pharmacoepidemiology: past, present and future

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Pharmacoepidemiolo Pharmacoepidemiolo gy: Past, present gy: Past, present and future and future Kathleen Bennett, PhD Kathleen Bennett, PhD Department of Pharmacology & Department of Pharmacology & Therapeutics, Trinity College Therapeutics, Trinity College Dublin Dublin [email protected] [email protected] 3 3 rd rd Sept 2009 Sept 2009

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Pharmacoepidemiology: Past, present and future. Kathleen Bennett, PhD Department of Pharmacology & Therapeutics, Trinity College Dublin [email protected] 3 rd Sept 2009. ‘A desire to take medicine is, perhaps, the great feature which distinguishes man from other animals’ William Osler,1891. - PowerPoint PPT Presentation

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Page 1: Pharmacoepidemiology: Past, present and future

Pharmacoepidemiology: Pharmacoepidemiology: Past, present and futurePast, present and future

Kathleen Bennett, PhDKathleen Bennett, PhDDepartment of Pharmacology & Department of Pharmacology &

Therapeutics, Trinity College DublinTherapeutics, Trinity College [email protected]@tcd.ie

33rdrd Sept 2009 Sept 2009

Page 2: Pharmacoepidemiology: Past, present and future

‘‘A desire to take A desire to take medicine is, medicine is, perhaps, the great perhaps, the great feature which feature which distinguishes man distinguishes man from other animals’from other animals’

William Osler,1891William Osler,1891

Page 3: Pharmacoepidemiology: Past, present and future

What is pharmacoepidemiology?What is pharmacoepidemiology?

Defined as the study of the utilization and effects Defined as the study of the utilization and effects of drugs in large numbers of people. of drugs in large numbers of people.

PharmacoepidemiologyPharmacoepidemiology borrows from both borrows from both pharmacology and epidemiology, a bridge pharmacology and epidemiology, a bridge science spanning both pharmacology and science spanning both pharmacology and epidemiology.epidemiology.

PharmacoepidemiologyPharmacoepidemiology can also be defined can also be defined as the application of epidemiological methods to as the application of epidemiological methods to pharmacological issues.pharmacological issues.

Page 4: Pharmacoepidemiology: Past, present and future

Pharmacoepidemiology in practicePharmacoepidemiology in practice

To quantify adverse events with medicines To quantify adverse events with medicines in the populationin the population

Patterns of drug utilisation, including Patterns of drug utilisation, including adherenceadherence

Hypothesis generatingHypothesis generating

Page 5: Pharmacoepidemiology: Past, present and future

Pharmacoepidemiology – Pharmacoepidemiology – Observational studiesObservational studies

Without treatment allocation by chance, Without treatment allocation by chance, bias due to different baseline risks for bias due to different baseline risks for disease in users and non-users of drugs disease in users and non-users of drugs cannot be ruled out completely - cannot be ruled out completely - confounding by indicationconfounding by indication..The potential for confounding is probably The potential for confounding is probably larger in observational studies assessing larger in observational studies assessing medications than in studies assessing medications than in studies assessing lifestyle factors. lifestyle factors.

Page 6: Pharmacoepidemiology: Past, present and future

PharmacovigilancePharmacovigilance

There are also some areas that are altogether There are also some areas that are altogether unique to pharmacoepidemiology, e.g. unique to pharmacoepidemiology, e.g. pharmacovigilance. pharmacovigilance. PharmacovigilancePharmacovigilance is a type of continual is a type of continual monitoring for unwanted effects and other safety-monitoring for unwanted effects and other safety-related aspects of drugs that are already on the related aspects of drugs that are already on the market. market. PharmacovigilancePharmacovigilance refers almost exclusively to refers almost exclusively to the spontaneous reporting systems which allow the spontaneous reporting systems which allow health care professionals and others to report health care professionals and others to report adverse drug reactions to a central agency. adverse drug reactions to a central agency. It relies heavily on reporting of safety events by It relies heavily on reporting of safety events by health professionals.health professionals.

Page 7: Pharmacoepidemiology: Past, present and future

PharmacoeconomicsPharmacoeconomics

Pharmacoeconomics is that branch of health economics that focuses upon the costs and benefits of drug therapy.

Definition: The comparative analysis of alternative courses of action in terms of BOTH their costs and consequences.

Page 8: Pharmacoepidemiology: Past, present and future

Pharmacoeconomic EvaluationPharmacoeconomic Evaluation

Page 9: Pharmacoepidemiology: Past, present and future

Pharmaceutical Pharmaceutical Expenditure Expenditure Under Under the Community Drug Schemes: the Community Drug Schemes:

1991-20071991-2007

170 190 200 210 240 260 300350

430

560

700

880

11001210

1320

1500

1745

0

200

400

600

800

1000

1200

1400

1600

1800

2000

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Year

Mill

ion

s (e

uro

)

Source: Primary Care Reimbursement Service (PCRS)*Pharmaceutical expenditure includes payment to pharmacies for the cost of medicines, dispensing fees and payment to wholesalers under the High Tech Drug Scheme

Page 10: Pharmacoepidemiology: Past, present and future

Pharmacoeconomics & Pharmacoeconomics & pharmacoepidemiologypharmacoepidemiology

Inter-related disciplinesInter-related disciplines Used byUsed by Industry for marketing/price settingIndustry for marketing/price setting HSE - reimbursement decisionsHSE - reimbursement decisions Public health - e.g. vaccination programmesPublic health - e.g. vaccination programmes

Can help identify whether particular sub-Can help identify whether particular sub-groups of patients will benefit most from a groups of patients will benefit most from a new drug and in which it is most cost-new drug and in which it is most cost-effective.effective.

Page 11: Pharmacoepidemiology: Past, present and future
Page 12: Pharmacoepidemiology: Past, present and future

Historical backgroundHistorical background

US law, Pure Food and Drug Act, passed in US law, Pure Food and Drug Act, passed in 1906, followed by FD and cosmetic Act in 1938. 1906, followed by FD and cosmetic Act in 1938. Preclinical toxicity testing and clinical data about Preclinical toxicity testing and clinical data about drug safety required before drug marketed.drug safety required before drug marketed.‘‘Thalidomide disaster’ in 1961 led to Thalidomide disaster’ in 1961 led to establishment of committee of safety of establishment of committee of safety of medicines in 1968 in UK and changes medicines in 1968 in UK and changes elsewhere.elsewhere.‘‘Pharmacoepidemiology’ first appeared in Pharmacoepidemiology’ first appeared in medical literature (BMJ) in 1984.medical literature (BMJ) in 1984.

Page 13: Pharmacoepidemiology: Past, present and future
Page 14: Pharmacoepidemiology: Past, present and future

Drug ToxicityDrug Toxicity

ThalidomideThalidomide

Chloramphenicol and Grey Baby SyndromeChloramphenicol and Grey Baby Syndrome

Gynaecological cancer in offspring of women Gynaecological cancer in offspring of women receiving Diethyl Stilboestrolreceiving Diethyl Stilboestrol

Oculomucocutaneous syndrome with practololOculomucocutaneous syndrome with practolol

Liver disease from benoxaprofenLiver disease from benoxaprofen

Valvular heart disease from DexfenfluramineValvular heart disease from Dexfenfluramine

Cardiac arrhythmias with terfenadineCardiac arrhythmias with terfenadine

Multiple drug interactions with mibefradilMultiple drug interactions with mibefradil

Page 15: Pharmacoepidemiology: Past, present and future

What papers have shaped What papers have shaped Pharmacoepidemiology?Pharmacoepidemiology?

Page 16: Pharmacoepidemiology: Past, present and future
Page 17: Pharmacoepidemiology: Past, present and future
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Page 19: Pharmacoepidemiology: Past, present and future

ControversiesControversies

Page 20: Pharmacoepidemiology: Past, present and future

Pharmacoepidemiology in IrelandPharmacoepidemiology in Ireland

Since 1968 Ireland has participated in the WHO Since 1968 Ireland has participated in the WHO International Drug Monitoring System and International Drug Monitoring System and pharmacoepidemiology was mainly in the area pharmacoepidemiology was mainly in the area of Adverse drug reaction (ADR) reporting. of Adverse drug reaction (ADR) reporting.

The Yellow Card Scheme for ADR reporting has The Yellow Card Scheme for ADR reporting has operated through the Irish Medicines Board operated through the Irish Medicines Board since 1996 and the National Drugs Advisory since 1996 and the National Drugs Advisory Board (NDAB) before that. However, ADR Board (NDAB) before that. However, ADR reporting rates are low; <10% of all serious and reporting rates are low; <10% of all serious and 2-4% of non-serious ADRs reported.2-4% of non-serious ADRs reported.

Page 21: Pharmacoepidemiology: Past, present and future

The Pill ScareThe Pill ScareIn October 1995, the Committee of Safety of Medicines In October 1995, the Committee of Safety of Medicines (CSM) issued a warning on the increased risk of (CSM) issued a warning on the increased risk of thromboembolism associated with the third-generation thromboembolism associated with the third-generation oral contraceptive steroids.oral contraceptive steroids.This ‘Pill Scare’ led to some users stopping the oral This ‘Pill Scare’ led to some users stopping the oral contraceptive steroids mid-cycle and a rise contraceptive steroids mid-cycle and a rise subsequently in abortions and pregnancies was noted.subsequently in abortions and pregnancies was noted.The Irish Medicines Board did not advise discontinuation The Irish Medicines Board did not advise discontinuation of third -generation oral contraceptives , but advised of third -generation oral contraceptives , but advised further study and analysis of the previous studies to further study and analysis of the previous studies to evaluate the impact of biases and confounders.evaluate the impact of biases and confounders.No regulatory action was taken.No regulatory action was taken.

Page 22: Pharmacoepidemiology: Past, present and future
Page 23: Pharmacoepidemiology: Past, present and future

Percentage uptake of oral contraceptives by

generation between J anuary 1995 and November

1996.

0

10

20

30

40

50

60

J anu

ary-

95

Mar

ch- 9

5

May

- 95

J uly-

95

Sept

embe

r-95

Novem

ber-

95

J anu

ary-

96

Mar

ch- 9

6

May

- 96

J uly-

96

Sept

embe

r-96

Novem

ber-

96

Month

Perc

enta

ge

1st

2nd

3rd

Norgestimate

Page 24: Pharmacoepidemiology: Past, present and future
Page 25: Pharmacoepidemiology: Past, present and future

Examples of Examples of pharmacoepidemiology databasespharmacoepidemiology databases

GPRD – GP research database in UKGPRD – GP research database in UK

MEMO – Scottish record linkage dataMEMO – Scottish record linkage data

Saskatchewan Health Services - Canada

Kaiser Permanente – US

Odense database- Denmark

HSE-PCRS – prescribing data only IrelandHSE-PCRS – prescribing data only Ireland

Page 26: Pharmacoepidemiology: Past, present and future

HSE-Primary Care Reimbursement HSE-Primary Care Reimbursement Services (PCRS)Services (PCRS)

The PCRS is part of the HSE, and is responsible for The PCRS is part of the HSE, and is responsible for making payments to healthcare professionals, e.g. making payments to healthcare professionals, e.g. doctors, dentists and pharmacists, for the free or reduced doctors, dentists and pharmacists, for the free or reduced costs services they provide to the public.costs services they provide to the public.

It supports the delivery of primary healthcare by providing It supports the delivery of primary healthcare by providing reimbursement services in their own community.reimbursement services in their own community.

There are many schemes under the HSE-PCRS but for There are many schemes under the HSE-PCRS but for drug prescribing the three main ones are: GMS medical drug prescribing the three main ones are: GMS medical card scheme, Drug payment (DPS) and Long Term card scheme, Drug payment (DPS) and Long Term Illness (LTI) schemes.Illness (LTI) schemes.

Page 27: Pharmacoepidemiology: Past, present and future

HSE-PCRS pharmacy claims HSE-PCRS pharmacy claims databasedatabase

The number of GMS eligible persons by The number of GMS eligible persons by December 2007 was 1.28 million people ( ~ December 2007 was 1.28 million people ( ~ 30% of population). 30% of population).

Not fully representative - socially Not fully representative - socially disadvantaged persons, children and the disadvantaged persons, children and the elderly are over-represented.elderly are over-represented.

Accounts for approximately 70% of all Accounts for approximately 70% of all prescribed medicines.prescribed medicines.

Limitations – no diagnosis or outcome dataLimitations – no diagnosis or outcome data

Page 28: Pharmacoepidemiology: Past, present and future

ExamplesExamples

Quality prescribing indicatorsQuality prescribing indicators Elderly population exposed to potentially Elderly population exposed to potentially

inappropriate medications; generic prescribinginappropriate medications; generic prescribing

European drug utilisation studiesEuropean drug utilisation studies Statins, PPIs, SSRIs, ACE/ARBsStatins, PPIs, SSRIs, ACE/ARBs

Various disease areas including Various disease areas including adherence to tamoxifen in breast canceradherence to tamoxifen in breast cancer

Page 29: Pharmacoepidemiology: Past, present and future

Prevalence of potentially inappropriate Prevalence of potentially inappropriate medication use in those 65+ yearsmedication use in those 65+ years

Criteria- PIM Criteria- PIM Proportion of all Proportion of all patients (n=367,260)patients (n=367,260)

Proportion of patients Proportion of patients in the ERHAin the ERHA(n=101,935) (n=101,935)

Proportion of patients Proportion of patients in ERHA nursing in ERHA nursing homes (n=2085)homes (n=2085)

AntidepressantsAntidepressants amitriptyline, amitriptyline, doxepin, flouxetinedoxepin, flouxetine

9515 (2.59%)9515 (2.59%) 2340 (2.30%)2340 (2.30%) 43 (2.06%)43 (2.06%)

SedativesSedatives Long-acting Long-acting benzodiazepines benzodiazepines

39059 (10.64%)39059 (10.64%) 11963 (11.74%)11963 (11.74%) 332 (15.92%)332 (15.92%)

AntibacterialAntibacterial NitrofurantoinNitrofurantoin

7028 (1.91%)7028 (1.91%) 2277 (2.23%)2277 (2.23%) 87 (4.17%)87 (4.17%)

Potential Drug-Drug Potential Drug-Drug InteractionsInteractions

Anticoagulants and Anticoagulants and aspirinaspirin

4943 (1.35%)4943 (1.35%) 1588 (1.55%)1588 (1.55%) 28 (1.34)28 (1.34)

Anticoagulants and Anticoagulants and NSAIDsNSAIDs

6370 (1.73%)6370 (1.73%) 1767 (1.73%)1767 (1.73%) 35 (1.68%)35 (1.68%)

The 1-year risk of receiving at least one PIM using the combination of Beers and McLeod criteria was 20.6% using the national prescribing data (2004)

Page 30: Pharmacoepidemiology: Past, present and future

% of % of prescriptions dispensed prescriptions dispensed generically on the GMS in 200generically on the GMS in 20088

2.4%

15.9%

24.9%

56.8%

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

Unbranded generic Branded generic Proprietary drug with ageneric equivalent

Proprietary drug with nogeneric equivalent

Page 31: Pharmacoepidemiology: Past, present and future

Differences may reflect demographics and reimbursement issues

IInternternational Cnational Comparisons of omparisons of DDrug rug UUtilisation tilisation SStatisticstatistics

% utilisation generic omeprazole vs. all PPIs

0

20

40

60

80

100

120

Country

% U

tilisati

on

200120042007

Page 32: Pharmacoepidemiology: Past, present and future

BMJ 2005

Page 33: Pharmacoepidemiology: Past, present and future

Aliment Pharm Therap 2009

Page 34: Pharmacoepidemiology: Past, present and future

B J Clin Pharm 2007

On September 30, 2004, Merck and Co. On September 30, 2004, Merck and Co. voluntary withdrew rofecoxib (Vioxx) due voluntary withdrew rofecoxib (Vioxx) due to increased risk of CV eventsto increased risk of CV events

Page 35: Pharmacoepidemiology: Past, present and future

Eur J Clin Pharm 2006

Page 36: Pharmacoepidemiology: Past, present and future

Hormone treatment in cancerHormone treatment in cancer

Hormone therapy is designed to alter hormone Hormone therapy is designed to alter hormone production in the body so that cancer cells stop production in the body so that cancer cells stop growing or are killed completely. growing or are killed completely.

Breast cancer hormone therapies often focus on Breast cancer hormone therapies often focus on reducing estrogen levels (a common drug for this reducing estrogen levels (a common drug for this is tamoxifen) and prostate cancer hormone is tamoxifen) and prostate cancer hormone therapies often focus on reducing testosterone therapies often focus on reducing testosterone levels. levels.

In addition, some leukemia and lymphoma cases In addition, some leukemia and lymphoma cases can be treated with the hormone cortisone.can be treated with the hormone cortisone.

Page 37: Pharmacoepidemiology: Past, present and future

T I Barron1 R M Connolly2 K Bennett1 M J Kennedy2 J Feely1

1 Dept Pharmacology & Therapeutics,Trinity College Dublin.2 Academic Unit of Clinical & Molecular OncologyTrinity College Dublin & St. James’s Hospital.

Early Discontinuation Early Discontinuation of Tamoxifenof Tamoxifen

Email: [email protected]

Page 38: Pharmacoepidemiology: Past, present and future

BackgroundBackground

Adherence & PersistenceAdherence & PersistenceDefinitionsDefinitions

Adherence (Synonym: Compliance) is Adherence (Synonym: Compliance) is the extent to which a the extent to which a patient takes medication in accordance with the prescribed patient takes medication in accordance with the prescribed interval and dose.interval and dose.11

Persistence is the accumulation of time from initiation to Persistence is the accumulation of time from initiation to discontinuation of therapy.discontinuation of therapy.11

Significance?Significance?Substantial worsening of disease and mortality.Substantial worsening of disease and mortality.

Increased healthcare costs.Increased healthcare costs.

Healthy drug user effect.Healthy drug user effect.

1 ISPOR Medication Compliance & Persistence Special Interest Group.http://www.ispor.org/sigs/MCP_accomplishments.asp#definition

Page 39: Pharmacoepidemiology: Past, present and future

BackgroundBackground

TamoxifenTamoxifen5 years of treatment reduces the relative breast 5 years of treatment reduces the relative breast cancer recurrence risk by 46% and the relative risk cancer recurrence risk by 46% and the relative risk of death by 26%.of death by 26%.11

Comparisons of treatment durations indicate that Comparisons of treatment durations indicate that women receiving less than 5 years of treatment women receiving less than 5 years of treatment have significantly higher breast cancer recurrence have significantly higher breast cancer recurrence rates and mortality.rates and mortality.1,21,2

1 Lancet 1998; 351: 1451-67; 2 Lancet 2005; 365: 1687-717

Page 40: Pharmacoepidemiology: Past, present and future

AimsAims

AimsAimsTo evaluate persistence with tamoxifen therapy, in To evaluate persistence with tamoxifen therapy, in women aged 35 years or older, using prescription women aged 35 years or older, using prescription refill data from a national prescribing database.refill data from a national prescribing database.

Prescription refill data provide accurate and objective Prescription refill data provide accurate and objective estimates of medication use in large populations estimates of medication use in large populations over long periods of time.over long periods of time.

This is the first study to evaluate tamoxifen This is the first study to evaluate tamoxifen persistence using this method.persistence using this method.

Page 41: Pharmacoepidemiology: Past, present and future

MethodsMethods

HSE-PCRS 2000-2005HSE-PCRS 2000-2005All women over the age of 35 years , commenced on All women over the age of 35 years , commenced on tamoxifen as initial hormonal therapy between January tamoxifen as initial hormonal therapy between January 2001 and January 2004.2001 and January 2004.

Measurement of tamoxifen persistenceMeasurement of tamoxifen persistenceA period of 180 consecutive days of no tamoxifen supply.A period of 180 consecutive days of no tamoxifen supply.

Patients with no prescription for any item in the 12 Patients with no prescription for any item in the 12 months following non-persistence were reclassified as months following non-persistence were reclassified as lost to follow up.lost to follow up.

Patients starting alternative hormonal therapy before 180 Patients starting alternative hormonal therapy before 180 days of no tamoxifen were reclassified as treatment days of no tamoxifen were reclassified as treatment switchers.switchers.

Page 42: Pharmacoepidemiology: Past, present and future

MethodsMethods

Potential determinants of non-persistencePotential determinants of non-persistenceAge at initiation of tamoxifen.Age at initiation of tamoxifen.

Co-morbidities.Co-morbidities.

Number of pharmacological agents received.Number of pharmacological agents received.

Use of antidepressant, antipsychotic, or Use of antidepressant, antipsychotic, or anxiolytic/hypnotic agents.anxiolytic/hypnotic agents.

Treatment for cognitive or functional impairment Treatment for cognitive or functional impairment (Parkinson’s disease or dementia)(Parkinson’s disease or dementia)

Cox proportional hazards model.Cox proportional hazards model. Stepwise selection with criteria for entry of p <0.1.Stepwise selection with criteria for entry of p <0.1.

Page 43: Pharmacoepidemiology: Past, present and future

ResultsResultsStudy Cohort (n=2816)Study Cohort (n=2816)

Table 1: Characteristics of patients starting tamoxifen on the HSE-PCRS database (January 01-Table 1: Characteristics of patients starting tamoxifen on the HSE-PCRS database (January 01-January 04)January 04)

nn %% nn %%

Age (years)*Age (years)* Cognitive/functional impairment Cognitive/functional impairment ††

35-4435-44 262262 9.39.3 Parkinson’s DiseaseParkinson’s Disease 8181 2.92.9

45-5445-54 509509 18.118.1 DementiaDementia 2525 0.90.9

55-6455-64 592592 21.021.0 Number of co-morbidities Number of co-morbidities ††

65-7465-74 575575 20.420.4 00 19061906 67.767.7

>75>75 878878 31.231.2 ≥≥11 910910 32.332.3

Prescription Drug Use Prescription Drug Use †† Number of cognitive/functional impairments Number of cognitive/functional impairments ††

Benzodiazepine anxiolytic/hypnoticBenzodiazepine anxiolytic/hypnotic 11631163 41.341.3 00 27102710 96.296.2

AntidepressantAntidepressant 534534 19.019.0 ≥≥11 106106 3.83.8

Benzodiazepine related hypnoticBenzodiazepine related hypnotic 390390 13.813.8 Mean number of pharmacological agents per month Mean number of pharmacological agents per month ††

AntipsychoticAntipsychotic 375375 13.313.3 ≤≤11 951951 33.833.8

Co-morbidities Co-morbidities †† >1 >1 ≤3≤3 920920 32.732.7

Respiratory diseaseRespiratory disease 385385 13.713.7 >3 >3 ≤5≤5 502502 17.817.8

Cardiovascular diseaseCardiovascular disease 599599 21.321.3 >5>5 443443 15.715.7

DiabetesDiabetes 117117 4.24.2

* At tamoxifen initiation; † In 12 months prior to tamoxifen initiation* At tamoxifen initiation; † In 12 months prior to tamoxifen initiation

Page 44: Pharmacoepidemiology: Past, present and future

Results -Results -Tamoxifen non-persistenceTamoxifen non-persistence

Study cohort of 2816 women ≥35yrs commenced on tamoxifen as initial hormonal therapy (January 2000 – January 2004)

470 (16.7%)

Stop tamoxifen & switch hormonal therapy after 180 days

Stop tamoxifen & switch hormonal therapy before 180 days

Stop tamoxifen & restart tamoxifen after180 days

Stop tamoxifen & no subsequent hormonal therapy

Lost to follow up

716 (25.4%)

34 (1.2%)

143 (5.1%)

569 (20.2%)

884 (31.4%) Persist with tamoxifen

Non-persistent Population 746

(26.5%)

Fig 1: Outcomes for patients starting tamoxifen on the HSE-PCRS database (January 01 – January 04)

Study cohort of 2816 women ≥35yrs commenced on tamoxifen as initial hormonal therapy (January 2000 – January 2004)

470 (16.7%)

Stop tamoxifen & switch hormonal therapy after 180 days

Stop tamoxifen & switch hormonal therapy before 180 days

Stop tamoxifen & restart tamoxifen after180 days

Stop tamoxifen & no subsequent hormonal therapy

Lost to follow up

716 (25.4%)

34 (1.2%)

143 (5.1%)

569 (20.2%)

884 (31.4%) Persist with tamoxifen

Non-persistent Population 746

(26.5%)

Study cohort of 2816 women ≥35yrs commenced on tamoxifen as initial hormonal therapy (January 2000 – January 2004)

470 (16.7%)

Stop tamoxifen & switch hormonal therapy after 180 days

Stop tamoxifen & switch hormonal therapy before 180 days

Stop tamoxifen & restart tamoxifen after180 days

Stop tamoxifen & no subsequent hormonal therapy

Lost to follow up

716 (25.4%)

34 (1.2%)

143 (5.1%)

569 (20.2%)

884 (31.4%) Persist with tamoxifen

Non-persistent Population 746

(26.5%)

Page 45: Pharmacoepidemiology: Past, present and future

Results - Results - Determinants of non-persistenceDeterminants of non-persistenceTable 2: Crude & adjusted hazard ratios (HR) for potential determinants of tamoxifen non-persistenceTable 2: Crude & adjusted hazard ratios (HR) for potential determinants of tamoxifen non-persistence

Crude HRCrude HR 95% CI95% CI Adjusted Adjusted HRHR

95% CI95% CI

Age (years)Age (years) 35-4435-44 1.361.36 1.01 to 1.821.01 to 1.82 1.361.36 1.01 to 1.831.01 to 1.83

45-5445-54 ReferenceReference -- -- --

55-6455-64 1.071.07 0.84 to 1.370.84 to 1.37 1.111.11 0.86 to 1.420.86 to 1.42

65-7465-74 1.231.23 0.96 to 1.570.96 to 1.57 1.271.27 0.98 to 1.610.98 to 1.61

>75>75 1.421.42 1.14 to 1.771.14 to 1.77 1.461.46 1.16 to 1.831.16 to 1.83

Prescription Drug UsePrescription Drug Use Benzodiazepine anxiolytic/hypnoticBenzodiazepine anxiolytic/hypnotic 0.990.99 0.86 to 1.150.86 to 1.15 -- --

AntidepressantAntidepressant 1.311.31 1.10 to 1.561.10 to 1.56 1.411.41 1.18 to 1.701.18 to 1.70

Benzodiazepine related hypnotic (ZZZ)Benzodiazepine related hypnotic (ZZZ) 0.810.81 0.65 to 1.010.65 to 1.01 -- --

AntipsychoticAntipsychotic 1.161.16 0.95 to 1.430.95 to 1.43 -- --

Number of co-morbiditiesNumber of co-morbidities 00 ReferenceReference -- -- --

≥≥11 1.041.04 0.90 to 1.220.90 to 1.22 -- --

Number of cognitive/functional co-Number of cognitive/functional co-morbiditiesmorbidities

00 ReferenceReference -- ReferenceReference --

≥≥11 1.781.78 1.29 to 2.461.29 to 2.46 1.721.72 1.24 to 2.391.24 to 2.39

Mean number of pharmacological agents per Mean number of pharmacological agents per monthmonth

≤≤11 ReferenceReference -- ReferenceReference --

>1≤3>1≤3 0.890.89 0.74 to 1.050.74 to 1.05 0.840.84 0.71 to 1.000.71 to 1.00

>3≤5>3≤5 0.870.87 0.70 to 1.070.70 to 1.07 0.760.76 0.61 to 0.940.61 to 0.94

>5>5 0.900.90 0.72 to 1.120.72 to 1.12 0.720.72 0.58 to 0.920.58 to 0.92

* At tamoxifen initiation; † In 12 months prior to tamoxifen initiation; ‡ Adjusted * At tamoxifen initiation; † In 12 months prior to tamoxifen initiation; ‡ Adjusted for age, antidepressant use, number of cognitive or functional impairments for age, antidepressant use, number of cognitive or functional impairments and number of pharmacological agents per month.and number of pharmacological agents per month.

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DiscussionDiscussion

Non-persistence with tamoxifen in clinical Non-persistence with tamoxifen in clinical practice is higher than previously reported.practice is higher than previously reported.

35.2% of women discontinue tamoxifen by 3.5 years.35.2% of women discontinue tamoxifen by 3.5 years.

22.1% discontinue tamoxifen by 1 year.22.1% discontinue tamoxifen by 1 year.

The determinantsThe determinants Extremes of age, treatment with an antidepressant with non-Extremes of age, treatment with an antidepressant with non-persistencepersistence

Increasing numbers of prescribed medications associated Increasing numbers of prescribed medications associated with better tamoxifen persistence.with better tamoxifen persistence.

ConclusionConclusionPersistence with tamoxifen cannot be assumedPersistence with tamoxifen cannot be assumed

Raises concerns about persistence with other oral hormonal Raises concerns about persistence with other oral hormonal therapies/anti-neoplastics in generaltherapies/anti-neoplastics in general

Page 47: Pharmacoepidemiology: Past, present and future

Pharmacoepidemiology – Pharmacoepidemiology – Methodological developmentsMethodological developments

Studies based on large health care Studies based on large health care utilization databases tend to use data utilization databases tend to use data collected for reasons unrelated to the collected for reasons unrelated to the research hypothesis thus lacking data on research hypothesis thus lacking data on all important confounders. all important confounders. To address unmeasured confounding and To address unmeasured confounding and bias in database studies, several bias in database studies, several approaches have been proposed. approaches have been proposed.

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Some examples of methodological Some examples of methodological developmentsdevelopments

STROBE and ISPE good practice guideline STROBE and ISPE good practice guideline for conduct of PE studiesfor conduct of PE studiesPropensity scores Propensity scores Optimal selection of controlsOptimal selection of controlsTime dependency in cohort studiesTime dependency in cohort studiesImmortal time biasImmortal time biasValidation StudiesValidation StudiesCase-crossover designCase-crossover design

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Future researchFuture research

Linkage studiesLinkage studies Electronic record linkage now established between Electronic record linkage now established between

NCRI and HSE-PCRS for GMS patients (NCRI and HSE-PCRS for GMS patients (probabilistic probabilistic matching of matching of breast, colorectal cancers and continuing breast, colorectal cancers and continuing for all cancer sites).for all cancer sites).

Every GMS eligible patient on NCRI will have Every GMS eligible patient on NCRI will have prescribing data available from 2000 onwards.prescribing data available from 2000 onwards.

Will enable future studies Will enable future studies Outcomes from prescribing (protective or otherwise) Outcomes from prescribing (protective or otherwise) Drug utilisation before and after diagnosis of cancerDrug utilisation before and after diagnosis of cancer Pharmacoeconomics of cancer treatmentsPharmacoeconomics of cancer treatments Hypothesis generating, etc.Hypothesis generating, etc.

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Current proposalsCurrent proposals

Adherence to oral hormonal therapies and Adherence to oral hormonal therapies and outcomes in breast cancer.outcomes in breast cancer. Building on existing work but linked to breast cancer Building on existing work but linked to breast cancer

outcomes.outcomes.

Breast cancer and digoxinBreast cancer and digoxin There is recent laboratory work linking cardiac There is recent laboratory work linking cardiac

glycosides to hypoxia inducible factor (HIF-1) inhibition glycosides to hypoxia inducible factor (HIF-1) inhibition which has been show to inhibit tumour growth and which has been show to inhibit tumour growth and cancer metastasis. cancer metastasis.

Considering this effect it may be worthwhile to examine Considering this effect it may be worthwhile to examine the effect of digoxin (cardiac glycoside) on disease the effect of digoxin (cardiac glycoside) on disease progression and mortality in women who already have progression and mortality in women who already have a diagnosis of breast cancer.a diagnosis of breast cancer.

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Future scientific developmentFuture scientific development

Application of new epidemiological Application of new epidemiological methods to this areamethods to this area

Quality of life studies linked to prescribingQuality of life studies linked to prescribing

Individualising drug therapy Individualising drug therapy

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PharmacogenomicsPharmacogenomics

The rapidly advancing field of pharmacogenomics, The rapidly advancing field of pharmacogenomics, have created important new opportunities in cancer have created important new opportunities in cancer research and control. research and control.

Pharmacogenomics involves identifying an Pharmacogenomics involves identifying an individual's response to a drug based on his or her individual's response to a drug based on his or her genetic, genomic, and/or proteomic profile.genetic, genomic, and/or proteomic profile.

The concept that each patient's cancer or risk of The concept that each patient's cancer or risk of cancer has a unique genetic and/or molecular cancer has a unique genetic and/or molecular profile – this may provide new ways to personalize profile – this may provide new ways to personalize an individual's therapy for increased clinical benefit. an individual's therapy for increased clinical benefit.

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ExampleExample

Co-prescription rates of Co-prescription rates of tamoxifen and CYP2D6 inhibitorstamoxifen and CYP2D6 inhibitors Co-prescription rate of tamoxifen and Co-prescription rate of tamoxifen and

CYP2D6 inhibitors is 13.2%CYP2D6 inhibitors is 13.2% Literature suggests link to reduced breast Literature suggests link to reduced breast

cancer outcomecancer outcome Avoidance of moderate and potent CYP2D6 Avoidance of moderate and potent CYP2D6

inhibitors advised where possibleinhibitors advised where possible

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ConclusionConclusion

Pharmacoepidemiology is relatively new science in Pharmacoepidemiology is relatively new science in Ireland, but of increasing significance as drug Ireland, but of increasing significance as drug licensing and marketing take on a European licensing and marketing take on a European dimension. dimension.

From a public health perspective, it is important to From a public health perspective, it is important to assess the impact that vaccines and drugs have on assess the impact that vaccines and drugs have on the overall patterns of disease in the population. the overall patterns of disease in the population.

Finally, society is now more sensitive to the costs of Finally, society is now more sensitive to the costs of medical care and in particular drug use. medical care and in particular drug use. Pharmacoeconomics can help predict the economic Pharmacoeconomics can help predict the economic implications of drug use prior to their marketing. implications of drug use prior to their marketing.

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The young physician starts life with 20 drugs The young physician starts life with 20 drugs for each disease, and the old physician for each disease, and the old physician ends life with one drug for 20 diseases. ends life with one drug for 20 diseases.

William OslerWilliam Osler

AcknowledgementsAcknowledgementsHSE-PCRS for supply of data for research purposes.HSE-PCRS for supply of data for research purposes.Dr Ian Barron, Dr Lesley TilsonDr Ian Barron, Dr Lesley Tilson