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CLARIFY: Women and men with stable coronary artery disease have similar cardiovascular outcomes: observations from an international prospective cohort of 30 977 patients from 45 countries



Presenter: Philippe Gabriel Steg | see Discussant report

List of Authors: Prof. Ph. Gabriel Steg / France
Co-authors: Prof Roberto Ferrari, Italy; Prof  Ian Ford, UK, Prof Kim Fox, UK; Dr Nicola Greenlaw, UK; Dr Helene Abergel, France, Prof Stefan Kääb, Germany; Prof Jean-Claude Tardif, Canada; Prof Michael Tendera, Poland, on behalf of the CLARIFY registry



While there are gender differences in outcomes following myocardial infarction, only limited data are available regarding differences among patients with stable coronary artery disease (CAD). We assessed gender-specific differences in 1 year outcomes in outpatients with stable CAD using a large contemporary prospective database from 45 countries.
Methods and results
CLARIFY is an international, prospective, observational, longitudinal cohort of patients with proven stable CAD from 45 countries, enrolled between November 2009 and July 2010. 30 977 patients completed 1-year follow up (women, 22.6%). Compared with men, women were on average 3 years older (66.5 vs 63.4 years), had higher mean resting heart rate (69.6 vs 67.9 bpm) and mean systolic blood pressure (133 vs 130 mm Hg). They also had more frequent anginal symptoms (29 vs 21%), diabetes (33 vs 28%), hypertension (79 vs 69%), but lower rates of current smoking (7 vs 14%) or peripheral artery disease (8 vs 10%).
There were no differences in use of renin-angiotensin system inhibitors between the sexes, while women received lipid-lowering drugs (90 vs 93%) and aspirin (87 vs 88) less frequently; and more often calcium antagonists (32 vs 26%), long-acting nitrates (26 vs 21%) and diuretics 38 vs 27%).
After adjustment for risk factors, age and baseline differences, event rates were similar for both genders for all cause death (OR: 0.91, 95% CI: 0.73-1.13), fatal or nonfatal myocardial infarction  (OR: 0.81, 95% CI: 0.60-1.08), cardiovascular death or myocardial infarction (OR: 0.89, 95% CI: 0.70-1.13), all coronary events (OR: 0.98, 95% CI: 0.87-1.10), for a combined endpoint of cardiovascular death or nonfatal myocardial infarction or nonfatal stroke (OR: 0.93, 95% CI:0.75-1.15). Fewer women underwent revascularisation with percutaneous coronary intervention or coronary artery bypass graft surgery (OR: 0.77, 95% CI: 0.64-0.93).
In the large contemporary population of outpatients with stable CAD, death dates and CV event rates at 1-year follow-up were similar across genders, even though fewer women underwent revascularization. Further evaluation is required to understand the determinants of outcomes in relation to management differences across genders in stable CAD patients.

What is new compared to the latest presentation of the trial: This analysis for the first time evaluates gender-specific differences in 1 year outcomes in outpatients with stable CAD using a large contemporary prospective database from 45 countries.

Discussant: Eva Swahn | see Presenter abstract


The CLARIFY population is in this study analysed from a gender perspective. The CLARIFY,  being a prospective, observational, longitudinal registry of patients with stable coronary artery disease consisting of > 33 000 patients in 45 countries all over the world included at one year follow-up 7002 women and 23975 men. Stable CAD was defined as at least one of the following: documented MI > 3 months before enrolment; angiographic demonstration of coronary stenosis > 50 %; chest pain with evidence of myocardial ischaemia  (stress electrocardiogram); or CABG or PCI > 3 months before enrolment. The main outcome was defined as the composite of cardiovascular death, MI, and stroke.
The main results are, according to the authors, that despite substantial differences in baseline clinical characteristics and management, the rates of cardiovascular clinical outcomes were similar between men and women, both with and without adjustment.

What is then new knowledge from this analysis?  It is a well-known fact that comorbidities, risk factors, medication, management and sometimes but not always outcome differs. The authors claim that this as a large contemporary cohort of outpatients with stable CAD and broad geographic representation provides new information.

1. What is really the difference between this “stable” population that mostly consists of post-MI or post revascularization patients from other ACS registry populations? Who is a stable CAD patient? The one who has only stable angina and never had any event like revascularisation or MI? Or the one (as in CLARIFY) who did not have any event for 3 months after a first event? Thus the definition of stable CAD is not clear cut and gives us in CLARIFY a case-mix of patients leading to difficulties to interpret the results. Does it matter and should we divide the CAD patients in stable – unstable and acute? Is it not the same disease?
2. The patients seem to be highly selected as only 22.6 % were women and according to epidemiological investigations the prevalence usually is the same and in fact even slightly higher in women with angina (7, 8).
As the including physicians were requested to recruit 10-15 stable CAD outpatients this selection bias could have been avoided by requesting them to recruit 50-50 % women and men. This selection limits significantly the representativeness and generalisability of the results.
3. As in all registries on clinical practice, one limitation is the handling of missing data. This is also the case in CLARIFY. At 1-year follow-up 6.8% of the patients either withdrew their consent, had no follow-up or the follow-up was still ongoing. This is a high drop-out rate, whatever the reason. The 1202 patients who had not finished one year follow-up could have been waited for in order to decrease the drop-out rate considerably.
Furthermore, as in all observational data sets, the adjustment might be influenced by the lack of registration of some possible confounding e.g. non-cardiac co-morbidity, contraindications to specific treatment and reduced kidney function. Glomerular filtration rate <60 mL/min has recently been shown to be far more common in CAD women than men and could have been included in the adjustment (9, 10)
4. To secure the trustworthiness of the given data in any clinical trial it is of utmost necessity to monitor the results by an independent monitor. In CLARIFY this was done in only 5% of centers – events were accepted as reported by physicians and were not adjudicated.

Given these limitations the CLARIFY study adds value to the CAD gender knowledge as it included a large amount of patients from a wide geographical area. The results do anyhow have to be interpreted with caution.
Gender is associated with differences between women and men regarding behavior and disease, as well as with inequality of life conditions. Thus gender is, and should be, an important variable at the level of the individual physician, especially as it relates to interpersonal interactions with patients. It is also known that men and women have well-documented differences in how they communicate, and, not surprisingly, these differences also extend to how male and female physicians interact with their patients and themselves. This must always be taken into consideration, even whilst planning a clinical trial, RCT or observational.


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Clinical Trial & Registry Update I: Updates on Prevention and Markers

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.