BACKGROUND

Bleeding complications increase mortality in patients with acute coronary syndrome (ACS). Potential gender difference in bleeding regarding prevalence, location, severity and prognostic impact is still controversial and not well investigated. In regard to this aspect the relevance of triple antithrombotic therapy (TAT) is questioned. There is an ongoing debate on the clinical implications of TAT and furthermore assumed that bleeding complications, except impact on outcome, also are associated with great influence on health economy.

The main focus of this thesis was to further investigate the incidence and impact of bleeding complications in patients treated for ACS, with special reference to gender disparities, TAT and health economics. The thesis will highlight the importance of improved bleeding prevention strategies for both men and women.

METHOD

Paper I, II and III

Observational studies from the SWEDEHEART register.

In paper I we investigated patients hospitalised with myocardial infarction (MI) during 2006–2008. Outcomes were in-hospital bleedings, in-hospital mortality and one-year mortality in hospital survivors.

In paper II, all patients with MI, in the County of Östergötland, Sweden during 2010 were included and followed for one year. The patients' medical records were evaluated, in relation to short and long-term bleeding complications, bleeding location, withdrawal of platelet inhibiting drugs and nonfatal MI and death.

Paper III included all patients discharged with (TAT) in the County of Östergötland 2009-2015. Information about bleeds and ischemic complications during one-year follow-up were retrieved from the medical records. Estimation of the health care costs associated with bleeding episodes were added to the evaluation.

Paper IV

Patients with MI, scheduled for coronary angiography were recruited. All patients received clopidogrel and aspirin. A subgroup of patients received GP IIb/IIIa-inhibitor. Outcomes were platelet aggregation assessed at several time points, using a Multiplate impedance aggregometer, measurement of P-selectin in plasma, evaluation of high residual platelet reactivity (HRPR) and low residual platelet reactivity (LRPR) respectively and incidence of bleeding complications. A comparison between women and men was performed.

RESULTS

Paper I

A total number of 50.399 patients were included, 36.6% women. In-hospital bleedings were more common in women (1.9% vs. 3.1%, p<0.001) even after multivariable adjustment (OR 1.17, 95%, CI 1.01–1.37). The increased risk for women was found in STEMI (OR 1.46, 95% CI 1.10–1.94) and in those who underwent PCI (OR 1.80, 95% CI 1.45–2.24).

In contrast the risk was lower in medically treated women (OR 0.79, 95% CI 0.62–1.00). After adjustment, in-hospital bleeding was associated with higher risk of oneyear mortality in men (OR 1.35, 95% CI 1.04–1.74), whereas this was not the case in women (OR 0.97, 95% CI 0.72–1.31).

Paper II

In total 850 consecutive patients were included. The total incidence of bleeding events was 24.4% (81 women and 126 men, p=ns). The incidence of all in hospital bleeding events was 13.2%, with no gender difference. Women had significantly more minor nonsurgery related bleeding events than men (5% vs 2.2%, p=0.02). During follow-up, 13.5% had a bleeding, with more non-surgery related bleeding events among women, 14.7% vs 9.7% (p=0.03). The most common bleeding localisation was the gastrointestinal tract, more in women than men (12.1% vs 7.6%, p=0.03). Women also had more access site bleeding complications (4% vs 1.7%, p=0.04), while men had more surgery related bleeding complications (6.4% vs 0.9%, p≤0.001). Increased mortality was found only in men with non-surgery related bleeding events (p=0.008).

Paper III

Among 272 identified patients, 156 bleeds occurred post-discharge, of which 28.8% were of gastrointestinal origin. In total 54.4% had at least one bleed during or after the index event and 40.1% bled post-discharge of whom 28.7% experienced a TIMI major or minor bleeding. Women discontinued TAT prematurely more often than men (52.9 vs 36.1%, p=0.01) and bled more (48.6 vs. 37.1%, p=0.09). One-year mean health care costs were EUR 575 and EUR 5787 in non-bleeding and bleeding patients, respectively.

Paper IV

We recruited 125 patients (37 women and 88 men). We observed significantly more inhospital bleeding events in women as compared to men (18.9% vs 6.8%, p=0.04). There were no differences in platelet aggregation using three different agonists, reflecting treatment of GPIIb/IIIa inhibitors, clopidogrel and aspirin, at four different time-points nor were there any differences in p-selectin in plasma 3 days after admission.

CONCLUSION

There is a remarkably high bleeding incidence among patients treated with DAPT and even more so if treated with TAT. Female gender is an independent risk factor of inhospital bleeding after myocardial infarction, this higher bleeding risk in women appears to be restricted to invasively treated patients and STEMI patients. Even if women had higher short- and long-term mortality, there was no difference between the genders among those who bled. After multivariable adjustment the prognostic impact of bleeding complications was higher in men

Women seem to experience more minor/minimal bleeding complications than men, predominantly GI bleeding events and access site bleeding events, with no apparent impact on outcome.

In contrast men with non-surgery related bleeding complications had higher mortality. There is a lack of differences between the genders concerning platelet aggregation. Our results do not support gender disparities in platelet reactivity and excess dosing as a major explanation for increased bleeding risk in women. Improved bleeding prevention strategies are warranted for both men and women.