benefit 6.5
The analysis supports that most label-listed harms are not causally increased, which is clinically meaningful, but the detected excess risks are small in absolute terms (eg, combined liver test abnormality absolute annual excess 0.13%; oedema RR 1.07).
Implementability & Practicality 8.5
Findings are easy to apply at the point of prescribing (counseling and expectation-setting) with no new equipment or complex workflows; however, revising official labeling is outside clinician control.
Practice-Changing Potential 9.0
Strong evidence that many commonly cited statin adverse effects are not supported in blinded RCTs could materially change counseling, reduce nocebo-driven discontinuation, and influence product labeling and guidance.
9. 8.1
Therapy for Atrial Fibrillation in Patients with Drug-Eluting Stents.
Overall: This multicenter randomized trial reports clinically important reductions in a patient-relevant composite outcome and bleeding with NOAC monotherapy versus NOAC plus clopidogrel in stable post-DES atrial fibrillation, with results that are practical to implement and potentially practice-influencing despite an open-label design and some specialist-context dependence.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 6.0
Antithrombotic management in stable atrial fibrillation after prior drug-eluting stent placement is outpatient-relevant, but many such decisions are specialist-directed and the trial population is restricted to patients ≥1 year post-stent.
Validity, Bias Control & Precision 8.5
Multicenter randomized design with clear comparator, adequate sample size (n=960), and reported hazard ratios with confidence intervals; open-label design may introduce some bias, but major clinical outcomes and bleeding are relatively objective.
Patient-Oriented Outcomes 8.0
Primary composite includes death, MI, stent thrombosis, stroke/systemic embolism, and bleeding—largely patient-important outcomes, though the composite also includes clinically relevant nonmajor bleeding.
Magnitude of Net Benefit 8.5
Monotherapy reduced the primary composite (9.6% vs 17.2%; absolute difference −7.6%) and substantially reduced major or clinically relevant nonmajor bleeding (5.2% vs 13.2%), suggesting a clinically meaningful net benefit with less treatment burden.
Implementability & Practicality 9.0
Switching from NOAC plus clopidogrel to NOAC alone is straightforward deprescribing with minimal added monitoring and likely reduces bleeding-management workload.
Practice-Changing Potential 8.5
A randomized trial showing superiority for a common, high-stakes medication decision (long-term antithrombotic regimen post-PCI in AF) is likely to influence practice, though generalizability beyond the studied setting/population may still be considered.
10. 8.0
Oral anticoagulant monotherapy in patients with chronic coronary disease: An updated meta-analysis.
Overall: This RCT-only meta-analysis suggests oral anticoagulant monotherapy lowers bleeding meaningfully without worsening major ischemic outcomes versus dual therapy, making it a practical, potentially practice-influencing simplification for appropriate chronic coronary disease patients needing long-term anticoagulation.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 7.5
Addresses a common long-term outpatient decision (whether to continue antiplatelet therapy in chronic coronary disease patients who also need ongoing anticoagulation), though patient selection and follow-up are often shared with cardiology.
Validity, Bias Control & Precision 8.5
Updated meta-analysis restricted to randomized controlled trials with a moderate total sample (n=4964) and effect estimates with confidence intervals; however, the abstract provides limited detail on heterogeneity, trial quality, or analytic methods.
Patient-Oriented Outcomes 8.5
Includes clinically meaningful outcomes (death, MI, stroke) and major bleeding; the primary endpoint is a composite that mixes efficacy and safety but remains patient-important.
Magnitude of Net Benefit 7.5
Shows a substantial relative reduction in major bleeding (RR 0.49) without apparent increase in ischemic events, but absolute risks/NNT and treatment burden details are not reported in the abstract.
Implementability & Practicality 8.5
A simplified strategy (dropping antiplatelet therapy) is straightforward to implement using existing medications and monitoring, though coordination and individualized risk assessment are still needed.
Practice-Changing Potential 7.5
Findings support a simpler, safer regimen and could alter routine management for a relevant subgroup, but the abstract alone does not establish definitive guideline-level direction or identify key subpopulations.
Score Guide: 9-10 Exceptional 7-8 Strong 5-6 Moderate 3-4 Weak 1-2 Poor
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