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Evolocumab lowers first major cardiovascular events
In high-risk adults without prior heart attack or stroke, evolocumab reduced first major cardiovascular events without new safety concerns.
*Randomized, double-blind, placebo-controlled trial; Level 1b (OCEBM).

Citation

Bohula EA, Marston NA, Bhatia AK, et al.; VESALIUS-CV Investigators. Evolocumab in Patients without a Previous Myocardial Infarction or Stroke. N Engl J Med. 2026;394:117-127. doi:10.1056/NEJMoa2514428.

Background

Evolocumab is known to reduce cardiovascular events in people who already had a heart attack or stroke. This trial tested whether it can prevent a first major event in high-risk patients.

Patients

12,257 adults with atherosclerosis or diabetes, no prior heart attack or stroke, and low-density lipoprotein cholesterol ≥90 mg/dL on stable lipid-lowering therapy.

Intervention

Evolocumab 140 mg injection every 2 weeks.

Control

Matching placebo injections.

Outcome

Two primary composite outcomes: (1) coronary heart disease death, heart attack, or ischemic stroke; (2) the same plus ischemia-driven arterial revascularization.

Follow-up Period

Median 4.6 years (5-year event estimates reported).

Results

Outcome Evolocumab (5-year risk) Placebo (5-year risk) Relative effect Absolute risk reduction NNT (5 years)
Coronary heart disease death, heart attack, or ischemic stroke (primary) 6.2% 8.0% Hazard ratio 0.75 (95% CI, 0.65 to 0.86) 1.8% 56
Primary outcome plus ischemia-driven revascularization (primary) 13.4% 16.2% Hazard ratio 0.81 (95% CI, 0.73 to 0.89) 2.8% 36
Heart attack 2.7% 4.1% Hazard ratio 0.64 (95% CI, 0.52 to 0.79) 1.4% 72
Ischemia-driven arterial revascularization 10.1% 12.5% Hazard ratio 0.79 (95% CI, 0.70 to 0.88) 2.4% 42
Primary analyses were intention-to-treat. No between-group difference was seen in serious adverse events or discontinuation due to adverse events.

Limitations

Mostly White participants; some outcomes exploratory due to testing sequence; injection therapy may limit uptake.

Funding

Amgen funded; sponsor supplied drug and collected data.

Clinical Application

For high-risk patients without prior heart attack or stroke and persistently high cholesterol despite therapy, consider evolocumab to prevent first major events.

Top Journal Rankings - February 2026

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39 abstracts scored across 7 criteria. Click any article to expand criterion scores.
1. 8.8
Vitamin K2 in Managing Nocturnal Leg Cramps: A Randomized Clinical Trial.
Overall: This multicenter double-blind RCT in older community adults found vitamin K2 markedly reduced nocturnal leg cramp frequency (tight CI), with additional improvements in severity and duration and no reported treatment-related adverse events; the intervention is simple and highly applicable to primary care, though generalizability is somewhat limited by volunteer recruitment and substantial pre-randomization exclusions.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.5
Nocturnal leg cramps in community-dwelling older adults is a common outpatient complaint that primary-care clinicians manage; the intervention is an OTC-style supplement with straightforward decision relevance.
Validity, Bias Control & Precision 8.5
Multicenter, double-blind, placebo-controlled RCT with clear primary outcome and a tight 95% CI for the main effect; modest sample size (199) and substantial pre-enrollment exclusions limit certainty/generalizability but internal validity appears strong from the abstract.
Patient-Oriented Outcomes 7.5
Outcomes (cramp frequency, severity on an analog scale, and duration) are directly symptom-focused and meaningful to patients, though they are not hard clinical endpoints (e.g., function, sleep quality, falls).
Magnitude of Net Benefit 9.0
Large between-group improvement in weekly cramp frequency (difference −2.67/week with very tight CI) plus improvements in severity and duration; no treatment-related adverse events reported and daily oral dosing is low burden.
Implementability & Practicality 9.0
Simple once-daily oral capsule for 8 weeks with no monitoring described and no apparent workflow complexity, making it easy to implement in routine outpatient care.
Practice-Changing Potential 10.0
Addresses a common condition with limited proven options and shows a large symptomatic benefit versus placebo with good reported safety, providing a clear, actionable option based on an RCT.
2. 8.2
A Randomized Trial of Intensive versus Standard Blood-Pressure Control.
Overall: This large randomized trial shows that an SBP target <120 mm Hg lowers major cardiovascular events and all-cause mortality versus <140 mm Hg in high-risk adults without diabetes, but at the cost of more serious adverse events and greater management intensity.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Blood-pressure targets for high-risk, non-diabetic adults are a common outpatient/primary-care decision with broad real-world relevance.
Validity, Bias Control & Precision 9.0
Large randomized trial (n=9361) with clear targets, clinically meaningful follow-up, and precise effect estimates with CIs; early stopping slightly increases risk of overestimating benefit.
Patient-Oriented Outcomes 9.0
Primary endpoint includes major cardiovascular events, and all-cause mortality was reported as significantly reduced—both directly patient-important.
Magnitude of Net Benefit 7.0
Meaningful reductions in major CV events and all-cause mortality, but higher serious adverse events (hypotension, syncope, electrolyte abnormalities, acute kidney injury/failure) temper the net benefit.
Implementability & Practicality 6.0
Achieving and maintaining <120 mm Hg typically requires more medications and closer monitoring, and the abstract notes increased adverse events that would necessitate additional follow-up.
Practice-Changing Potential 9.0
A well-powered RCT showing lower mortality and CV events at a lower SBP target is highly influential and likely to change treatment targets for many high-risk patients without diabetes.
3. 8.1
A Digital Depression Treatment Program for Adults Treated in Primary Care: A Randomized Clinical Trial.
Overall: A large primary-care RCT shows a scalable digital behavioral activation program improves depression symptoms and remission versus usual care over 12 weeks, with generally strong credibility but limited reporting on harms and longer-term outcomes.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.5
Conducted in 22 primary care clinics among adults with moderate depression identified and managed in primary care, directly addressing a common primary-care treatment gap.
Validity, Bias Control & Precision 8.5
Decentralized 3-arm randomized clinical trial with a large sample (n=649) and reported effect estimates with SEs/CIs; however, the abstract does not describe blinding, attrition, or adherence handling, and follow-up is limited to 12 weeks.
Patient-Oriented Outcomes 7.0
Outcomes include symptom change, clinically significant improvement, and remission on validated depression scales, which are patient-meaningful but remain questionnaire-based rather than hard functional or morbidity outcomes.
Magnitude of Net Benefit 7.5
Moodivate groups showed substantially greater symptom improvement and higher odds of clinically significant improvement and remission vs usual care; harms, adverse effects, and burden are not reported, and engagement declines by 12 weeks.
Implementability & Practicality 8.5
A self-directed digital behavioral activation program is scalable and could be deployed broadly; EHR integration appears feasible, though uptake of EHR features by clinicians was low (14%) in the trial.
Practice-Changing Potential 7.5
Provides RCT evidence that a low-touch digital intervention can improve depression outcomes in primary care, likely influencing care options for untreated patients, but limited duration and incomplete implementation details may temper immediate widespread change.
4. 7.9
Aspirin, cardiovascular events, and major bleeding in older adults: extended follow-up of the ASPREE trial.
Overall: This large randomized trial follow-up reports patient-important outcomes showing no long-term cardiovascular benefit and increased bleeding (and possible increased post-trial MACE), supporting primary-care decisions to avoid routine aspirin for primary prevention in older adults.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.5
Directly addresses a common primary-care decision (whether to use low-dose aspirin for primary prevention) in community-dwelling older adults without prior cardiovascular disease.
Validity, Bias Control & Precision 8.5
Built on a large randomized, placebo-controlled trial (ASPREE) with substantial follow-up and reported hazard ratios with confidence intervals; post-trial follow-up includes consented participants only, which may introduce selection/attrition-related bias compared with the original randomized phase.
Patient-Oriented Outcomes 9.0
Reports clinically meaningful outcomes (major adverse cardiovascular events and major hemorrhage), which are patient-important rather than surrogate markers.
Magnitude of Net Benefit 6.5
Shows no long-term reduction in MACE overall (HR 1.04, CI crosses 1), with signals of increased post-trial MACE (HR 1.17) and increased major hemorrhage overall (HR 1.24), suggesting net harm or at best no benefit; absolute risks are not provided, limiting judgment of clinical magnitude.
Implementability & Practicality 9.0
The intervention (daily low-dose aspirin) is widely available and easy to implement in outpatient practice; applying the findings mainly involves deprescribing/avoiding initiation and discussing bleeding risk.
Practice-Changing Potential 5.0
Likely reinforces and adds longer-term evidence to existing guidance against routine aspirin initiation in older adults rather than overturning current practice, though the extended follow-up may strengthen confidence in avoiding use.
5. 7.9
Bright Light Therapy for Nonseasonal Depressive Disorders: A Systematic Review and Meta-Analysis.
Overall: This RCT-only meta-analysis (11 trials, n=858) reports substantially higher remission and response rates with adjunctive bright light therapy versus control, with modest heterogeneity and reasonably precise estimates, making it broadly relevant to outpatient depression care, though limited abstract reporting on adverse effects and real-world logistics constrains certainty about net benefit and implementation.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.0
Depression management is common in primary care, and the intervention is an adjunct to usual antidepressant care; the abstract does not specify primary-care settings but the population and decision point are broadly applicable.
Validity, Bias Control & Precision 8.5
Systematic review/meta-analysis of RCTs with 11 trials (n=858), low-to-moderate heterogeneity (I2 21% for remission; 41% for response) and reported CIs suggests reasonably precise, design-robust evidence, though trial-level risk-of-bias details are not provided in the abstract.
Patient-Oriented Outcomes 8.0
Remission and response are clinically meaningful outcomes for patients; depression scale changes are also included, but the key reported endpoints are symptom remission/response rather than purely physiologic surrogates.
Magnitude of Net Benefit 8.0
Absolute improvements appear large (remission 40.7% vs 23.5%; response 60.4% vs 38.6%), indicating potentially meaningful benefit; however, the abstract does not report adverse effects, tolerability, or treatment burden, limiting net-benefit certainty.
Implementability & Practicality 7.0
Bright light therapy is generally feasible as a nonpharmacologic adjunct, but the abstract provides no details on device specifications, dosing protocol, adherence, monitoring, or access/cost—practical barriers could vary.
Practice-Changing Potential 8.0
A JAMA Psychiatry meta-analysis showing sizable improvements in remission/response could reasonably prompt clinicians to consider BLT as adjunctive therapy for nonseasonal depression, though missing harms/burden details may temper immediate widespread adoption.
6. 7.8
Structured Exercise after Adjuvant Chemotherapy for Colon Cancer.
Overall: This large multicenter randomized trial reports meaningful improvements in disease-free and overall survival with a structured 3-year exercise program after adjuvant chemotherapy for resected colon cancer, at the cost of more musculoskeletal adverse events and notable program burden; the evidence is strong and potentially influential for survivorship care, though implementation may be resource-dependent.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 7.5
Applies to a common survivorship question (post–colon cancer adjuvant therapy) that primary-care clinicians often co-manage, but the population is oncology-defined and the intervention is delivered as a structured program rather than a typical brief primary-care action.
Validity, Bias Control & Precision 8.5
Large, multicenter phase 3 randomized trial (889 patients, 55 centers) with long follow-up (median 7.9 years) and reported hazard ratios and confidence intervals; blinding is not described and is difficult for exercise trials, but the design and precision are strong.
Patient-Oriented Outcomes 9.0
Disease-free survival and overall survival are patient-important outcomes, with absolute survival differences reported at 5 and 8 years.
Magnitude of Net Benefit 7.5
Clinically meaningful absolute improvements are shown (DFS +6.4% at 5 years; OS +7.1% at 8 years), but musculoskeletal adverse events were higher with exercise (18.5% vs 11.5%) and a 3-year program implies substantial time/burden.
Implementability & Practicality 6.0
Exercise itself is broadly accessible, but the intervention is a 3-year structured program, which may require supervised resources, sustained adherence support, and coordination beyond usual care; details on delivery intensity/cost are not provided.
Practice-Changing Potential 8.0
Provides level-1 randomized evidence that structured exercise after chemotherapy improves cancer outcomes (including survival signals), which could strengthen survivorship care recommendations, though real-world scaling and program specifics may affect uptake.
7. 7.8
Evaluation of glucose-lowering medications in older people: a comprehensive systematic review and network meta-analysis of randomized controlled trials.
Overall: A large RCT-based network meta-analysis in older adults with diabetes reports patient-important benefits for SGLT2 inhibitors and GLP-1RAs and substantial hypoglycemia harms with sulfonylureas, but abstract-level details on network robustness, absolute effects, and practicality constraints are limited.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 8.5
Targets a very common primary-care condition (type 2 diabetes) specifically in adults ≥65 years and compares medication classes that primary-care clinicians routinely prescribe or deprescribe.
Validity, Bias Control & Precision 7.5
Systematic review and network meta-analysis of RCTs with large total sample (22 trials; 41,654 participants) and CIs reported; however, the abstract does not report key network assumptions (e.g., consistency), heterogeneity, or detailed risk-of-bias results beyond stating RoB 2.0 was used.
Patient-Oriented Outcomes 8.5
Emphasizes patient-important outcomes including major adverse cardiovascular events, hospitalization for heart failure, renal composite outcomes, and hypoglycemia (including severe), not just glycemic markers.
Magnitude of Net Benefit 7.0
Reports clinically meaningful relative risk reductions for cardiovascular/heart failure/renal outcomes (e.g., RR 0.66 for HF hospitalization) and substantial hypoglycemia harm with sulfonylureas (RR 4.19 any; RR 7.06 severe), but absolute effects, discontinuation, and tolerability/burden are not provided in the abstract.
Implementability & Practicality 7.0
Findings relate to commonly used drug classes, but real-world feasibility in older adults (cost, injection burden for GLP-1RAs, monitoring, adverse effects) is not addressed in the abstract.
Practice-Changing Potential 8.0
Synthesizes RCT evidence in older adults and highlights clear benefit/harm tradeoffs (especially favoring SGLT2 inhibitors/GLP-1RAs and cautioning against sulfonylurea hypoglycemia), which could influence prescribing priorities, though results are not framed as specific actionable protocols.
8. 7.7
Antiviral Medications for Treatment of Nonsevere Influenza: A Systematic Review and Network Meta-Analysis.
Overall: A large, well-conducted network meta-analysis of RCTs directly relevant to outpatient influenza care shows modest symptom benefit (and possible small admission reduction in high-risk patients) with baloxavir, while most other antivirals show little patient-important benefit and oseltamivir likely increases adverse events.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Addresses outpatient/nonsevere influenza treatment decisions commonly made in primary care, including high-risk subgroups and comparisons among available antivirals.
Validity, Bias Control & Precision 8.5
Systematic review with network meta-analysis of 73 RCTs (34,332 participants), independent duplicate processes, and GRADE ratings; precision is good for several key comparisons (CIs reported), though some estimates are low certainty.
Patient-Oriented Outcomes 8.0
Reports patient-important endpoints (mortality, hospital/ICU admission) and symptom duration; includes adverse events and resistance, not just surrogate virologic outcomes.
Magnitude of Net Benefit 5.5
Benefits on hard outcomes are small/uncertain (e.g., high-risk admission RD around -1.6% with low certainty), while symptom improvement is about ~1 day for baloxavir; harms differ by drug (oseltamivir increases adverse events; baloxavir does not).
Implementability & Practicality 8.0
Findings apply to commonly used oral antivirals with straightforward outpatient prescribing; however, real-world access/cost barriers and timing constraints are not addressed in the abstract.
Practice-Changing Potential 7.0
Provides comparative effectiveness suggesting baloxavir may be preferable for symptom reduction and possibly admissions in high-risk patients, but the key hospitalization benefit is low certainty and absolute effects appear modest.
9. 7.4
Long-term trials of colchicine for secondary prevention of vascular events: a meta-analysis.
Overall: A large RCT meta-analysis suggests colchicine reduces major recurrent cardiovascular events without clear safety signals, with good credibility and reasonable real-world feasibility, though primary-care specificity and absolute effect size are not shown.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 6.0
Addresses secondary prevention after MI/stroke and recurrent vascular events—clinically important but often managed with cardiology co-management and not explicitly primary-care–based.
Validity, Bias Control & Precision 8.5
Systematic review/meta-analysis of 6 RCTs (n=21,800) with placebo control and ≥12-month follow-up; pooled HR reported with CI, though heterogeneity details and risk-of-bias methods are not provided in the abstract.
Patient-Oriented Outcomes 8.0
Primary endpoint is MACE including cardiovascular mortality, MI, ischemic stroke, and urgent revascularization, which are largely patient-important outcomes.
Magnitude of Net Benefit 7.0
Shows a meaningful relative reduction in MACE (HR 0.75) and reductions in several event components, with no detected differences in reported safety outcomes; absolute risk reduction and treatment burden details are not provided.
Implementability & Practicality 8.0
Colchicine is described as inexpensive and is generally straightforward to prescribe, making implementation plausible in outpatient care, though monitoring/interaction considerations are not discussed.
Practice-Changing Potential 7.0
An updated RCT meta-analysis suggesting fewer major vascular events could influence secondary-prevention choices, but the abstract provides limited detail on absolute benefits and practical adoption considerations.
10. 7.2
Effect of Colonoscopy Screening on Risks of Colorectal Cancer and Related Death.
Overall: A large pragmatic RCT in a primary-care-relevant screening question shows a modest reduction in colorectal cancer incidence with low uptake and no clear mortality benefit, supporting informed shared decision-making rather than a major practice shift.
View 6 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Directly addresses a core primary-care decision—population screening for colorectal cancer—in generally healthy adults aged 55–64 using a pragmatic, population-registry approach.
Validity, Bias Control & Precision 8.5
Large randomized pragmatic design with intention-to-screen analysis and 10-year follow-up; however, only 42% underwent colonoscopy in the invited group, diluting effects and limiting precision for mortality (wide CI crossing no effect).
Patient-Oriented Outcomes 9.0
Reports patient-important endpoints: colorectal cancer incidence, colorectal cancer mortality, and all-cause mortality, plus major procedure harms.
Magnitude of Net Benefit 4.5
Absolute reduction in CRC incidence at 10 years is small (0.22%; NNI 455) with no clear reduction in CRC death or all-cause death; procedure-related major bleeding occurred (15 cases), and colonoscopy carries meaningful burden.
Implementability & Practicality 6.0
Colonoscopy screening is established but resource-intensive and dependent on capacity and patient uptake; the trial’s 42% completion after invitation highlights real-world implementation friction.
Practice-Changing Potential 6.0
High-quality evidence in a common preventive area, but the modest absolute benefit and lack of demonstrated mortality reduction in intention-to-screen analyses may temper immediate changes and could shift discussions toward alternative screening strategies.
Score Guide: 9-10 Exceptional 7-8 Strong 5-6 Moderate 3-4 Weak 1-2 Poor
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