Gender-related differences in post-discharge bleeding among
patients with acute coronary syndrome on dual antiplatelet
therapy: a BleeMACS Sub-study
Abstract
Introduction:
Bleeding is an independent risk factor of mortality in patients with acute coronary syndromes (ACS). Females are exposed to a in greater risk of bleeding compared to men due to gender-related differences in anatomy and physiology. BleeMACS project focuses on long-term bleeding events after hospital discharge.Aim:
Evaluation of gender-related related differences in post-discharge bleeding among patients with ACS.Methods:
13,727 ACS patients treated with PCI and discharged on DAPT (either with clopidogrel or prasugrel/ticagrelor) were included into this sub-analysis of BleeMACS database. Endpoint was defined as intracranial bleeding or any other bleeding leading to hospitalization and/or red blood transfusion. Follow-up covered 1 year after discharge.Results:
Post-discharge bleeding was reported more frequently in females as compared with males (3.7% vs. 2.7%, log-rank P=0.0001). Females (n=3165, 23%) were older compared to men (69.0 vs. 61.5 years, P<0.001) and with more comorbidities like diabetes, hypertension and congestive heart failure. Hence, in multivariate analysis female sex was not identified as an independent risk factor of bleeding (HR 1.012, CI 0.805 to 1.274, P=0.816). Administration of novel antiplatelet agents compared to clopidogrel was associated with over twofold greater bleeding rate in females (7.3% vs. 3.5%, log-rank P=0.004), but not in males (2.6% vs. 2.7%, log-rank P=0.887). This was confirmed in multivariate analysis, where novel agents were found to be independent risk factor for bleeding only in women (HR 2.775, CI 1.613 to 4.774, P<0.001).not independent predictor of post-discharge major bleedings. Administration of novel antiplatelet agents was identified as independent risk factor of bleeding after hospital discharge in female gender, but not in male patients.
Introduction
Bleeding is the most common non-cardiac complication occurring in patients treated for acute coronary syndromes (ACS). Observed incidence rates differ between studies due to variety of adopted endpoint definitions, however its association with reduced survival has been strongly evidenced. [1-4] Moreover, female sex is a proven predictor for developing bleeding – probably in a result of gender-related differences in body surface area, drug metabolism and pharmacokinetics. [5-9]. Reduction of Minimalizing the risk of bleeding through appropriate choice of medication allows, thus, to improve treatment outcomes. Dual antiplatelet therapy (DAPT) – combination of aspirin and a P2Y12 platelet receptor inhibitor – is currently considered to be a gold standard of antiplatelet therapy in patients with ACS, who underwent percutaneous coronary intervention (PCI). Both men and women benefit from the application of aspirin at the time of ACS, whereas addition of the P2Y12 inhibitor f significantly reduces risk of death and major vascular events. [10] Up-to-date guidelines recommend using novel P2Y12 inhibitors in majority of ACS population as they provide favorable clinical effect through greater inhibition and consistency than clopidogrel, which, nonetheless, is still drug of first choice in many countries for economic and safety reasons. [11] PLATO and TRITON-TIMI 38 studies proved superiority of novel antiplatelet agents in reducing adverse events after PCI, but also revealed their association with increase of major bleedings. [12,13] Those were heretofore studied mainly in periprocedural period, thus lack of specific data on bleeding after hospital discharge in a long-term with particular reference to gender disparities. BleeMACS database offers unique opportunity of insight into bleeding
incidents up to one year after discharge in all-comers. The aim of proposed study was therefore to evaluate gender-related differences in post-discharge bleeding among patients with ACS respectively to the DAPT regimen.
Methods
The present study is a post-hoc sub-analysis of the Bleeding complications in a
Multicenter registry of patients discharged after an Acute Coronary Syndrome project
(BleeMACS), which involved fifteen centers on four continents: Europe (Germany, Poland, Netherlands, Spain, Italy, Greece), Asia (China and Japan), North America (Canada) and South America (Brazil) with 15,401 consecutive patients enrolled in total. Briefly, all patients treated with PCI between 2003 and 2014 due to ACS: ST-segment elevation myocardial infarction (STEMI), non-ST segment elevation myocardial infarction (NSTEMI) or unstable angina (UA), who survived hospitalization were included into the study. Detailed protocol was discussed in previous paper and published at clinicaltrials.gov (Identifier: NCT02466854).
The study was conducted in accordance with the Declaration of Helsinki and sub-analysis was approved by scientific committee of the BleeMACS initiative.
Data collection
Data on demographic features, clinical history, physical examination, in-hospital management and outcomes was derived from the BleeMACS database designed by project coordinators. Physicians from the participating centers collected data retrospectively. Centers providing forms with more than 5% of missing values were excluded.
Data definitions
History of bleeding included prior bleeding and in-hospital bleeding. Prior bleeding included any episode of serious bleeding before the qualifying ACS hospitalization and was defined as intracranial bleeding or any other bleeding leading to hospitalization and/or red blood cell transfusion. In-hospital bleeding was defined as any TIMI (Thrombolysis In Myocardial Infarction) major or minor bleeding, or any GUSTO (Streptokinase and t-PA for Occluded Coronary Arteries) moderate or severe bleeding, or any BARC (Bleeding Academic Research Consortium) type 3 bleeding. Malignancy was defined as any active cancer or any non-active cancer, diagnosed during the last 5 years.
Endpoint definition
Episode of serious bleeding, defined as intracranial bleeding or any other bleeding leading to hospitalization and/or red blood transfusion and occurring up to 1-year after hospital discharge was primary endpoint in our study. Events occurring during or after any type of surgery were excluded from the analysis.
Follow-up
Patients were systematically followed for 1 year to assess bleeding complications. Data were obtained from hospital and/or administrative data records, by contacting the patients or their relatives by phone. Primary care physicians were contacted whether additional information was necessary. For patients treated for adverse events at other medical institutions, the medical records and discharge records were systematically collected and reviewed.
Statistical analysis
Shapiro-Wilk test was used to confirm or reject normal distribution of continuous variables, which were expressed as means ± SD and compared with Student’s t-test or Mann– Whitney U test depending on the distribution pattern. Chi-square test was used for comparison of categorical variables expressed as percentages. Impact of DAPT regimen (DAPT with clopidogrel vs DAPT with novel antiplatelet agents) on incidence of bleeding events was assessed with a log-rank test with Kaplan Meier curves. Cox proportional hazard regression model was used to identify predictors of the endpoint among variables listed in
Table 1. Variables impacting prognosis in univariate analysis (with a P value ≤0.10) were
included into multivariate analysis. Results are presented as adjusted hazard ratio (HR) with 95% confidence intervals (CI). All probability values are 2-sided and a value <0.05 was considered to be significant. All data were processed using the SPSS software, version 23 (IBM SPSS Statistics, New York, US).
Results
For the sub-analysis purposes, patients on single antiplatelet therapy (SAPT, n=770), receiving oral anticoagulants (n=680) and treated with thrombolysis (n=224) were excluded leaving 13,727 patients on DAPT: 10,562 men and 3,165 women. (Figure 1)
Detailed characteristics of patients included into the study and divided accordingly to the gender is featured in Table 1. Women with ACS were older than men and with more comorbidities such as: diabetes mellitus (DM), hypertension (HTA) and history of congenital heart failure (CHF). However, invasive treatment of coronary artery disease (CAD) in the past and history of ACS was more prevalent in men, who were more frequently diagnosed with STEMI. Occurrence of bleeding events in the past did not differ between genders, but females had higher incidence of in-hospital bleedings and more often required transfusions.
Gender-related differences in bleeding
Women had greater incidence of bleeding after hospital discharge compared to men (3.7% vs 2.7%, log-rank P=0.001; Figure 2). Rates of bleeding did not differ between DAPT regimens in males (2.7% vs 2.6%, log-rank P=0.887; Figure 3a), however administration of new P2Y12 inhibitors in female patients was associated with over twofold greater prevalence of bleeding events (3.5% vs 7.3%, log-rank P=0.004; Figure 3b).
Multivariate Cox proportional hazard regression did not identify female sex as independent risk factor for bleeding in overall population (HR 1.012, CI 0.805 to 1.274, P=0.816; Table 2). Further gender-specific multivariate cox proportional hazard regression revealed that novel antiplatelet agents are independent risk factor of bleeding in females (HR 2.775, CI 1.613 to 4.774, P<0.001; Table 3), but not in male sex.
Discussion
The first key finding of the present analysis is that women with ACS undergoing PCI experience PDB more frequently than men, however female sex is not independently associated with PDB. Secondly, novel antiplatelet agents were surprisingly found to be related with increased PDB in females, in whom administration of more potent drugs was the strongest independent risk factor of PDB.
Growing body of evidence supports a sex-related difference in a bleeding after ACS. [5-9] Multiple studies demonstrated that women are at substantially greater risk of in-hospital bleeding, however factors influencing short-term prognosis cannot be simply translated into long-term, where significant gap in understanding remains. [14] BleeMACS project in its unique design focuses strictly on events occurring after hospital discharge and extents prior literature by including all three oral P2Y12 receptor inhibitors.
Literature concerning the value of gender as predictor of long-term PDB is still inconsistent. Increased bleeding rates among women are explained either with true gender-related differences in biology or selection bias arising from differences in baseline characteristic between males and females experiencing ACS. [2] Our results seem to support second theory, just as reports from ADAPT-DES database and HMORN-Stent registry, which however pre-date the introduction of newer antiplatelet options. [9,14] Present paper complements them by including populations from different geographical locations treated with prasugrel as well as with ticagrelor in largest evaluation of incidence and predictors of PDB.
Introduction of novel and more potent antiplatelet agents reduced the risk of both MACE and all-cause mortality in patients with ACS – however, at the price of higher bleeding rates. Recent meta-analysis of randomized controlled trials by Lau et al. comparing potent P2Y12 inhibitors in men versus women demonstrated similar increase in risk of major bleeding in both genders. [15] Contrarily, in our real-life observational study, administration of more potent antiplatelet agents was strongly associated with increase of PDB risk in female patients, while in male cohort no difference in comparison to clopidogrel was observed.
There are several potential mechanisms that may contribute to enhanced risk of PDB in women: altered drug bioavailability by lower lean to fat tissue ratio; lower body mass index and higher levels of circulating lipids influencing drug exposure and volume of distribution; or higher prevalence of comorbidities affecting platelet responsiveness. [16,17] That significant gender disparities should lead to reconsideration of paradigm shift from one-size-fits-all to tailor-made therapy. TROPICAL-ACS demonstrated that antiplatelet therapy can be safely de-escalated allowing to benefit from initial potent platelet inhibition using prasugrel, followed later by guided switch to clopidogrel. [18] Expanding availability of platelet-testing systems and increasing selection of antiplatelet drugs create opportunity to optimize
antiplatelet-therapy with respect to baseline characteristic of patients. Therefore, research on peculiarities of specific patients’ groups is needed to identify those, who may benefit from tailored treatment strategies the most.
Study limitations
There are several limitations to our work. Firstly, study is inherent to its retrospective design. We were unable to systematically capture data on minor bleeds that did not lead to hospitalization and/or transfusion, but may be significant factor in process of medication decision-making. Secondly, disproportions between compared groups (males vs females; clopidogrel vs novel antiplatelet agents) may limit statistical power to detect further differences.
Conclusions
Bleeding events occur more frequently in women. However, we didn’t identify female sex itself as an independent risk factor for post-discharge bleedings, which suggests that females are more prone to suffer from bleeding complications rather due to less favorable baseline characteristic than true differences in physiology related to gender. Moreover, significant increase in bleeding rates among women, in whom novel antiplatelet agents were administered, legitimize further research on differences among specific groups of patients to determine potential targets for future tailored antiplatelet therapies.
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