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  Oral Fluoroquinolones andRisk of Mitral and Aortic Regurgitation Mahyar Etminan, P HARM D, MS C , a, b Mohit Sodhi, BS C , MS C , a Saeed Ganjizadeh-Zavareh, MD, MS C , c Bruce Carleton, BP HARM , P HARM D, a,d Abbas Kezouh, P H D, e James M. Brophy, MD, P H D f  ABSTRACTBACKGROUND  Recent studies have linked  󿬂 uoroquinolones (FQs) to cardiac adverse events, including aortic dissectionand aneurysm. To date, whether FQs can increase the risk of aortic or mitral regurgitation has not been studied. OBJECTIVES  This disproportionality analysis and case-control study examined whether FQs increase the risk of aorticand mitral regurgitation. METHODS  Data from the U.S. Food and Drug Administration ’ s adverse reporting system database was used to under-take a disproportionality analysis, and a random sample of 9,053,240 patients from the U.S. PharMetrics Plus database(IQVIA) was used for the matched nested case-control study. Current FQ exposure implied an active prescription at theindex date or 30 days prior to the event date. Recent FQ exposure was de 󿬁 ned as FQ use within days 31 to 60 and pastwithin days 61 to 365 prior to the event date. Rate ratios (RRs) were compared to users of amoxicillin and azithromycin.Conditional logistic regression was used to compute RRs adjusting for confounders. RESULTS  The reported odds ratio for the disproportionality analysis was 1.45 (95% con 󿬁 dence interval [CI]: 1.20 to1.77). A total of 12,505 cases and 125,020 control subjects were identi 󿬁 ed in the case-control study. The adjusted RRs forcurrent users of FQ compared with amoxicillin and azithromycin users were 2.40 (95% CI: 1.82 to 3.16) and 1.75 (95% CI:1.34 to 2.29), respectively. The adjusted RRs for recent and past FQ users when compared with amoxicillin were 1.47(95% CI: 1.03 to 2.09) and 1.06 (95% CI: 0.91 to 1.21), respectively. CONCLUSIONS  These results show that the risk of aortic and mitral regurgitation is highest with current use followedby recent use. No risk was observed with past use of FQs. Future studies are necessary to con 󿬁 rm or refute theseassociations. (J Am Coll Cardiol 2019;74:1444 – 50) © 2019 by the American College of Cardiology Foundation. F luoroquinolones (FQs) are one of the most pre-scribed classes of antibiotics and are favoredover other agents for their broad spectrum of antibacterial activity and high oral absorption. Inrecent years, a number of adverse events have beenlinked to these drugs. Some of these adverse eventsinclude retinal detachment, which has producedmixed results (1 – 3), but others, including aortic aneu-rysm and dissection (4 – 6), peripheral neuropathy(7,8), and cardiac arrhythmias (9 – 11), are more consis-tent with a causal link with FQs and are now includedin a warning from the U.S. Food and Drug Administra-tion (FDA). The putative mechanism behind theseadverse events is FQs ’  in vitro ability to damage con-nective tissue and collagen throughout the body(4,12 – 14). A recent case report has described a patientwho developed aortic valve prolapse shortly afterstarting cipro 󿬂 oxacin (15) for 2 days without any ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2019.07.035 From the  a Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia,Canada;  b Therapeutic Evaluation Unit, British Columbia Provincial Health Services Authority, Vancouver, British Columbia,Canada;  c Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; d Division of Translational Therapeutics, Department of Pediatrics, and Pharmaceutical Outcomes Programme, British ColumbiaChildren ’ s Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada;  e Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada; and the  f  Departments of Medicine, Epidemiology,and Biostatistics, McGill University, Montreal, Quebec, Canada. This study was funded by the Therapeutic Evaluation Unit of theBritish Columbia Provincial Health Services Authority. The funding source had no role in the design and conduct of the study. Theauthors have reported that they have no relationships relevant to the contents of this paper to disclose.Manuscript received May 17, 2019; revised manuscript received June 20, 2019, accepted July 2, 2019. Listen to this manuscript ’ saudio summary byEditor-in-Chief Dr. Valentin Fuster onJACC.org . JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 74, NO. 11, 2019 ª  2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATIONPUBLISHED BY ELSEVIER  other reasonable explanation for this acute adverseevent.Like the aorta, the healthy human aortic and mitralvalves are also made up of collagen and connectivetissue delicately woven in its extracellular matrix thatis integral to its function (16). When the valve con-nective tissue is compromised, it can lead to mitralvalve prolapse and mitral regurgitation (16). Forexample, in patients with Marfan syndrome, systemicdamage of the connective tissue leads to higher ratesof mitral valve prolapse (17), which can progress tosevere mitral regurgitation via chordal rupture lead-ing to heart failure and, in some cases, suddendeath (18).We hypothesized that FQs could damage the con-nective tissue of the aortic and mitral valve appa-ratus, thus increasing the risk of valvularregurgitation. Given their widespread use, establish-ing the magnitude of any potential FQ risk of valvularregurgitation is a pertinent question for both clini-cians and their patients. To address this question, we 󿬁 rst undertook a disproportionality analysis using theU.S. Food and Drug Administration Adverse EventsReporting Systems (FAERS) database to identify casesof FQ-related valvular regurgitation reported to theFDA and compared these cases to valvular regurgita-tion cases reported for other non-FQ drugs. We alsoperformed a case-control study to further quantifythe valvular regurgitation secondary to FQs. METHODS DATA SOURCES.  For the disproportionality analysis,we accessed the FDA ’ s FAERS database, which cap-tures all prescription drug related adverse events re-ported by health professionals and patients (19).FAERS was accessed through OpenVigil (2.1) (20), afreely available web-based pharmacovigilance toolthat identi 󿬁 ed all FDA-reported adverse events from2004 to 2018 (19,20).For the case-control study, we used the U.S. Phar-Metrics Plus database (IQVIA), a large health claimsdatabase that captures demographics, physicianvisits, hospitalizations, and prescription drugs for > 150 million enrollees. All medical diagnoses arecaptured through International Classi 󿬁 cation of Dis-eases, Ninth and Tenth Editions (ICD-9 and -10). Thisdatabase also captures all outpatient prescriptiondrugs. This includes drug identi 󿬁 cation, dose pre-scribed, and treatment duration. This database pro-vides adequate representation of all geographicareas of the United States (21). The study design was acase-control nested within a random sampleof 9,053,240 subjects who we had access tofrom 2006 to 2016. We followed the reportingof studies conducted using the RECORD-PE(REporting of studies Conducted usingObservational Routinely collected healthData statement for PharmacoEpidemiology)(22) reporting guidelines throughout the pa-per. Ethics approval was obtained from theUniversity of British Columbia research ethics board. STUDY DESIGN AND ANALYSIS. Disproportionality analysis.  This is a drugadverse event  “ signal ” -driven analysis that compares,in our case, the number of valvular regurgitation re-ports related to FQ with the number for all other drugs(23) in FAERS. We searched OpenVigil (2.1) for thefollowing terms:  aortic valve replacement, aortic valverepair, aortic valve incompetence, aortic valve disease,mitral valve replacement, mitral valve repair, mitralvalve disease, mitral valve incompetence,  and  mitralvalve prolapse.  Then, we identi 󿬁 ed the number of these events reported from 2004 to 2018 with thefollowing oral  󿬂 uoroquinolones:  cipro  󿬂  oxacin, levo-  󿬂  oxacin, moxi  󿬂  oxacin, gemi  󿬂  oxacin, gati  󿬂  oxacin,lome  󿬂  oxacin, and nor   󿬂  oxacin.  Although gati 󿬂 oxacinhas been taken off market, it was still included in thelist to examine a class effect. Reported odds ratios(ORs) and corresponding 95% con 󿬁 dence intervals(CIs) were computed comparing the number of valvular regurgitation secondary to FQ use to thesame events with all other drugs. A reporting OR > 1.0signaled increased risk. Case-control study.  We identi 󿬁 ed incident cases of valvular regurgitation identi 󿬁 ed as those with  󿬁 rstphysician visit codes for the following conditions: mitral valve disease or insuf   󿬁 ciency, aortic valve dis-ease or insuf   󿬁 ciency, aortic valve or mitral valve dis-orders, and aortic valve or mitral valve regurgitation (ICD-9 394.9, 396.3, 396.8, 396.9, 424.0, and 424.1;ICD-10, I34, and I35) ( Central Illustration ). Conditionsfor which FQs can be prescribed and that can inde-pendently increase the risk of valvular regurgitation,including rheumatic fever, strep throat, and endo-carditis, were excluded prior to the identi 󿬁 cationof cases and control subjects to prevent protopathic bias ( Central Illustration ). After these exclusions,there were 8,272,981 subjects in our base cohort( Figure 1 ). For each case, the pool of potential controlsubjects without any history of valvular regurgitationwas identi 󿬁 ed, and 10 control subjects were matchedto a case by follow-up time, calendar time (to controlfor prescribing trends that may lead to differential SEE PAGE 1451 ABBREVIATIONSAND ACRONYMS CI  =  con 󿬁 dence interval FAERS  =  U.S. Food and DrugAdministration Adverse EventsReporting System FDA  =  U.S. Food and DrugAdministration FQ  =  󿬂 uoroquinolones ICD  =  InternationalClassi 󿬁 cation of Diseases OR  =  odds ratio RR  =  rate ratio J A C C V O L . 7 4 , N O . 1 1 , 2 0 1 9  Etminan  et al . S E P T E M B E R 1 7 , 2 0 1 9 : 1 4 4 4  –  5 0  Fluoroquinolones and Cardiac Valve Regurgitation 1445  prescribing of FQs among cases and control subjects),age, and index date (date of registration of the case inthe database). Control subjects were allowed to befuture cases and could have been selected more thanonce. This incident density-based sampling approachfor control selection generates ORs that are close ap-proximations of the rate ratios (RRs) (24). Separateanalyses were done looking at all valvular regurgita-tion events as well as a strati 󿬁 ed analysis looking atthe type of regurgitation (aortic vs. mitral).We identi 󿬁 ed all oral  󿬂 uoroquinolone pre-scriptions (cipro 󿬂 oxacin, gemi 󿬂 oxacin, levo 󿬂 oxacin,moxi 󿬂 oxacin, o 󿬂 oxacin, and nor 󿬂 oxacin) in the yearprior to the index date. We created 3 distinct riskperiods. Current FQ exposure implied an active pre-scription at the index date or in the 30 days preced-ing that date. Recent FQ exposure was de 󿬁 ned as FQ use within days 31 to 60 and past within days 61 to365. These risk periods were created to re 󿬂 ect po-tential etiological windows as the damage to theconnective tissue of the heart valve by FQs has beenshown to occur within a few days (15). To control forconfounding by infection, we also identi 󿬁 ed users of 2 antibiotics with distinct spectra of coverage. CENTRAL ILLUSTRATION  Oral Fluoroquinolones and Mitral and Aortic Regurgitation Risk:Inclusion and Exclusion Criteria Study cohort (n = 8,272,981) Cases of Valvulopathy (n = 12,502)  and controls (n = 125,020) Adjusted† RR for Mitral or Aortic Regurgitation for Current Users of FQs vs. Amoxicillin:2.40 (95% CI: 1.82-3.16) Included:  Mitral Valve Disease or Insufficiency, Aortic Valve Disease or Insufficiency,Aortic Valve or Mitral Valve Regurgitation and Mitral Valve Prolapse% of Exposed Cases*: FQs vs.Amoxicillin* 2.4% vs. 1.6%% of Exposed Controls*: FQs vs.Amoxicillin 0.53% vs. 0.79%Break down of type of FQs*Ciprofloxacin (48.5%)Levofloxacin (44.2%)Moxifloxacin (7%)Gemifloxacin (0.3%) Etminan, M. et al. J Am Coll Cardiol. 2019;74(11):1444 – 50. The initial cohort included > 9 million patients from the PharMetrics Plus Database. We then proceeded to exclude conditions that might havebeen potential confounders (780,000 patients). The  󿬁 nal cohort included 12,502 cases of valvular regurgitation and  > 125,020 controlsubjects. We then report the percentage exposed to  󿬂 uoroquinolones (FQs) and amoxicillin among the cases and control subjects and presentthe breakdown of the type of FQs among the cases. The  󿬁 nal adjusted rate ratio (RR) for mitral or aortic regurgitation for current FQ usersversus amoxicillin users was 2.40 (95% con 󿬁 dence interval [CI]: 1.82 to 3.16). *For the comparison of current FQ users versus currentamoxicillin users.  † Adjusted for variables in  Table 2 . Etminan  et al .  J A C C V O L . 7 4 , N O . 1 1 , 2 0 1 9 Fluoroquinolones and Cardiac Valve Regurgitation  S E P T E M B E R 1 7 , 2 0 1 9 : 1 4 4 4  –  5 0 1446  Amoxicillin was used as it is a commonly prescribed,narrow spectrum antibiotic that has not been asso-ciated with valvular regurgitation. We furthercontrolled for confounding by infection by alsocomparing the risk of valvular regurgitation withusers of azithromycin, a macrolide with a broadspectrum of activity used for more severecommunity-acquired bacterial infections. A condi-tional logistic regression model was used to computecrude and adjusted RRs. RRs were adjusted for thefollowing variables: sex, age, atrial  󿬁  brillation, dia- betes, hypertension, coronary artery disease, stroke,chronic heart failure, chronic renal failure, and drugsthat might increase the risk of valvular regurgitationincluding statins, cabergoline, pergolide, and phen-termine. Finally, we estimated the magnitude of anunmeasured confounder that is needed to reverse apotential harmful association between FQ use andvalvular regurgitation by using the metric E value(25) where E  ¼  RR þ O ð RR ½ RR  1 Þ  and RR is the rateratio for users of FQ compared with amoxicillin orazithromycin users. RESULTS In the disproportionality analysis, there were a totalof 102 reported events of FQ valvular regurgitationand 6,099 reports with other drugs from 2004 to 2018 FIGURE 1  Description of Included and Excluded Conditions in the Primary Cohort Initial cohort (n = 9,053,240) Study cohort (n = 8,272,981) Cases of Valvulopathy (n = 12,502) and controls (n = 125,020)Included: Mitral Valve Disease or Insufficiency, AorticValve Disease or Insufficiency, Aortic Valve or Mitral ValveRegurgitation and Mitral Valve Prolapse Excluded: Rheumatic Aortic Stenosis (n = 2,697) Rheumatic Heart Disease (n = 1,357) Disease of Tricuspid Valve (n = 54,062) Other diseases of Mitral Valve (n = 5,688) Rheumatic Fever (n = 5,657) Mitral Stenosis (n = 620) Endocarditis (n = 11,619) Myocarditis (n = 1,332) Strep Throat (n = 697,227) Final N = 780,259 TABLE 1  Results of the Disproportionality Analysis DrugNumber ofCases ROR 95% CI Cipro 󿬂 oxacin 44 1.67 1.24 – 2.25Gati 󿬂 oxacin 6 2.87 1.29 – 6.39Levo 󿬂 oxacin 52 1.80 1.37 – 2.37Moxi 󿬂 oxacin 11 0.73 0.41 – 1.32Lome 󿬂 oxacin 0 N/A N/AGemi 󿬂 oxacin 0 N/A N/ANor 󿬂 oxacin 0 N/A N/A Total  113*Combined 102 1.45 1.20 – 1.77 *When searching all exposures and all outcomes, it is possible that a patient wasprescribed multiple  󿬂 uoroquinolones, therefore the combined number may besmaller.CI  ¼  con 󿬁 dence interval; N/A  ¼  not applicable; ROR  ¼  reporting odds ratio. J A C C V O L . 7 4 , N O . 1 1 , 2 0 1 9  Etminan  et al . S E P T E M B E R 1 7 , 2 0 1 9 : 1 4 4 4  –  5 0  Fluoroquinolones and Cardiac Valve Regurgitation 1447
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