### Harm Scenario

You are a nurse practitioner working in a family practice setting. One of your patients is a 28-year old woman who has been taking oral contraceptives (OCs) for the past 6 years. She telephones you to say that she is growing increasingly anxious about taking OCs because recently she has read in magazines and heard from friends that they may increase the risk of cardiovascular disease. She has never smoked, is in good health, and has no history of cardiovascular disease in her family. She asks to see you to discuss whether she should discontinue taking the OCs and begin using a different birth control method.

You admit to yourself that it has been some time since you reviewed the literature on this topic and at that time, most of the studies were case controls. You recall from an editorial in Evidence-Based Nursing (1999;2:4-6) that case control studies are weaker than randomized controlled trials or cohort studies because they begin with the outcome of interest (e.g., cardiovascular disease) and look back for exposure to the causative agent (e.g., OCs). The limitations of this retrospective design are the difficulties in: establishing that the exposure actually occurred before the outcome (temporality); obtaining accurate information about exposure to a causative agent that occurred in the past (relies on accuracy of people’s memory or on completeness and accuracy of medical records); and identifying a control group that is similar in all other factors that may have influenced the outcome.

In preparation for your appointment with your patient, you decide to formulate a question and search for prospective studies. You formulate the question, “In women taking oral contraceptives, is there an association between their use and cardiovascular disease?”

Searching terms and evidence source:
You begin an advanced search on PubMed using the search terms “oral contracept” AND “cardiovascular disease” AND “risk factor“. Combining these 3 terms yields a total of 832 citations. To further narrow your search, you enter the terms “cohort stud*” AND “prospective” (because you have learned that for studies of harm, prospective cohort studies have fewer methodological problems than case-control or cross-sectional studies) – 10 citations are identified. The first citation you look at seems promising — 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.

• Is the evidence from this randomised trial valid?
• If valid, is this evidence important?
• If valid and important, can you apply this evidence in caring for your patient?

### 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?

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.
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.
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”?
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.
No, there was no significant relation between duration of OC use and risk of cardiovascular disease.
Is there positive evidence from a “dechallenge-rechallenge” study?
No
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.
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?

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?

Can the study results be extrapolated to your patient?
Yes. The results for non-smokers can be extrapolated to this patient.
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):

$$mathit{NNH} = frac{mathit{PEER}(mathit{OR}-1)+1}{mathit{PEER}(mathit{OR}-1)times(1-mathit{PEER)}}$$

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.
What are your patient’s preferences, concerns and expectations from this treatment?
Need to be determined.
What alternative treatments are available?
There are numerous other birth control methods; however, most are not as effective or convenient as OCs.

• Women already known to be at risk for myocardial infarction or stroke are unlikely to be prescribed OCs.
• 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 Âµg of oestrogen.

### Cardiovascular Disease – Oral contraceptive may increase risk

#### Clinical Bottom Line

Increased risk of stroke in patients taking OCs. Lower dose pills are now in common use and may be safer than the higher dose pills examined in this study. Even with the older higher dosages, the absolute risks of ischaemic stroke in OC users are low; 5880 women would need to take OCs for 1 year to cause 1 additional stroke.

#### 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.

#### Clinical Question

What is the association between oral contraceptive use in women and the risk for cardiovascular disease?

#### Search Terms

PubMed was searched using the terms “oral contracept” AND “cardiovascular disease” AND “risk factor” AND “cohort stud*” AND “prospective”.

#### The Study

17,032 women aged 25 to 39 years were recruited between 1968 and 1974 from 17 family planning clinics in England and Scotland. They provided information annually about contraception method. 15,292 (90%) were still participating at age 45. Women were categorised in terms of OC use. Hospital-confirmed diagnoses of cardiovascular events (myocardial infarction, angina, ischaemic stroke, subarachnoid haemorrhage, intracerebral haemorrhage, and transient ischaemic attack) were recorded.

#### The Evidence

Outcome Relative Risk* 95% Confidence Interval
MI 1.5 0.6 to 3.2
Angina 0.5 0.1 to 1.4
Ischaemic Stroke 2.9 1.3 to 6.7
* Adjusted for age, parity, social class, smoking, comorbidity