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Centre for Evidence-
Based Medicine

Completed Harm Worksheet for Evidence-Based Nursing

Citation

Mant J, Painter R, Vessey M. Risk of myocardial infarction, angina and stroke in users of oral contraceptives: an updated analysis of a cohort study. Br J Obstet Gynaecol 1998;105:890-6.

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?
    17, 032 women were recruited from 17 family planning clinics in England and Scotland between 1968 and 1974. All women were British, married, Caucasian, and between 25 and 39 years old at study entry. 15, 292 women (90%) were followed to age 45 at which time they were divided into 3 groups: never-users of OCs (n=5881); users of OCs for > 8 years (n=3520); and the remainder (n=5891). Although data were not provided to compare the similarity of groups on the following variables, event rates were adjusted for these potential confounders: age, social class, smoking and obesity for all outcome diagnoses, and parity for myocardial infarction and angina only. The potential confounder of comorbidity was addressed by conducting a restricted analysis excluding women with hypertension, diabetes, or hyperlipidaemia. The authors noted that they did not examine the effects of alcohol, diet, and exercise as potential confounders. Although not specifically stated, it is fairly certain that the women were free of the outcomes of interest (myocardial infarction, angina, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and transient ischaemic attack) at study entry.
  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. Women were followed annually by interview at the family planning clinic or by postal questionnaire for changes in contraceptive practices and reasons for hospital referrals. Nonresponders were telephoned or visited. Only hospital-confirmed diagnoses of cardiovascular events were recorded.
  3. Was the follow-up of study patients complete and long enough?
    Women were recruited between 1968 and 1974 and followed until 1994; therefore, follow-up ranged from 20 to 26 years. 15, 292 of the 17, 032 women (90%) were still participating at age 45.

Do the results satisfy some "diagnostic tests for causation"?

  1. Is it clear that the exposure preceded the onset of the outcome?
    Yes. Women were assessed for OC use prior to experiencing the cardiovascular events of interest.
  2. Is there a dose-response gradient?
    No, there was no significant relation between duration of OC use and risk of cardiovascular disease.
  3. Is there positive evidence from a "dechallenge-rechallenge" study?
    No
  4. Is the association consistent from study to study?
    Yes. The results of this study concur with the results of the only other prospective study of OCs conducted in the UK. Both studies observed an increased risk of MI in OC users who were heavy smokers and an increased risk of ischaemic stroke in current users of OCs but not ex-users. The results are also consistent with the recent WHO Collaborative case control studies.
  5. Does the association make biological sense?
    Yes. The pathology of OC-related heart disease is connected with changes in coagulation.

Are the valid results from this harm study important?

Adverse Outcome Totals
Present (case) Absent (case)
Exposed to the Treatment Yes (Cohort)

a

b

a + b

No (Cohort)

c

d

c + d

Totals

a + c

b + d

a + b + c + d

Although we are told the number of women who used and didn't use OCs and the number who experienced cardiovascular events, it would be inaccurate to complete the table using these raw data. The authors have very appropriately adjusted rates and relative risks for age, parity, social class, obesity, and comorbidity. Based on the adjusted analyses, there was no increased risk of myocardial infarction (RR=1.5, 95% CI 0.6 to 3.2) except in heavy smokers. An increased risk of myocardial infarction was observed in OC users who were heavy smokers compared with non-users (RR=4.9, 95% CI 1.2 to 23.6). There was no increased risk of angina (RR=0.5, 95% CI 0.1 to 1.4), but there was an increased risk of ischaemic stroke (RR=2.9, 95% CI 1.3 to 6.7) that did not persist once OCs were discontinued.

Should these valid, potentially important results of a critical appraisal about a harmful treatment change the treatment of your patient?

  1. Can the study results be extrapolated to your patient?
    Yes. The results for non-smokers can be extrapolated to this patient.
  2. What are your patient's risks of the adverse outcome?

    To calculate the NNH (the Number of patients you Need to treat to Harm one of them) for any Odds Ratio (OR) and your Patient's Expected Event Rate for this adverse event if they were NOT exposed to this treatment (PEER):

    NNH = (PEER(OR-1)+1)/(PEER(OR-1)x(1-PEER))
    This patient is not at increased risk of angina and because she is not a smoker, she is also not at increased risk of myocardial infarction. Her OC use is associated with an increased risk of ischaemic stroke but this needs to be considered in the context of the very low absolute risk of cardiovascular disease in this population. The NNH is 5880; that is, 5880 women would need to take OCs for 1 year to cause 1 additional stroke.
  3. What are your patient's preferences, concerns and expectations from this treatment?
    Need to be determined.
  4. What alternative treatments are available?
    There are numerous other birth control methods; however, most are not as effective or convenient as OCs.

Additional Notes

  1. Women already known to be at risk for myocardial infarction or stroke are unlikely to be prescribed OCs.
  2. 68% of the woman's years of exposure to OCs in this study was to pills with 50 μg of oestrogen, which is higher than the standard doses in use today. By 1987 only 2.7% of OCs prescribed in the UK contained 50 µg of oestrogen.

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