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Systematic Review: Shorter Antibiotic Courses Often Prove Non-Inferior for Common Bacterial Infections

3 Feb, 2025 | 10:00h | UTC

Background: The overuse of antibiotics contributes significantly to the global rise in antimicrobial resistance (AMR). Shorter antibiotic treatment courses have gained traction as an important antimicrobial stewardship intervention. They can potentially reduce drug-related side effects, healthcare costs, and selection pressure favoring resistant pathogens. This review synthesizes findings from randomized controlled trials (RCTs) on antibiotic duration across various common bacterial infections—including respiratory tract, genitourinary, skin and soft tissue, bone/joint, and intra-abdominal infections—to inform practical, day-to-day clinical decision-making.

Objective:

To assess the comparative efficacy of short- versus long-course antibiotic therapy for frequent bacterial infections.
To highlight key evidence gaps, particularly for severe infections, critically ill populations, and low- to middle-income settings.
To propose practical treatment durations in light of current guidelines and study outcomes.

Methods:

Comprehensive search of MEDLINE and Embase through July 2024 (PROSPERO 2021, CRD42021276209).
Inclusion: RCTs that compared differing antibiotic durations for bacterial infections or perioperative prophylaxis, reporting clinical cure, relapse, or mortality.
Exclusion: Non-bacterial infections (viral/fungal), pilot studies, non-randomized designs.
Data extraction: Patient demographics, infection type, interventions, outcomes, adherence, and risk-of-bias assessment per the RoB 2 tool.
Guideline review: Major international guidelines (e.g., IDSA, NICE, WHO) were examined to contextualize trial findings.

Results:

A total of 315 RCTs were included; 85% concluded no difference, non-inferiority, or equivalence of shorter compared with longer antibiotic courses.
Shorter therapy (often 5–7 days) is well-supported for uncomplicated bacterial sinusitis, community-acquired pneumonia (CAP), simple urinary tract infections (UTIs), cellulitis, and intra-abdominal infections with adequate surgical source control.
Evidence for reducing duration in severe infections (e.g., bloodstream infections, ventilator-associated pneumonia caused by non-fermenting Gram-negative bacilli) or in critically ill populations remains limited.
Only 7% of RCTs involved intensive care unit (ICU) patients, and 14% were conducted in low- or middle-income countries.
Methodologically, 15% of trials posed a low risk of bias; however, non-adherence to assigned durations was common (median 11% per study). Very few trials tracked emergence of resistant organisms through follow-up cultures.

Key findings:

Acute GAS Pharyngotonsillitis:
10 days of penicillin V or amoxicillin remains the conventional standard to ensure microbiological eradication and minimize rheumatic fever risk. While 5 days of azithromycin may be used in macrolide-responsive settings, it is not preferred as first-line therapy due to broader-spectrum activity and limited evidence for preventing complications, particularly in high-risk populations.
Community-Acquired Pneumonia (CAP):
- Outpatient adults with mild to moderate CAP typically improve with 5 days of appropriate therapy (e.g., amoxicillin, doxycycline, or a macrolide), provided patients show clinical stability.
- Severe CAP or complicated presentations (e.g., MRSA, Pseudomonas, multi-lobar involvement) may need 7–10 days or until clinical stability is achieved.
Acute Bacterial Sinusitis (Adults):
- 5–7 days of amoxicillin/clavulanate or other first-line agents usually suffice if the diagnosis is certain.
Genitourinary Infections:
- Uncomplicated Cystitis (Non-Pregnant Women):
  - 3–5 days of nitrofurantoin or trimethoprim/sulfamethoxazole is often adequate, reflecting strong RCT support.
- Pyelonephritis or Complicated UTIs (e.g., in men, catheter-associated):
  - While some RCTs show 7 days can be as effective as 14 days in afebrile males with mild UTI, a trial in febrile males demonstrated inferior outcomes with shorter courses. Clinicians should exercise caution in febrile or higher-risk cases.
Skin and Soft Tissue Infections (e.g., Cellulitis):
- 5–6 days of effective oral therapy is sufficient for uncomplicated cellulitis if there is marked clinical improvement by Day 5.
- For recurrent abscesses or complicated scenarios, duration may need to be extended or individualized.
Bone and Joint Infections:
- 6 weeks is often sufficient for vertebral osteomyelitis in stable patients.
- For prosthetic joint infections with retained hardware, 6 weeks of therapy was inferior to 12 weeks in a key trial, necessitating individualized duration based on surgical management.
Intra-Abdominal Infections:
- With adequate source control, 4–5 days of antibiotics commonly yields outcomes on par with extended courses.
- Longer therapy (≥7 days) may be needed when abscesses are not fully drained or in immunocompromised patients.
Perioperative Prophylaxis:
- A single preoperative dose (possibly repeated if surgery is prolonged or blood loss is excessive) is sufficient in most procedures.
- Continuing prophylaxis beyond 24 hours rarely provides additional benefit and may increase adverse events.

Conclusions: Numerous well-conducted RCTs support shorter antibiotic courses for many common bacterial infections. Nonetheless, high-quality data are sparse for severe or complex infections, pediatric populations with significant comorbidities, and low-resource settings. Clinicians should tailor antibiotic duration to the infection type, disease severity, patient factors, and local resistance patterns—while remaining cognizant that shorter courses can safely balance efficacy, safety, and stewardship aims in many cases.

Study Strengths and Limitations:

Strengths: Large volume of RCTs, broad infection scope, and inclusion of diverse study designs. Substantial evidence supports shortening antibiotic regimens for multiple common infections.
Limitations: Underrepresentation of severe, ICU-level infections, children with serious comorbidities, and low-resource settings. High variation in diagnostic criteria, antibiotic choices, and adherence monitoring. Many trials reported low event rates, posing potential non-inferiority bias.

Future Research:

Well-powered RCTs focusing on severe infections (e.g., MDR Gram-negative bloodstream infections, staphylococcal bacteremia, ventilator-associated pneumonia with resistant pathogens).
Trials in low- and middle-income countries with robust microbiological and economic assessments.
Studies using adaptive designs and validated biomarkers to refine duration–response relationships and detect shifts in AMR at the population level.

Reference: Mo Y, Tan WC, Cooper BS. Antibiotic duration for common bacterial infections—a systematic review. JAC-Antimicrobial Resistance. 2025;7(1):dlae215. DOI: https://doi.org/10.1093/jacamr/dlae215

Network Meta-analysis: Oseltamivir Fails to Improve Key Outcomes in Nonsevere Influenza

20 Jan, 2025 | 11:17h | UTC

Background: Influenza causes significant respiratory morbidity and can lead to severe complications, especially in high-risk individuals. Current guidelines endorse antiviral therapy, yet the evidence for reducing mortality, hospital admission, and symptom duration in nonsevere cases remains controversial. Recent recommendations have often focused on neuraminidase inhibitors (e.g., oseltamivir), despite uncertainties regarding clinical impact and adverse effects. An editorial accompanying this study underscores the need to reexamine routine antiviral use, especially oseltamivir, given minimal benefit observed in outpatient populations.

Objective: To assess and compare the efficacy and safety of direct-acting antiviral medications (baloxavir, oseltamivir, laninamivir, zanamivir, peramivir, umifenovir, favipiravir, and amantadine) in treating patients with nonsevere influenza.

Methods: This systematic review and network meta-analysis included 73 randomized clinical trials (N=34,332) that evaluated antivirals vs placebo, standard care, or another antiviral. Eligible studies enrolled nonhospitalized patients with confirmed or suspected influenza. Outcomes included mortality, hospital admission, time to symptom alleviation, adverse events, and emergence of antiviral resistance. Risk of bias was assessed with a modified Cochrane tool, and the certainty of evidence was rated using the GRADE approach. Pooled estimates were generated with a frequentist random-effects model, focusing on both absolute risk differences and relative measures.

Results:

Mortality: Across all antiviral agents, there was high-certainty evidence of little or no effect on mortality in both low-risk and high-risk patients compared with standard care or placebo.
Hospital Admission: In low-risk patients, none of the antivirals significantly altered admission rates (high certainty). In high-risk patients, oseltamivir had little or no effect on hospitalization (high certainty), whereas baloxavir may reduce admissions (low certainty).
Time to Alleviation of Symptoms: Baloxavir shortened symptom duration by approximately one day (moderate certainty) without increasing adverse events. Oseltamivir and zanamivir likely produced smaller decreases (<1 day; moderate certainty). Umifenovir may also shorten symptoms (low certainty).
Adverse Events: Baloxavir did not increase treatment-related adverse events (high certainty) but may lead to viral resistance in around 10% of cases (low certainty). Oseltamivir probably increases adverse events such as nausea and vomiting (moderate certainty).
Serious Outcomes (ICU Admission, Duration of Hospitalization): Data were limited, with uncertainty regarding meaningful reductions in these measures.

Conclusions: Baloxavir may reduce hospital admissions for high-risk patients and significantly shorten symptom duration without notable treatment-related adverse events. Oseltamivir shows little effect on mortality or hospitalization for nonsevere influenza, with only modest (likely not clinically important) reductions in symptom duration and a higher rate of adverse events. Other antivirals either demonstrate uncertain clinical benefits or likely provide no major advantages in this patient population.

Implications for Practice: These findings suggest that routine use of oseltamivir for outpatients with nonsevere influenza should be reconsidered, especially in low-risk groups. Baloxavir appears favorable for high-risk patients, though clinicians should monitor potential drug resistance. Given the minimal impact on major outcomes and the cost considerations, prescribers should weigh the benefits and harms of these antivirals, aligning treatment decisions with patient risk profiles and clinical judgment.

Study Strengths and Limitations: Strengths include a comprehensive search, large pooled population, and rigorous GRADE-based analysis of certainty. Limitations involve low event rates for hospital admissions and mortality, limiting power for certain outcomes, and sparse data on some antivirals (e.g., amantadine). Additionally, few trials reported ICU admissions or mechanical ventilation needs, restricting conclusions about severe complications.

Future Research: Further high-quality studies should evaluate patient-important outcomes such as mechanical ventilation and severe complications in diverse populations. Investigations into combination strategies, alternative dosing, and resistance patterns would help clarify the long-term viability of baloxavir and other antivirals, particularly in high-risk cohorts.

Reference:

Gao Y, Zhao Y, Liu M, et al. Antiviral Medications for Treatment of Nonsevere Influenza: A Systematic Review and Network Meta-Analysis. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7193
Baghdadi JD, Grady D, Morgan DJ. The Limited Role for Antiviral Therapy in Influenza. JAMA Internal Medicine. Published online January 13, 2025. DOI: http://doi.org/10.1001/jamainternmed.2024.7258

Network Meta-Analysis: Distinct Benefit–Risk Profiles of GLP-1 Receptor Agonists, DPP-4 Inhibitors, and SGLT2 Inhibitors

19 Jan, 2025 | 12:27h | UTC

Background: Type 2 diabetes (T2D) is a global health challenge due to its high prevalence and associated risks for cardiovascular (CV) and renal complications. Newer glucose-lowering drug (GLD) classes—dipeptidyl peptidase 4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i)—offer unique benefits and safety profiles. Although many large randomized outcome trials have demonstrated their efficacy, the benefit–risk balance among these agents remains incompletely understood, especially regarding non-traditional outcomes such as psychiatric disorders and neurodegenerative diseases. Given their generally higher costs and frequent industry sponsorship of the trials, it is critical to evaluate these classes in a systematic and impartial manner.

Objective: To systematically compare the benefits and risks of DPP4i, GLP-1RAs, and SGLT2i in adults with T2D, heart failure, or chronic kidney disease, focusing on 21 outcomes spanning macrovascular and microvascular events, infections, psychiatric outcomes, and cancer risk.

Methods: Researchers searched PubMed, Embase, and CENTRAL through November 2023 for randomized placebo-controlled cardiovascular and kidney outcome trials of DPP4i, GLP-1RAs, or SGLT2i in adults with T2D, heart failure, or chronic kidney disease. Twenty-six trials (N=198,177 participants) met inclusion criteria. A novel PAtient-centered treatment ranking via Large-scale Multivariate network meta-analysis (PALM) approach was used to synthesize population-averaged odds ratios (ORs) with 95% confidence intervals (CIs). This approach allowed for the simultaneous evaluation of multiple outcomes and the generation of weighted origami plots to visualize treatment rankings across different disease categories. Heterogeneity (I²) and publication bias (Egger’s test) were also assessed.

Results:

Macrovascular: GLP-1RAs reduced major adverse cardiovascular events (MACE) versus placebo (OR 0.85, 95% CI 0.79–0.92) and DPP4i. GLP-1RAs also lowered stroke risk (OR range 0.82–0.85 vs comparators). SGLT2i yielded the largest reduction in hospitalization for heart failure (OR 0.68, 95% CI 0.64–0.73 vs placebo). DPP4i had a lower amputation risk relative to SGLT2i (OR 0.85, 95% CI 0.75–0.95).
Microvascular: SGLT2i most effectively reduced renal composite outcomes versus DPP4i and placebo (OR ~0.67). However, DPP4i was linked to higher neuropathy risk (OR 1.10, 95% CI 1.02–1.18 vs placebo).
Psychiatric and Neurodegenerative: DPP4i was associated with a reduced risk of depression, suicide, and alcohol use disorder compared to placebo. A lower Parkinson’s disease risk (OR 0.54, 95% CI 0.32–0.92) was also noted. GLP-1RAs showed a possible increased risk of suicidal ideation vs DPP4i, though evidence remains inconclusive.
Infections/Inflammation: SGLT2i substantially increased genital infections (OR 3.11, 95% CI 2.15–4.50 vs placebo). DPP4i had higher pancreatitis risk vs all comparators.
Cancer: GLP-1RAs were linked to increased thyroid cancer risk (OR range 1.58–2.70), though overall cancer risk and pancreatic cancer did not differ significantly across treatments.

Conclusions: Each newer GLD class offers specific advantages along with distinct safety considerations. GLP-1RAs appear particularly effective for macrovascular endpoints but carry a signal for thyroid malignancy. SGLT2i provide notable cardioprotective and renoprotective effects, offset by risk of genital infections and an increased risk of amputation compared to DPP4i. DPP4i tend to have neutral CV/renal outcomes yet may protect against certain psychiatric issues and neurodegenerative conditions, balanced by increased pancreatitis risk. Personalized treatment strategies, with attention to comorbidities and adverse event profiles, remain essential—particularly given the generally elevated costs of these newer agents. It is important to note that these findings are largely based on indirect comparisons in the absence of head-to-head trials, which is a limitation.

Implications for Practice: Clinicians should weigh cardiovascular risk, kidney function, mental health status, and potential malignancy when prescribing GLDs. SGLT2i may be favored in patients with heart failure or chronic kidney disease, while GLP-1RAs may be ideal for those with high atherosclerotic CV risk. DPP4i could be considered in patients with psychiatric or neurologic comorbidities but require caution regarding pancreatitis. Cost considerations and access may also influence real-world use.

Study Strengths and Limitations: Strengths include a large number of participants, broad outcome coverage, and a multivariate network meta-analysis that accommodates indirect comparisons. Limitations arise from underreported outcomes (e.g., psychiatric, neurodegenerative), heterogeneous trial populations, potential publication bias for some outcomes, and possible off-target influences not fully captured. Furthermore, sponsor involvement in all included trials warrants cautious interpretation of benefit–risk claims.

Future Research: Head-to-head trials comparing newer GLDs for psychiatric and neurologic endpoints, along with detailed reporting of rare adverse events (e.g., pancreatitis, cancer subtypes), are needed. Studies on real-world cost-effectiveness and access issues could clarify how to optimize therapy in routine practice. Additional investigations into long-term safety signals (including suicidality and thyroid malignancies) would further guide clinical decision-making.

Reference: Tang H, Zhang B, Lu Y, Donahoo WT, Singh Ospina N, Kotecha P, Lu Y, Tong J, Smith SM, et al. “Assessing the benefit–risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials.” Diabetes, Obesity and Metabolism. First published: 26 December 2024. DOI: http://doi.org/10.1111/dom.16147

Network Meta-Analysis: TMP-SMX May Need Reassessment as First-Line Therapy for PCP in People With HIV

13 Jan, 2025 | 10:25h | UTC

Background: Pneumocystis jirovecii pneumonia (PCP) remains a severe opportunistic infection in people living with HIV (PWH), especially those with low CD4 counts. Trimethoprim–sulfamethoxazole (TMP-SMX) is widely recommended as first-line therapy; however, its toxicity profile can limit use. Alternative regimens such as dapsone–trimethoprim, clindamycin–primaquine, atovaquone, and pentamidine have been explored, but comprehensive comparative data are scarce.

Objective: This systematic review and network meta-analysis aimed to compare the efficacy (treatment failure, mortality) and tolerability (treatment change due to toxicity) of PCP treatment regimens in PWH. The goal was to determine whether TMP-SMX maintains superiority across these outcomes or if alternative regimens offer similar efficacy with improved safety profiles.

Methods: Researchers systematically searched Embase, Medline, and CENTRAL (inception through 3 February 2024) for randomized controlled trials (RCTs) comparing at least two PCP treatment regimens in PWH. Independent reviewers screened titles/abstracts and performed full-text reviews. Data extraction included population demographics, treatment arms, outcomes (treatment failure, all-cause mortality, treatment change), and risk-of-bias assessments using the Cochrane Risk-of-Bias 2 tool. A network meta-analysis using a frequentist random-effects model was performed to integrate direct and indirect comparisons, estimating relative treatment effects (risk ratios with 95% confidence intervals) and generating rankings via the surface under the cumulative ranking curve (SUCRA).

Results: Fourteen RCTs (1983–1996) with 1,788 participants across 27 treatment arms were included. No regimen demonstrated significant superiority over TMP-SMX in direct comparisons, although TMP-SMX outperformed atovaquone and trimetrexate plus folinic acid in reducing treatment failure. In the network analysis, clindamycin–primaquine, intravenous pentamidine, and TMP-SMX all had favorable SUCRA values for preventing treatment failure. For all-cause mortality, dapsone–trimethoprim and intravenous pentamidine ranked highest, while TMP-SMX was better than atovaquone in direct comparison. Notably, for tolerability, all alternative regimens tended to be safer than TMP-SMX, which ranked worst for toxicity. Inhaled pentamidine, trimetrexate plus folinic acid, and atovaquone were the best-tolerated therapies.

Conclusions: These findings suggest that TMP-SMX, although commonly used, might not be universally superior to all other regimens when balancing efficacy and safety in PWH with PCP. When the risk of renal or hematologic complications is high, considering clindamycin–primaquine or intravenous pentamidine may provide comparable efficacy with a more favorable safety profile. Inhaled pentamidine or atovaquone may offer good tolerability but should be carefully assessed for efficacy in moderate-to-severe disease.

Implications for Practice: When managing PCP in PWH, TMP-SMX may not always be the ideal standalone first-line choice, especially in patients at high risk for renal or hematologic complications. Clindamycin–primaquine and intravenous pentamidine could represent viable alternatives for clinicians seeking to balance efficacy with improved safety. Inhaled pentamidine or atovaquone may offer strong tolerability but should be carefully evaluated for their effectiveness in moderate-to-severe disease.

Study Strengths and Limitations: Strengths include a robust search strategy, strict inclusion criteria of RCTs, and the use of a network meta-analysis to integrate direct and indirect comparisons. Limitations involve the older timeframe of the included trials (most conducted before the modern ART era) and heterogeneous definitions of treatment failure, which may limit generalizability to broader contemporary clinical settings. Women and other high-risk populations were underrepresented, presenting another limitation.

Future Research: Contemporary RCTs should address the optimal dose and duration of TMP-SMX and alternative agents, include underrepresented groups (women, older adults, patients with renal impairment), and consider modern management of HIV and critical care practices. Ongoing investigations of novel agents like rezafungin may further refine first-line PCP treatment strategies.

Reference: Hatzl S, Posch F, Scholz L, … Bassetti M, Hoenigl M, Krause R. Comparative efficacy and safety of treatment regimens for Pneumocystis jirovecii pneumonia in people living with HIV: a systematic review and network meta-analysis of randomized controlled trials. Clinical Microbiology and Infection, Published online December 26, 2024. DOI: http://doi.org/10.1016/j.cmi.2024.12.024

SR: Lower BP Targets Reduce Stroke Risk and Cardiovascular Events in Older Adults

16 Jan, 2025 | 12:42h | UTC

Background: Hypertension is a prevalent condition in older adults and a major risk factor for cardiovascular morbidity and mortality. Despite widely accepted benefits of treating blood pressure (BP) above 160 mmHg in this population, the optimal BP target remains uncertain. Many guidelines recommend a systolic BP (SBP) goal of < 140 mmHg in all adults, including those aged ≥ 65 years. However, evidence suggests older, possibly frail individuals might experience different benefit–risk ratios with more relaxed BP targets. This Cochrane review updates the previous 2017 analysis to determine whether aiming for higher BP targets in older adults (e.g., < 150–160 mmHg systolic) confers comparable or better outcomes than standard or more aggressive targets (< 140 mmHg).

Objective: To assess the effects of a higher BP target (SBP < 150–160 mmHg or diastolic BP < 95–105 mmHg) versus a lower (conventional or more aggressive) BP target (< 140/90 mmHg or lower) on mortality, stroke, and serious cardiovascular events in hypertensive adults aged ≥ 65 years.

Methods:

Design and Searches: This is an updated Cochrane systematic review of randomized controlled trials (RCTs) comparing higher vs lower BP targets in older adults with hypertension. Databases searched through June 2024 included MEDLINE, Embase, CENTRAL, the Cochrane Hypertension Specialised Register, and ClinicalTrials.gov.
Inclusion Criteria: RCTs of ≥ 1 year’s duration enrolling participants aged ≥ 65 years with baseline systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg. Trials had to compare a higher BP target range (SBP < 150–160/DBP < 95–105 mmHg) to a lower BP target (< 140/90 mmHg).
Outcomes: Primary outcomes were all-cause mortality, stroke, institutionalization, and serious cardiovascular adverse events (including myocardial infarction, heart failure, and renal failure). Secondary outcomes included cardiovascular mortality, non-cardiovascular mortality, total serious adverse events, and withdrawals due to adverse effects.

Results:

Included Studies: Four open-label RCTs (N = 16,732) from Japan and China, with mean ages around 70 years (range 65–77). Mean follow-up ranged from 2 to 4 years.
Mortality: Lower BP targets may result in little to no difference in all-cause mortality (RR 1.14, 95% CI 0.95–1.37; low-certainty).
Stroke Prevention: A lower BP target clearly reduced the risk of stroke (RR 1.33, 95% CI 1.06–1.67; high-certainty), with an absolute reduction of approximately 6 stroke events per 1000 individuals treated over ~3 years.
Serious Cardiovascular Events: A lower BP target likely reduced total serious cardiovascular adverse events (RR 1.25, 95% CI 1.09–1.45; moderate-certainty), equating to roughly 10 fewer cardiovascular events per 1000 people treated.
Adverse Effects: Lower BP targets likely did not increase withdrawals due to adverse effects (RR 0.99, 95% CI 0.74–1.33; moderate-certainty). Data on other adverse events (e.g., hypotension) were limited but showed small absolute differences.

Conclusions: Treating older adults’ systolic BP to < 140 mmHg (vs < 150–160 mmHg) reduces stroke and likely reduces overall serious cardiovascular events without clearly affecting all-cause mortality or increasing dropouts due to adverse effects. While these findings support standard BP targets (< 140 mmHg) for many older patients, the absolute reduction in events is modest. Caution may be warranted in individuals aged ≥ 80 years or those who are frail, as the included studies had fewer such participants.

Implications for Practice: For most older adults, targeting SBP < 140 mmHg can prevent a modest but meaningful number of cardiovascular events, particularly stroke. Clinicians should balance these benefits against patient-specific concerns, such as frailty, multiple comorbidities, and polypharmacy. Monitoring for hypotension, renal function changes, and other adverse effects remains important.

Study Strengths and Limitations:

Strengths: Inclusion of four RCTs with low attrition rates; assessment of major vascular endpoints relevant to older adults.
Limitations: All trials were open-label, increasing risk of bias in subjective outcomes. Adverse event reporting was incomplete, and very elderly or frail individuals were often underrepresented. Most data originated from Asian populations, limiting generalizability to other regions.

Future Research: Further RCTs in populations aged ≥ 80 years, those with significant frailty, or living in nursing homes are essential to clarify optimal BP targets. Studies should capture quality-of-life measures and long-term safety outcomes, especially regarding adverse drug–drug interactions in complex older patients.

Reference: Falk JM, Froentjes L, Kirkwood JE, Heran BS, Kolber MR, Allan GM, Korownyk CS, Garrison SR. Higher blood pressure targets for hypertension in older adults. Cochrane Database of Systematic Reviews. 2024; Issue 12. DOI: http://doi.org/10.1002/14651858.CD011575.pub3

SR: Efficacy and Safety of Non-Pharmacological, Pharmacological, and Surgical Treatments for Hand Osteoarthritis

16 Jan, 2025 | 10:54h | UTC

Background: Hand osteoarthritis (OA) affects a substantial proportion of older adults, contributing to pain, reduced grip strength, and functional limitations. While several clinical guidelines recommend patient education, exercise, and topical or oral non-steroidal anti-inflammatory drugs (NSAIDs), the level of evidence remains varied. In 2018, a systematic review identified efficacy data from 126 studies. This updated review includes 65 new randomized controlled trials (RCTs) published through December 2023, aiming to provide the most current evidence on hand OA treatments.

Objective: To summarize and evaluate the efficacy and safety of non-pharmacological, pharmacological, and surgical interventions for hand OA, highlighting both short-term (<3 months) and long-term (≥3 months) outcomes for pain, function, and grip strength.

Methods: The authors searched PubMed/MEDLINE, Embase, and Cochrane CENTRAL for RCTs published from June 2017 to December 2023. Risk of bias was assessed using the RoB2 tool, and certainty of evidence was evaluated with GRADE criteria. Interventions included hand exercises, orthoses, assistive devices, thermal modalities, pharmacologic therapies (e.g., oral/topical NSAIDs, glucocorticoids, disease-modifying anti-rheumatic drugs), and various surgical techniques. Meta-analyses were conducted when appropriate, and outcomes were expressed as standardized mean differences or relative risks with 95% confidence intervals.

Results:

Non-Pharmacological Interventions: Low- to moderate-certainty evidence supports hand exercises, thumb orthoses, and assistive devices for improving pain and function. Hand exercises showed a small long-term effect on pain, while thumb orthoses offered a moderate long-term effect on pain. Assistive devices demonstrated a moderate long-term benefit for function. Few mild adverse events were reported in these categories.
Pharmacological Interventions: There is high-certainty evidence for a very small short-term functional improvement with topical NSAIDs and low-certainty evidence of moderate short-term pain relief with oral NSAIDs. Oral glucocorticoids likely yield a small, short-term functional benefit. Methotrexate showed a possible small long-term effect on pain but no clear impact on function. No new data support intra-articular steroid injections, hydroxychloroquine, or biologic DMARDs for meaningful improvements; in these trials, sponsor bias and cost considerations underscore the need for critical appraisal, given the typically higher expense of advanced agents like biologics.
Surgical Interventions: Ten new studies compared various surgical techniques but did not include robust controls versus nonsurgical management or sham surgery. Heterogeneity precluded pooling of results, and no definitive superiority emerged for any particular procedure.

Conclusions: This systematic review reaffirms the central role of non-pharmacological interventions, especially exercise, orthoses, and assistive devices, for improving pain and function in hand OA with minimal adverse events. Pharmacological treatments offer modest short-term benefits, particularly oral NSAIDs, although cost, side-effect profiles, and real-world adherence should be considered. Surgical approaches lack high-quality comparative data, highlighting the need for well-designed trials.

Implications for Practice: Clinicians should prioritize patient education, exercises, and readily accessible interventions (e.g., orthoses, assistive devices) given their demonstrated safety and moderate efficacy. Oral or topical NSAIDs remain suitable options for acute pain management, with the understanding that longer-term use warrants caution due to possible adverse effects. In contexts where advanced pharmacologic agents (such as biologics) are evaluated, practitioners must scrutinize costs, potential sponsor influence, and marginal benefits relative to standard care.

Study Strengths and Limitations: Strengths of this review include a comprehensive literature search, systematic appraisal of risk of bias, and application of GRADE to gauge certainty. However, most RCTs were small in size or had high or unclear risk of bias, and considerable heterogeneity in study designs reduced comparability. Additional limitations include the scarcity of direct comparisons for surgical versus non-surgical approaches and inconsistent reporting of adverse events.

Future Research: High-quality, larger-scale RCTs are needed to clarify subtypes of hand OA and tailor treatments accordingly. Trials should evaluate long-term outcomes, systematically measure adverse events, and compare surgery directly with non-surgical options. Studies employing mobile health (mHealth) tools and addressing ways to enhance grip strength may further advance evidence-based hand OA management.

Reference:
Kjeken I, Bordvik DH, Osteras N, Haugen IK, Fjeldstad KAA, Skaalvik I, Kloppenburg M, Kroon FPB, Tveter AT, Smedslund G. Efficacy and safety of non-pharmacological, pharmacological and surgical treatments for hand osteoarthritis in 2024: a systematic review. RMD Open. 2024; e004963. DOI: https://doi.org/10.1136/rmdopen-2024-004963

Systematic Review: GLP-1 Receptor Agonists and Co-Agonists Facilitate Significant Weight Loss in Adults Without Diabetes

8 Jan, 2025 | 11:04h | UTC

Background: Obesity is increasingly treated as a chronic disease requiring long-term management. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were originally developed for type 2 diabetes but subsequently demonstrated substantial weight loss benefits in individuals with overweight or obesity. Although several GLP-1 RAs and related dual or triple co-agonists have been assessed in diverse populations, their overall efficacy and safety profile among adults without diabetes had not been thoroughly evaluated.

Objective: To systematically appraise the efficacy and safety of GLP-1 RAs (including single, dual, and triple agonists) for weight loss in otherwise healthy adults with overweight or obesity and without diabetes.

Methods: Investigators searched MEDLINE, Embase, and Cochrane CENTRAL through 4 October 2023 for placebo-controlled randomized controlled trials (RCTs). Eligible studies enrolled adults with body mass index (BMI) ≥27 kg/m^2 (plus one weight-related comorbidity) or ≥30 kg/m^2, in the absence of diabetes or other major diseases. Trials had to last at least 16 weeks and report changes in body weight and safety outcomes. The primary endpoint was percent or absolute change in body weight from baseline. Safety assessments included adverse events (AEs), serious AEs (SAEs), and gastrointestinal (GI) events.

Results: Twenty-six RCTs encompassing 15,491 participants (72% female; mean BMI range, 30–41 kg/m^2; mean age range, 34–57 years) evaluated 12 agents. Three drugs (liraglutide, semaglutide, tirzepatide) are commercially available for weight management; nine are premarket (e.g., retatrutide, orforglipron, mazdutide). Treatment periods ranged from 16 to 104 weeks (median, 43 weeks). Across studies, GLP-1 RAs and co-agonists consistently demonstrated significant weight reductions compared with placebo. Tirzepatide (15 mg weekly) reached up to a 17.8% (95% CI, 16.3% to 19.3%) weight reduction after 72 weeks, whereas semaglutide (2.4 mg weekly) achieved up to 13.9% (95% CI, 11.0% to 16.7%) after 68 weeks. Liraglutide produced more modest losses of up to 5.8% (95% CI, 3.6% to 8.0%) after 26 weeks. Novel agents, particularly the triple agonist retatrutide (12 mg weekly), reported greater average weight losses of up to 22.1% (95% CI, 19.3% to 24.9%) after 48 weeks. Although AEs were often very common (GLP-1 RA vs. placebo: 80%–97% vs. 63%–100%), most were GI-related (47%–84% vs. 13%–63%) and mild or moderate. Importantly, only a smaller proportion of participants (0%–26% vs. 0%–9%) discontinued treatment due to AEs, and SAEs (0%–10% vs. 0%–12%) occurred at relatively lower rates overall. While select SAEs of interest, including severe GI events, biliary disorders, pancreatitis, and psychiatric disorders, were inconsistently reported, they were generally rare (severe GI and biliary disorders, ≤3.5%; pancreatitis, <2%; psychiatric disorders, ≤15% [including less severe events, such as insomnia and mood alterations]).

Conclusions: GLP-1 RAs and co-agonists appear highly efficacious for weight reduction in adults without diabetes, with GI events as the principal safety concern. Among emerging agents, retatrutide in particular has shown even greater efficacy, though further research is needed to clarify comparative effectiveness, costs, and real-world feasibility.

Implications for Practice: Clinicians considering GLP-1 RAs or dual and triple co-agonists for obesity treatment should monitor for GI side effects and counsel patients about long-term use to sustain weight loss. As these newer treatments often come with higher price points and uncertain insurance coverage, cost-effectiveness and sponsor bias should be weighed. Careful patient selection, ongoing monitoring, and discussion of adherence requirements are critical to optimize outcomes in real-world practice.

Study Strengths and Limitations: This review incorporated RCTs with substantial sample sizes and used predefined inclusion criteria focused on healthy adults without diabetes, ensuring a clearer understanding of weight-loss outcomes in this group. However, head-to-head comparisons among agents were lacking, and heterogeneity in trial designs (varying lifestyle interventions, follow-up durations, and dose-escalation approaches) precluded meta-analysis of pooled data. Reporting of specific adverse outcomes was also inconsistent.

Future Research: Larger, longer-term head-to-head RCTs are warranted to evaluate comparative effectiveness, durability of weight loss, and cost implications. Investigations should also explore safety beyond GI events, including rare but serious outcomes such as thyroid disease, gallbladder disorders, or pancreatitis, and determine whether combination therapies (e.g., cagrilintide–semaglutide) confer added benefits.

Reference: Moiz A, Filion KB, Toutounchi H, Tsoukas MA, Yu OHY, Peters TM, Eisenberg MJ. Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes: A Systematic Review of Randomized Controlled Trials. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-01590

Meta-Analysis: Tailored Hydration Strategies Decrease CI-AKI and MACE in Coronary Angiography

6 Jan, 2025 | 13:00h | UTC

Background: Contrast-induced acute kidney injury (CI-AKI) poses a considerable burden on patients undergoing coronary angiography or percutaneous coronary intervention (PCI). Beyond the direct tubular toxicity of iodine contrast, several risk factors, including chronic kidney disease (CKD) and hemodynamic instability, further increase the likelihood of renal damage. Although guideline-based prevention strategies recommend peri-procedural intravenous hydration, the optimal volume and method remain unclear.

Objective: This meta-analysis aimed to determine whether patient-tailored intravenous fluid administration (using parameters other than body weight alone) can reduce the incidence of CI-AKI, as well as major adverse cardiovascular events (MACE), compared with conventional non-tailored hydration protocols in patients undergoing coronary angiography and/or PCI.

Methods: A systematic review of randomized controlled trials (RCTs) was performed, including 13 studies and 4,458 participants. Tailored hydration strategies encompassed left ventricular end-diastolic pressure (LVEDP)-guided infusion, diuresis-driven matched replacement (RenalGuard®), bioimpedance vector analysis, central venous pressure, or inferior vena cava ultrasound measurements. These were compared against standard non-tailored fluid protocols. The primary outcome was CI-AKI (variously defined but measured within 7 days), and secondary outcomes included MACE, all-cause mortality, and renal replacement therapy (RRT).

Results: Across 12 RCTs (n=3,669), tailored hydration significantly reduced CI-AKI rates (risk ratio 0.56, 95% CI [0.46–0.69], p<0.00001; I²=26%). Ten studies (n=3,377) revealed lower MACE incidence in the tailored hydration arm (RR=0.57, 95% CI [0.42–0.78], p=0.0005; I²=12%). A significant reduction in all-cause mortality (RR=0.57, 95% CI [0.35–0.94], p=0.03) and RRT requirement (RR=0.51, 95% CI [0.29–0.89], p=0.02) was also observed, with no significant increase in pulmonary edema. Subgroup analyses (e.g., CKD) supported the overall benefit of individualizing fluid regimens.

Conclusions: Tailored hydration strategies appear superior to standard approaches in lowering the risk of CI-AKI, MACE, mortality, and RRT after coronary angiography or PCI. Although LVEDP-guided protocols are simple to implement and effective, the RenalGuard® system may offer additional benefits in selected populations, albeit at higher cost and complexity.

Implications for Practice: Clinicians should consider personalized hydration based on physiological or hemodynamic parameters to optimize fluid volume, reduce renal injury, and potentially improve clinical outcomes. Nevertheless, practical challenges include access to specialized equipment and the need for close monitoring in some techniques.

Study Strengths and Limitations: This systematic review highlights consistent treatment effects across diverse RCTs and methods. However, potential biases due to lack of blinding, varying CI-AKI definitions, and limited head-to-head comparisons among tailored approaches constrain definitive conclusions. The small sample size of certain studies and underpowered subgroup analyses also limit the generalizability of findings.

Future Research: Further large-scale trials are warranted to compare various tailored protocols directly, focusing on cost-effectiveness, ease of implementation, and patient-centered endpoints. Ongoing investigations, such as the NEPTUNE trial, aim to clarify whether combining multiple parameters (like LVEDP and contrast volume/eGFR ratio) yields optimal renal protection.

Reference: Cossette F, Trifan A, Prévost-Marcotte G, et al. Tailored Hydration for the Prevention of Contrast-Induced Acute Kidney Injury After Coronary Angiogram or PCI: A Systematic Review and Meta-Analysis. American Heart Journal. Published online January 4, 2025. DOI: http://doi.org/10.1016/j.ahj.2025.01.002

Meta-analysis: Therapeutic-Dose Heparin Improves 28-Day Mortality in COVID-19 Hospitalized Patients

6 Jan, 2025 | 12:00h | UTC

Background: High rates of thrombotic events and systemic inflammation among COVID-19 hospitalized patients led researchers to test whether intensified anticoagulation strategies could reduce morbidity and mortality. Previous trials yielded conflicting results, partly due to varying doses of anticoagulants—prophylactic, intermediate, or therapeutic—and heterogeneous patient severity. This comprehensive investigation, conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, aimed to clarify the benefits and risks of escalated anticoagulation dosing in patients hospitalized for COVID-19.

Objective: To estimate whether higher-dose anticoagulation (therapeutic or intermediate) improves 28-day all-cause mortality compared with lower-dose anticoagulation (prophylactic or intermediate), and to evaluate secondary outcomes, including progression to mechanical ventilation, thromboembolic events, and major bleeding.

Methods: This prospective meta-analysis included randomized trials comparing higher- versus lower-dose anticoagulation for hospitalized COVID-19 patients. Investigators collected trial-level summary data, focusing primarily on heparins. Dosing categories—therapeutic, intermediate, and prophylactic—were predefined. The main outcome was 28-day mortality; secondary outcomes included progression to invasive mechanical ventilation (IMV), venous or arterial thrombotic events, and major hemorrhage. Data were analyzed using a fixed-effects model, with odds ratios (ORs) pooled across trials.

Results: Overall, 22 trials (over 11 000 total participants) contributed data, primarily evaluating heparins. For therapeutic versus prophylactic-dose heparin, 28-day mortality was significantly reduced (OR, 0.77; 95% CI, 0.64–0.93), especially among patients requiring low-flow oxygen or no supplemental oxygen. Therapeutic dose reduced thromboembolic events (OR 0.48; 95% CI, 0.36-0.64) but increased major bleeding (OR 1.90; 95% CI, 1.19-3.05) compared to prophylactic dose. In contrast, when therapeutic was compared to intermediate-dose heparin, the summary OR for 28-day mortality was 1.21 (CI, 0.93–1.58), suggesting a potential trend toward higher mortality that did not reach statistical significance. Intermediate versus prophylactic-dose comparisons revealed no conclusive mortality difference (OR, 0.95; CI, 0.76–1.19). Across all higher-dose arms, thromboembolic events decreased, while the risk of major bleeding increased, underscoring the delicate risk–benefit balance. Subgroup analyses by respiratory support level, D-dimer, and baseline severity did not indicate strong interaction effects, although sample sizes were limited in more severe illness subgroups.

Conclusions: Therapeutic-dose heparin reduces 28-day mortality relative to prophylactic-dose in hospitalized patients with COVID-19, mainly among those not requiring invasive ventilation. Mortality was similar or potentially worse when therapeutic was compared to intermediate-dose. Clinicians must weigh the lower rate of thrombotic complications against the higher bleeding risk, particularly in critically ill patients.

Implications for Practice: Although higher anticoagulant dosing appears beneficial for certain hospitalized COVID-19 patients, especially those with mild to moderate respiratory compromise, individualized assessment remains key. Current guidelines broadly recommend prophylactic dosing for the critically ill and suggest considering higher doses only in carefully selected patients. Evolving viral variants and changes in standard of care further complicate direct application of these findings to present-day hospital settings.

Study Strengths and Limitations: Strengths include prospective planning, collaboration with multiple trials, and a large pooled sample. Limitations encompass heterogeneity in dose definitions, partial reliance on published data where individual-level parameters could not be fully harmonized, and potential temporal changes in COVID-19 clinical profiles. Moreover, bleeding severity beyond major hemorrhage was not universally reported, limiting robust safety assessments.

Future Research: Further studies should focus on individualized anticoagulant strategies that consider biomarkers (for example, D-dimer) and evolving treatment protocols. Investigations examining optimal timing, duration, and post-discharge management will help refine anticoagulation practices.

Reference:

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Anticoagulation Among Patients Hospitalized for COVID-19: A Systematic Review and Prospective Meta-analysis. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-00800

Shappell CN, Anesi GL. Anticoagulation for COVID-19: Seeking Clarity and Finding Yet More Gray. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-03244

Meta-Analysis: Glutamatergic Agents May Improve Obsessive-Compulsive and Related Disorder Symptoms

4 Jan, 2025 | 12:08h | UTC

Background: Obsessive-compulsive and related disorders (OCRDs) affect approximately 2% to 3% of the general population and encompass conditions such as OCD, skin-picking disorder, and trichotillomania, leading to substantial distress and impaired daily functioning. Glutamatergic dysfunction within cortico-striatal-thalamo-cortical circuits has emerged as a potential target, prompting investigations into whether glutamatergic agents can enhance outcomes either alone or alongside selective serotonin reuptake inhibitors (SSRIs).

Objective: To determine whether glutamatergic medications, used as monotherapy or as augmentation to SSRIs, can improve clinical symptoms across different OCRDs compared to placebo, with emphasis on changes in standardized measures such as the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).

Methods: This systematic review and meta-analysis included 27 double-blind, placebo-controlled randomized clinical trials involving 1369 participants with OCRDs. Eligible studies examined agents including N-acetylcysteine (NAC), memantine, lamotrigine, riluzole, and topiramate, among others. Data extraction focused on changes in symptom severity, and pooled effect sizes were calculated using random-effects meta-analysis. Subgroup analyses evaluated potential moderators, such as disorder subtype, age group, refractoriness, and augmentation strategies, while sensitivity analyses and publication bias assessments (e.g. Egger test) were performed to ensure robustness.

Results: Overall, glutamatergic medications showed a large effect size in reducing OCRD symptoms (Cohen’s d = −0.80). Specifically for OCD (n=23 trials), a significant mean reduction in Y-BOCS scores (−4.17 points) indicated clinically meaningful improvement. Publication bias was detected in the broader OCRD meta-analysis but not in the OCD-specific analysis. Heterogeneity was high across studies, reflecting varied populations and treatment designs. Despite these findings, the certainty of evidence ranged from low to moderate, mandating cautious interpretation.

Conclusions: Glutamatergic interventions appear promising for OCRDs, particularly OCD, where moderate-certainty evidence suggests meaningful symptom improvement. Nevertheless, elevated heterogeneity and signs of publication bias highlight the need for larger, more rigorous trials to confirm optimal dosing parameters and elucidate which patient subsets may benefit most.

Implications for Practice: Clinicians might consider adding or switching to glutamatergic agents for individuals with inadequate response to SSRIs. However, these findings do not warrant unrestrained enthusiasm. Each case should be weighed individually, taking into account possible mild to moderate gastrointestinal side effects (particularly with NAC).

Study Strengths and Limitations: Strengths include the focus on double-blind RCTs, diverse glutamatergic agents, and robust statistical approaches. Limitations comprise high between-study heterogeneity, limited data for less common disorders (e.g., body dysmorphic disorder), and potential publication bias. Additionally, few trials specifically tested novel agents like ketamine.

Future Research: Studies with larger sample sizes, clearly defined outcomes, and detailed dose-response evaluations are needed. Future trials should explore underrepresented OCRDs, such as hoarding disorder, and newer glutamatergic compounds (e.g., troriluzole) to further optimize therapeutic strategies.

Reference: Coelho DRA, Yang C, Suriaga A, et al. Glutamatergic Medications for Obsessive-Compulsive and Related Disorders: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025;8(1):e2452963. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52963

Meta-Analysis: Long Half-Life Phosphodiesterase Inhibitors Reduce HbA1c in Adults with Elevated Baseline Levels

6 Jan, 2025 | 08:00h | UTC

Background: Phosphodiesterase type 5 (PDE5) inhibitors are traditionally used to treat erectile dysfunction and pulmonary arterial hypertension. Recent evidence suggests that PDE5 inhibitors could also be repurposed to lower hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Given the disparity in half-lives among these agents, this meta-analysis focused on whether longer half-life PDE5 inhibitors (tadalafil, PF-00489791) produce a more sustained HbA1c reduction compared to short half-life PDE5 inhibitors (sildenafil, avanafil).

Objective: To evaluate the effect of PDE5 inhibitors on HbA1c levels in individuals with baseline values above 6%, comparing agents with short and long half-lives to assess differential clinical benefits in glycemic control.

Methods: This systematic review and meta-analysis included only randomized controlled trials (RCTs) in which participants received any PDE5 inhibitor for at least four weeks, with control or placebo for comparison. Major databases (Cochrane CENTRAL, PubMed Central, ClinicalTrials.gov, and WHO ICTRP) were searched through September 2024 without language restrictions. Statistical analyses were performed using a random-effects model, reporting mean differences in HbA1c. Secondary outcomes (HOMA-IR, lipid profiles, fasting glucose, and others) were also explored.

Results: Thirteen RCTs were eligible (N=1083). Long half-life agents showed a significant mean reduction of approximately −0.40% in HbA1c (p=0.002) in the overall analysis, whereas short half-life PDE5 inhibitors exhibited no significant change. In more stringent subgroup analyses (≥8 weeks’ duration, exclusive type 2 diabetes, baseline HbA1c ≥6.5%), long half-life PDE5 inhibitors maintained a significant decrease (−0.50%), while short half-life agents paradoxically showed a slight but significant increase (+0.36%, p=0.03). In trials enrolling patients with poorly controlled diabetes (baseline HbA1c near 10%), tadalafil’s HbA1c reductions were considerably larger, aligning with the efficacy of other standard oral antidiabetic medications.

Conclusions: Long half-life PDE5 inhibitors appear to confer meaningful reductions in HbA1c, comparable to established oral antidiabetic agents, particularly in patients whose HbA1c is inadequately controlled. In contrast, short half-life PDE5 inhibitors did not show a consistent benefit and may paradoxically raise HbA1c in certain subgroups, although further large-scale studies are warranted to confirm these findings.

Implications for Practice: Long half-life PDE5 inhibitors could serve as an adjunctive therapy in type 2 diabetes management, especially in individuals with higher baseline HbA1c. Yet, caution is advised given limited data on adverse events and the short duration of most included trials. Physicians should remain prudent until more robust evidence, especially in populations with markedly elevated HbA1c, becomes available.

Study Strengths and Limitations: Strengths include a direct comparison between short and long half-life PDE5 inhibitors in a clinically relevant population, plus systematic subgroup analyses. Limitations involve heterogeneity in trial designs, relatively low baseline HbA1c in most participants, and a lack of long-term follow-up data or major clinical endpoints.

Future Research: Subsequent trials should target populations with poorly controlled diabetes (HbA1c ≥9.0%) and assess longer durations (≥3 months) to capture the full impact of PDE5 inhibitor therapy. A deeper examination of combination regimens, pharmacokinetic optimization, and clinical outcomes like cardiovascular events would further clarify the role of these agents in diabetes care.

Reference: Kim J, Zhao R, Kleinberg LR, Kim K. (2025) “Effect of long and short half-life PDE5 inhibitors on HbA1c levels: a systematic review and meta-analysis.” eClinicalMedicine, 80, 103035. Available at: DOI: http://doi.org/10.1016/j.eclinm.2024.103035

Dose-Response Meta-Analysis: At Least 150 Weekly Minutes of Aerobic Exercise Needed for Significant Waist and Fat Reduction

2 Jan, 2025 | 09:30h | UTC

Background: Elevated body weight and adiposity remain major public health concerns worldwide, with overweight and obesity affecting nearly half of the adult population. Although various guidelines advocate for aerobic exercise as a core strategy in weight management, robust meta-analyses exploring dose-response relationships are scarce.

Objective: To clarify how different doses and intensities of supervised aerobic exercise affect body weight, waist circumference, and body fat in adults with overweight or obesity.

Methods: This systematic review and meta-analysis encompassed 116 randomized clinical trials (RCTs) including a total of 6880 participants (mean [SD] age, 46 [13] years). All studies involved supervised continuous aerobic interventions (e.g., walking or running) for at least 8 weeks. Comparisons were made against sedentary or usual-activity controls. Frequency, duration (minutes per week), and intensity (moderate, vigorous, or combined) of aerobic sessions were extracted.

Results: Across all trials, each additional 30 minutes per week of aerobic exercise was linked to a mean reduction of 0.52 kg in body weight (95% CI, −0.61 to −0.44), 0.56 cm in waist circumference, and 0.37 percentage points in body fat. Body weight and waist circumference showed largely linear decreases with increasing weekly exercise, whereas body fat percentage displayed a pattern suggesting that at least 150 minutes per week may be required to achieve clinically meaningful reductions (>2% reduction in body fat). Aerobic training was generally well tolerated, although a modest increase in mild musculoskeletal complaints was noted (risk difference, 2 more events per 100 participants).

Conclusions: Engaging in up to 300 minutes per week of aerobic exercise was associated with progressively greater benefits for weight control, waist circumference, and body fat. While even small doses yielded modest improvements, these findings suggest that an intensity of at least moderate level and a duration of at least 150 minutes per week may be necessary to achieve clinically important reductions in central obesity and fat percentage.

Implications for Practice: Clinicians managing patients with overweight or obesity can recommend a minimum of 150 minutes per week of moderate-to-vigorous aerobic training to achieve significant anthropometric changes. Gradual progression is essential to balance effectiveness and safety, especially in individuals with musculoskeletal constraints.

Study Strengths and Limitations: Strengths include the large number of RCTs, robust dose-response analyses, and consistent directions of effects. However, high heterogeneity, publication bias for certain fat measures, and limited data on medication use and health-related quality of life in longer trials were noted.

Future Research: Further trials should explore additional subgroup analyses (e.g., older adults, individuals with chronic comorbidities), longer durations of follow-up, and the integration of resistance training to optimize cardiometabolic outcomes.

Reference: Jayedi A, Soltani S, Emadi A, et al. Aerobic Exercise and Weight Loss in Adults: A Systematic Review and Dose-Response Meta-Analysis. JAMA Network Open. 2024;7(12):e2452185. DOI: http://doi.org/10.1001/jamanetworkopen.2024.52185

Systematic Review and Bayesian Meta-Analysis: Higher Protein Delivery May Increase Mortality in Critically Ill Patients

2 Jan, 2025 | 08:30h | UTC

Background: Nutritional guidelines often recommend higher protein doses (approximately 1.2–2.0 g/kg/d) to mitigate muscle loss in critically ill patients. However, recent multicenter trials have raised concerns that elevated protein targets might increase mortality and adversely affect patient-centered outcomes. This study applied a Bayesian approach to synthesize current evidence regarding the effect of higher versus lower protein delivery on mortality, infections, mechanical ventilation duration, and health-related quality of life in critically ill adults.

Objective: To estimate the probability of beneficial or harmful effects of increased protein delivery on clinically important outcomes, with emphasis on quantifying the likelihood of mortality benefit versus risk.

Methods: A systematic review and Bayesian meta-analysis were conducted according to a preregistered protocol (PROSPERO CRD42024546387) and PRISMA 2020 guidelines. Twenty-two randomized controlled trials comparing higher (mean 1.5 g/kg/d) versus lower (mean 0.9 g/kg/d) protein delivery in adult ICU patients were included, ensuring similar energy intake in both groups. A hierarchical random-effects Bayesian model was applied, using vague priors to estimate relative risks for mortality and infections, mean differences for ventilator days, and standardized mean differences for quality of life.

Results: A total of 4,164 patients were analyzed. The posterior probability that higher protein intake increases mortality was 56.4%, compared with a 43.6% probability of any mortality benefit. Probabilities for a clinically relevant (≥5%) mortality decrease were low (22.9%), while the probability of at least a 5% increase reached 32.4%. Infections were slightly more likely with higher protein, although the likelihood of a major detrimental effect remained modest. The probability of a clinically meaningful difference in ventilator days was negligible, suggesting near equivalence for that endpoint. Conversely, quality of life might be negatively impacted by higher protein dosing, although few trials measured this outcome.

Conclusions: Under a Bayesian framework, current evidence suggests that high protein delivery in critically ill patients might pose a meaningful risk of increased mortality. Although a beneficial effect cannot be fully excluded, its probability appears comparatively small. These findings challenge the longstanding assumption that more protein universally translates to better outcomes.

Implications for Practice: Clinicians should exercise caution when aiming for higher protein targets. Individual patient characteristics, such as severity of illness, renal function, and underlying comorbidities, may modulate outcomes. The data support considering a personalized protein prescription rather than routinely pushing intake beyond conventional targets.

Study Strengths and Limitations: Strengths include a robust Bayesian analysis that evaluates probabilities of both benefit and harm across multiple thresholds, as well as the inclusion of recently published large trials. Limitations involve heterogeneity in protein dosing strategies, potential publication bias (indicated by Egger’s test), and limited data on quality of life.

Future Research: Ongoing trials, such as TARGET Protein and REPLENISH, will provide valuable insights into optimal protein dosing, particularly in specific subgroups. Further investigation should explore mechanistic underpinnings of how high protein intake could adversely affect recovery in critically ill patients.

Reference: Heuts S, Lee ZY, Lew CCH, et al. Higher Versus Lower Protein Delivery in Critically Ill Patients: A Systematic Review and Bayesian Meta-Analysis. Critical Care Medicine. December 27, 2024. DOI: http://doi.org/10.1097/CCM.0000000000006562

Meta-analysis: One-day Low-residue Diet Achieves Comparable Bowel Cleansing Compared to Multi-day Regimens

26 Dec, 2024 | 18:21h | UTC

Background: Colorectal cancer remains a leading cause of cancer-related morbidity worldwide, making early detection through colonoscopy essential. Adequate bowel preparation is crucial to maximize mucosal visibility and detect lesions effectively. Although low-residue diets (LRDs) are commonly recommended before colonoscopy, guidelines vary regarding the optimal duration (one day versus multiple days). This systematic review and meta-analysis evaluated whether a one-day LRD regimen is non-inferior to multi-day protocols in achieving satisfactory bowel cleansing and lesion detection.

Objective: To compare the efficacy of 1-day versus >1-day LRD regimens for bowel preparation in adult patients undergoing elective colonoscopy, focusing on bowel cleanliness, polyp detection, and adenoma detection rates.

Methods: A comprehensive search of PubMed, Cochrane Central Register of Controlled Trials, ScienceDirect, Scopus, and ClinicalTrials.gov was conducted for randomized controlled trials (RCTs) comparing 1-day with >1-day LRD regimens. Six RCTs involving 2,469 participants met inclusion criteria. Patients were randomized to either a 1-day LRD (n=1,237) or a multi-day LRD (n=1,232). Adequate bowel preparation was primarily defined by a Boston Bowel Preparation Scale (BBPS) score ≥2 in each segment or total BBPS ≥6. Secondary outcomes included polyp detection rate (PDR), adenoma detection rate (ADR), withdrawal time, cecal intubation rate, and cecal intubation time.

Results: Both groups demonstrated similar rates of adequate bowel preparation (87.2% in the 1-day LRD vs. 87.1% in the multi-day group), with no significant difference (OR=1.03, 95% CI, 0.76–1.41; p=0.84; I2=0%). PDR was likewise comparable (OR=0.91, 95% CI, 0.76–1.09; p=0.29; I2=16%), as was ADR (OR=0.87, 95% CI, 0.71–1.08; p=0.21; I2=0%). Withdrawal time did not differ (MD=–0.01 minutes, 95% CI, –0.25 to 0.24; p=0.97; I2=63%), and cecal intubation parameters were also statistically similar. Across studies, the pooled mean global BBPS revealed minimal difference (MD=0.16, 95% CI, –0.02 to 0.34; p=0.08; I2=15%), confirming the non-inferiority of a shorter LRD protocol.

Conclusions: A one-day LRD achieves bowel cleansing outcomes comparable to those of multi-day LRDs, without compromising polyp or adenoma detection. This shorter regimen may help optimize patient adherence, reduce dietary restriction burden, and simplify procedural logistics, especially for busy endoscopy practices.

Implications for Practice: Adopting a 1-day LRD can streamline preparation, improve patient satisfaction, and maintain high-quality visualization. Clinicians should weigh individual patient factors such as chronic constipation or comorbidities but may generally favor a shorter dietary restriction period to enhance compliance and comfort.

Study Strengths and Limitations: This meta-analysis included only RCTs, strengthening its internal validity. Heterogeneity for primary outcomes was minimal. However, the included trials employed varied dietary protocols and bowel preparation solutions. Additionally, some studies lacked uniform reporting of cecal intubation endpoints, limiting direct comparisons. Future investigations with standardized outcome measures could offer more definitive guidance.

Future Research: Further large-scale RCTs should assess cost-effectiveness, patient-reported outcomes, and LRD composition in specific populations. Identifying optimal dietary instructions for individuals with slower colonic transit or specific nutritional needs would refine colonoscopy preparation guidelines and potentially increase detection of precancerous lesions.

Reference: Putri RD, et al. One-day low-residue diet is equally effective as the multiple-day low-residue diet in achieving adequate bowel cleansing: a meta-analysis of randomized controlled trials. Clinical Endoscopy. 2024. DOI: https://doi.org/10.5946/ce.2024.061

Meta-analysis: Incidence Rate Difference of Adverse Events from Canabinoids in Middle-Aged and Older Adults

25 Dec, 2024 | 12:19h | UTC

Background: Growing evidence suggests that cannabinoid-based medicines (CBMs) are increasingly prescribed to individuals aged 50 years and above for various clinical conditions. While these agents may offer therapeutic benefits, questions remain about the incidence of adverse events (AEs), particularly in older adults with multiple comorbidities. This systematic review and meta-analysis aims to quantify the incidence rate difference (IRD) of AEs and determine whether weekly doses of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are associated with any dose-dependent increase in risk.

Objective: To evaluate whether adults aged ≥50 years exposed to CBMs, including THC-alone formulations and THC combined with CBD, experience a higher incidence of AEs than controls, and to assess how variations in weekly THC and CBD doses might affect AE rates.

Methods: Researchers searched MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library, and ClinicalTrials.gov from January 1, 1990, to June 12, 2023. Randomized clinical trials involving middle-aged and older adults (mean age ≥50 years) using medicinal CBMs for all indications were included. Data on common and serious AEs, withdrawals, and deaths were extracted and pooled using a random-effects model. Further meta-regression analyses examined THC and CBD weekly doses as predictors of AEs in THC-only and THC:CBD trials.

Results: Fifty-eight randomized clinical trials (n=6611) met inclusion criteria, with 3450 participants receiving CBMs. Compared to controls, individuals on THC-alone experienced significantly higher incidence of dizziness, somnolence, impaired coordination, dissociative symptoms, and dry mouth, often in a dose-dependent manner. Similarly, THC:CBD combinations increased nausea, vomiting, fatigue, dizziness, and disorientation. The incidence of serious AEs, withdrawals, or mortality did not differ significantly between CBM and control groups, although neurological or psychiatric side effects were more pronounced with higher THC doses.

Conclusions: THC-containing CBMs can provoke dose-related gastrointestinal, neurological, and psychiatric adverse events, posing additional risks in older adults susceptible to falls and cognitive disturbances. However, the meta-analysis found no significant increases in serious AEs or deaths. Clinicians should weigh potential benefits against the likelihood of common side effects, especially when prescribing higher THC doses or combining cannabinoids with other medications frequently used by older patients.

Implications for Practice:

Physicians should exercise caution when initiating or escalating THC-based therapies in middle-aged and older adults, monitoring for neurological or psychiatric AEs.
Using lower THC doses, titrating gradually, and adding CBD may mitigate some side effects.
Though severe AEs are uncommon, vigilance is warranted in individuals with complex medication regimens.

Study Strengths and Limitations:

Strength: This review merges diverse clinical conditions and provides a comprehensive assessment of THC vs. THC:CBD. Its large pooled population allows for more precise IRD estimates.
Limitation: Short treatment durations in many trials limit understanding of long-term toxicity, and some studies lacked rigorous reporting of randomization and outcome measures, potentially introducing bias.

Future Research:

Longer-duration trials focused on older populations are needed to clarify chronic safety profiles.
Studies exploring drug-drug interactions between CBMs and medications commonly prescribed to older adults will further elucidate real-world tolerability.

Reference: Velayudhan L, Pisani S, Dugonjic M, McGoohan K, Bhattacharyya S. Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference. Age and Ageing. 2024;53(11):afae261. DOI: https://doi.org/10.1093/ageing/afae261

Bayesian Network Meta-Analysis: Chlorpromazine IV/IM Emerges as a Top Choice for Acute Migraine Relief in the ED

25 Dec, 2024 | 11:18h | UTC

Background: Acute migraine is a prevalent cause of emergency department (ED) visits, necessitating prompt pain control. Although numerous drugs are available, there is debate about the most effective and safest options. Traditional pairwise meta-analyses fail to capture all treatment comparisons in a single framework, making network meta-analyses, particularly Bayesian, an appealing approach to inform clinical decision-making.

Objective: This systematic review and Bayesian network meta-analysis aimed to compare multiple pharmacologic therapies—single agents or combinations—for acute migraine relief in adults presenting to the ED. The goal was to identify those most likely to achieve adequate pain relief, reduce rescue medication use, and minimize significant adverse reactions.

Methods: The authors searched MEDLINE, Embase, and Web of Science from inception to February 9, 2024, for randomized controlled trials comparing any pharmacologic therapy to another or to placebo in ED patients with migraine. Four primary outcomes were analyzed: (1) adequate pain relief at two hours, (2) change in pain intensity at one hour, (3) need for rescue drug at two hours, and (4) significant adverse reaction (eg, sedation, akathisia, hypotension).

Results: Twenty-four to twenty-seven trials contributed to each outcome network. Chlorpromazine IV/IM was ranked highest for adequate pain relief (SUCRA=87.3%) and also significantly reduced the need for rescue medication (SUCRA=93.2%). Ibuprofen IV and valproate IV emerged among the least effective for pain relief, while dexamethasone IV was the most probable to cause fewer serious adverse reactions (SUCRA=79.5%). However, most comparisons were of low or very low certainty, limiting the strength of the findings.

Conclusions: Chlorpromazine IV/IM appears among the most effective single agents for acute migraine in the ED, although it may carry higher risks of sedation or hypotension. Certain analgesics (eg, ibuprofen IV, valproate IV, and possibly ketorolac IV/IM) demonstrated lower efficacy. Due to variability in trial size, dosing, and participant characteristics, the overall certainty of evidence remains limited.

Implications for Practice: Clinicians may consider parenteral chlorpromazine for rapid migraine relief, balancing its adverse event profile with potential efficacy. Dexamethasone’s lower probability of serious side effects could make it a complementary option. The findings highlight the need for individualized treatment, taking into account patient comorbidities and preferences.

Study Strengths and Limitations: This network meta-analysis offers a broad comparative perspective on diverse pharmacologic interventions for ED-based migraine management. Nonetheless, there is notable heterogeneity in study methodologies, small sample sizes, and sparse direct comparisons for many interventions, all of which reduce certainty in the estimates.

Future Research: Larger, more standardized trials are needed to confirm these results and directly compare drugs like chlorpromazine, prochlorperazine, and metoclopramide-NSAID combinations. Rigorous safety reporting is crucial to clarify adverse reaction risks for various agents, especially those with less available evidence.

Reference: deSouza IS, Anthony N, Thode H Jr, et al. Effectiveness and Safety of Pharmacologic Therapies for Migraine in the Emergency Department: A Systematic Review and Bayesian Network Meta-analysis. Annals of Emergency Medicine. DOI: http://doi.org/10.1016/j.annemergmed.2024.11.004

Network Meta-Analysis: Triplet and Quadruplet Chemotherapy Regimens for Advanced Pancreatic Cancer

22 Dec, 2024 | 17:38h | UTC

Background: Advanced pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival, as most patients present with metastatic or unresectable disease. While gemcitabine monotherapy was the mainstay for decades, subsequent trials found survival gains with multi-agent regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel. However, head-to-head data comparing these regimens are limited. This systematic review and Bayesian network meta-analysis aimed to consolidate available evidence on first-line treatment options, focusing on both efficacy and safety outcomes.

Objective: To compare different chemotherapy regimens for unresectable locally advanced or metastatic PDAC, determining which options confer the greatest benefit in progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity profiles.

Methods: Phase 2–3 randomized controlled trials published since 2000 were searched in PubMed, Cochrane Central, and Embase, and from oncology conference proceedings. Eligible studies enrolled previously untreated patients with advanced PDAC, examining at least one regimen containing gemcitabine, fluorouracil, oxaliplatin, irinotecan, nab-paclitaxel, or liposomal irinotecan. Hazard ratios (HRs) and odds ratios (ORs) were computed within a Bayesian framework, ranking therapies using surface under the cumulative ranking curves. Risk of bias was assessed with Cochrane’s RoB 2 tool; evidence certainty was appraised using GRADE.

Results: Seventy-nine trials (22,168 patients) were included. PFS analysis showed gemcitabine plus nab-paclitaxel alternating FOLFOX (HR 0.32), PAXG (0.35), and NALIRIFOX (0.43) offered the highest benefit versus gemcitabine alone, followed by FOLFIRINOX (0.55) and gemcitabine plus nab-paclitaxel (0.62). For OS, the top three regimens were PAXG (HR 0.40), gemcitabine plus nab-paclitaxel alternating FOLFOX (0.46), and NALIRIFOX (0.56), with FOLFIRINOX (0.66) and gemcitabine plus nab-paclitaxel (0.67) close behind. NALIRIFOX demonstrated relatively lower rates of hematologic toxicity compared with FOLFIRINOX and gemcitabine plus nab-paclitaxel, although diarrhea and neuropathy remained frequent across most multi-drug regimens. Overall, the certainty of evidence was low, largely because of indirect comparisons and high heterogeneity among trials.

Conclusions: Among triplet options, NALIRIFOX and FOLFIRINOX appear most favorable for patients who can tolerate intensified therapy, with gemcitabine plus nab-paclitaxel remaining a viable option for less fit patients. Quadruplet regimens, either administered concurrently or sequentially, show promising efficacy but warrant validation in phase 3 trials.

Implications for Practice: Clinical decision-making should balance potential survival benefits with toxicity, patient performance status, and cost-effectiveness considerations. While more intensive combinations can prolong survival, adverse effects and patient quality of life must be carefully monitored.

Study Strengths and Limitations: This is the largest systematic review and network meta-analysis to date in this setting, synthesizing 79 trials. Nevertheless, the evidence base is limited by phase 2 studies, inconsistent reporting of toxicities, and relatively few direct head-to-head comparisons. Most trials lacked central radiographic review.

Future Research: Prospective phase 3 trials evaluating quadruplet or sequential regimens are needed. Additional biomarker-driven strategies, personalized chemotherapy scheduling, and earlier integration of palliative care may also help enhance survival and preserve quality of life in this population.

Reference: Mastrantoni L, Chiaravalli M, Spring A, et al. Comparison of first-line chemotherapy regimens in unresectable locally advanced or metastatic pancreatic cancer: a systematic review and Bayesian network meta-analysis. The Lancet Oncology. 2024;25(12). DOI: http://doi.org/10.1016/S1470-2045(24)00511-4

Meta-Analysis: Endovascular Therapy for Vertebrobasilar Occlusion Improves Functional Outcomes

19 Dec, 2024 | 22:56h | UTC

Background: Acute vertebrobasilar artery occlusion (VBAO) is associated with high mortality and severe neurological deficits. Previous randomized trials of endovascular therapy (EVT) for VBAO have shown inconsistent results, leaving uncertainty about its efficacy across different patient subgroups.

Objective: To determine whether EVT confers improved 90-day functional outcomes compared with standard medical therapy alone in patients with acute VBAO and to explore treatment effect heterogeneity in prespecified subgroups.

Methods: This individual patient data meta-analysis included all four major randomized controlled trials (ATTENTION, BAOCHE, BASICS, BEST) that enrolled patients with VBAO treated within 24 hours of estimated onset. Participants received either EVT or best medical therapy. The primary outcome was a favorable functional status at 90 days (modified Rankin Scale [mRS] score 0–3). Secondary outcomes included functional independence (mRS 0–2), distribution of mRS scores (shift analysis), symptomatic intracranial hemorrhage (sICH), and all-cause mortality at 90 days.

Results: Among 988 patients (556 EVT; 432 control), median age 67 years, EVT significantly increased the proportion achieving mRS 0–3 (45% vs 30%; adjusted odds ratio [aOR] 2.41, 95% CI 1.78–3.26) and mRS 0–2 (35% vs 21%; aOR 2.52, 95% CI 1.82–3.48). EVT improved the overall distribution of functional outcomes (aOR for mRS shift 2.09, 95% CI 1.61–2.71) and reduced 90-day mortality (36% vs 45%; aOR 0.60, 95% CI 0.45–0.80). Although sICH was more common with EVT (5% vs <1%; aOR 11.98, 95% CI 2.82–50.81), the net clinical benefit remained strongly in favor of EVT. Subgroup analyses showed broadly consistent benefit, though the advantage was uncertain for patients with mild baseline severity (NIHSS <10).

Conclusions: EVT for acute VBAO significantly improves functional outcomes and reduces mortality despite a higher sICH risk. These results support EVT as a standard consideration in appropriately selected patients with moderate-to-severe VBAO. The benefit’s magnitude is comparable to that seen in anterior circulation large vessel occlusions, although caution is advised in mild cases and those with extensive baseline infarction.

Implications for Practice: Clinicians should consider EVT for most patients presenting with acute VBAO. While sICH risk is increased, the substantial improvements in function and survival justify its use in suitable candidates. Careful imaging and clinical assessment remain critical for optimal patient selection.

Study Strengths and Limitations: Strengths include a pooled individual patient dataset from all major VBAO EVT trials, allowing detailed subgroup analyses. Limitations involve early trial termination, underrepresentation of women, predominance of Asian populations, and exclusion of patients with very mild symptoms or large baseline infarcts, potentially limiting generalizability.

Future Research: Further trials are needed to define EVT’s role in patients with mild symptoms, isolated vertebral occlusion, large infarcts, or those presenting beyond 24 hours. Additional studies should assess real-world applicability and diverse patient populations.

Reference: Nogueira RG, et al. Endovascular therapy for acute vertebrobasilar occlusion (VERITAS): a systematic review and individual patient data meta-analysis. DOI: http://doi.org/10.1016/S0140-6736(24)01820-8

Meta-analysis: Low/Moderate-Intensity Statins with Ezetimibe May Offer Better LDL-C Reduction and Safety over High-Intensity Statins

24 Nov, 2024 | 20:01h | UTC

Background: Despite widespread use of high-intensity statin therapy, achieving target LDL-C levels and reducing cardiovascular events remain challenging in patients with or at high risk of atherosclerotic cardiovascular disease (ASCVD). High-intensity statins can have dose-dependent adverse effects, limiting their tolerability. Combining low/moderate-intensity statins with ezetimibe, a cholesterol absorption inhibitor, may enhance lipid-lowering efficacy with fewer side effects.

Objective: To compare the clinical effectiveness and safety of low/moderate-intensity statins combined with ezetimibe versus high-intensity statin monotherapy in reducing major adverse cardiovascular events (MACEs) and lowering LDL-C levels.

Methods: A systematic review and meta-analysis were conducted according to PRISMA guidelines. Fifteen studies (6 randomized controlled trials [RCTs] and 9 observational studies) encompassing 251,450 participants were included. The primary outcome was a composite of cardiovascular death or major cardiovascular events. Secondary outcomes included lipid-lowering efficacy and safety measures such as muscle-related adverse events and liver enzyme elevations.

Results: Observational studies indicated that combination therapy was associated with lower rates of the primary composite outcome (HR = 0.76; 95% CI [0.73, 0.80]), cardiovascular death (HR = 0.80; 95% CI [0.74, 0.88]), all-cause death (HR = 0.84; 95% CI [0.78, 0.91]), and non-fatal stroke (HR = 0.81; 95% CI [0.75, 0.87]). RCTs showed that combination therapy resulted in a greater number of patients achieving LDL-C levels < 70 mg/dL (RR = 1.27; 95% CI [1.21, 1.34]) and significant reductions in LDL-C (MD = –7.95 mg/dL; 95% CI [–10.02, –5.89]) and total cholesterol (MD = –26.77 mg/dL; 95% CI [–27.64, –25.89]). Combination therapy also reduced muscle-related adverse events (RR = 0.52; 95% CI [0.32, 0.85]) and liver enzyme elevations (RR = 0.51; 95% CI [0.29, 0.89]) in RCTs.

Conclusions: Combining low/moderate-intensity statins with ezetimibe may offer superior lipid-lowering effects and better safety profiles compared to high-intensity statin monotherapy. While observational studies suggest improved clinical outcomes, these findings need confirmation from large-scale, long-term RCTs.

Implications for Practice: The combination therapy could be a viable option for patients intolerant to high-intensity statins or those requiring additional LDL-C lowering to reach target levels. However, clinicians should interpret these potential benefits cautiously due to reliance on observational data for clinical outcomes and the lack of robust RCT evidence.

Study Strengths and Limitations: Strengths include a comprehensive search strategy and a large patient population. Limitations involve heavy reliance on observational studies for clinical outcomes.

Future Research: Large, well-designed RCTs with longer follow-up periods are needed to confirm the clinical benefits and safety of the combination therapy over high-intensity statin monotherapy across diverse populations.

Reference: Sydhom P, et al. The clinical effectiveness and safety of low/moderate-intensity statins & ezetimibe combination therapy vs. high-intensity statin monotherapy: a systematic review and meta-analysis. BMC Cardiovascular Disorders. 2024; DOI: https://doi.org/10.1186/s12872-024-04144-y

Meta-analysis: Urea May be Effective for the Treatment of SIADH-Induced Hyponatremia

15 Nov, 2024 | 14:01h | UTC

Background: Hyponatremia, defined as a serum sodium level below 135 mEq/L, is the most common electrolyte disorder in clinical practice, associated with increased mortality and prolonged hospital stays. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a frequent cause of euvolemic hyponatremia, particularly among hospitalized patients. Traditional treatments like fluid restriction and hypertonic saline have limitations, and guidelines are inconsistent regarding their use. Urea, an osmotic diuretic, has been proposed as an alternative therapy but is underutilized due to concerns about efficacy, safety, and patient tolerability.

Objective: To evaluate the effectiveness and safety of urea in treating hyponatremia caused by SIADH.

Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Searches of MEDLINE, EMBASE, Cochrane CENTRAL, and Google Scholar up to November 2023 identified studies involving patients with SIADH-related hyponatremia treated with oral or nasogastric urea. Inclusion criteria encompassed clinical trials and observational studies reporting outcomes on serum sodium levels, symptom resolution, or adverse effects.

Results: Sixteen observational studies involving 518 patients (430 treated with urea) met inclusion criteria. Urea treatment significantly increased serum sodium levels (mean difference [MD], 9.21 mEq/L [95% CI, 7.36-11.06]; P < 0.01) despite high heterogeneity (I² = 89%). Subgroup analyses showed significant sodium increases at 24 hours and at 2, 3, 5, 7, 14 days, and 1 year post-treatment. Patients with severe hyponatremia (<120 mEq/L) experienced greater sodium increases (MD, 18.04 mEq/L [95% CI, 13.68-22.39]) compared to those with moderate (120-129 mEq/L) or mild (130-135 mEq/L) hyponatremia. Urea’s efficacy was comparable to fluid restriction (MD, 0.81 mEq/L [95% CI, –0.93 to 2.55]; P = 0.4) and vaptans (MD, –2.43 mEq/L [95% CI, –6.31 to 1.45]; P = 0.2), and superior to no treatment (MD, 7.99 mEq/L [95% CI, 6.25-9.72]; P < 0.01). Adverse events were minor; poor palatability was the most common complaint.

Conclusions: Urea is an effective and safe treatment for SIADH-induced hyponatremia, significantly increasing serum sodium levels, particularly in severe cases. It offers a viable alternative to fluid restriction and vaptans with minimal adverse effects.

Implications for Practice: Urea should be considered a valuable treatment option for SIADH-induced hyponatremia, especially in resource-limited settings or when other therapies are contraindicated or poorly tolerated. Its cost-effectiveness and ease of administration may improve patient outcomes and reduce healthcare costs.

Study Strengths and Limitations: Strengths include a comprehensive search strategy and inclusion of diverse studies across multiple settings. Limitations are the reliance on observational studies due to the absence of randomized controlled trials, significant heterogeneity among studies, and the potential for publication bias.

Future Research: Randomized controlled trials are necessary to confirm urea’s efficacy and safety, establish standardized dosing regimens, and develop strategies to enhance palatability and patient adherence.

Reference: Chander S, et al. Urea to Treat Hyponatremia Due to Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Systematic Review and Meta-Analysis. American Journal of Kidney Diseases. 2024. DOI: http://doi.org/10.1053/j.ajkd.2024.07.011

Meta-Analysis: Spinal Cord Stimulation May Be Effective for Chronic Back and Leg Pain

15 Nov, 2024 | 13:43h | UTC

Background: Chronic back and leg pain causes significant disability worldwide. Spinal cord stimulation (SCS) offers treatment for patients unresponsive to conventional medical management (CMM). The comparative efficacy of conventional and novel SCS forms versus CMM is debated, requiring thorough evaluation.

Objective: To evaluate the efficacy of conventional and novel SCS therapies compared with CMM in adults with chronic back or leg pain who had not previously used SCS.

Methods: A systematic review and Bayesian network meta-analysis per PRISMA guidelines were performed. MEDLINE, Embase, and Cochrane Library were searched up to September 2, 2022. Thirteen RCTs with 1,561 patients were included. Interventions were conventional SCS, novel SCS modalities (e.g., high-frequency, burst stimulation), and CMM. Primary outcomes were pain intensity (visual analog scale) and responder rates (≥50% pain relief) in back or leg. Secondary outcomes were quality of life (EQ-5D index) and functional disability (Oswestry Disability Index).

Results: At 6 months, both conventional and novel SCS were superior to CMM in five of six outcomes. For back pain responder rates, conventional SCS had an OR of 3.00 (95% CrI, 1.49–6.72) and novel SCS had an OR of 8.76 (95% CrI, 3.84–22.31) versus CMM. Pain intensity in the back decreased significantly with conventional SCS (MD, –1.17; 95% CrI, –1.64 to –0.70) and novel SCS (MD, –2.34; 95% CrI, –2.96 to –1.73). Leg pain intensity also decreased significantly with conventional SCS (MD, –2.89; 95% CrI, –4.03 to –1.81) and novel SCS (MD, –4.01; 95% CrI, –5.31 to –2.75) compared to CMM. Quality of life improved with both SCS therapies (conventional SCS MD, 0.15; 95% CrI, 0.09–0.21; novel SCS MD, 0.17; 95% CrI, 0.13–0.21). Functional disability improved significantly with conventional SCS (MD, –7.10; 95% CrI, –10.91 to –3.36).

Conclusions: Both conventional and novel SCS therapies are associated with significant improvements in pain relief, quality of life, and functional ability compared with CMM in patients with chronic back and leg pain at 6 months.

Implications for Practice: The results support integrating SCS therapies into clinical practice for patients with chronic back and leg pain unresponsive to CMM.

Study Strengths and Limitations: Strengths include inclusion of recent RCTs and use of Bayesian network meta-analysis, allowing comprehensive evidence synthesis with both direct and indirect comparisons, enhancing reliability. Limitations involve potential biases due to challenges in blinding participants and assessors, as patients can perceive whether a device is active. Heterogeneity among studies in patient populations and interventions may affect generalizability. Inability to include long-term efficacy data due to crossover in many trials limits understanding of sustained outcomes.

Future Research: Long-term RCTs are needed to assess sustained efficacy and safety of SCS therapies. Future studies should compare different SCS modalities directly and identify patient subgroups most likely to benefit.

Reference: Huygen FJPM, et al. Spinal Cord Stimulation vs Medical Management for Chronic Back and Leg Pain: A Systematic Review and Network Meta-Analysis. JAMA Network Open. 2024; doi: http://doi.org/10.1001/jamanetworkopen.2024.44608

Cochrane: Galantamine Improves Cognitive Function in Alzheimer’s Disease but Not in Mild Cognitive Impairment

10 Nov, 2024 | 13:40h | UTC

Background: Alzheimer’s disease is the leading cause of dementia. While incurable, symptomatic treatments like galantamine, a cholinesterase inhibitor, are approved for Alzheimer’s disease.

Objective: To assess the clinical effects and adverse events of galantamine in people with Alzheimer’s disease or mild cognitive impairment.

Methods: A systematic review of double-blind, parallel-group, randomized controlled trials comparing oral galantamine with placebo in people with Alzheimer’s disease or mild cognitive impairment. Outcomes included cognitive function, global function, activities of daily living, functional disability, behavioral function, and adverse events.

Results: Twenty-one studies with 10,990 participants were included. Treatment durations ranged from eight weeks to two years. In Alzheimer’s disease, galantamine at 16 mg to 24 mg/day for six months significantly improved cognitive function compared to placebo (MD –2.86 on ADAS-cog, 95% CI –3.29 to –2.43; six studies, 3049 participants; high-certainty evidence). Functional disability improved (MD 2.12 on DAD, 95% CI 0.75 to 3.49; three studies, 1275 participants), as did behavioral function (MD –1.63 on NPI, 95% CI –3.07 to –0.20; two studies, 1043 participants). Participants receiving galantamine had higher rates of premature discontinuation (OR 1.41, 95% CI 1.19 to 1.68; six studies, 3336 participants) and nausea (OR 2.89, 95% CI 2.40 to 3.49; seven studies, 3616 participants). Death rates were reduced in the galantamine groups (OR 0.56, 95% CI 0.33 to 0.96; six studies, 3493 participants).

In mild cognitive impairment, galantamine did not improve cognitive function (MD –0.21 on ADAS-cog/MCI, 95% CI –0.78 to 0.37; two studies, 1901 participants; low-certainty evidence) or activities of daily living (MD 0.30 on ADCS-ADL-MCI, 95% CI –0.26 to 0.86). Adverse events and discontinuation rates were higher with galantamine.

Conclusions: Galantamine at 16 mg to 24 mg/day improves cognitive function, functional ability, and behavior over six months in Alzheimer’s disease, with clinically meaningful changes. Gastrointestinal adverse events are common and may limit tolerability. Galantamine is not effective in mild cognitive impairment.

Implications for Practice: Galantamine may be considered for symptomatic treatment in mild to moderate Alzheimer’s disease to improve cognition, daily functioning, and behavior, weighing the benefits against the increased risk of gastrointestinal adverse events. It is not recommended for people with mild cognitive impairment.

Study Strengths and Limitations: Strengths include a large sample size and high-certainty evidence for key outcomes in Alzheimer’s disease. Limitations involve high attrition rates and potential bias due to higher discontinuation in galantamine groups. The evidence for mild cognitive impairment is of low certainty due to risk of bias and imprecision.

Future Research: Further trials are needed in more diverse clinical populations, including those with severe Alzheimer’s disease and over longer durations. Research should focus on quality of life outcomes, cost-effectiveness, and subgroup analyses based on individual-level factors.

Reference: Lim AWY, et al. Galantamine for dementia due to Alzheimer’s disease and mild cognitive impairment. Cochrane Database of Systematic Reviews 2024. DOI: http://doi.org/10.1002/14651858.CD001747.pub4

Meta-analysis: Hemodiafiltration Reduces Mortality in Kidney Failure Patients Compared to Hemodialysis

7 Nov, 2024 | 12:19h | UTC

Background: Kidney failure patients undergoing hemodialysis face high mortality rates, with approximately 50% dying within five years of initiating treatment. Hemodiafiltration, a convection-based therapy that removes a broader spectrum of uraemic toxins, has been proposed to improve survival outcomes. Previous studies have shown mixed results regarding its efficacy, and uncertainties remain about its effects on specific patient subgroups, dose-response relationships with convection volume, and cause-specific mortality.

Objective: To compare the effects of online hemodiafiltration versus standard hemodialysis on all-cause and cause-specific mortality in patients with kidney failure.

Methods: An individual patient data meta-analysis of five randomized controlled trials was conducted, encompassing 4,153 patients (2,083 on hemodiafiltration and 2,070 on hemodialysis). Databases including MEDLINE, Embase, and the Cochrane Central Register were searched up to July 17, 2024. The primary outcome was all-cause mortality. Subgroup analyses based on patient characteristics and dose–response analyses using convection volume were performed.

Results: Over a median follow-up of 30 months, all-cause mortality occurred in 477 patients (23.3%) receiving hemodiafiltration and 559 patients (27.0%) receiving hemodialysis. Hemodiafiltration significantly reduced all-cause mortality (hazard ratio [HR] 0.84, 95% CI 0.74–0.95) compared to hemodialysis. Cardiovascular mortality was also lower in the hemodiafiltration group (HR 0.78, 95% CI 0.64–0.96), particularly deaths due to cardiac causes (HR 0.67, 95% CI 0.50–0.89). No differential effects were observed across predefined patient subgroups. A dose-dependent relationship was found between higher convection volumes and reduced mortality risk.

Conclusions: Hemodiafiltration significantly reduces all-cause and cardiovascular mortality in patients with kidney failure compared to standard hemodialysis. The mortality benefit is dose-dependent, with higher convection volumes associated with greater risk reductions.

Implications for Practice: These findings support the adoption of online hemodiafiltration as a superior alternative to conventional hemodialysis. Clinicians should consider implementing high-dose hemodiafiltration to improve survival outcomes in patients with kidney failure.

Study Strengths and Limitations: Strengths include the large sample size and use of individual patient data, allowing for comprehensive subgroup and dose–response analyses. Limitations involve heterogeneity among the included studies and potential biases due to open-label designs. The lack of blinding may have influenced outcome reporting.

Future Research: Further studies are needed to evaluate the long-term benefits of hemodiafiltration on patient-reported outcomes, cost-effectiveness, and environmental impacts. Investigations into the optimal convection volumes and the mechanisms underlying the observed mortality reductions are also warranted.

Reference: Vernooij RWM, Hockham C, Strippoli G, Green S, Hegbrant J, Davenport A, et al. Hemodiafiltration versus hemodialysis for kidney failure: an individual patient data meta-analysis of randomised controlled trials. The Lancet. 2024 Oct 25;404(10464). DOI: http://doi.org/10.1016/S0140-6736(24)01859-2

RCT: ICS-Formoterol and ICS-SABA Reduce Severe Asthma Exacerbations Compared With SABA Alone

28 Oct, 2024 | 18:12h | UTC

Background: Asthma affects millions worldwide and is managed using inhaled relievers to alleviate acute symptoms. While short-acting β agonists (SABA) are commonly used, combining inhaled corticosteroids (ICS) with SABA or formoterol may enhance outcomes. Recent guidelines recommend ICS-formoterol as the preferred reliever, but the optimal choice remains uncertain, especially following the recent FDA approval of ICS-SABA.

Objective: To compare the efficacy and safety of SABA alone, ICS-SABA, and ICS-formoterol as reliever therapies in asthma.

Methods: This systematic review and network meta-analysis included 27 randomized controlled trials involving 50,496 adult and pediatric asthma patients. Trials compared SABA alone, ICS-SABA, and ICS-formoterol as reliever therapies, ensuring similar maintenance treatments across groups. Outcomes assessed were severe asthma exacerbations, asthma symptom control (Asthma Control Questionnaire-5 [ACQ-5]), asthma-related quality of life (Asthma Quality of Life Questionnaire [AQLQ]), adverse events, and mortality.

Results: Compared with SABA alone, both ICS-containing relievers significantly reduced severe exacerbations:

ICS-formoterol: Risk ratio (RR) 0.65 (95% CI, 0.60–0.72); risk difference (RD) –10.3% (95% CI, –11.8% to –8.3%).
ICS-SABA: RR 0.84 (95% CI, 0.73–0.95); RD –4.7% (95% CI, –8.0% to –1.5%).

Compared with ICS-SABA, ICS-formoterol further reduced severe exacerbations (RR 0.78; RD –5.5%). Both ICS-containing relievers modestly improved asthma symptom control compared with SABA alone. No increase in adverse events was observed with either ICS-containing therapy.

Conclusions: Both ICS-formoterol and ICS-SABA as reliever therapies reduce severe asthma exacerbations and improve symptom control compared with SABA alone, without increasing adverse events. ICS-formoterol may offer additional benefits over ICS-SABA in reducing exacerbations.

Implications for Practice: These findings support the use of ICS-containing reliever therapies over SABA alone in asthma management to reduce severe exacerbations and improve control. ICS-formoterol may be preferred when a greater reduction in exacerbations is desired.

Study Strengths and Limitations: High-certainty evidence strengthens these conclusions, but the lack of direct comparisons between ICS-formoterol and ICS-SABA and limited pediatric data are notable limitations.

Future Research: Direct head-to-head trials comparing ICS-formoterol and ICS-SABA, particularly in pediatric populations, are needed to confirm these findings.

Reference: Rayner DG, Ferri DM, Guyatt GH, et al. Inhaled Reliever Therapies for Asthma: A Systematic Review and Meta-Analysis. JAMA. Published online October 28, 2024. DOI: http://doi.org/10.1001/jama.2024.22700

Psychedelic-Assisted Therapy May Reduce Anxiety and Depression in Patients with Life-Threatening Diseases

20 Oct, 2024 | 18:02h | UTC

Background: Anxiety, depression, and existential distress are prevalent among individuals facing life-threatening illnesses, significantly impacting their quality of life. Traditional treatments often have limited efficacy in this population. Psychedelic-assisted therapy, involving substances like psilocybin and LSD under professional supervision, has been proposed as a potential intervention. However, these substances are illegal in most countries and pose potential risks.

Objective: To assess the benefits and harms of psychedelic-assisted therapy compared to placebo or active comparators in treating anxiety, depression, and existential distress in people with life-threatening diseases.

Methods: This Cochrane systematic review included six randomized controlled trials conducted in the USA and Switzerland between 2011 and 2022. A total of 149 participants (140 analyzed), aged 36 to 64 years with life-threatening illnesses (e.g., cancer), were randomized to receive psychedelic-assisted therapy using classical psychedelics (psilocybin or LSD) or MDMA. Interventions included preparatory sessions, the psychedelic experience, and integration sessions. Comparators were active placebos (e.g., low-dose psychedelic or niacin) or placebo. Primary outcomes were anxiety, depression, and existential distress measured 1 to 12 weeks post-intervention.

Results: Psychedelic-assisted therapy with classical psychedelics may reduce anxiety and depression compared to active placebo:

Anxiety: Mean difference (MD) of −8.41 points on the STAI-Trait scale (20–80 range; 95% CI, −12.92 to −3.89; 5 studies, 122 participants; low-certainty evidence).
Depression: MD of −4.92 points on the Beck Depression Inventory (0–63 range; 95% CI, −8.97 to −0.87; 4 studies, 112 participants; low-certainty evidence).

The effect on existential distress was mixed and very uncertain. No treatment-related serious adverse events or grade 3/4 adverse events were reported. Common mild to moderate adverse events included elevated blood pressure, nausea, anxiety, and transient psychotic-like symptoms, which resolved shortly after the sessions.

Conclusions: Psychedelic-assisted therapy with classical psychedelics may reduce symptoms of anxiety and depression in patients with life-threatening diseases, but the evidence is of low certainty due to methodological limitations and small sample sizes. The effects of MDMA-assisted therapy are very uncertain.

Implications for Practice: While findings are promising, clinicians should exercise caution due to the low certainty of evidence and legal restrictions surrounding psychedelic substances.

Study Strengths and Limitations: Strengths include randomized designs and standardized therapeutic protocols involving preparation and integration sessions. Limitations are high risk of bias due to unblinding, small sample sizes, potential expectation bias, and cross-over designs with carry-over effects.

Future Research: Larger, well-designed RCTs with rigorous blinding are needed to confirm these findings. Future studies should explore long-term outcomes, diverse patient populations, and strategies to mitigate bias, such as using active placebos and measuring expectancy effects.

Reference: Schipper S, et al. (2024). Psychedelic-assisted therapy for treating anxiety, depression, and existential distress in people with life-threatening diseases. Cochrane Database of Systematic Reviews. DOI: https://doi.org/10.1002/14651858.CD015383.pub2

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