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Among patients with acute coronary syndromes (ACS), women benefit from the superior risk-benefit profile of ticagrelor as much as men, according to a subanalysis of the PLATO trial published online March 28, 2014, ahead of print in the European Heart Journal. Moreover, female sex does not appear to be an independent risk factor for adverse outcomes, as has been previously suggested.

Preliminary data from the substudy were originally presented at the American College of Cardiology/i2 Scientific Session in Chicago, IL, in March 2012.

The multicenter PLATO trial, published in the New England Journal of Medicine in September 2009, randomized 18,624 ACS patients with or without STEMI to ticagrelor (180-mg loading dose followed by 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose followed by 75 mg daily thereafter). At 12 months, ticagrelor reduced cardiovascular death, MI, and stroke (primary endpoint) compared with clopidogrel (9.8% vs 11.7%, P < 0.001) without increasing PLATO-defined major bleeding.

In a prespecified substudy, investigators led by Steen Husted, MD, DSc, of Hospital Unit West (Herning, Denmark), assessed the relationship between sex and clinical outcomes and treatment-related complications. There was no significant difference in the allocation of randomized treatments between men and women, who comprised 28.4% of the study cohort.

Female Sex Not an Independent Risk Factor

In the overall population, after adjustment for baseline characteristics, female sex was not associated with risk of the primary efficacy endpoint, all-cause death, definite stent thrombosis, or non-CABG-related major bleeding. However, women experienced lower rates of CABG-related bleeding (adjusted HR 0.57; 95% CI 0.49-0.67)—likely due to less CABG use in women—as well as PLATO-defined major bleeding (adjusted HR 0.81; 95% CI 0.71-0.92) and major and minor bleeding.

When the association of sex with outcomes was assessed by randomized treatment, a similar advantage or equivalence of ticagrelor vs clopidogrel was seen in women and men across all major efficacy and safety endpoints (table 1).

Table 1. Outcomes at 12 Months by Sex: Ticagrelor vs Clopidogrel

 

urther analyses of associations among sex, randomization, and either final diagnosis (STEMI vs NSTEMI, unstable angina, or ‘other’) or planned treatment (invasive vs medically managed) showed no interactions for efficacy or safety endpoints.

In addition, the higher rates of dyspnea and ventricular pauses with ticagrelor reported in the main study carried over to the female-male stratification, with no interaction between sex and either complication (range of P for interaction = 0.34-0.89).

A ‘Clinically Relevant Question’

The paper addresses “a clinically relevant question since multiple studies have previously documented important differences in the management and outcomes of men vs women with ACS,” Andrew T. Yan, MD, of the University of Toronto (Toronto, Canada), told TCTMD in an email.

“This subgroup analysis may alleviate some lingering concerns about the efficacy and safety of potent antiplatelet therapies in women, thereby promoting the appropriate use of evidence-based therapies and reducing gender-related care gaps in real-world practice,” he added.

Similarly, in a telephone interview with TCTMD, Sonia Anand, MD, PhD, of McMaster University (Hamilton, Canada), said the analysis “is helpful so that clinicians don’t shy away from using a therapy that has been proven to be effective in a large clinical trial.

“Sometimes women have not been given usual care because there is a perception or a small study that suggests that they respond differently [to certain ACS-related drugs],” she continued. “And people tend to look for provocative headlines. This study is of value in that it helps guide clinicians in terms of their ACS care.”

The “rather surprising finding” that women had less overall major and minor bleeding than men may be due in part to “extensive adjustment for differences in baseline characteristics between men and women,” Dr. Yan observed.

“[Though] perhaps more important,” he added, “is the patient selection inherent in most clinical trials. Patients at higher risk of bleeding, perhaps proportionally more women, might have been underrepresented in PLATO both by virtue of the inclusion and exclusion criteria and implicit ‘selection bias’ by the investigators. This may explain the discrepant findings between PLATO and observational registries, such as GRACE and CRUSADE, which enrolled less-selected ACS patients. In contrast to this PLATO subgroup analysis, the registry-derived prediction rules for major bleeding include female gender as an independent [risk] factor.”

Guidance by Risk Score, Not Sex

Female sex is associated with other clinical features that may predispose to bleeding, Dr. Yan said, but “whether female sex itself plays a true independent ‘causative role’ can never be definitively answered; in practice, whether female gender affords incremental value in predicting serious bleeding would depend on what other factors (eg, age, BMI, creatinine clearance) have already been considered. I believe that validated risk scores are a better way to evaluate bleeding risk than ‘subjective,’ non-systematic assessment of these risk factors, alone or in combination.”

Dr. Yan added that “based on the totality of evidence,” patient sex per se should not affect the choice of ticagrelor vs clopidogrel. “If a more tailored treatment approach is desired, both the antithrombotic benefit and bleeding risk should be carefully assessed for the individual patient,” he recommended.

“This prespecified subgroup analysis should provide further assurance about the efficacy and safety of ticagrelor across the spectrum of patients studied in PLATO,” Dr. Yan concluded. “Both the intention-to-treat and exploratory on-treatment analyses of this [randomized, controlled trial] can be informative. Ultimately, observational studies of a broad spectrum of less-selected ACS patients may yield additional insights as to the effectiveness and safety of these newer antiplatelet therapies as prescribed in routine clinical practice in the ‘real world.’”

Study Details

All patients also received daily aspirin (75-100 mg) unless intolerant. The assigned study treatment was continued for at least 6 months and up to a maximum of 12 months.

Women were more likely than men to be at least 75 years of age and have dyslipidemia, hypertension, and higher serum levels of glucose and hemoglobin A1C. They also more often had a history of angina, CHF, TIA, or non-hemorrhagic stroke. Men more frequently reported habitual smoking, PAD, MI, PCI, or CABG. 

Following study entry, women more often received a final diagnosis of unstable angina than men but less often a final diagnosis of STEMI. Interventional procedures, including CABG, were more frequent in men. 

 

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Source:
Husted S, James SK, Bach RG, et al. The efficacy of ticagrelor is maintained in women with acute coronary syndromes participating in the prospective, randomized PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2014;Epub ahead of print.

 

 

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