عنوان

בחינת בטיחות קרדיווסקולרית של תרופות תוך שימוש בשיטות מתקדמות של מטה אנליזה ואנליזת דיספרופרציונליות במאגר דיווחי תופעות לוואי

شماره

TLpq2526064879

زبان متن نوشتاري يا گفتاري و مانند آن

انگلیسی

عنوان اصلي

בחינת בטיחות קרדיווסקולרית של תרופות תוך שימוש בשיטות מתקדמות של מטה אנליזה ואנליזת דיספרופרציונליות במאגר דיווחי תופעות לוואי

نام عام مواد

[Thesis]

نام نخستين پديدآور

Gorelik, Einat

نام ساير پديدآوران

Matok, Ilan

نام ناشر، پخش کننده و غيره

The Hebrew University of Jerusalem (Israel)

تاریخ نشرو بخش و غیره

2019

نام خاص و کميت اثر

120

جزئيات پايان نامه و نوع درجه آن

Ph.D.

کسي که مدرک را اعطا کرده

The Hebrew University of Jerusalem (Israel)

امتياز متن

2019

متن يادداشت

Background: At the launching of a new drug, data are incomplete regarding its safety, due to limitations of clinical trials. Therefore, it is essential to collect and monitor postmarketing data on drug safety. Observational pharmacoepidemiological studies are one strategy to monitor drug safety. Such studies enable high volume exposure with relatively long follow-up periods. They also analyze a broad sample of patients with more diverse medical conditions and concomitant drugs than in clinical trials. Postmarketing studies may yield changes in conclusions regarding drug safety. Metaanalysis methods provide tools to assess, analyze and integrate results from several independent studies and to provide statistically valid aggregate measures of treatments and harmful effects. Disproportionality reporting analyses in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) is a very useful way to detect early signals and evaluate potential safety concerns of drug usage in the real world. The aim of this thesis was to present the viability of advanced metaanalysis research methods and disproportionality analysis to assess the cardiovascular (CV) safety of drugs. I used fluoroquinolone antibiotics, macrolide antibiotics and anti-obesity drugs as test cases. Cardiovascular adverse effects of antibiotics: Fluoroquinolones and macrolide antibiotics are widely prescribed for the treatment of common infections such as respiratory infections and urinary tract infections. A number of studies reported the association of fluoroquinolones and macrolide antibiotics with arrhythmias and CV death, but other studies did not find such association. Cardiovascular adverse effects of anti-obesity drugs: Several safety concerns including cardiotoxicity have been associated with antiobesity drug use. Eight anti-obesity drugs have been withdrawn from the market due to CV adverse reactions. Two of the main concerns were valvulopathy and pulmonary hypertension, which were reported for serotonergic appetite suppressants. An increased risk of myocardial infarction (MI) and stroke was reported for sibutramine. The history of anti-obesity drug withdrawal highlights the need for continuous monitoring of the risks of drug therapy for this indication and for the evaluation of benefit-risk balance. Objectives: The aim of my research was to evaluate if advanced methods of meta-analysis and disproportionality analysis can contribute to the assessment of the CV safety of drugs. Specific objectives: 1. To evaluate the CV safety of macrolide antibiotics using advanced meta-analysis methods. 2. To evaluate the CV safety of fluoroquinolones using advanced meta-analysis methods. 3. To evaluate the CV safety signals of the anti-obesity drugs lorcaserin, phentermine/topiramate and bupropion/ naltrexone using disproportionality analysis of the FAERS database. Methods: For study objectives 1 & 2, conventional meta-analysis was used. The PRISMA 2009 guidelines were followed for systematical data selection and extraction. Outcomes were pooled using random effects models. Direct and indirect comparisons in network meta-analysis were done using frequentist methods. For study objective 3, a disproportionality analysis was performed for defined CV adverse events of three anti-obesity drugs: lorcaserin, naltrexone-bupropion and phentermine-topiramate, using the FAERS. Results: 1. Macrolides and the risk for cardiotoxicity meta-analysis study: A total of 33 studies were retrieved and included in the meta-analysis. Macrolide use was not associated with the risk of arrhythmia or CV mortality. Macrolide use was associated with a small but statistically significant 15% increase in the risk for MI (Odds Ratio (OR) = 1.15 [95% Confidence Interval (CI), 1.01 to 1.30]). In an indirect network metaanalysis, erythromycin and clarithromycin were ranked considerably more likely to be associated with a higher risk for MI, and significantly associated with an increased risk of MI compared to azithromycin. Published: Antimicrob Agents Chemother (2018) May 25;62(6). doi: 10.1128/AAC.00438-18. 2. Fluoroquinolones and the risk for cardiotoxicity meta-analysis study: Thirteen studies were included. Fluoroquinolone use was associated with a statistically significant 2 increase, of 85%, in the risk for arrhythmia, OR=1.85 [95% CI 1.22-2.81]) and an increase of 71% in the risk for CV mortality (OR=1.71 [95%CI 1.39-2.09]). In the network meta-analysis, moxifloxacin ranked most likely to have the highest risk for arrhythmia and for CV mortality. Published: Drug Saf. (2018) Oct 27. doi: 10.1007/s40264-018-0751-2. 3. Anti-obesity drugs and the risk for CV adverse events: In a disproportionality analysis, lorcaserin use was associated with a significantly greater proportion of reports for valvular disorders and a small but statistically significant increase in the proportion of reports of pulmonary hypertension (Reporting Odds Ratio (ROR)= 7.32; 95%CI 4.81-11.15, ROR=1.91; 95%CI 1.05-3.45, respectively). No additional CV safety signals for the three anti-obesity drugs: lorcaserin, phentermine-topiramate and naltrexone-bupropion were detected. Unpublished. Currently under review. Discussion and conclusions: We used a number of pharmacoepidemiologic non-interventional tools to explore CV adverse events of antibiotics (macrolides and fluoroquinolones) and anti-obesity drugs (lorcaserin, phentermine-topiramate and naltrexone-bupropion). Our findings indicate that macrolide antibiotics as a group are associated with a significant risk for MI but not for arrhythmia and CV mortality. Among the macrolides, erythromycin and clarithromycin were associated with a greater risk of MI. However, the possibility arises that the association observed between macrolide use and the risk of MI is due to residual confounding. Fluoroquinolone use was associated with a statistically significant increase in the risk for arrhythmia, and in the risk for CV mortality. Among the fluoroquinolones, moxifloxacin ranked most likely to have the highest risk for arrhythmia and for CV mortality. Among the anti-obesity drugs, lorcaserin use was associated with a significantly greater proportion of reports of valvular disorder and pulmonary hypertension events. No other CV safety signals were detected for any of the three anti-obesity drugs investigated. The results of these studies support the feasibility of advanced meta-analysis methods and disproportionality analysis to detect and quantify drug-induced CV adverse outcomes. This thesis demonstrated the significant value of several pharmacoepidemiological methods in the continuous monitoring of drug safety and, therefore, the crucial role of such methods in protecting public health.

موضوع مستند نشده

Cardiac arrhythmia

موضوع مستند نشده

Drug therapy

موضوع مستند نشده

Infections

موضوع مستند نشده

Mortality

موضوع مستند نشده

Patients

موضوع مستند نشده

Potassium

مستند نام اشخاص تاييد نشده

Gorelik, Einat

مستند نام اشخاص تاييد نشده

Matok, Ilan

نام الکترونيکي

فرمت انتشار

p

نوع ماده

[Thesis]

کد کاربرگه

276903

سطح دسترسي

a

تكميل شده

Y