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JAMA May 2024Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly... (Comparative Study)
Comparative Study
IMPORTANCE
Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation.
OBJECTIVE
To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024.
EXPOSURES
Diltiazem and metoprolol.
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting.
RESULTS
The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26).
CONCLUSIONS AND RELEVANCE
In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Atrial Fibrillation; Diltiazem; Drug Therapy, Combination; Embolism; Factor Xa Inhibitors; Hemorrhage; Hospitalization; Medicare; Metoprolol; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; United States
PubMed: 38619832
DOI: 10.1001/jama.2024.3867 -
The Medical Letter on Drugs and... May 2024
Review
Topics: Humans; Hypertension; Antihypertensive Agents; Blood Pressure
PubMed: 38771738
DOI: 10.58347/tml.2024.1703a -
Therapie 2024Drug-induced hyperglycemia and diabetes have negative and potentially serious health consequences but can often be unnoticed. (Review)
Review
BACKGROUND
Drug-induced hyperglycemia and diabetes have negative and potentially serious health consequences but can often be unnoticed.
METHODS
We reviewed the literature searching Medline database for articles addressing drug-induced hyperglycemia and diabetes up to January 31, 2023. We also selected drugs that could induce hyperglycemia or diabetes according official data from drug information databases Thériaque and Micromedex. For each selected drug or pharmacotherapeutic class, the mechanisms of action potentially involved were investigated. For drugs considered to be at risk of hyperglycemia or diabetes, disproportionality analyses were performed using data from the international pharmacovigilance database VigiBase. In order to detect new pharmacovigilance signals, additional disproportionality analyses were carried out for drug classes with more than 100 cases reported in VigiBase, but not found in the literature or official documents.
RESULTS
The main drug classes found to cause hyperglycemia are glucocorticoids, HMG-coA reductase inhibitors, thiazide diuretics, beta-blockers, antipsychotics, fluoroquinolones, antiretrovirals, antineoplastic agents and immunosuppressants. The main mechanisms involved are alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Pharmacovigilance signal were found for a majority of drugs or pharmacological classes identified as being at risk of diabetes or hyperglycemia. We identified new pharmacovigilance signals with drugs not known to be at risk according to the literature or official data: phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, sodium oxybate, biphosphonates including alendronic acid, digoxin, sartans, linosipril, diltiazem, verapamil, and darbepoetin alpha. Further studies will be needed to confirm these signals.
CONCLUSIONS
The risks of induced hyperglycemia vary from one drug to another, and the underlying mechanisms are multiple and potentially complex. Clinicians need to be vigilant when using at-risk drugs in order to detect and manage these adverse drug reactions. However, it is to emphasize that the benefits of appropriately prescribed treatments most often outweigh their metabolic risks.
Topics: Humans; Adverse Drug Reaction Reporting Systems; Diabetes Mellitus; Hyperglycemia; Pharmacovigilance; Drug-Related Side Effects and Adverse Reactions; Databases, Factual
PubMed: 37985310
DOI: 10.1016/j.therap.2023.09.010 -
Prehospital Emergency Care Mar 2024This study assesses the likelihood of clinical improvement and adverse events from EMS-administered diltiazem. Current prehospital protocols direct paramedics to...
OBJECTIVE
This study assesses the likelihood of clinical improvement and adverse events from EMS-administered diltiazem. Current prehospital protocols direct paramedics to administer diltiazem, a calcium channel blocker, to decrease the heart rate (HR) of symptomatic, hemodynamically stable patients with rapid atrial fibrillation. However, diltiazem can also cause systemic hypotension and bradycardia, which can precipitate end-organ injury. .
METHODS
To assess whether the rate control benefit of prehospital diltiazem outweighs the risk of adverse events, we conducted a retrospective chart review of all adult patients who received diltiazem from Maryland Advanced Life Support EMS clinicians between January 1, 2019, and March 31, 2022. Collected data included patient demographics, vital signs, diltiazem dose, transport times, administered medications, and procedures. The main outcomes were clinical improvement (HR <100 beats per minute or ≥20% decrease from the maximum HR) and adverse events (bradycardia or hypotension). Multivariable logistic regression was used for statistical analysis.
RESULTS
During the study period, 2396 patients received prehospital diltiazem and 94% of these patients ( = 2254) were included in the study. Overall, 1414 (63.8%) patients improved clinically, 604 (27.3%) patients achieved rate control as defined by a HR of <100 beats per minute, and 78 patients (3.5%) experienced an adverse event. Patients over the age of 50 were less likely to clinically improve with diltiazem administration. Adverse events were more likely in patients with systolic blood pressures (SBP) less than 140 mmHg, patients with maximum HR of less than 120 beats per minute, and patients who received nitroglycerin.
CONCLUSIONS
Prehospital diltiazem is effective and safe for most patients. Adverse events are more likely in patients with baseline SBP less than 140 mmHg, HR less than 120 beats per minute, and concurrent nitroglycerin administration. Future opportunities for research include examining the relationship between adverse events and underlying etiology as well as investigating downstream outcomes.
PubMed: 38436598
DOI: 10.1080/10903127.2024.2326598 -
The Medical Letter on Drugs and... Jan 2024
Topics: Humans; Atrial Fibrillation
PubMed: 38180321
DOI: 10.58347/tml.2024.1693a -
Chinese Journal of Integrative Medicine Dec 2023To explore the protective effect of Huoxin Pill (HXP) on acute myocardial ischemia-reperfusion (MIRI) injury in rats.
OBJECTIVE
To explore the protective effect of Huoxin Pill (HXP) on acute myocardial ischemia-reperfusion (MIRI) injury in rats.
METHODS
Seventy-five adult SD rats were divided into the sham-operated group, model group, positive drug group (diltiazem hydrochloride, DH), high dose group (24 mg/kg, HXP-H) and low dose group (12 mg/kg, HXP-L) of Huoxin Pill (n=15 for every group) according to the complete randomization method. After 1 week of intragastric administration, the left anterior descending coronary artery of the rat's heart was ligated for 45 min and reperfused for 3 h. Serum was separated and the levels of creatine kinase (CK), creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA), hypersensitive C-reactive protein (hs-CRP) and interleukin-1β (IL-1β) were measured. Myocardial ischemia rate, myocardial infarction rate and myocardial no-reflow rate were determined by staining with Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC). Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN) databases were used to screen for possible active compounds of HXP and their potential therapeutic targets; the results of anti-inflammatory genes associated with MIRI were obtained from GeneCards, Drugbank, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Datebase (TTD) databases was performed; Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the intersected targets; molecular docking was performed using AutoDock Tools. Western blot was used to detect the protein expression of Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NFκB)/NOD-like receptor protein 3 (NLRP3).
RESULTS
Compared with the model group, all doses of HXP significantly reduced the levels of LDH, CK and CK-MB (P<0.05, P<0.01); HXP significantly increased serum activity of SOD (P<0.05, P<0.01); all doses of HXP significantly reduced the levels of hs-CRP and IL-1β (P<0.05, P<0.01) and the myocardial infarction rate and myocardial no-reflow rate (P<0.01). GO enrichment analysis mainly involved positive regulation of gene expression, extracellular space and identical protein binding, KEGG pathway enrichment mainly involved PI3K-Akt signaling pathway and lipid and atherosclerosis. Molecular docking results showed that kaempferol and luteolin had a better affinity with TLR4, NFκB and NLRP3 molecules. The protein expressions of TLR4, NFκB and NLRP3 were reduced in the HXP group (P<0.01).
CONCLUSIONS
HXP has a significant protective effect on myocardial ischemia-reperfusion injury in rats, and its effect may be related to the inhibition of redox response and reduction of the inflammatory response by inhibiting the TLR4NFκB/NLRP3 signaling pathway.
Topics: Humans; Rats; Animals; NF-kappa B; Myocardial Reperfusion Injury; NLR Family, Pyrin Domain-Containing 3 Protein; Rats, Sprague-Dawley; C-Reactive Protein; Toll-Like Receptor 4; Phosphatidylinositol 3-Kinases; Molecular Docking Simulation; Signal Transduction; Myocardial Infarction; Creatine Kinase; L-Lactate Dehydrogenase; Superoxide Dismutase
PubMed: 37608040
DOI: 10.1007/s11655-023-3640-1 -
Journal of Education & Teaching in... Jan 2024Emergency medicine residents and medical students on emergency medicine rotation.
AUDIENCE
Emergency medicine residents and medical students on emergency medicine rotation.
BACKGROUND
Calcium channel blocker (CCB) overdoses can be severe with potentially serious adverse outcomes. CCBs work by blocking the calcium channels on smooth and cardiac muscle tissue. At low dose ranges, dihydropyridine CCBs (such as nifedipine, amlodipine, and nicardipine) block the L-type calcium receptors in the peripheral vasculature, whereas non-dihydropyridine CCBs (such as: verapamil and diltiazem) affect the L-type calcium receptors in the myocardium.1 Because of this distinction, dihydropyridine CCB toxicity manifests as arterial vasodilation and non-dihydropyridine CCB toxicity is associated with cardiac manifestations such as bradycardia and negative inotropy.2 It is important to note that in high concentrations (such as in overdoses), CCBs lose specificity for their specific receptors and can show all the manifestations of toxicity such as bradycardia, peripheral vasodilation, and hypotension. Patients can develop both vasoplegic shock from peripheral vasodilation and cardiogenic shock. This is a high acuity low occurrence case with infrequently used but specific treatments, and thus this case provides educational value.
EDUCATIONAL OBJECTIVES
At the end of this oral board session, examinees will: (1) demonstrate ability to evaluate a patient with undifferentiated shock with bradycardia and discuss the differential diagnosis, (2) recognize the signs and symptoms of calcium channel blocker overdose, (3) demonstrate ability to manage treatment of a patient with calcium channel overdose.
EDUCATIONAL METHODS
This oral board case followed the standard American Board of Emergency Medicine-style case in a tertiary care hospital with access to all specialists and resources needed. This case was tested using 12 resident volunteers ranging from PGY 1-2 in an ACGME (Accreditation Council for Graduate Medical Education) accredited emergency medicine residency program.
RESEARCH METHODS
Immediate feedback was solicited both from the learners and from the evaluators following the debriefing session. Residents were asked to evaluate the educational value of the case using a 1-5 Likert scale (5 being excellent). Evaluators were asked to score the residents using the ACGME core competencies with a scale of 1-8, 1-4 being unacceptable and 5-8 being acceptable.
RESULTS
Seven PGY1 residents and five PGY2 residents, thus twelve residents in total, completed the case. The average score was 5.10/8. Three residents missed zero critical actions. The most common critical action missed was consulting cardiology or cardiothoracic surgery for circulatory support options. Many residents failed to recognize that the patient did not have a perfusing blood pressure at the beginning of the case and did not start CPR. Although most residents recognized the patient's hemodynamic collapse was from a calcium channel blocker overdose, most did not know the treatment for this beyond atropine and intravenous fluids.The learners rated the educational value of the case as 4.9/5. Seven residents reported that the case definitely increased their medical knowledge; five residents reported that it somewhat increased their medical knowledge. All residents rated the case as helpful in preparing to manage this medical condition.
DISCUSSION
The educational content from this case was effective. This is a high acuity low occurrence case that has unique treatments that are not commonly used. This makes this case excellent for practice and discussion. We learned during implementation that this case has a high degree of difficulty compared to other cases, and junior learners will need more prompting. It is also important for the proctor to keep the case moving because there is a lot to cover in the allotted amount of time.
TOPICS
Calcium channel blocker overdose, toxicology.
PubMed: 38344049
DOI: 10.21980/J8CQ07