Differences in management and outcomes between male and female patients with atherothrombotic disease: results from the REACH Registry in Europe

Abstract

IntroductIon

Atherothrombosis remains a leading cause of mortality in both men and women worldwide. Women experience cardiovascular events on average 10 years later than men, but overall, more women die from cardiovascular disease.¹ Indeed, the decline in cardiovascular mortality over the last decade has been greater in men than women. ² The differences in risk profile between women and men with cardiovascular disease are well documented.³ Although guidelines, including the European guidelines for cardiovascular disease prevention,⁴ non-ST-segment elevation acute coronary syndromes ⁵ and acute ST-segment elevation myocardial infarction,⁶ largely recommend the same evaluation and treatment for men and women, differences in management and outcomes between the sexes have been seen.

In coronary artery disease (CAD), lower rates of invasive procedures in female compared with male patients have been observed for nearly two decades^7,8 and continue to be identified.^9–13 However, to our knowledge, differences in procedure rates between the sexes have not been investigated in a population with stable disease. Recent studies suggest that women receive less intensive medical therapy than men^13–15 and women with ACS are less likely to be referred to cardiac rehabilitation programmes.¹⁶ Higher mortality in women than men observed in some studies has been attributed to older age at presentation and associated increased comorbidities.^10,13,17

Fewer data are available regarding sex differences in stroke and peripheral arterial disease (PAD). Some existing literature on stroke suggests that women receive fewer relevant evidence-based diagnostic examinations and less aggressive medical treatment than men.¹⁸ It is not known whether such sex-related differences have an effect on the outcomes of stroke. Women have also been found to have a poorer risk profile and worse risk-factor control than men in PAD.^19,20

To date, sex differences in the management of patients with the spectrum of atherothrombotic disease have not been assessed across Europe. This study of patients enrolled in the REduction of Atherothrombosis for Continued Health (REACH) Registry in Europe aimed to investigate the risk profile, management and associated outcomes of male and female patients.

Methods

Full details of the rationale and design,²¹ baseline,²² 1-year²³ and 3-year²⁴ data of the REACH Registry have been published earlier. In brief, REACH is an international, prospective, observational registry providing up to 48 months of clinical follow-up of over 68 000 outpatients from more than 5000 sites in 44 countries (18 in Europe).²² Patients enrolled were aged 45 years or over with at least one of the following four criteria: documented symptomatic CAD [angina, myocardial infarction (MI), or angioplasty/stent/bypass] (i), cerebrovascular disease [CVD; ischemic stroke, or transient ischemic attack (TIA)] (ii), PAD (historical or current intermittent claudication associated with ankle-brachial index <0.9)

(iii), or asymptomatic patients with at least three predefined atherothrombotic risk factors (treated diabetes mellitus, diabetic nephropathy, ankle-brachial index less than 0.9, asymptomatic carotid stenosis ≥ 70%, carotid intima-media thickness at least 2 times adjacent sites, systolic BP ≥ 150 mmHg despite therapy ≥ 3 months, treated hypercholesterolemia, current smoking (≥15 cigarettes/day), men aged ≥ 65 years, or women aged ≥ 70 years (iv). The same standardized procedures and definitions were applied in all participating countries.²¹

Participants were recruited consecutively, mainly by general practitioners (39%) and internists (28%).²² They were evaluated at baseline for a range of demographic, medical and laboratory characteristics, before being re-evaluated annually for up to 48 months post-baseline to ascertain whether they experienced any clinical events or hospitalizations. All the information was collected by the treating physician and ethnic origin was the only self-reported variable. The study design was approved by the Institutional Review Board in each participating country and all patients included in the analysis provided signed, informed consent.

Two primary study outcomes were defined. The first is a combined endpoint of non-fatal stroke, non-fatal MI, and cardiovascular death. The second is a combined endpoint of cardiovascular death, non-fatal stroke, non-fatal MI, and hospitalizations for atherothrombotic events. The individual cardiovascular events described are the predefined secondary endpoints of the study.

Absolute unadjusted numbers and percentages are shown for categorical variables to describe the patient population, and means with standard deviations for continuous variables. Binary variables (yes/no response variables) were compared between subgroups by the Pearson's χ² test and continuous variables (numeric values) by the Mann—Whitney—Wilcoxon test. Descriptive statistics were calculated for the available cases. A significance level of 0.05 was assumed for the statistical tests and all P values are results of two-tailed tests. Multivariate logistic regression models were used to test for the differences between men and women in medical treatments at baseline, and cardiovascular event rates and surgical outcomes at the time of the 2-year follow-up. These models were predefined to be adjusted for risk factors including age, diabetes mellitus, history of MI, hypertension, congestive heart failure and smoking habit (never smoked vs. current/former smoker). All statistical analyses were performed using SAS statistical software, version 9.1 (Cary, North Carolina, USA).

Results

Of 23,728 patients enrolled in the REACH Registry in Europe, 22,028 completed the 2-year follow-up. The proportion of participants of each sex was consistent between countries (men, 0.68 ±0.04). Women patients were older than men in both the symptomatic and asymptomatic (multiple risk factors only) groups (Table 1). At baseline, higher proportions of symptomatic women than symptomatic men had diabetes, hypertension despite treatment, elevated cholesterol or triglyceride levels, or were obese. However, a much lower proportion of women than men were former or current smokers. The differences in smoking behaviour were marked; current smoking was noted in 11.9% of symptomatic women versus 19.5% of symptomatic men (P < 0.0001). Fewer differences were observed between men and women in the asymptomatic group.

Small but significant differences were seen between men and women in baseline medications (Table 2). Within the symptomatic population, women received antithrombotic agents (or aspirin), and lipid-lowering agents (or statins) less frequently than men (Table 1). Fewer differences were observed within the asymptomatic population, where women received lipid-lowering and cardiovascular agents more often than men.

At the 2-year follow-up, fewer symptomatic women than men had undergone coronary, carotid or peripheral revas-cularizations. These differences remained significant for coronary revascularizations after multivariate adjustment (Figure 1). There were no differences in other outcomes between the sexes, apart from a higher rate of TIA in women than men in the symptomatic group (Table 3).

Figure 1.

Multivariate analysis of treatments at baseline, cardiovascular event rates and surgical outcomes at 2 years in symptomatic patients (adjusted odds ratios and 95% confidence interval). CV, cardiovascular; Hosp, hospitalization; MI, myocardial infarction.

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Discussion

This study identifies considerable differences between women and men included in the REACH Registry in Europe in risk profile and revascularization procedures, as well as some aspects of medical therapy. Most of these differences were confined to the symptomatic population. Despite the disparities in risk profile and management, no differences were found between the sexes in primary outcomes for symptomatic or asymptomatic patients at the 2-year follow-up. A significantly higher rate of TIA was found in symptomatic women compared with men, which could be attributable to more women patients being enrolled with CVD. Interestingly, far fewer symptomatic women than men were enrolled. Although our data cannot explain this finding, a previous study found that a higher proportion of women than men refused to participate in a community-based study of MI.²⁵

Our data also highlight the risk of cardiovascular events in patients with PAD in both sexes, in accordance with earlier findings from the REACH Registry.²³ PAD in particular is often underdiagnosed and undertreated^26–27 and women with PAD experienced the highest levels of events in the present study.

The INTERHEART study showed that similar risk factors contribute to MI risk in men and women and suggested that higher levels of risk factors in younger men, particularly lipid abnormalities and smoking, might explain the male tendency to earlier events.²⁸ Participants in the present study were not young and a higher proportion of symptomatic women had developed lipid abnormalities. However, nearly three-quarters of the symptomatic men were former or current smokers.

A number of studies have shown less aggressive risk factor control in women compared with men across the spectrum of primary and secondary prevention of cardiovascular disease.^{15,18,29–31} In this study, despite higher levels of treatable risk factors in women, the intensity of antithrombotic and lipid-lowering medical therapy was lower in symptomatic women than symptomatic men, in accordance with global REACH data.²⁴ This difference remained significant for antithrombotic agents after adjustment for age and comorbidities. The finding that symptomatic women less often receive antithrombotic agents is consistent with other studies.^12,15,32 This practice is not justified by the current guidelines for patients with CAD, PAD and CVD, which recommend the same risk management measures for both sexes.⁴ In patients with risk factors only, this relationship was reversed, with men receiving fewer lipid-lowering and cardiovascular agents, presumably explained by differences in risk profiles.

It has been suggested that differences between the management of men and women can be explained by age differences. A study based in Wales found that most management differences between men and women did not persist after adjustment for age. The investigators suggested that the initial differences were in fact because of a bias against performing investigations and treatments in older patients.³³ In this study, women were older than men by a mean of 3 years. This would be consistent with the later presentation of both raised multifactorial risk and cardiovascular disease in women; however, the differences in coronary revascularization rates between the sexes persisted after adjustment for age.

Although we are not able to ascertain the reasons for performing or withholding revascularization procedures, we can hypothesize that physicians might have been influenced by studies showing increased adverse events following such procedures in women compared with men.³⁴ The relative benefits and risks of invasive strategies in women ACS patients vary between studies.^35–37 Nevertheless, a recent study in ACS patients highlighted an increase in mortality in women only in the nonintervention sub-group. This suggests that fewer interventions might be associated with higher mortality.³⁸ A large prospective study based in the US found that although 1-year mortality was higher in women than men following percutaneous coronary intervention, this difference did not persist after adjustment for comorbidities. Bleeding complications were, however, more common in women.³⁹ The ESC guidelines for non-ST-segment elevation acute coronary syndromes recognize that further studies are required to fully establish the benefit of a routine invasive approach in women, and recommend an early invasive strategy primarily in women at high risk.⁵ ESC guidelines for acute ST-segment elevation myocar-dial infarction do not distinguish between men and women, except for some threshold levels.⁶

Limitations of this study include the possibility of selection bias (Registry physicians could be more likely to comply with guidelines), lack of details of contraindications for medications and procedures and limited external validity of reported events and clinical measurements. In addition, the 2-year duration of follow-up may be too short to reveal differences because of the baseline medication.

In conclusion, although differences exist between the risk profile and management of women and men included in the REACH Registry in Europe, there are no obvious differences in cardiovascular event rates after 2 years of follow-up. Men appear to receive less intensive primary prevention than women but this could be explained by poorer risk-profiles in the asymptomatic women enrolled. Women could benefit from improvements in secondary prevention according to evidence-based guidelines (potentially antithrombotics and revascularization procedures) and further studies are needed to determine whether there is potential to improve outcomes in women by different patterns of intervention use. Increased efforts should be made to reduce smoking rates in men.

Acknowledgements

The REACH Registry is endorsed by the World Heart Federation. A complete list of REACH investigators is accessible online at www.reachregistry.org  . The REACH Registry enforces a no ghost-writing policy. This manuscript was written and edited by the authors, who take full responsibility for its content. The first draft was written by J.M. The authors thank Deborah Burrage, PhD, for her assistance with coordinating revisions and providing editorial help in preparing this manuscript including editing, checking content and language, formatting, referencing and preparing tables and figures, and T.L. for his support with statistical analyses. The Institut für Herzinfarktforschung Ludwigshafen verified all statistical analyses.

The REACH Registry is sponsored by sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan).

Conflict of interest statements

J.M. has received honoraria from Astra Zeneca, Bristol Myers Squibb, Genzyme, MSD, Novartis, sanofi aventis, Schering Plough, Servier, Solvay Healthcare, Takeda, Pfizer and Unilever. U.Z. has received research grants and speaker honoraria from Bristol-Myers-Squibb and sanofi aventis. I.B.: none. T.L.: none. J.R. has received honoraria and consulting fees from sanofi-aventis, Bristol-Myers Squibb, Lundbeck and Boehringer Ingelheim. D.L.B. has received research grants (to the institution) from: AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis, and The Medicines Company. D.L.B. has served as a consultant (honoraria waived or donated for past 3 years) for: Arena, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Car-dax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering Plough, Scios, Takeda, The Medicines Company, and Vertex. P.G.S. has received research grant from sanofi-aventis (1999-2008); is on the Speaker's Bureau for Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Menarini, Medtronic, Nycomed, Pierre Fabre, sanofi-aventis, Servier, and The Medicines Company; is on the consulting/advisory boards for Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Endotis, GlaxoSmithKline, Medtronic, MSD, Nycomed, sanofi-aventis, Servier, and The Medicines Company; and is a stockholder for Aterovax.

References

Author notes