Pharmacoepidemiology methods: application to pharmacvigilance in Vietnam Vu Dinh Hoa National Drug information and Adverse Drug Event Monitoring Center Hanoi University of Pharmacy... Tr[r]
(1)Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Pharmacoepidemiology methods: application to pharmacvigilance in Vietnam Vu Dinh Hoa National Drug information and Adverse Drug Event Monitoring Center Hanoi University of Pharmacy (2) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Pharmacovigilance ADR Detection Assessment Understanding Drug quality Prevention ME Treatment failure Activity Rational drug use Targeted object Improve health care quality Goal (3) Trung tâm DI&ADR Quốc gia Pharmacoepidemiology methods applied in Pharmacovigilance Descriptive study (no control) PE methods applied to PV Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Case report/case series/disproportional method Surveillance Analytical study (with control) Cohort study Case-control study (4) Trung tâm DI&ADR Quốc gia Anaphylactic reaction of alphachymotripsin and disproportional method Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN (5) Trung tâm DI&ADR Quốc gia Alpha chymotrypsin Pancretic enzyme, proteolysis Complex structure, protein nature Use: Post surgery, trauma (evidence) Cataract surgery (evidence) Upper respiratory-tract disorders: sorethroat, broncholitis,… Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN (6) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Alpha chymotrypsin – Efficacy/safety Efficacy Safety Clinical used since 1958 US: ophthalmic products, discontinued EU: France, all products withdrawed since 2011 Available in serveral countries In Vietnam: The orally tablet common used for inflammatory condition with/without infections (mostly upper respiratory inflammation) The IM injection is use post surgery or trauma Although alphachymotrypsin monograph is available in Vietnames National Formulary, efficacy profile of these products might be questioned Early of 2017, PV center received three reports of mortality that probably due to alpha chymotrypsin injection => Official letters to Drug administration of Vietnam (7) Trung tâm DI&ADR Quốc gia Alpha chymotrypsin-case series Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Certain Possibly Possibly Possibly Possibly Possibly First two quarters of 2017: cases with mortality, possibly related to Vintrypsine Official letter to Drug Administration of Vietnam (alphachymotripsin), IM injection (8) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Alpha chymotrypsin - signal Reported Odd Ratio Disproportional method: Signal generated 3.66 2.27 1.99 1.89 2.12 0.5 2009 2010 2011 2012 2013 2014 2015 Year Case/non-case of anaphylactic reactions for alpha chymotrypsin ROR and 95%CI: represented cumulative data from 2010 Case: anaphylactic shock/reaction Non-case: all other report that not related to anaphylactic reaction/shock (9) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Alpha chymotrypsin No Brandname Attachment of official letter to Drug Administration of Vietnam Total report Alphachymotrypsin* 141 Alphachoay 36 Vintrypsin 14 Alphadeka DK Katrypsin Alpha kiisin Alpha tryesil Aldozen Alpha trypsin 10 Tazenase 11 Amfaneo 12 Bevichymo Chymogreen 13 Medoalpha 21 14 Alphadaze 15 16 Chymodk (*): Brandnames were not specified in reports Report with Anaphylactic reactions Urgent (death) 43 1 0 0 0 - (10) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Alpha chymotrypsin – compared with Vigibase Year 2010 2011 2012 2013 2014 2015 2016 First quarters 2017 Total ADR reports in Vietnam Anaphylactic Total report reaction/shock n (%) 11 (27) 16 (19) 33 (24) 55 10 (18) 12 (42) 57 16 (28) 45 11 (24) 20 (45) 249 65 (26) Data from Vietnam may not sent to Vigibase due to work-load Vigibase Anaphylactic reaction/shock Total report n (%) (50 ) 23 (13) (0) (38) 64 (14) 69 12 (17) 71 11 (15) 55 (5) 298 43 (14) (11) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Alpha chymotrypsin – Reaction from authority Narrow down the indication of oral alphachymotrypsin Official announcement to healthcare system about the safety concern Inspection and withdraw the subquality product… (12) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Disproportional studies from PV database Fig Number of ADR reports in Vietnamese database SIDCA Swedish International Development Cooperation Agency, DAV Drug Administration of Vietnam, NPVC National Pharmacovigilance center, ADR Adverse Drug Reaction Nguyen KD et al Drug Saf 2018 Feb;41(2):151-159 (13) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Disproportional studies from PV database (14) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Disproportional studies from PV database Drug Saf 2018 Nov 27 (15) Trung tâm DI&ADR Quốc gia Pharmacoepidemiology methods applied in Pharmacovigilance Descriptive study (no control) Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Case report/case series/disproportional method Useful for detect signal, No way to determine prevalence… Surveillance PE methods applied to PV Analytical study (with control) Cohort study Case-control study (16) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Adverse effects during the treatment of MDR-TB in Viet Nam a cohort event monitoring (17) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Why surveillance? NTP started treatment for thousands MDRTB patients since 2009 • HIV coinfection • Comobidities • Longterm (20 mo.) Scale up MDR-TB treatment to many facilities national wide • High toxicitiy Efficacy of standardized regimens were identified (71% success) Safety was still questioned; Spontaneous AE reports (volunteer) to DI&ADR center was very limitted Effectiveness Safety Standardized regimens Z E Km/Cm Lfx Pto Cs (PAS) A cohort events monitoring was warrant (18) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Methods treatment sentinel sites in 9/63 provinces of VN Patients: Newly MDR-TB diagnosed, adult (age >16), exclude patients in other trials (eg STREAM) Data collection: • • • Treatment initiation: Registry paper-based form Follow up: AE paper-based form (AE description,, serverity and seriousness, clinical solutions, regimens ect.); clinical judgement and/or laboratory results Monthly sent to DI&ADR center (19) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Methods Access database SPSS 22.0 AEs classification: WHO-ART, physicians’ judgment based on NTP internal guidance Data input and cleaning: Access, SPSS syntax; missing data: MICE (multiple imputation by chained equations) Survival analysis for event occurences: Cox regression (20) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Results Type and seriousness of adverse events Convulsions Hypothyroidism Hematologic disorders Nephrotoxicity Peripheral neuropathy Hypokalaemia Vision disorders Psychiatric disorders Hearing loss/vestibular disorders Hepatic disorders Anorexia Hyperuricemia Vomit Arthralgia 34 15 10 Patient with SAE 19 39 Patient with non-SAE 51 57 22 47 85 24 76 11 170 10 178 189 15 195 223 50 100 150 200 Number of patient experience at least one AE (n=659) 250 (21) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Results Consequence of adverse events (n=659) Consequence of the adverse events With at least one AE Required any medication/medical intervention With at least one clinical significant AE Drug switching Dose reduction Temporary/permanent drug discontinuation With at least one SAE Hospitalization or prolongation Life-threatening Persistent disability Death$ No patients (%) 489 (74.2) 338 (51.3) 154 (23.4) 16 (2.4) 29 (4.4) 53 (8.0) 120 (18.2) 95 (14.4) 27 (4.1) 10 (1.5) (0.3) SAE: serious adverse event; Clinical significant AE = SAE and AE required TB-regimen modification; $: relationship with AE could not be ruled out (22) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Results Predictor for Hyperuricemia/Nephrotoxicity/Hepatotoxicity Adeverse event Covariates (n/N) Hyperuricemia Alcoholic No (180/643) Yes (13/16) Drug addiction No (181/637) Yes (12/22) Alcoholic No (43/643) Yes (6/16) Diabetes mellitus No (36/555) Yes (13/104) Previous renal failure No (47/654) Yes (2/5) Injectable drugs daily dose (mg/kg) Alcoholic No (28/643) Yes (3/16) Nephrotoxicity Hepatotoxicity aHR (90% CI) p-value 5.66 (3.16-10.14) 0.000 2.11 (1.16-3.83) 0.014 12.43 (4.75-32.54) <0.001 2.18 (1.09 – 4.38) 0.028 10.99 (2.59 – 46.59) 1.21 (1.14 – 1.30) 0.001 <0.001 6.84 (1.89 – 24.73) 0.003 (23) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Contrast media induced nephropathy in Bach Mai hospital Prospectively screening from lab result (24) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Contrast induced nephropathy (CIN) (25) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Screening process Patients with CM n = 1346 Without baseline Scr result (n = 297) Medical record is not assessible (n= 19) Renal replacement theraphy (n = 7) Without Scr after using CM (n =457) Patient included for analysis n= 566 Bui Thi Ngoc Thuc, Tap chi Duoc hoc 11/2015 (số 475 năm 55) (26) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN RIFLE classification for contrast induced nephropathy N % of patient with CIN (n=40) % of whole sample (n=566) Risk (Scr elevated 1.5 – time) 10 25% 1.8% Injury (Scr elevated 2- time) 10% 0,6% Failure (Scr elevated >3 times) 5% 0.4% Total 16 40% 2.8% RIFLE criteria Prevalence of CIN: 40/566 ~ 7% 26 Bui Thi Ngoc Thuc, Tap chi Duoc hoc 11/2015 (số 475 năm 55) (27) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Predictors for contrast induced nephropathy Variables Univariate analysis Multivariate analysis p OR (CI 95%) p OR (CI 95%) Age >70 0,004 2,26 (1,37 – 5,01) 0,024 2,28 (1,11 – 4,68) Diabetes 0,05 2,13 (1,00 – 4,55) Heart failure 0.746 1,17 (0,44 – 3,12) Early myocardial infarction (<24h) 0,200 2,29 (0,64 – 8,12) Baseline eGFR (ml/min/1,73m2) 45 ≤ eGFR < 60 30 ≤ eGFR <45 eGFR < 30 0,369 0,866 0,000 1,46 (0,64 – 3,37) 0,88 (0,20 – 3,87) 10,86 (3,57 – 33,02) 1,000 0,499 0,000 1,00 (0,41 – 2,42) 0,59 (0,13 – 2,70) 7,97 (2,49 – 25,57) With NSAIDs 0,207 1,51 (0,79 – 2,88) With Aminosid Constrast media injection vol (ml) ≤ 100 101 – 200 > 200 0,677 0,64 (0,08 – 4,96) 0,067 0,180 0,029 1,7 (0,78 – 3,69) 3,12 (1,12 – 8,68) 0,015 0,051 0,011 2,08 (0,99 – 4,34) 3,57 (1,35 – 9,48) Bui Thi Ngoc Thuc, Tap chi Duoc hoc 11/2015 (số 475 năm 55) (28) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Contrast induced nephropathy (CIN) Prevalence of CIN is 7% However, other factors could increase the Scr also (disease condition, co-medication…) Is Injectable contrast media an independence risk factor for CIN occurrence? (29) Trung tâm DI&ADR Quốc gia Pharmacoepidemiology methods applied in Pharmacovigilance Descriptive study (no control) Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Case report/case series/disproportional method Surveillance PE methods applied to PV Can estimate prevalence, not risk… Analytical study (with control) Cohort study Case-control study (30) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Cohort study CIN Patient with contrast media No CIN 15 = Odd Ratio CIN Patient WITHOUT contrast media No CIN ? ? (31) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Contrast media induced nephropathy in Transportation hospital A Cohort study (32) Contrast induced nephropathy (CIN) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Propensity score matching (PSM) Before matching Screaning Patient with X-ray, CT, MRI With/Without Contrast media(1503/12771) Excluded • Without baseline Scr • Without follow up Scr • RRT • Medical record not available 198 with contrast media 779 without contrast media After matching 198 122 779 237 PSM with variables: Age, sex, Charlson score, Baseline Scr, Baseline eGFR, Nguyễn Thu Hương và cs, Nghiên cứu Dược và Thông tin thuốc, 2, 2018 (33) Contrast induced nephropathy (CIN) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Multivariate analysis Variable OR [CI 95%] p Contrast media (CM) 1,974 [0,560 - 6,961] 0,290 Urinary tract obstruction (UTO) 1,208 [1,015 - 1,437] 0,033 Hypertension 1,009 [0,911 - 1,117] 0,869 Diabetes 0,948 [0,817 - 1,101] 0,485 CM x UTO 1,227 [1,067 - 1,411] 0,004 UTO related to higher risk of CIN Using Contrast media on UTO patient may increase the risk of CIN Nguyễn Thu Hương và cs, Nghiên cứu Dược và Thông tin thuốc, 2, 2018 Contrast media MAY NOT independent risk factor for CIN (34) Trung tâm DI&ADR Quốc gia Pharmacoepidemiology methods applied in Pharmacovigilance Descriptive study (no control) Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Case report/case series/disproportional method Surveillance PE methods applied to PV Analytical study (with control) Cohort study For rare event, cohort study is not appropriate Case-control study (35) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Hyperkalemia in Huu Nghi hospital A case-control study (36) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN 1,1% – 10% [1] In Vietnam - Data on hyperkalemia is limited - Health care staff did not report event to Pharmacovigilance center Nyirenda M J., Tang J I., et al (2009), "Hyperkalaemia" (37) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Screening for hyperkalemia from lab result 77263 lab result Causality assessment WHO classification: Result K <5,6 mmol/L • • • • • • • Technical failure • RRT • Medical record not available Certain Probable Possible Unlikely Unclassified Unclassifiable 118 (1,5%) hyperkalemia Nguyen Do Quang Trung, Y hoc Vietnam 464 (3) (38) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Medication on patient with hyperkalemia ATC code A02B J01D B01A B05B J01M A12B C03D C08C C09A J01X C07A C09C M01A Therapeutic group PPI Other beta lactam Anticoagulant Venous infusion fluid Quinolons Potassium (oral/IV) potassium sparing diuretics Calcium channel blockers ACEIs Other antimicrobial agents Beta blockers angiotensin receptor blocker NSAIDs Others Drug-event pair (n = 556) (%) 67 43 34 30 28 27 20 20 19 11 8 86 12,1 7,7 6,1 5,4 5,0 4,9 3,6 3,6 3,4 2,0 1,4 1,4 1,3 15,5 Nguyen Do Quang Trung, Y hoc Vietnam 464 (3) (39) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN CHỌN NHÓM ĐỐI CHỨNG 8208 patient 118 patients with hyperkalemia 8090 patient WITHOUT hyperkalemia Propensity score matching 1:2 92 hyperkalemia Patient with normal K level 3,5 mmol/L <[K+]< 5,5 mmol/L, (WHO criteria) Age, Sex, Baseline eGFR, diabetes, renal failure, heart falure 165 control Pham Thi Dieu Huyen, Msc thesis (40) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN After matching Variable Age Sex Diabetes p 0.508 0.405 0.480 Heart failure Renal failure eGFR 0.443 0.068 0.077 Pham Thi Dieu Huyen, Msc thesis (41) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Drug associate with hyperkalemia Hyperkalemia (n=92) Control (n=165) ORa (KTC 95%) ORb (KTC 95%) PPIs 63 (68,5) 83 (50,3) 2,15 (1,26-3,67) 1,71 (0,90-3,25) Spironolacton 16 (17,4) (4,2) Potassium suppliment 60 (65,2) 41 (24,8) 5,67 (3,25-9,88) 4,91 (2,57-9,37) NSAIDs 13 (14,1) 22 (13,3) 1,07 (0,51-2,24) - RAAs inhibitor 25 (27,2) 70 (42,4) 0,50 (0,29-0,88) 0,28 (0,14-0,56) Medication a confounding 4,75 (1,88-12,04) 4,78 (1,55-14,75) : Crude Odd Ratio b: Adjusted for the use of other drugs Pham Thi Dieu Huyen, Msc thesis (42) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Drug associate with hyperkalemia Medication Beta blocker CCB Digoxin Antibiotics Trimethoprim Furosemid a Hyperkalemia (n=92) Control (n=165) ORa (KTC 95%) ORb (KTC 95%) (7,6) 17 (10.3) 0,72 (0,29-1,79) _ 27 (29,3) 58 (35.2) 0,77 (0,44-1,33) _ (9,8) (4,8) 2,13 (0,79-5,72) _ 63 (68,5) 66 (40.0) 3,26 (1,90-5,59) 1,64 (0,85-3,15) (2,2) (0,6) 3,64 (0,33-40,74) _ 50 (54,3) 59 (35,8) 2,14 (1,27-3,59) 1,00 (0,53-1,93) Confounded Confounded : Crude Odd Ratio b: Adjusted for the use of other drugs Pham Thi Dieu Huyen, Msc thesis (43) Trung tâm DI&ADR Quốc gia Conclusions Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN Pharmacoepidemiology methodology is core element of Pharmacovigilance activities to promote the safety use of drugs We can apply proper PE method to generate the answer for specific questions related to drug safety (44) Trung tâm DI&ADR Quốc gia Tài liệu chia sẻ miễn phí CANHGIACDUOC.ORG.VN (45)