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Taking a gender perspective in the treatment of patients with acute coronary syndrome

Cardiovascular disease has long been looked upon as mainly a male disease, yet it remains the leading cause of mortality in both women and men in the Western world 

Eva Swahn
Department of Medical and Health
Division of Cardiology
Linköping University

Afflicting almost 50% of both genders, coronary heart disease (CHD) accounts for most cardiovascular events, and myocardial infarction (MI) is the single most important contributor to mortality and morbidity.[1] The noted continuous decrease in MI mortality of 4-6% yearly per 100,000 inhabitants in Sweden is valid for women as well as men. And it is not only mortality that is decreasing, but also the incidence of MI.

ACS manifestation
The most common manifestation of CHD is acute coronary syndrome (ACS), which includes sudden cardiac death, ST elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI) and unstable angina pectoris (UAP). Due to similarities in pathophysiology and treatment, NSTEMI and UAP are often referred to as non-ST elevation
ACS (NSTE ACS). However, this population is very heterogeneous, with a wide variation in risk for death and new ischaemic events, and therefore risk stratification is a key part of the management of these patients. In patients with ACS, the proportion of NSTEMI to STEMI, and in NSTE ACS the proportion of UAP to NSTEMI, is higher for women than for men.[2]
Although in-hospital mortality is higher in STEMI than NSTE ACS, long-term mortality is comparable. However, with the development of new treatment strategies, the distinction between STEMI and NSTEMI upon presentation has become more important to guide early treatment and decision making – for example, fibrinolysis or referral for primary percutaneous coronary intervention (PCI).

Historically, fewer women than men have been included in CHD studies. Whether this is due to lower incidence in women or actual exclusion of women from the trials have been debated.[3,4] The consequence is that the evidence base for
management of women with ACS is less clear
than it is for men.
During the last two decades, increased attention has been paid to gender differences in the treatment of ACS. However, as there are major differences in baseline characteristics between men and women with ACS that may affect the attending physician’s choice of treatment, appropriateness of a certain treatment and maybe even the patient’s preferences for a
certain treatment, this will influence the care of the patient.
For example, women have less often received reperfusion therapy, early antithrombotic therapy and antiplatelet therapy at discharge. Moreover, men have more often been referred for coronary angiography.[5,6] These treatment differences can be
explained by the knowledge that after adjustment for age, comorbidity and severity of disease, most of the gender differences disappear.[7]
Another example of maybe a real gender difference is when women appear to have less benefit from a routine early invasive strategy compared to men. The reason is most likely a combination of several factors, among them differences between the genders in risk profile and difference in risk associated with invasive procedures. Both men and women with high risk, defined as elevated markers of myocardial necrosis, seem to benefit from an invasive strategy. In low-risk patients with ACS, there has been an indication of harm with a routine
invasive strategy in women that could not be seen in men.[8]
The clinical challenge today is to identify individual patients with the highest risk for ischaemic events without unreasonably
elevated early risk for complications with an invasive strategy. For example, actions to minimise bleeding complications, including dose adjustments according to renal function, weight
and age, are of importance for both genders, but particularly for women. However, an individually tailored treatment strategy to balance early procedural risk with long-term reduction of
cardiac events will benefit both men and women with ACS.
Bleeding complications are the most frequent non-ischaemic complications in ACS patients and recent trials have highlighted
a strong impact on prognosis with bleeding in these patients.[9,10,11] Female sex has been appointed as an independent predictor of bleeding in several ACS trials with different anticoagulation strategies.[10]
There are several factors that may explain worse outcome associated with major bleeding. Among them, potential confounders such as older age, comorbidity and renal failure, but also more causative factors such as hemodynamic instability and the possibility that bleeding triggers prothrombotic and pro-inflammatory processes. Furthermore, discontinuation of antiplatelet and antithrombotic therapy as a consequence of bleeding has been put forward as a major reason for increased risk of ischaemic events.[12] Women appear to be at higher risk for excess doses of antithrombotic medication and, as a consequence, higher bleeding rate.[13,14]

There is a myth that women have less ‘typical’ angina symptoms when experiencing acute coronary syndrome than men. This possible sex difference in symptoms in the ACS population has been debated for a long time and is still somewhat controversial, even if new knowledge speak in the opposite direction – that is, more similarities than differences.
A recent Swedish study with MI patients aged 25 to 74 years could find no statistically significant sex difference in the proportion of patients with chest pain, which was prevalent in 90-95% of the patients. Nausea, back pain, dizziness and
palpitations were significantly more common in women, and women as a group reported more symptoms than men.[15] A recent study from the GRACE registry showed similar results, over 90% of both men and women with ACS had chest  pain.[16] Thus it is important to emphasise the fact that chest pain of any sort is the most common symptom in either sex with ACS.

Future research
It is a very important issue to find gender similarities and differences regarding management of patients with acute coronary syndromes. It is a fact that over the years women
have been included in fewer numbers than men in clinical trials, for whatever reason. Even if it has become better, the facts are that still too few women are included in trials, as shown in a recent, updated analysis of the enrolment of women in
mixed-gender NHLBI-sponsored randomised controlled trials with primary outcomes of stroke, myocardial infarction or death published between 1997 and 2006, where the proportion
of women was 27% and only 13 of 19 studies included in this analysis reported gender-based outcomes in their primary report.[17]
In the cardiovascular clinical trials performed almost exclusively in European countries in the same period, the proportion of women enrolled varied between 16 and 25%, although the female prevalence of the clinical condition under study in the general population was similar to that of men.[18]
Women have an increased bleeding tendency and more renal failure than men with ACS, which both influence the  management and thus the prognosis. Whether this is a dosing question or the fact that women have a different metabolism
than men is not clear and has to be clarified. There is therefore a need for more research in this area in order to not harm women with our treatment because of a paucity of knowledge.
It is also as important not to withdraw proper treatment from women when they can benefit from it. For the future, it is of utmost importance to individualise the management of the patient, disregarding gender and age. To get there, it is
necessary to have enough numbers of patients from both  genders and all ages included in trials, to be able to draw proper conclusions. Until now, most results regarding women and ACS were based on sub-study analyses without enough statistical power, which, incidentally, is also valid for the men included.

1. The Swedish National board of Health and Welfare. National Cause of Death Register.
2. Hochman JS et al. N Engl J Med 1999;341:226-32.
3. Meinert CL. Science 1995;269:795-6.
4. Lee PY et al. JAMA 2001;286:708-13.
5. Chandra NC et al. Arch Intern Med 1998;158:981-8.
6. Mahon NG et al. Am J Cardiol 2000;85:921-6.
7. Blomkalns AL et al. J Am Coll Cardiol 2005;45:832-7.
8. Swahn E et al. Eur Heart J 2009.
9. Moscucci M et al. Eur Heart J 2003;24:1815-23.
10. Manoukian SV et al. J Am Coll Cardiol 2007;49:1362-8.
11. Budaj A et al. Eur Heart J 2009;30:655-61.
12. Eikelboom JW et al. Circulation 2006;114:774-82.
13. Alexander KP et al. JAMA 2005;294:3108-16.
14. Alexander KP et al. Circulation 2006;114:1380-7.
15. Berg J et al. Gend Med 2009;6:454-62.
16. Dey S et al. Heart 2009;95:20-6.
17. Kim C et al. J Am Coll Cardiol 2008;52:672-3.
18. Stramba-Badiale M. Red Alert on Women’s Hearts. Women and Cardiovascular Research in Europe. European Heart Health Strategy, EuroHeart Project, Work Package 6, Women and
Cardiovascular Diseases.