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Some combinations are better tolerated than single drugs
In short-term trials, treatment stopping due to side effects differed by drug type, and some two-drug combinations were tolerated as well as or better than placebo.
*Systematic review and network meta-analysis of randomized trials; Level 1a.

Citation

Wang N, Van Der Hoorn S, Pant R, et al. Adverse effects and treatment discontinuation of blood pressure–lowering drugs and combinations: A network meta-analysis. JAMA. 2026;335(24):2135-2145. doi:10.1001/jama.2026.6214

Background

Concerns about side effects from blood pressure–lowering medicines can delay starting treatment and lead to early stopping. This study compared short-term side effects and stopping rates across major drug classes and combinations.

Patients

Adults in double-blind randomized trials (mostly hypertension; mean age 54.6 years; 44% women). Excluded: trials longer than 26 weeks and trials with an active “run-in” period.

Intervention

Blood pressure–lowering drugs from 5 major classes and their combinations.

Control

Placebo or another active drug regimen.

Outcome

Stopping assigned treatment due to side effects (primary); dizziness, headache, swelling of legs/ankles, cough (secondary).

Follow-up Period

4–26 weeks (mean 8.6 weeks).

Results

716 trials (159,362 participants). Compared with placebo, the following differences were significant:
Outcome Regimen vs placebo Effect Absolute change Number needed to treat (or harm)
Stopped treatment due to side effects (primary) Calcium channel blockers Odds ratio 1.43 (1.23–1.67) +1.2% Harm: 84
Stopped treatment due to side effects (primary) Angiotensin-converting enzyme inhibitor + calcium channel blocker Odds ratio 1.46 (1.13–1.87) +1.1% Harm: 91
Stopped treatment due to side effects (primary) Beta-blocker + thiazide diuretic Odds ratio 1.58 (1.04–2.47) +1.7% Harm: 59
Stopped treatment due to side effects (primary) Angiotensin II receptor blocker Odds ratio 0.73 (0.61–0.86) −0.8% Treat: 125
Stopped treatment due to side effects (primary) Angiotensin II receptor blocker + calcium channel blocker Odds ratio 0.61 (0.47–0.79) −1.2% Treat: 84

Limitations

Short follow-up (weeks), so later side effects and long-term stopping were not assessed. Results rely on network meta-analysis assumptions and trial-level (not individual) data. Absolute differences in stopping were small (about 1–2%).

Funding

Australia’s National Health and Medical Research Council; no role in study conduct.

Clinical Application

When choosing initial therapy, consider an angiotensin II receptor blocker (often with a calcium channel blocker) to reduce early stopping; counsel about dizziness and monitor for swelling.

Top Journal Rankings - August 2026

1686 abstracts scored across 7 criteria. Click any article to expand criterion scores.
1. 8.5
Assessment of adverse effects attributed to statin therapy in product labels: a meta-analysis of double-blind randomised controlled trials.
Overall: This large, rigorous analysis is highly relevant to primary care and may substantially improve statin risk counseling by showing that most labeled adverse effects lack support from blinded randomized evidence.
View 8 Criterion Scores
Primary-Care Relevance & Applicability 9.5
Statin prescribing and counseling about adverse effects are common, directly applicable decisions in US primary care.
Validity, Bias Control & Precision 9.5
This individual-participant-data meta-analysis included 123,940 participants from large, long-term, double-blind randomized trials and used confidence intervals and false-discovery-rate control.
Patient-Oriented Outcomes 8.5
It assessed numerous potential adverse effects important to patients, including cognitive, mood, sleep, neurologic, and edema outcomes, although some significant findings were laboratory abnormalities.
Magnitude of Net Benefit 6.0
The study provides substantial reassurance that most labeled adverse effects are not causally supported, while identified absolute excesses were generally small; it did not directly measure improvements in treatment uptake or clinical outcomes.
Implementability & Practicality 9.0
The findings can be incorporated readily into routine statin counseling without new tests, equipment, monitoring systems, or complex workflow changes.
Practice-Changing Potential 8.5
The strong evidence could materially change counseling and attribution of symptoms and supports revision of product labels, although label changes require action beyond individual practices.
Cardiology Relevance & Applicability 9.7
Statin initiation, intensification, monitoring, and counseling about adverse effects are routine cardiology decisions in the US. The large, broadly relevant trial populations and commonly used statins make the findings highly transferable, although the labeling framework referenced is primarily non-US.
Internal Medicine Relevance & Applicability 9.6
US general internists routinely prescribe statins and evaluate reported adverse effects in both outpatient and inpatient practice. The findings directly inform counseling, continuation decisions, and interpretation of laboratory abnormalities, with only minor limitations from the non-US product-label framing.
2. 8.3
Bleeding Risk with Apixaban vs. Rivaroxaban in Acute Venous Thromboembolism.
Overall: This large randomized head-to-head trial found a clinically meaningful reduction in bleeding with apixaban using an intervention that is immediately applicable to outpatient VTE treatment, although recurrent thrombotic outcomes were not presented.
View 8 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Acute venous thromboembolism is common, and choosing between apixaban and rivaroxaban is directly relevant to US outpatient clinicians managing anticoagulation.
Validity, Bias Control & Precision 8.5
This was a large international randomized trial with blinded endpoint assessment, balanced allocation, little apparent loss after randomization, and a precise primary estimate, although treatment was open-label.
Patient-Oriented Outcomes 8.0
Clinically relevant bleeding is important to patients, but the primary composite combined major and clinically relevant nonmajor bleeding without reporting their separate effects.
Magnitude of Net Benefit 7.0
Apixaban reduced clinically relevant bleeding from 7.1% to 3.3%, an absolute reduction of 3.8 percentage points, while other serious adverse events were similar; however, comparative recurrent thrombosis results were not reported.
Implementability & Practicality 9.0
Both drugs are commonly used oral anticoagulants with familiar dosing regimens, so clinicians can readily apply the finding without new equipment, training, or monitoring systems.
Practice-Changing Potential 8.5
The direct randomized comparison provides compelling evidence favoring apixaban when bleeding risk informs selection between these commonly used treatments, though absent comparative efficacy results limit certainty about overall superiority.
Hematology Relevance & Applicability 9.0
Choosing between apixaban and rivaroxaban for acute pulmonary embolism or proximal deep-vein thrombosis is a routine hematology decision in US practice. The medications, dosing regimens, and bleeding outcome are directly applicable to typical US anticoagulation pathways despite the international setting.
Internal Medicine Relevance & Applicability 9.0
US general internists and hospitalists commonly initiate and manage oral anticoagulation for acute venous thromboembolism. This direct comparison addresses an everyday treatment choice using regimens readily feasible in US inpatient and outpatient care.
3. 8.3
High-Dose vs Standard-Dose Influenza Vaccines in Older Adults: A Meta-Analysis.
Overall: High-Dose vs Standard-Dose Influenza Vaccines in Older Adults: A Meta-Analysis provides strong, precise, and directly applicable evidence that high-dose vaccination reduces hospitalization outcomes in older adults, though absolute benefits, adverse effects, and mortality improvement are not demonstrated.
View 9 Criterion Scores
Primary-Care Relevance & Applicability 10.0
Influenza vaccination of adults aged 65 years or older is a common US primary-care decision, and the comparison involves vaccines used in routine outpatient care.
Validity, Bias Control & Precision 9.0
This meta-analysis included 8 randomized trials and 605,098 participants, used independent review and risk-of-bias assessment, and reported consistent sensitivity analyses with relatively precise estimates.
Patient-Oriented Outcomes 9.0
The principal outcomes were hospitalizations and all-cause mortality, which are directly important to patients, although no mortality benefit was found.
Magnitude of Net Benefit 6.0
High-dose vaccination reduced several hospitalization outcomes, including influenza hospitalization, but absolute risk reductions and adverse effects were not reported, and mortality was unchanged.
Implementability & Practicality 9.0
Substituting one influenza vaccine formulation for another fits existing vaccination workflows and requires no additional diagnostic testing or follow-up described in the abstract.
Practice-Changing Potential 7.0
The large randomized evidence synthesis can strengthen vaccine recommendations and formulation choice, although the abstract notes that superior protection had already been demonstrated.
Geriatrics Relevance & Applicability 9.0
Choosing influenza vaccine formulation for adults aged 65 years or older, including nursing home residents and those with cardiovascular disease, is a routine geriatric-care decision. The intervention and outcomes are directly applicable to typical US vaccination workflows, although study locations are not reported.
Infectious Disease Relevance & Applicability 8.0
Influenza prevention and vaccine selection in high-risk older adults are common infectious disease concerns, particularly in consultation, immunization, and institutional settings. The comparison is feasible in US practice, though much routine administration occurs in primary care or pharmacy settings and trial locations are unspecified.
Public Health Relevance & Applicability 9.0
Comparative vaccine effectiveness for hospitalization and mortality directly informs influenza immunization recommendations, procurement, and policy for older adults. The large, broad populations and policy-relevant outcomes support strong applicability, although the abstract does not specify study settings.
4. 8.2
Pharmacological blood-pressure lowering for the prevention of cardiovascular disease and death across the full spectrum of chronic kidney disease severity: an individual-participant data meta-analysis.
Overall: A large, precise randomized-trial meta-analysis supports blood-pressure lowering to prevent major cardiovascular events throughout CKD, but absent absolute effects and harms limit conclusions about net benefit.
View 8 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Hypertension and CKD are common in US primary care, and blood-pressure treatment is a routine outpatient decision.
Validity, Bias Control & Precision 9.0
This prespecified individual-participant meta-analysis included 285,124 participants from 46 eligible RCTs, used time-to-event methods, and reported a precise cardiovascular estimate.
Patient-Oriented Outcomes 9.0
The primary composite comprised fatal or nonfatal stroke, ischemic heart disease, heart-failure hospitalization, and cardiovascular death.
Magnitude of Net Benefit 6.5
A 5 mm Hg systolic reduction was associated with a modest but clinically meaningful relative cardiovascular risk reduction in CKD, but absolute benefits and treatment harms were not reported.
Implementability & Practicality 8.5
Blood-pressure lowering uses familiar medications and monitoring pathways that are readily available in routine US outpatient practice.
Practice-Changing Potential 7.0
The findings strengthen treatment across CKD stages and blood-pressure thresholds, although they largely reinforce established blood-pressure management rather than define a new regimen.
Cardiology Relevance & Applicability 8.5
Blood-pressure management to prevent cardiovascular events in patients with CKD is a routine cardiology decision, and the large, broadly assembled RCT dataset evaluates standard antihypertensive strategies across clinically relevant subgroups. Applicability is slightly limited by the unspecified mix of health systems and exclusion of patients with heart failure.
Nephrology Relevance & Applicability 9.0
Blood-pressure treatment across CKD stages, proteinuria categories, diabetes status, and antihypertensive classes directly informs decisions routinely made by US nephrologists. The interventions fit typical US care pathways, although trial settings are not explicitly US-specific and some clinically complex patients were excluded.
5. 8.1
Therapy for Atrial Fibrillation in Patients with Drug-Eluting Stents.
Overall: Therapy for Atrial Fibrillation in Patients with Drug-Eluting Stents provides strong randomized evidence that a simpler NOAC-only regimen substantially reduces clinically important events, mainly bleeding, although applicability beyond the South Korean trial population and detailed ischemic safety remain less certain.
View 7 Criterion Scores
Primary-Care Relevance & Applicability 7.5
Atrial fibrillation and long-term antithrombotic therapy are common outpatient issues, although post-stent treatment decisions are often shared with cardiology and the trial was conducted in South Korea.
Validity, Bias Control & Precision 8.0
This was a multicenter randomized trial with 960 participants, a prespecified noninferiority margin, and reasonably precise estimates; its open-label design and 12-month follow-up are limitations.
Patient-Oriented Outcomes 8.0
The primary composite included death, myocardial infarction, stent thrombosis, stroke, systemic embolism, and clinically important bleeding, although separate ischemic outcome results were not reported.
Magnitude of Net Benefit 8.5
Monotherapy reduced net adverse events by 7.6 percentage points and bleeding by approximately 8 percentage points, representing a large clinically meaningful benefit with less treatment burden.
Implementability & Practicality 9.5
Stopping clopidogrel while continuing an established NOAC is straightforward, reduces medication burden, and requires no new equipment, testing, or specialized workflow.
Practice-Changing Potential 7.0
The findings strongly reinforce NOAC monotherapy after the first post-stent year, but the abstract notes that guidelines already recommend this approach.
Cardiology Relevance & Applicability 8.5
US cardiologists routinely decide whether to continue antiplatelet therapy in patients with atrial fibrillation more than 1 year after drug-eluting stent implantation, and both compared regimens fit typical US workflows. The South Korean setting and relatively specific post-stent population modestly limit direct applicability.
6. 8.1
Infant Outcomes, Risk Factors, and Diagnostic Yield After a Brief Resolved Unexplained Event: A Systematic Review and Meta-Analysis.
Overall: This robust meta-analysis supports a practical, risk-informed approach to BRUE and may meaningfully reduce low-yield testing while preserving attention to serious diagnoses.
View 9 Criterion Scores
Primary-Care Relevance & Applicability 7.5
BRUE is relevant to US pediatric and family medicine, particularly for initial assessment and follow-up, although acute evaluation often occurs in emergency or hospital settings.
Validity, Bias Control & Precision 8.5
This systematic review included 24 studies and 6603 infants, used verified extraction, random-effects meta-analysis, and GRADE; however, the included designs were largely observational and mortality estimates remained imprecise.
Patient-Oriented Outcomes 9.0
Serious underlying diagnoses and 3-month mortality are directly important to patients, while diagnostic yield also informs avoidance of unnecessary testing.
Magnitude of Net Benefit 7.0
The extremely low yields of routine tests support reducing low-value investigations and false-positive findings, although the review did not directly measure outcomes from implementing a targeted strategy.
Implementability & Practicality 8.0
Focusing testing on multiple events and prematurity while avoiding blanket investigations is practical and could reduce cost and burden, though the abstract does not provide a complete clinical algorithm.
Practice-Changing Potential 8.5
The findings challenge routine testing and the use of age 60 days or younger as an independent risk factor, providing a strong basis for guideline revision and more selective evaluation.
Pediatric Emergency Medicine Relevance & Applicability 9.2
BRUE risk stratification and decisions about diagnostic testing, observation, and disposition are routine in US pediatric emergency care. Use of AAP BRUE criteria and evaluation of common investigations make the findings highly transferable, although the included studies’ health-system settings are not specified.
Pediatric Hospital Medicine Relevance & Applicability 8.7
Pediatric hospitalists commonly manage infants admitted or observed after BRUE and decide whether further testing is warranted. The risk factors and low diagnostic yields directly inform this care, though the abstract does not describe the contributing study settings.
Pediatrics (General) Relevance & Applicability 7.8
General pediatricians encounter BRUE presentations and provide initial assessment, referral, and follow-up counseling, so prognosis and risk features are clinically useful. Acute diagnostic testing and observation decisions are often made in emergency or hospital settings, making applicability somewhat less direct.
7. 7.9
Stroke and Bleeding Risks With Non-Vitamin K Oral Anticoagulants in Nonvalvular Atrial Fibrillation.
Overall: This large, directly applicable US cohort supports apixaban as having the most favorable comparative benefit-harm profile in younger adults with atrial fibrillation, but residual confounding and absent absolute event rates temper confidence.
View 8 Criterion Scores
Primary-Care Relevance & Applicability 9.0
Choosing an oral anticoagulant for nonvalvular atrial fibrillation is a common US outpatient decision, and the FDA Sentinel population is directly relevant to US practice.
Validity, Bias Control & Precision 7.5
This was a very large claims-based cohort using inverse probability weighting and reporting confidence intervals, but its nonrandomized design remains vulnerable to residual confounding.
Patient-Oriented Outcomes 9.0
The study evaluated clinically important outcomes, including thromboembolic stroke, intracranial hemorrhage, gastrointestinal bleeding, and major extracranial bleeding.
Magnitude of Net Benefit 6.0
Apixaban was associated with substantially less major and gastrointestinal bleeding than rivaroxaban without a significant stroke difference, but absolute event rates and absolute benefits were not reported.
Implementability & Practicality 9.0
The findings can be implemented through selection among commonly prescribed oral anticoagulants without adding tests, visits, procedures, or specialized infrastructure.
Practice-Changing Potential 7.0
The results may strengthen preference for apixaban in adults younger than 65 years, although the observational design and need for further investigation limit stand-alone practice-changing certainty.
Cardiology Relevance & Applicability 9.5
Choosing among NOACs for nonvalvular atrial fibrillation is a routine cardiology decision, and the US FDA Sentinel claims setting makes the findings directly applicable to US practice. The focus on adults younger than 65 years addresses a common population not covered by prior Medicare-based comparisons.
Hematology Relevance & Applicability 3.0
Bleeding and anticoagulant management overlap with hematology, particularly for consultation in complex cases, but routine NOAC selection for nonvalvular atrial fibrillation is generally managed by cardiology or primary care. Thus, the study has limited direct applicability to typical hematology decisions.
8. 7.9
Asundexian for Secondary Stroke Prevention.
Overall: This large, rigorous trial found a modest but clinically meaningful reduction in recurrent ischemic stroke without a demonstrated increase in major bleeding, making the findings likely to influence secondary prevention practice.
View 8 Criterion Scores
Primary-Care Relevance & Applicability 8.0
Secondary prevention after noncardioembolic stroke or high-risk TIA is highly relevant to longitudinal US primary care, although treatment initiation may involve hospital-based or specialist care.
Validity, Bias Control & Precision 9.0
This was a large phase 3 double-blind randomized placebo-controlled trial with 12,327 participants, balanced groups, and a precise primary estimate, although follow-up duration and attrition are not reported in the abstract.
Patient-Oriented Outcomes 9.5
The primary outcome was recurrent ischemic stroke, with major cardiovascular events, major bleeding, serious adverse events, and death from cardiovascular causes also assessed.
Magnitude of Net Benefit 6.0
Asundexian reduced ischemic stroke from 8.4% to 6.2%, an absolute reduction of 2.2%, while major bleeding and overall serious adverse events were similar between groups.
Implementability & Practicality 7.0
Once-daily oral therapy is operationally straightforward, but it adds another medication to antiplatelet therapy, and the abstract does not address cost, access, monitoring, or treatment duration.
Practice-Changing Potential 8.0
A positive, large phase 3 trial showing fewer recurrent strokes without significantly more major bleeding could alter secondary-prevention regimens, subject to regulatory approval and guideline adoption.
Cardiology Relevance & Applicability 6.0
Cardiologists commonly participate in vascular risk management after stroke or TIA, but initiation of secondary antithrombotic therapy for noncardioembolic events is more often led by neurology or stroke specialists. The intervention is nevertheless feasible within US cardiovascular care pathways and directly affects major cardiovascular outcomes.
Neurology Relevance & Applicability 9.5
This directly addresses a routine, high-impact decision for US neurologists: early secondary prevention after noncardioembolic ischemic stroke or high-risk TIA. The large, clinically recognizable population and addition to standard antiplatelet therapy make the findings highly applicable to typical stroke-care workflows.
9. 7.9
Discontinuation of Beta-Blocker Therapy after Myocardial Infarction.
Overall: This randomized trial provides clinically meaningful evidence that stable patients without heart failure or substantial systolic dysfunction may discontinue beta-blockers after the first post-infarction year without worse major clinical outcomes.
View 7 Criterion Scores
Primary-Care Relevance & Applicability 7.5
Long-term beta-blocker management after myocardial infarction is a common outpatient decision, although the trial was conducted entirely in South Korea and included relatively few women.
Validity, Bias Control & Precision 8.0
This was a multicenter randomized trial with prespecified noninferiority methods and 3.1 years of median follow-up; limitations include its open-label design, relatively few events, and a noninferiority margin allowing a hazard ratio up to 1.4.
Patient-Oriented Outcomes 9.0
The primary composite consisted entirely of important clinical outcomes: all-cause death, recurrent myocardial infarction, and hospitalization for heart failure.
Magnitude of Net Benefit 6.0
Discontinuation was noninferior, with 4-year event estimates of 7.2% versus 9.0% and similar serious adverse events, but superiority and improvements in symptoms, quality of life, or medication burden were not demonstrated.
Implementability & Practicality 9.0
Stopping a long-term medication is straightforward and requires no specialized equipment, although clinicians must confirm stable post-infarction status, ejection fraction of at least 40%, and absence of heart failure.
Practice-Changing Potential 8.0
The findings directly support deprescribing beta-blockers after at least one year in a defined post-infarction population, potentially changing a common long-term prescribing practice.
Cardiology Relevance & Applicability 8.5
US cardiologists routinely decide whether to continue beta-blockers long term in stable post-MI patients without heart failure or substantial LV systolic dysfunction. Although conducted in South Korea, the contemporary secondary-prevention setting and straightforward discontinuation strategy are readily transferable to typical US cardiology practice.
10. 7.8
Mobile Chat Messaging for Smoking Relapse Prevention: A Randomized Clinical Trial.
Overall: A well-conducted randomized trial found a large, clinically meaningful improvement in validated smoking abstinence, although its Hong Kong cessation-service setting and live-counselor requirements modestly limit direct US implementation.
View 8 Criterion Scores
Primary-Care Relevance & Applicability 7.0
Smoking relapse is common and directly relevant to US primary care, although the trial involved two Hong Kong smoking-cessation services rather than routine US practices.
Validity, Bias Control & Precision 8.5
This randomized trial used a contact control, intention-to-treat analysis, biochemical validation, 98% retention, and confidence intervals, although masking was not reported.
Patient-Oriented Outcomes 8.5
Sustained smoking abstinence and relapse are meaningful outcomes, and the primary outcome was biochemically validated rather than based solely on self-report.
Magnitude of Net Benefit 8.5
Validated abstinence improved by 10.4 percentage points, corresponding to an approximate NNT of 10, while relapse fell by 11.9 points; harms were not reported and live counseling adds burden.
Implementability & Practicality 7.0
Messaging and chatbot support are scalable, but three months of access to a live counselor requires staffing and workflow resources not available in every practice.
Practice-Changing Potential 7.5
The intervention could strengthen relapse-prevention care for a common problem, but adoption in US primary care may require confirmation of transferability and a workable counseling model.
Addiction Medicine Relevance & Applicability 4.0
Smoking relapse prevention is directly relevant to addiction medicine, and mobile counseling could fit routine care. However, the trial was conducted entirely within Hong Kong cessation services and provides no explicit evidence that its workflow transfers to US practice.
Public Health Relevance & Applicability 4.0
A scalable mobile intervention to sustain tobacco abstinence is highly relevant to population-level tobacco control. Applicability is limited because the study was confined to Hong Kong clinics and does not establish transferability to US public health systems or populations.
Score Guide: 9-10 Exceptional 7-8 Strong 5-6 Moderate 3-4 Weak 1-2 Poor
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