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Centre for Evidence-
Based Medicine

Completed Harm Worksheet for Evidence-Based Purchasing

Citation

Beral V, Hermon C, Kay C, Hannaford P, Darby S, Reeves G. Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46,000 women from Royal College of General Practitioners' oral contraception study. BMJ 1999;318:96-100

Are the results of this harm study valid?

  1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?
    Yes. Although the article does not contain a table comparing characteristics of women in the two groups, the results controlled for possible confounding factors: age, social class, parity and smoking (p.100).
  2. Were treatment exposures and clinical outcomes measured the same ways in both groups (e.g., was the assessment of outcomes either objective (e.g., death) or blinded to exposure)?
    Yes. In both groups, exposure to oral contraception was measured from GPs' prescribing records every six months, and death from all causes was measured from English and Scottish central registers (p.96).
  3. Was the follow-up of study patients complete and long enough?
    Yes. Although only about 75% of the original participants were followed up, the other 25% left only because their GPs had left the study before original participants had been flagged - not because of systematic differences of the patients. Subsequent checking showed that those who left the study had similar mortality rates to the 75% who remained.

Do the results meet "causation criteria"? (also known as the Bradford Hill criteria)?

  1. Is it clear that the exposure preceded the onset of the outcome?
    Yes
  2. Is there a dose-response gradient?
    Kind of. The study did not control for different strengths or types of oral contraception (most were the combined pill containing 50lg of oestrogen (p.99), but it did take into account duration of exposure (Tables 4 & 5).
  3. Is there positive evidence from a "dechallenge-rechallenge" study?
    No
  4. Is the association consistent from study to study?
    Don't know (would need to look at other studies)
  5. Does the association make biological sense?
    Yes

Are the valid results from this harm study important?

Adverse Outcome
(death from all causes*)
Totals
Present (case) Absent (case)
Exposed to the Treatment Yes (Cohort)

0.0018

a

0.9982

b

a + b

No (Cohort)

0.0019

c

0.9981

d

c + d

Totals

a + c

b + d

a + b + c + d

* note that you could use this table to analyse risks of death from specific causes using the data in Tables 4 & 5. These figures are taken from the "ever vs. never" used columns in table 1, with the person-year denominators (517,519 vs 335,998) in the ever vs never groups on page 97.
** note that the death rates uses person-years as the denominator, rather than people. That is, if you take the pill for one year, you can expect a death rate from all causes of 0.18% = 945 deaths/517,519 person years [page 97]
*** In this study, relative risk = RR = 0.0018/0.0019 = 0.95, and when adjusted for several baseline differences, RR to 1.1 (95% CI 0.9-1.1, p value of 0.7) i.e. there is no significant difference in death between the two groups.

Additional Notes

There are many different figures that you could analyse from this large study. For example, you could pull out the risks from a specific form of death. One possible learning point to draw out is the use of the more accurate measure of exposure, person-years, as a denominator, rather than just people.

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