1 st october 2010

Hormonal contraception and risk of venous thromboembolism:national follow-up study

BMJ Sept 2009;339:b2890

1st October 2010

A critical appraisal by Mark Chadwick

Hormonal contraception and risk of VTE

– Presentation of paper

– Critical appraisal

– Questions

– Thoughts for the weekend

Introduction

• Studies show increased risk in VTE on OCP

– Higher in first yr– Higher with desogestrel / gestodene– Lower with levonorgestrel

• Shift from 50mcg to 40-20mcg ethinylestradiol

– Theoretical lower risk– Equivocal evidence

Objective

• To assess risk of VTE in current users of different types of hormonal contraception

Methods

– Stated Cohort study

– Linkage of 4 National registries

• Central personal registry• Prescriptions• Education• Health

Methods

– Study Population

• 01 Jan 1995 – 31 Dec 2005• All Danish women, 15-49 yrs• Prior Malignancy & CVD excluded

• New diagnoses censored• Emigrants censored• Pregnancy excluded +12/+4wks

Methods

– End points

• First time VTE diagnosis

Methods

Current Use Valid Rx at time of hospital admission

Previous Use Any previous use during study period

Never Use No record

Non-Use Previous Use + Never Use

IUDs 3yrs from insertionUnless Rx within 6yrs => continuous use

Length = Sum of valid Rx – periods of no valid Rx

– Groupings

Methods

– Contraception Categories

• Time of usage• Regime (OCP / POP / IUD)• Oestrogen dose• Progestogen• Current usage (<1yr, 1-4yrs, >4yrs)• POP type

Methods

– Statistics

• Poisson regression

• Time at risk (women yrs)

• Number of VTEs

• Group

Methods

– Confounders

• drugs for DM, HT, Diuretics, β/Ca blockers, ACE-I, Statins

• Schooling / Education

Results

Results

Confounding Factors

POSITVE (Δ>5%) NEGATIVE

Age Diabetic drugs

Calendar Year Heart drugs

Education Hypertension drugs

Statins

Results

Group Woman Yearsx 10^6

First VTE Crude Rate per 10,000 woman years

Total 10.4 4213 4.03

Current use

3.4 (3.25) 2405 6.29

Non-use 7.2 2168 3.01

Former use

2.3 667 2.93

Never use 4.8 1467 3.05

Results

– Age Related use– Young use newer OCPs , short intervals

Results

– VTE risk increased with– Age– Study period 1.05 (95%CI 1.04 – 1.06)/yr– Decreasing education– First year use– Some longer term use

– POP No increased VTE risk cf non-users– Levonorgestrel /noresthisterone 0.59 (CI 0.33 –

1.04)– Desogestrel 1.1 (CI 0.35 – 3.41)

– IUD – 0.89 (95CI 0.64 – 1.26)

Discussion

– Aims achieved

– Factors causing VTE– Excluding cancer /CHD => increased risk

estimate

– Pregnancy / POP => decrease risk

– Change over time– Better detection

Discussion

Take home Points

• The risk of VTE

– Decreases with dose of oestrogen

– desogestrel / gestodene > levonorgestrel

– Unchanged by POP & IUDs

• Absolute risk of VTE in any COP in young women is <1:1000 user yrs




– Questions


AUTHOR

Critical appraisal

– Is the paper interesting and relevant?

YES

– Who wrote the paper?

– Do they or the institution have a proven academic record?

– Appropriate Experience– Area of Expertise– Previous publications

Prof. Øjvind Lidegaard, Copenhagen, Denmark

– 81 graduated Copenhagen University

– 81-87 Clinical residences in neurology, internal medicine, gastro enterology, psychiatry, pediatrics

– 92 Specialist in O&G

– 93-97 senior resident O&G at Herlev Uni Hospital

– 97-06 Appointed consultant & associate Professor

– 06- Professor of the Gynecological Clinic at Copenhagen Uni


– published 135 scientific publications• first author on 102

– Majority epidemiological studies on risk factors

• female cancers• cardiovascular diseases

– ‘96 dissertation on oral contraceptives and thrombotic strokes


– Member of Board of Directors, Danish Society of Medical Informatics, 1988–1993.

– Head of “Working group on gynecological technology assessment and quality assurance”, Danish Society of Obstetrics and Gynecology (DSOG) 1990–1997.

– Head of “Committee on postgraduate education”, DSOG, April 1992 to April 1996.

– Head of “Scandinavian Committee on postgraduate education”, Scandinavian Society of Obstetrics and Gynecology (NFOG) August 1994 to August 1996.

– Consultant in “Committee on postgraduate education”, Danish Medical Association, 1991–1996.

– Consultant in WHO on the project “Obstetrical quality indicators”, 1991–1995.

– Head of guideline group in gynaecological reproduction, DSOG, 2000–2008.

– Member of guideline group in hormone replacement therapy, DSOG 2000–2003

– Member of guideline group in contraception,

– DSOG 2000–2008.

– Member of Climate and health working group, Danish Medical Association since 2008.

INTRODUCTION

Introduction

– Title

• Clear / Concise / Appropriate

– YES

• Was the study original?

– No, but follow-up to original

Introduction

– Literature Review

• Did the study introduction address the relevant points?

– Yes

• Method / Extent / Up to date

– Yes

Introduction

– Hypothesis

• Were the hypotheses/aims clearly stated?

– YES

– Purpose

• Who sponsored - Uni , pharm companies ? who

• Who benefits -

• Need for answer - YES

METHOD / DATA

Methods 1

– Type of research? • Objective / Subjective / Questionnaire / Interview

Methods 1

– Type of research? • Objective / Subjective / Questionnaire / Interview

– Was there Ethics approval?• DATA PROTECTION ONLY AS NOT REQUIRED

Methods 1

– Was there Validation?• YES … but ..

– 10% VTE uncertain– Therefore of remainder

» 97% imaged, 2% treated» 94% imaged & treated

– Uncertainty <1%

– NO 11%

Methods 2

– Level of Evidence?

• Ia Meta-analysis of RCCT

• Ib RCCT

• IIa controlled trial NOT randomised

• IIb quasi-experimental study

• III descriptive study

• IV expert opinion

Methods 3

– Was the study design appropriate?

• Review - systematic or meta-analysis

• Drug treatment - randomised controlled trail

• Causation - case - control study

• Prognosis - cohort study

Methods 3

– Was the study design appropriate?

• Review - systematic or meta-analysis

• Drug treatment - randomised controlled trail

• Causation - case - control study

• Prognosis - cohort study » Unclear if historic

» Previously was case-control !

….!!! Time Out !!!…..

• Cohort Study

– an observational study that takes a

group (cohort) of patients and

follows their progress in order to

measure outcomes such as disease

or mortality rates, and make

comparisons according to the

treatments that patients received.A Daly, 2008

Cohort Study

Study population

Exposed

Non-exposed

Disease +

Disease +

Disease -

Disease -

Cohort Study

• Case-Control Study

– a study that starts with the identification of a

group of individuals sharing the same

characteristics (disease) and a suitable

comparison group (no disease). All subjects

are then assessed with respect to things that

happened in the past that might be related

to contracting the disease. A Daly, 2008

Study Population

Cases

Controls

Exposed

Non-exposed

Exposed

Non-exposed

Case-Control Study

Study population

Exposed

Non-exposed

Disease +

Disease +

Disease -

Disease -

Retrospective Cohort Study

• Cohort Analysis

– Analysis of results is a matter of calculating and comparing

rates, which are commonly expressed in terms of person-

years of observation.

– 1 person is observed for 10 years, = 10 person-years.

– 2 years observation of 5 persons, = 10-person years.

– The use of person-years is a convenient way to generate

larger numbers for calculation of rates that are more

stable than with smaller numbers over numerous

timelines.J Last, enotes.com

Sample

– Inclusion / Exclusion criteria?

• Imigrants

• Previous VTE

– Was an appropriate group of subjects studied?

• Age

Groupings

Current Use Valid Rx at time of hospital admission

Previous Use Any previous use during study period

Never Use No record

Non-Use Previous Use + Never Use

IUDs 3yrs from insertionUnless Rx within 6yrs => continuous use

Length = Sum of valid Rx – periods of no valid Rx

Sample 2

– Were measurements valid and reliable?

• Not as clear as would like

– Were all patients entered into the study properly accounted for?

• Questionable

– Were the outcome measures stated and relevant?

• Yes?

Statistics

– Were the statistical methods described? • Poisson correct for Cohort• No regression calculations demonstrated

– Does the tests chosen reflect the type of data• Yes as groups and years different for each

– Was systematic bias avoided or minimized? • Confounding Factors were looked for

– Schooling / diabetes / ACE– 5% estimated risk

• Confounding factor

– a factor that influences a study that

can contribute to misleading findings

• i.e. Two groups - one exercising regularly the other not

(the groups have a significant age difference but this is not

considered). In relation to cardiovascular events the

outcomes are influenced as much by age as exercising.

Age is therefore the confounding factor.

A Daly, 2008

• Confounder

• Selection bias:– Non-response during data collection– Losses to follow up– Healthy worker effect

• Misclassification on exposure or event– Random– Systematic

Cohort Study – Bias

RESULTS

Results 1

– Clearly displayed– YES

– Tables stand out alone– YES

– Data

– Precise (numbers)

– Typo errors ie 3,253,131 became 3,400,000

Results 2

– Length / completeness of follow-up– 11 YRS, Follow on to CASE-CONTROL

– How large was the treatment effect? – Larger than previous studies

– Partially Significant

– How precise was the estimate of the treatment effect?

– There are assumptions

Discussion 1

– Were the aims of the study fulfilled?– YES

– Sources of error / weakness discussed?– YES

– Are the relevant findings justified? – YES

– Are the conclusions of the paper justified?

– YES

Discussion 2

– What is the impact of the paper? – High impact journal (12.287)

– Relevant info not possible to generate here

– Generalisation to other populations? – Not commented on

– Assumption as Western Europe Population

Overall

– What do you think of the paper?

• Sound if statistics ok

– If you were BMJ editor would you

• Publish article

• Advise minor alterations

• Re-write but accept

• Reject

• Advise minor alterations




– Questions


Thoughts for the weekend ….

Avoid bad habits...Avoid bad habits...

Always be ready for any Always be ready for any surprises in life...surprises in life...

Go and have fun in the Go and have fun in the meadows...meadows...

1 st october 2010

Documents

risk of vtepresentation

pop iudsabsolute risk

decrease risk change

risk of venous thromboembolism

insertionunless rx

young women

danish women

sum of valid rx periods