Efficacy of diltiazem 2% rectal gel in the treatment of chronic anal fissure: a retrospective observational study.

OBJECTIVE: The aim of this study is to describe the effectiveness and safety of a magistral formulation of diltiazem 2% rectal gel as a treatment for chronic anal fissure. MATERIAL AND METHODS: A retrospective observational study of all patients that began treatment with diltiazem 2% gel during 2019. The primary endpoint of the study was anal fissure healing. We also looked for differences in effectiveness between those initiating treatment and those who had been previously treated, long-term effectiveness through a 2-year follow-up and frequency of adverse effects. RESULTS: Of the 166 patients included in the study, anal fissure healed in 72.9%. We detected adverse effects in 12 patients, the most common was local irritation. After 2 years of follow-up, 88% of patients did not relapse. CONCLUSION: In this study, use of topical diltiazem 2% has been shown to be effective and safe in the treatment of anal fissure and should be considered as the first line of therapy.

OBJETIVO: El objetivo de este estudio es describir la efectividad y la seguridad de una fórmula magistral de diltiazem 2% gel rectal, como tratamiento de la fisura anal crónica. MATERIAL Y MÉTODOS: Un studio observacional retrospectivo de todos los pacientes que comenzaron a ser tratados con diltiazem 2% gel durante el año 2019. La variable principal del estudio fue la cicatrización de la fisura anal. También se buscaron diferencias de efectividad entre aquellos que iniciaban el tratamiento y los que ya habían sido tratados previamente, efectividad a largo plazo mediante un seguimiento de 2 años y frecuencia de aparición de efectos adversos. RESULTADOS: De los 166 pacientes incluidos en el estudio, el 72,9% cicatrizaron la fisura anal. No detectamos diferencias estadísticamente significativas de efectividad entre los pacientes naive y aquellos que ya habían sido tratados. Detectamos efectos adversos en 12 pacientes, siendo el más frecuente la irritación local. Tras 2 años de seguimiento, el 88% de los pacientes no presentaron ninguna recaída. CONCLUSIÓN: En este estudio, el uso de diltiazem 2% tópico ha mostrado ser efectivo y seguro en el tratamiento de la fisura anal y debería considerarse como primera línea terapéutica.

Comparing the efficacy and safety of different analgesic strategies after open hemorrhoidectomy: a systematic review and network meta-analysis.

PURPOSE: To evaluate the clinical efficacy and safety of different analgesic interventions in the treatment of pain after open hemorrhoidectomy by systematic review and network meta-analysis. METHODS: Randomized controlled trials that met the inclusion criteria in PubMed, Cochrane Library, Embase, Web of Science, Scopus, CNKI, WANFANG DATA, and VIP were searched from the date of database construction to June 28, 2022. RESULTS: Among the 13 randomized controlled trials (RCTs), 731 patients were included in the network meta-analysis. Most interventions are more effective than placebo in relieving postoperative pain. 24 h postoperative Visual Analogue Scale (VAS): glyceryl trinitrate (GTN) (mean difference (MD) - 4.20, 95% CI - 5.35, - 3.05), diltiazem (MD - 1.97, 95% CI - 2.44, - 1.51), botulinum toxin (BT) (MD - 1.50, 95% CI - 2.25, - 0.75), sucralfate (MD - 1.01, 95% CI - 1.53, - 0.49), and electroacupuncture (EA) (MD - 0.45, 95% CI - 0.87, - 0.04). 48 h postoperative VAS: diltiazem (MD - 2.45, 95% CI - 2.74, - 2.15), BT (MD - 2.18, 95% CI - 2.52, - 1.84), and sucralfate (MD - 1.41, 95% CI - 1.85, - 0.97). 7 d postoperative VAS: diltiazem (MD - 2.49, 95% CI - 3.20, - 1.78) and sucralfate (MD - 1.42, 95% CI - 2.00, - 0.85). The first postoperative defecation VAS: EA (MD - 0.70, 95% CI - 0.95, - 0.46). There are few data on intervention safety, and additional high-quality RCTs are expected to study this topic in the future. CONCLUSION: Diltiazem ointment may be the most effective medication for pain relief following open hemorrhoidectomy, and it can dramatically reduce pain within one week of surgery. The second and third recommended medications are BT and sucralfate ointment. GTN has a significant advantage in alleviating pain 24 h after open hemorrhoidectomy, but whether it causes headache is debatable; thus, it should be used with caution. EA's analgesic efficacy is still unknown. There was limited evidence on the safety of the intervention in this study, and it was simply presented statistically.

Comparison of various calcium antagonist on vasospastic angina: a systematic review.

BACKGROUND: Coronary artery vasospasm is an abnormal spasm of coronary arteries that cause transient or complete occlusion without exertion. It causes stable angina to ACS. However, this can be prevented by calcium channel blockers (CCBs) which suppress Ca2+ influx into the vascular muscle cells. Nevertheless, several CCBs adverse effects are harmful for these patients. Selecting the right CCBs would give the best clinical practice. METHOD: The studies were obtained from four major medical databases by various keywords. Inclusion and exclusion criteria were implemented as adult >18 years, observational study, English language and drug of interest. Duplicates were eliminated, and the remaining studies were reviewed. Final full-texts assessment was conducted independently by Newcastle-Ottawa Scale and Revised Cochrane. RESULTS: The search found 1378 articles. However, six studies were selected after implementing the study criteria. Diltiazem was found to decrease angina and increase quality of life until 12th week of treatment; however, some adverse effects include atrioventricular block and recurrent angina up till 4th week were found. Meanwhile, nifedipine was found to decrease vasospastic angina (VSA) by the fourth and eighth weeks of treatment. Nevertheless, it caused excessive drop in BP and increase heart rate by eighth week. In addition, slow-release preparation of both CCBs were found to increase efficacy and compliance. Lastly amlodipine was also found to decrease VSA by 17%±140% and 33% after 6 weeks, but further studies needed. CONCLUSION: Diltiazem, nifedipine and amlodipine are potent in decreasing VSA, however, tailoring specific CCBs adverse reactions to patient condition and the drug preparation would be substantially beneficial for the outcome.

Association between concurrent use of diltiazem and DOACs and risk of bleeding in atrial fibrillation patients.

BACKGROUND: Diltiazem is a commonly used medication in patients with atrial fibrillation (AF) with potential for a drug-drug interaction (DDI) with direct oral anticoagulants (DOACs). We aimed to assess the risk of major bleeding after co-prescription of diltiazem and DOACs among adults with AF. METHODS: We conducted a population-based, nested case-control study in Ontario, Canada. The study population included all patients with AF > 66 years on a DOAC between April 1, 2011, and March 31, 2018. Cases were patients admitted with major bleeding (index date). Each case was matched to two controls. We categorized exposure to diltiazem before the index date as: (a) current users (diltiazem use within 7 days); (b) recent users (diltiazem use within 8 to 90 days); and (c) unexposed (no diltiazem prescription or diltiazem prescription > 90 days before index date). Conditional logistic regression models were used to examine the association between bleeding and diltiazem co-prescription. RESULTS: Among 86,679 AF patients on a DOAC, the median age of AF patients was 80 years (interquartile range 75-85); 48.3% were women. We identified 2,766 cases (3.2%) who were hospitalized with major bleeding. After multivariable adjustment, there was a significant association between major bleeding and current use of diltiazem (adjusted odds ratio (aOR) 1.37; 95% confidence interval (CI) 1.08-1.73, p < 0.009) but no significant association between major bleeding and recent use of diltiazem (aOR 1.19, 95% CI 0.99-1.42, p = 0.06) as compared with the unexposed group. CONCLUSIONS: Current use of diltiazem was associated with major bleeding among AF patients receiving a DOAC.

DOsing Strategy Effectiveness of Diltiazem in Atrial Fibrillation With Rapid Ventricular Response.

STUDY OBJECTIVE: To evaluate the dose-dependent comparative safety and effectiveness between weight-based and alternative dosing strategies for diltiazem in atrial fibrillation with rapid ventricular response. METHODS: This retrospective cohort study included adult patients presenting to the emergency department (ED) with atrial fibrillation with rapid ventricular response who received treatment with intravenous diltiazem. Groups were retrospectively categorized according to the initial dose: low (<0.1875 mg/kg), weight-based (0.1875 to 0.3125 mg/kg), and high (>0.3125 mg/kg). The primary outcome was rate control (heart rate <100 beats/min) within 30 minutes of treatment. RESULTS: Of 345 records, 252 were included. Because of scarcity (N=6), outcomes for the high-dose group were not analyzed. By 30 minutes, the weight-based dosing group had more often achieved rate control (weight-based 55%; low 27%; difference 29% [95% confidence interval (CI) 17% to 40%]). Regression analysis identified the weight-based dosing group (odds ratio 3.63, 95% CI 2.06 to 6.39) and initial heart rate of less than 145 beats/min (odds ratio 2.56, 95% CI 1.46 to 4.51) as variables associated with the primary outcome. The weight-based dosing group less often required rescue therapy (weight-based 6%; low 17%; difference -12% [95% CI -20% to -4%]) relative to the low-dose group. Mortality was higher in the low-dose group than in the weight-based dosing group (low 7%; weight-based 1%; difference 6% [95% CI 1% to 11%]). CONCLUSION: This study shows dose-dependent hemodynamic effects with diltiazem in patients with atrial fibrillation with rapid ventricular response. Weight-based diltiazem (0.25 mg/kg) was associated with greater rate control with no evidence of increased adverse effects. There was no perceived advantage in using lower, alternative doses.

Concomitant Use of Diltiazem With Direct Oral Anticoagulants and Bleeding Risk in Atrial Fibrillation.

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m2. At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m2) (P for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.

Efficacy of Diltiazem to Improve Coronary Vasomotor Dysfunction in ANOCA: The EDIT-CMD Randomized Clinical Trial.

BACKGROUND: Diltiazem is recommended and frequently prescribed in patients with angina and nonobstructive coronary artery disease (ANOCA), suspected of coronary vasomotor dysfunction (CVDys). However, studies substantiating its effect is this patient group are lacking. OBJECTIVES: The randomized, placebo-controlled EDIT-CMD (Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial) evaluated the effect of diltiazem on CVDys, as assessed by repeated coronary function testing (CFT), angina, and quality of life. METHODS: A total of 126 patients with ANOCA were included and underwent CFT. CVDys, defined as the presence of vasospasm (after intracoronary acetylcholine provocation) and/or microvascular dysfunction (coronary flow reserve: <2.0, index of microvascular resistance: ≥25), was confirmed in 99 patients, of whom 85 were randomized to receive either oral diltiazem or placebo up to 360 mg/d. After 6 weeks, a second CFT was performed. The primary end point was the proportion of patients having a successful treatment, defined as normalization of 1 abnormal parameter of CVDys and no normal parameter becoming abnormal. Secondary end points were changes from baseline to 6-week follow-up in vasospasm, index of microvascular resistance, coronary flow reserve, symptoms (Seattle Angina Questionnaire), or quality of life (Research and Development Questionnaire 36). RESULTS: In total, 73 patients (38 diltiazem vs 35 placebo) underwent the second CFT. Improvement of the CFT did not differ between the groups (diltiazem vs placebo: 21% vs 29%; P = 0.46). However, more patients on diltiazem treatment progressed from epicardial spasm to microvascular or no spasm (47% vs 6%; P = 0.006). No significant differences were observed between the diltiazem and placebo group in microvascular dysfunction, Seattle Angina Questionnaire, or Research and Development Questionnaire 36. CONCLUSIONS: This first performed randomized, placebo-controlled trial in patients with ANOCA showed that 6 weeks of therapy with diltiazem, when compared with placebo, did not substantially improve CVDys, symptoms, or quality of life, but diltiazem therapy did reduce prevalence of epicardial spasm. (Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial [EDIT-CMD]; NCT04777045).

Lessons of the month 2: A case of inappropriate drug-drug interaction in kidney transplant.

Carbamazepine remains a first-line antiepileptic medication for the treatment of partial seizures. Despite its widespread use, carbamazepine has significant neurotoxicity and hypersensitivity reactions. We report a case of a patient post-kidney transplant who was on regular carbamazepine for childhood epilepsy and developed nystagmus, diplopia and a broad-base gait after receiving diltiazem. Understanding of the interaction between diltiazem and carbamazepine is necessary to prevent the neurotoxic effects.

Intravenous Metoprolol Versus Diltiazem for Rate Control in Atrial Fibrillation.

BACKGROUND: Currently, it remains unclear whether ß-blockers or nondihydropyridine calcium channel blockers are preferred for the acute management of atrial fibrillation (AF). OBJECTIVE: The objective of this study was to compare the efficacy and safety of intravenous (IV) metoprolol and diltiazem for rate control. METHODS: This was a single-center, retrospective cohort study of patients who presented to the emergency department between 2015 and 2019 with AF with rapid ventricular rate (RVR) and received IV metoprolol or diltiazem. The primary outcome was the percentage of patients who achieved rate control (defined as heart rate < 100 beats per minute). Secondary outcomes included time to rate control, percentage of patients requiring additional agents for rate control, and incidence of cardioversion, bradycardia, and hypotension. RESULTS: A total of 200 patients were included in this study. Rate control was achieved in 35% and 41% of the metoprolol and diltiazem groups, respectively (P = 0.38). Mean time to rate control was not significantly different between the metoprolol and diltiazem groups (35 vs 21 minutes, P = 0.23). One patient developed hypotension, no patient developed bradycardia, and 4 patients required electric cardioversion. No adverse events were observed in patients with ejection fraction ≤40%. CONCLUSION AND RELEVANCE: There was no difference in the achievement of rate control between IV metoprolol and diltiazem. This is the largest study to date comparing the two classes of agents for acute rate control in AF. No patient-specific factors were identified that would influence the preferential use of one medication over the other.

BRASH Syndrome with Hyperkalemia: An Under-Recognized Clinical Condition.

BRASH syndrome is characterized by bradycardia, renal failure, use of an atrioventricular nodal blocker (AVNB), shock, and hyperkalemia. These symptoms represent an ongoing vicious cycle in a patient with a low glomerular filtration rate taking an AVNB. Decreased clearance of the medication and hyperkalemia associated with renal failure synergize to cause bradycardia and hypoperfusion. This reaction causes renal function to worsen, thereby perpetuating the cycle of BRASH syndrome.

Diltiazem-associated Photodistributed Hyperpigmentation.

Diltiazem is a calcium-channel blocker commonly used for the treatment of hypertension. Common adverse effects include dizziness, headache, and edema. Fewer than 20 cases of diltiazem-associated photodistributed hyperpigmentation have been reported in the literature. Here, we present the case of a 71-year-old woman with new-onset facial hyperpigmentation 6 months after initiating treatment with diltiazem.

Acute Airway Inflammation Caused By Incomplete Ingestion of Extended-Release Diltiazem: A Case Report.

BACKGROUND: Diltiazem in its extended-release formulation is widely prescribed and is generally well-tolerated. Currently, there are no published case reports of localized inflammation related to extended-release diltiazem causing either significant pill esophagitis or airway inflammation when swallowed incompletely. CASE REPORT: We present a case of an 85-year-old female who reported difficulty swallowing roughly 18 h after incomplete ingestion of an extended-release diltiazem tablet. She had mild stridor and visible right-sided neck swelling on examination. Imaging revealed a large inflammatory mass, which was believed to be a subacute to chronic neoplastic process when reviewed both by radiology and otolaryngology. Two days after presentation, however, the patient's symptoms and the inflammatory mass had resolved entirely. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Extended-release diltiazem can cause an inflammatory mass when ingested incompletely, leading to possible acute airway compromise. Any invasive airway intervention should be approached with caution, given the degree of acute inflammation. Even in patients who do not require intervention, close observation until clinical improvement is warranted in symptomatic patients with a history of recent incomplete ingestion of extended-release diltiazem.

Treatment of chronic anal fissure: a feasibility study on Levorag® Emulgel versus Diltiazem gel 2.

PURPOSE: To compare the standard treatment, diltiazem gel 2%, with Levorag® Emulgel for chronic anal fissures. METHODS: This was a single-blinded, randomised, controlled, clinical trial with a non-inferiority design. Patients with a chronic anal fissure were randomised to treatment with diltiazem or Levorag® Emulgel twice daily for 8 weeks. Primary endpoint was complete healing of the anal fissure after 12 weeks. Secondary endpoints included incidence of adverse events and efficacy on pain relief. RESULTS: In total, 55 patients were included. Inclusion was terminated prematurely due to a slow inclusion rate. Complete fissure healing at 12 weeks follow-up was overall achieved in 31 of 55 (56%) patients, 18 of 29 (62%) in the diltiazem group compared with 13 of 26 (50%) in the Levorag® Emulgel group (P = 0.424). Pain relief was significantly better at day seven in patients treated with diltiazem (P = 0.040) compared with Levorag® Emulgel, whereas there were no differences in early (3 days) or late (12 weeks) pain relief. Three patients (10.3%) developed severe perianal exanthema during diltiazem treatment, whereas no side effects were observed in the Levorag® Emulgel group. CONCLUSION: The study demonstrated statistical non-inferiority of Levorag® Emulgel compared with diltiazem in the treatment of chronic anal fissure. Diltiazem resulted in a more prompt pain relief and also in a substantial number of local allergic reactions. Levorag® Emulgel may therefore be an alternative in these patients. TRIAL REGISTRATION: Clinicaltrials.gov no. NCT02158013.