Local anaesthetic to reduce injection pain in patients who are prescribed intramuscular benzathine penicillin G: a systematic review and meta-analysis.

Background: Three to 4-weekly intramuscular injections of benzathine penicillin G (BPG) for a prolonged period (e.g., 10 years, until age 40 years, or lifelong) are recommended for preventing group A streptococcal infections that cause recurrent acute rheumatic fever (ARF) and potential progression to rheumatic heart disease (RHD). The duration of treatment, frequency and local pain associated with BPG injections may lead to reduced compliance. Shorter courses of BPG are recommended for the treatment of syphilis and Streptococcal infections. We aimed to assess the effects of local anaesthesia in reducing injection pain in patients who are being treated with BPG. Methods: In this systematic review and meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Conference Proceedings Citation Index-Science and LILACS from database inception up to May 4, 2024, and performed additional searches for grey literature. Randomised controlled trials comparing BPG vs. BPG administered alongside local anaesthetics were included. Randomized controlled trials using BPG, irrespectively of indication, and testing any local anaesthetic agent for pain alleviation were considered eligible. We applied GRADE to assess the quality of evidence. Summary data were extracted from included trials. The primary outcome was injection pain, assessed through mean differences. A random-effects model was utilized to account for study heterogeneity. This study is registered with PROSPERO, CRD42022342437. Findings: Database searches identified a total of 3958 records, and 3 additional records were retrieved from grey literature searches. After removal of duplicates, screening of abstracts and full-text review, eight trials were included, combining a total of 489 patients (151 patients with RHD). Immediate pain level, as reported by patients, was of high intensity in most studies. Low intensity pain was still reported at 24 h. Administration of lidocaine mixed with BPG was associated with a significant reduction in immediate post-injection pain (mean difference -3.84, 95% confidence interval -6.19 to -1.48, P = 0.0001; 4 studies; I2 = 98%; GRADE: moderate quality), pain at 5 min (mean difference -2.85, 95% CI confidence interval -3.78 to -1.92, P < 0.0001; 1 study; GRADE: moderate quality), and pain at 20 min (mean difference -1.85, 95% confidence interval -2.61 to -1.09, P < 0.0001; 1 study; GRADE: moderate quality) on a 1 to 10 scale. One study assessed lidocaine cream applied to the skin prior to BPG injection and showed no significant reduction in injection pain (mean difference = -0.54, 95% CI confidence interval -1.17 to 0.09, P = 0.13; 1 study; GRADE: low quality). Mepivacaine mixed with BPG in patients with syphilis showed a significant reduction of immediate post-injection pain (mean difference -2.19, 95% CI confidence interval -2.49 to -1.89, P < 0.0001; 1 study; GRADE: moderate quality). Two studies assessed procaine mixed with BPG and reported: lower immediate pain levels or pain assessed at 1 h (mean difference and 95% CI confidence intervals not provided, P = 0.001 and P = 0.008, respectively; 1 study; GRADE: low quality), or less immediate pain and pain at 24 h on the buttock injected with procaine mixed with BPG (mean difference and 95% CI confidence intervals not provided, P < 0.001 for both; 1 study; Grade: low quality). No severe adverse reactions were reported. Interpretation: In patients receiving intramuscular BPG injections, moderate quality quantitative evidence suggests that BPG injections diluted with lidocaine or mepivacaine may improve post-injection pain scores compared to BPG injections diluted with sterile water. Procaine may also have a benefit, but quality of evidence was lower. Most studies included small patient samples and assessed pain levels at different timepoints. Due to insufficient data we were not able to assess the impact of injection volume, and local anaesthetics' dose on pain intensity and duration of pain relief. Funding: WHO.

Alcohol consumption and heart failure: a dose-response meta-analysis.

OBJECTIVES: This is a protocol for a Cochrane Review (prototype). The objectives are as follows: Main objective To assess the effects of alcohol consumption on the progression to symptomatic (stage C) heart failure in people at risk for heart failure (stage A) or in people with pre-heart failure (stage B). Secondary objectives To assess the effects of alcohol consumption on progression of left ventricular dysfunction in people with stage A or stage B heart failure. We will assess the effect of alcohol consumption on the development of heart failure with reduced ejection fraction, mildly reduced ejection fraction, and preserved ejection fraction. We also aim to evaluate the effects of alcohol consumption on the development of symptomatic (stage C) heart failure over the short, medium and long term.

Oral Class I and III antiarrhythmic drugs for maintaining sinus rhythm after catheter ablation of atrial fibrillation.

BACKGROUND: Recurrence of atrial tachyarrhythmias (ATa) following catheter ablation for atrial fibrillation (AF) is a common problem. Antiarrhythmic drugs have been used shortly after ablation in an attempt to maintain sinus rhythm, particularly Class I and III agents. However, it still needs to be established if the use of Class I or III antiarrhythmic medications, or both, reduce the risk of recurrence of ATa. OBJECTIVES: To assess the effects of oral Class I and III antiarrhythmic drugs versus control (standard medical therapy without Class I or III antiarrhythmics, or placebo) for maintaining sinus rhythm in people undergoing catheter ablation for AF. SEARCH METHODS: We systematically searched CENTRAL, MEDLINE, Embase, Web of Science Core Collection, and two clinical trial registers without restrictions on language or date to 5 August 2022. SELECTION CRITERIA: We sought published, unpublished, and ongoing parallel-design, randomised controlled trials (RCTs) involving adult participants undergoing ablation for AF, with subsequent comparison of Class I and/or III antiarrhythmic use versus control (standard medical therapy or non-Class I and/or III antiarrhythmic use). DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane and performed meta-analyses with risk ratios (RR) and Peto odds ratios (Peto OR). Our primary outcomes were recurrence of atrial tachyarrhythmias; adverse events: thromboembolic events; adverse events: myocardial infarction; adverse events: new diagnosis of heart failure; and adverse events: requirement for one or more hospitalisations for atrial tachyarrhythmia. Our secondary outcomes were: all-cause mortality; and requirement for one or more repeat ablations. Where possible, we performed comparison analysis by Class I and/or III antiarrhythmic and divided follow-up periods for our primary outcome. We performed comprehensive assessments of risk of bias and certainty of evidence applying the GRADE methodology. MAIN RESULTS: We included nine RCTs involving a total of 3269 participants. Participants were on average 59.3 years old; 71.0% were male; and 72.9% and 27.4% had paroxysmal and persistent AF, respectively. Class I and/or III antiarrhythmics may reduce recurrence of ATa at 0 to 3 months postablation (risk ratio (RR) 0.74, 95% confidence interval (CI) 0.59 to 0.94, 8 trials, 3046 participants, low-certainty evidence) and likely reduce recurrence at > 3 to 6 months, our a priori primary time point (RR 0.85, 95% CI 0.78 to 0.93, 5 trials, 2591 participants, moderate-certainty evidence). Beyond six months the evidence is very uncertain, and the benefit of antiarrhythmics may not persist (RR 1.14, 95% CI 0.84 to 1.55, 4 trials, 2244 participants, very low-certainty evidence). The evidence suggests that Class I and/or III antiarrhythmics may not increase the risk of thromboembolic events, myocardial infarction, all-cause mortality, or requirement for repeat ablation, at 0 to 3, > 3 to 6, and > 6 months (where data were available; low- to very low-certainty evidence). The use of Class I and/or III antiarrhythmics postablation likely reduces hospitalisations for ATa by approximately 57% at 0 to 3 months (RR 0.43, 95% CI 0.28 to 0.64, moderate-certainty evidence). No data were available beyond three months. No data were available on new diagnoses of heart failure. Fewer data were available for Class I and III antiarrhythmics individually. Based on only one and two trials (n = 125 to 309), Class I antiarrhythmics may have little effect on recurrence of ATa at 0 to 3, > 3 to 6, and > 6 months (RR 0.88, 95% CI 0.64 to 1.20, 2 trials, 309 participants; RR 0.54, 95% CI 0.25 to 1.19, 1 trial, 125 participants; RR 0.87, 95% CI 0.57 to 1.32, 1 trial, 125 participants; low-certainty evidence throughout); requirement for hospitalisation for ATa at 0 to 3 months (low-certainty evidence); or requirement for repeat ablation at 0 to 3 months (low-certainty evidence). No data were available for thromboembolic events, myocardial infarction, new diagnosis of heart failure, or all-cause mortality at any time points, or hospitalisation or repeat ablation beyond three months. Class III antiarrhythmics may have little effect on recurrence of ATa at up to 3 months and at > 3 to 6 months (RR 0.76, 95% CI 0.50 to 1.16, 4 trials, 599 participants, low-certainty evidence; RR 0.82, 95% CI 0.62 to 1.09, 2 trials, 318 participants, low-certainty evidence), and beyond 6 months one trial reported a possible increase in recurrence of ATa (RR 1.95, 95% CI 1.29 to 2.94, 1 trial, 112 participants, low-certainty evidence). Class III antiarrhythmics likely reduce hospitalisations for ATa at 0 to 3 months (RR 0.40, 95% CI 0.26 to 0.63, moderate-certainty evidence), and may have little effect on all-cause mortality (low- to very low-certainty evidence). The effect of Class III antiarrhythmics on thromboembolic events and requirement for repeat ablation was uncertain (very low-certainty evidence for both outcomes). No data were available for myocardial infarction or new diagnosis of heart failure at any time point, outcomes other than recurrence beyond 6 months, or for hospitalisation and repeat ablation > 3 to 6 months. We assessed the majority of included trials as at low or unclear risk of bias. One trial reported an error in the randomisation process, raising the potential risk of selection bias; most of the included trials were non-blinded; and two trials were at high risk of attrition bias. AUTHORS' CONCLUSIONS: We found evidence to suggest that the use of Class I and/or III antiarrhythmics up to 3 months after ablation is associated with a reduced recurrence of ATa 0 to 6 months after ablation, which may not persist beyond 6 months, and an immediate reduction in hospitalisation for ATa 0 to 3 months after ablation. The evidence suggests there is no difference in rates of all-cause mortality, thromboembolic events, or myocardial infarction between Class I and/or III antiarrhythmics versus control.