Abstract
To investigate if gender bias is present in today's setting of an early invasive strategy for patients with acute coronary syndrome in Denmark (population 5 million).
We identified all patients admitted to Danish hospitals with acute coronary syndrome in 2005–07 (9561 women and 16 406 men). Cox proportional hazard models were used to estimate the gender differences in coronary angiography (CAG) rate and subsequent revascularization rate within 60 days of admission. Significantly less women received CAG (cumulative incidence 64% for women vs. 78% for men, P < 0.05), with a hazard ratio (HR) of 0.68 (95% CI 0.65–0.70, P < 0.0001) compared with men. The difference was narrowed after adjustment for age and comorbidity, but still highly significant (HR 0.82, 95% CI 0.80–0.85, P < 0.0001). Revascularization after CAG was less likely in women with an HR of 0.68 (95% CI 0.66–0.71, P < 0.0001) compared with men. More women (22%) than men (10%) (P < 0.0001) had no significant stenosis on their coronary angiogram. However, after adjustment for the number of significant stenoses, age, and comorbidity women were still less likely to be revascularized (HR 0.91, 95% CI 0.87–0.95, P < 0.0001).
Women with ACS are approached in a much less aggressively invasive way and receive less interventional treatment than men even after adjusting for differences in comorbidity and number of significant stenoses.
Introduction
Gender disparity in cardiac diagnosis and treatment has been investigated thoroughly since Ayanian first described this phenomenon. In 1991, he observed that women were less likely than men to undergo diagnostic coronary angiography (CAG) and coronary revascularization.1 However, data have been inconsistent, with some studies contradicting the presence of a gender bias,2,3 and others supporting it4,5—thus, the debate is ongoing.6,7
Gender differences in the invasive management of acute coronary syndrome (ACS) have been described in both observational and randomized clinical studies.8–10 It has been shown that women are less likely to undergo reperfusion therapy after ACS.10,11 Some of the difference has been attributed only to differences in age and comorbidity with no gender difference when these factors were taken into account.12 It has also been suggested that differences in coronary artery disease (CAD) could account for some of the difference, and this has been shown in selected populations.13,14
A reason for possible differences in the invasive approach to men and women with ACS could be that controversy exists with respect to the benefit of revascularization treatment in women. Thus, subgroup analysis in the FRISC 2 (Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease) trial15 and RITA 3 (The Randomized Intervention Trial of unstable Angina) trial16 showed that an invasive strategy may be associated with an increased risk of death or myocardial infarction (MI) in women compared with a conservative strategy. In contrast, the results of the TACTICS-TIMI 18 (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18) trial17 supported that both women and men had improved outcomes, and women with a high-risk profile had the most benefit from revascularization.
Supporting the results of TACTICS-TIMI 18 a recent meta analysis of randomized clinical trials (RCT), comparing an early invasive strategy with a conservative treatment strategy in patients with non-ST-segment elevation myocardial infarction (non-STEMI) and unstable angina pectoris (UAP), found that men and high-risk women benefit from an early invasive strategy.18
Currently available data on invasive treatment in ACS and the gender issue are limited to only RCTs or from registries from an earlier period, when patients were generally treated with thrombolysis.
In Denmark, current guidelines recommend a very early invasive strategy for all patients with STEMI following the results of the DANAMI 2 trial,19 and an early invasive strategy for non-STEMI patients following the results of the FRISC 2 trial.15
To examine if a gender difference exists with respect to invasive treatment of ACS in the present real-world setting, and to determine at which stage and which factors might influence the choice of strategy, we used nationwide registries to investigate all admissions with ACS in Denmark (5.4 million inhabitants) in 2005–2007. We included data on revascularization, coronary angiograms, morbidity, type of admitting hospital, and the number of hospitals each patient was transferred to during their hospital stay.
Methods
Study population
The study was designed as a prospective observational cohort study of all patients in Denmark admitted to a hospital with ACS in 2005–07.
All residents in Denmark have a unique and permanent personal civil registration number, which allows linkage between nationwide registries on an individual level.
Information on admissions and comorbidity was obtained from the Danish National Patient Registry, which holds information on all admissions to all Danish hospitals since 1978.
Each admission is registered by one primary diagnosis and, if appropriate, one or more secondary diagnoses according to the International Classification of Diseases (ICD)—before 1994, the 8th revision (ICD-8) and after 1994 the 10th revision (ICD-10). The diagnoses registered in the Danish National Patient Registry are the final discharge diagnoses.
We identified all patients 30–90 years old admitted with MI or UAP as the primary discharge diagnosis (ICD-10, codes I20-I22). Day of admission was 1 January 2005 to 31 December 2007. To study first admission with ACS, we excluded all patients with a previous diagnosis of MI 1978–93 (Using ICD-8 code 410), or ACS since 1994. The definition of MI and UAP in Denmark follow the guidelines of the European Society of Cardiology. All patients discharged on the day of admission were excluded to ensure that diagnosis was based on reliable observation and sufficient blood tests. Patients not surviving the day of admission were excluded because of insufficient time to begin treatment and possible problems with assertion of diagnosis.5,20 The diagnosis of acute MI in the registry has been validated by comparison with the results from the MONICA database.21 The sensitivity and specificity are 90–95%. A recent study found a positive predictive value of 92.4% for the diagnosis of MI and 80.1% for ACS; this was with the same inclusion criteria as our study, but without applying the strict exclusion criteria we have used.22 To ensure the robustness of the results we did sensitivity analyses on only those patients with an MI.
In a recent Danish study of 132 290 persons, the incidence rate of ACS admissions by direct observation differed insignificantly from the incidence rate of ACS found in the National Patient Registry.23 Information on the patient's vital status (alive or date of death) was obtained from The Danish Civil Registration System, where all persons residing in Denmark are registered from birth or time of immigration.
Explanatory variables
Age
The age of each patient was categorized into 10 year intervals and was used as categorical variables.
Extent of coronary artery disease
Information on the extent of CAD among patients examined by CAG was obtained in the Danish Heart Registry (www.dhreg.dk),24 which includes all invasive examinations and procedures performed at Danish hospitals since the year 2000. A significant lesion was defined as at least 50% stenosis in a major epicardial vessel or coronary artery bypass graft. The procedures and examination results were validated by comparison of a stratified random sample of 200 procedures in the registry (50 CAG, 50 PCI, 50 CABG and 50 valve replacements) with local registries and written patient records. All 200 procedures could be confirmed to have taken place, and the result of the 50 coronary angiographies was found to be in accordance with the patient's records.25
Comorbidity
Primary and secondary diagnoses, both at the index admission and at admissions up to 1 year before the index admission, were used to define comorbidity.26 Diagnoses of congestive heart failure, cardiogenic shock, arrhythmia, and pulmonary oedema gave indications of the severity of the heart disease, while diagnoses of malignancy, diabetes with complications, cerebrovascular disease, acute renal failure, and chronic renal failure indicated comorbidity. This method is an extension of the Ontario MI mortality prediction rule27 with translation to ICD-10 codes validated by So et al.,28 hence this ICD-10 coding was used. As a proxy for smoking, chronic obstructive pulmonary disease was included independently in the model (ICD-10; J40–J44, J47). Sex, age, admission year, and each of the risk factors were retained in the model regardless of their significance level.
Regional variation
The Danish Society of Cardiology has nationwide guidelines on the treatment of ACS.
Patients were categorized into two groups according to whether they lived in a county with a hospital performing revascularization procedures.
Previous revascularization within 5 years of index event was recorded for each patient, as this might affect the decision to initiate an invasive examination.
Outcomes
We estimated the effect of gender on the execution of CAG and on subsequent revascularization (time to either PCI or CABG) for those having had a CAG performed within 60 days of admission. A 60-day observation period was used to include as many examinations and procedures as possible and, at the same time, to avoid angiographies made because of reinfarction. To choose the observation period, a separate sensitivity analysis was performed. We analysed proportions revascularized within 30, 60, 90, 120, 150, and 180 days. We found that the majority of patients were revascularized within 60 days, which was therefore chosen as the observation period.
We estimated the mortality rate in the 60 days after the event using the Kaplan–Meier estimator, averaging the estimated survival for both genders to a 70-year-old person.
Since differences in mortality could potentially influence the rate of procedures we used a competing risks model to analyse the data as described by Andersen et al.29 Cumulative incidence curves were calculated for the incidence of CAG in the whole population and of revascularization in the CAG population, and the cumulative incidence at 60 days was read from the curves.
Timing of procedures
Differences in the presentation of the disease could lead to differences in the timing of the invasive examination and subsequent treatment. We, therefore, performed a stratified analysis of procedures, dividing them into acute, being on the day of admission or the day after, and sub-acute from Day 2 until Day 60.
Statistical analysis
Continuous variables are presented as mean±standard deviation (SD) for characteristics with appropriately near-symmetrical distributions or as median (interquartile range). Discrete data are presented as frequencies and percentages. Differences between sexes in the baseline characteristics were evaluated using Pearson χ2-test for categorical variables and the non-parametric Mann–Whitney U-test for continuous variables.
Cumulative incidence curves were estimated in a competing risks model with the SAS-macro developed by Rosthoj et al.30
Gender differences in outcome were estimated using Cox proportional hazards regression, both uni- and multivariable.
Outcome variables were CAG in the whole population, and revascularization in the group who had CAG performed. In the multivariable analysis age, year of admission, place of residence, prior PCI or CABG (within 5 years of index event), and comorbidity were included in the model along with sex. Model assumptions—linearity, proportional hazards, and interactions—were tested and found valid unless otherwise indicated. All hypothesis tests had a 0.05 significance level. All tests were two-sided.
As a sensitivity analysis, we used propensity score analysis to identify a set of cases (women) and controls (men) who were matched on age, comorbidity, admission year, admission diagnosis, and previous revascularization. A propensity score was quantified by multivariable logistic regression. The C statistic was 0.65, indicating a reasonable discriminative power of the model. A Greedy matching macro (by Lori S. Parsons, accessed 14 April 2009, at http://www2.sas.com/proceedings/sugi26/p214-26.pdf) was used to match each case to one control. A multivariable-adjusted Cox-model was fitted including the propensity score.
All analyses were performed with SAS statistical software package version 9.13 (SAS Institute, Inc., Cary, NC, USA).
Ethics
The Danish National Board of Health, the Danish Data Protection Agency, and the Board of the Danish Heart Registry all approved the project, which was carried out in accordance with current rules of ethics and legislature. Register-based studies do not require ethical approval in Denmark.
Results
In Denmark 25 967 patients were admitted with ACS from 1 January 2005 to 31 December 2007. Among all the patients, 40% of the women and 62% of the men were finally revascularized. In all 1015 patients were excluded, 515 were discharged on the day of admission, and 500 patients did not survive the day of admission. Thus, 24 952 patients had a hospital stay of at least one day, and a discharge diagnosis of MI or UAP. Among these patients, CAG was undertaken in 5845 of 9132 women (64%) and in 12 416 of 15 818 men (78%) during the 2 months of follow-up, P < 0.0001 (28 vs. 40% in the acute phase P < 0.0001).
Baseline characteristics
Baseline characteristics of the study population are shown in Table 1. Mean age of women was 6 years higher than that of men. Men were more often than women diagnosed with an MI (84 vs. 82%). Comorbidities including congestive heart failure, arrhythmia, chronic obstructive pulmonary disease, and diabetes with complications were significantly more frequent in women than in men. There was no difference in place of residence. Women were more often admitted directly to hospitals without invasive facilities (54 vs. 49%). Furthermore, women were less likely to have been to more than one hospital, i.e. transferral to a second (or third) centre was less likely (58 vs. 49%). Figure 1 shows estimated mortality in the first 60 days after admission for a 70-year-old male and for a 70-year-old female (P = 0.32).
Estimated mortality curves for a 70-year-old woman/man in the first 60 days among patients admitted with acute coronary syndrome.
Estimated mortality curves for a 70-year-old woman/man in the first 60 days among patients admitted with acute coronary syndrome.
Baseline characteristics of patients
| Women | Men | |
|---|---|---|
| Number (%) | 9132 (37.8) | 15 820 (62.2) |
| Mean age in years (SD) | 71.1 (12.7) | 65.1 (12.6)* |
| Place of residence, n (%) | ||
| County with invasive hospital | 3662 (40) | 6262 (40) |
| County without invasive hospital | 5470 (60) | 9558 (60) |
| Length of admission period | ||
| Median time in days (Q1–Q3) | 6 (4–11) | 5 (4–10)* |
| Preceding admissions, n (%) | ||
| Admission 1 week prior | 1043 (11) | 1503 (10)* |
| Hospital category of first admission, n (%)* | ||
| Hospital without invasive facilities | 4923 (54) | 7822 (49) |
| Hospital with CAG facilities | 2068 (23) | 3582 (23) |
| Hospital with invasive centre | 2141 (23) | 4416 (28) |
| Number of hospitals during admission period, n (%)* | ||
| 1 hospital | 5284 (58) | 7806 (49) |
| 2 hospitals | 2031 (22) | 4365 (28) |
| 3 hospitals | 1615 (18) | 3257 (21) |
| More than 3 hospitals | 202 (2) | 392 (2) |
| Previous revascularization, n (%) | ||
| Revascularization the last 5 years | 240 (3) | 643 (4)* |
| Comorbidity, n (%) | ||
| Congestive heart failure | 1066 (12) | 1442 (9)* |
| Pulmonary oedema | 98 (1) | 101 (1)* |
| Shock | 59 (1) | 87 (1) |
| Arrhythmia | 1224 (13) | 1685 (11)* |
| Cerebrovascular disease | 531 (6) | 698 (4)* |
| Chronic obstructive pulmonary disease | 741 (8) | 743 (5)* |
| Diabetes with complications | 522 (6) | 709 (4)* |
| Chronic renal failure | 128 (1) | 278 (2)* |
| Acute renal failure | 73 (1) | 153 (1) |
| Malignancy | 231 (3) | 423 (3) |
| Examinations, n (%) | ||
| CAG within 1 day | 2592 (28) | 6276 (40)* |
| CAG within 60 days | 5845 (64) | 12 417 (78)* |
| Discharge diagnosis, n (%) | ||
| Acute myocardial infarction | 7532 (82) | 13 305 (84)* |
| Unstable angina pectoris | 1600 (18) | 2515 (16)* |
| Women | Men | |
|---|---|---|
| Number (%) | 9132 (37.8) | 15 820 (62.2) |
| Mean age in years (SD) | 71.1 (12.7) | 65.1 (12.6)* |
| Place of residence, n (%) | ||
| County with invasive hospital | 3662 (40) | 6262 (40) |
| County without invasive hospital | 5470 (60) | 9558 (60) |
| Length of admission period | ||
| Median time in days (Q1–Q3) | 6 (4–11) | 5 (4–10)* |
| Preceding admissions, n (%) | ||
| Admission 1 week prior | 1043 (11) | 1503 (10)* |
| Hospital category of first admission, n (%)* | ||
| Hospital without invasive facilities | 4923 (54) | 7822 (49) |
| Hospital with CAG facilities | 2068 (23) | 3582 (23) |
| Hospital with invasive centre | 2141 (23) | 4416 (28) |
| Number of hospitals during admission period, n (%)* | ||
| 1 hospital | 5284 (58) | 7806 (49) |
| 2 hospitals | 2031 (22) | 4365 (28) |
| 3 hospitals | 1615 (18) | 3257 (21) |
| More than 3 hospitals | 202 (2) | 392 (2) |
| Previous revascularization, n (%) | ||
| Revascularization the last 5 years | 240 (3) | 643 (4)* |
| Comorbidity, n (%) | ||
| Congestive heart failure | 1066 (12) | 1442 (9)* |
| Pulmonary oedema | 98 (1) | 101 (1)* |
| Shock | 59 (1) | 87 (1) |
| Arrhythmia | 1224 (13) | 1685 (11)* |
| Cerebrovascular disease | 531 (6) | 698 (4)* |
| Chronic obstructive pulmonary disease | 741 (8) | 743 (5)* |
| Diabetes with complications | 522 (6) | 709 (4)* |
| Chronic renal failure | 128 (1) | 278 (2)* |
| Acute renal failure | 73 (1) | 153 (1) |
| Malignancy | 231 (3) | 423 (3) |
| Examinations, n (%) | ||
| CAG within 1 day | 2592 (28) | 6276 (40)* |
| CAG within 60 days | 5845 (64) | 12 417 (78)* |
| Discharge diagnosis, n (%) | ||
| Acute myocardial infarction | 7532 (82) | 13 305 (84)* |
| Unstable angina pectoris | 1600 (18) | 2515 (16)* |
*Statistically significant difference between genders (P-value <0.05).
Coronary angiography
Among the 18 262 patients examined with CAG, women were more frequently without significant lesions at CAG (Table 2) (22 vs. 10% in men, P < 0.0001), even if restricted to patients with a diagnosis of confirmed MI (18.1 vs. 7.6% P < 0.0001). Accordingly, men more often had 1-, 2-, and 3-vessel disease (Table 2). The probability in the competing risk model of invasive examination within 60 days was 0.64 for women and 0.78 for men. (Figure 2).
Cumulative incidence curves showing gender differences in invasive examination rate in the first 60 days among patients admitted with acute coronary syndrome.
Cumulative incidence curves showing gender differences in invasive examination rate in the first 60 days among patients admitted with acute coronary syndrome.
Result of coronary angiography and subsequent invasive treatment
| Women | Men | |
|---|---|---|
| Number of patients having CAG performed (%) | 5845 (32) | 12 417 (68) |
| Extent of disease at angiography, n (%)a (*) | ||
| No significant stenosis | 1298 (22) | 1181 (10) |
| 1 vessel disease | 2281 (39) | 5187 (42) |
| 2 vessel disease | 1032 (18) | 2890 (23) |
| 3 vessel disease | 926 (16) | 2487 (20) |
| Missing result | 308 (5) | 672 (5) |
| Revascularization, n (%) | ||
| Revascularization within 60 days | 3861 (66) | 10 104 (81*) |
| PCI within 60 days | 3496 (60) | 8846 (71*) |
| CABG within 60 days | 434 (7) | 1538 (12*) |
| Women | Men | |
|---|---|---|
| Number of patients having CAG performed (%) | 5845 (32) | 12 417 (68) |
| Extent of disease at angiography, n (%)a (*) | ||
| No significant stenosis | 1298 (22) | 1181 (10) |
| 1 vessel disease | 2281 (39) | 5187 (42) |
| 2 vessel disease | 1032 (18) | 2890 (23) |
| 3 vessel disease | 926 (16) | 2487 (20) |
| Missing result | 308 (5) | 672 (5) |
| Revascularization, n (%) | ||
| Revascularization within 60 days | 3861 (66) | 10 104 (81*) |
| PCI within 60 days | 3496 (60) | 8846 (71*) |
| CABG within 60 days | 434 (7) | 1538 (12*) |
CAG, coronary angiography; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.
aDiseased vessel defined as at least 50% stenosis in a major epicardial vessel or coronary artery bypass graft.
*Statistically significant difference between genders (P-value <0.05).
In the univariable Cox-model, the hazard ratio (HR) of having a CAG performed was 0.68 (95% CI, 0.66–0.70, P < 0.0001) for women compared with men (Table 3). When including the age groups in the Cox-model, HR was 0.83 (95% CI, 0.80–0.85, P < 0.0001) for women of having a CAG performed. After including all variables in the Cox-model, the HR did not change appreciably (Table 3). Both in the acute and sub-acute phases, women were less likely to receive CAG. The results were similar when restricting the analysis to patients with confirmed MI (data not shown).
Successively adjusted relationship between gender and coronary angiography in patients admitted with acute coronary syndrome
| Outcome measure | Observation time (days) | Women vs. men hazard ratio (95% confidence interval) | ||
|---|---|---|---|---|
| Model 1a | Model 2b | Model 3c | ||
| CAG | 60 | 0.68 (0.65–0.70) | 0.83 (0.80–0.85) | 0.82 (0.80–0.85) |
| CAG acute | 1 | 0.66 (0.63–0.69) | 0.78 (0.74–0.82) | 0.78 (0.75–0.82) |
| CAG non-acute | 59 | 0.69 (0.66–0.72) | 0.87 (0.83–0.91) | 0.86 (0.82–0.89) |
| Outcome measure | Observation time (days) | Women vs. men hazard ratio (95% confidence interval) | ||
|---|---|---|---|---|
| Model 1a | Model 2b | Model 3c | ||
| CAG | 60 | 0.68 (0.65–0.70) | 0.83 (0.80–0.85) | 0.82 (0.80–0.85) |
| CAG acute | 1 | 0.66 (0.63–0.69) | 0.78 (0.74–0.82) | 0.78 (0.75–0.82) |
| CAG non-acute | 59 | 0.69 (0.66–0.72) | 0.87 (0.83–0.91) | 0.86 (0.82–0.89) |
CAG, coronary angiography.
aUnadjusted.
bAdjusted for age group.
cAdjusted for age group, year of admission, place of residence, previous revascularization and comorbidity (all as categorical variables).
In the propensity score matched analysis 8497 women were matched one-to-one to 8497 men. The propensity adjusted Cox-model yielded an HR of 0.84 (95% CI 0.81–0.87, P < 0.0001) of receiving CAG if you were a woman in comparison to a similar man.
Revascularization
Of the patients examined with CAG, 66% of women (3861/5845) and 81% of men (10 104/12 417) received revascularization, P < 0.0001. The probability in the competing risk model of revascularization within 60 days was 0.67 for women and 0.81 for men (Figure 3).
Cumulative incidence curves showing gender differences in revascularization rate in the first 60 days among patients undergoing coronary angiography.
Cumulative incidence curves showing gender differences in revascularization rate in the first 60 days among patients undergoing coronary angiography.
In the univariable Cox-model, the HR of revascularization was 0.68 (95% CI, 0.66–0.71, P < 0.0001) for women (Table 4). This did not change appreciably after inclusion of age groups and the other variables. However, when the result of the CAG was included in the model as an indicator of severity of CAD, there was less difference between sexes, but still significantly less invasive revascularizations of women (HR 0.91, 95% CI 0.87–0.95, P < 0.0001). The propensity adjusted Cox-model, with the result of the CAG included, yielded an HR of 0.92 (95% CI 0.88–0.96, <0.0001) of receiving revascularization if you were a woman.
Successively adjusted relationship between gender and revascularization in those patients who had a coronary angiography performed
| Outcome measure | Observation time (days) | Women vs. men hazard ratio (95% confidence interval) | ||
|---|---|---|---|---|
| Model 1a | Model 2b | Model 3c | ||
| Revascularization | 60 | 0.68 (0.66–0.71) | 0.69 (0.66–0.71) | 0.91 (0.87–0.95) |
| CABG | 60 | 0.59 (0.53–0.65) | 0.55 (0.50–0.62) | 0.83 (0.74–0.93) |
| PCI | 60 | 0.74 (0.71–0.77) | 0.75 (0.72–0.78) | 0.93 (0.89–0.97) |
| PCI acute | 1 | 0.76 (0.72–0.80) | 0.79 (0.75–0.83) | 0.93 (0.89–0.98) |
| PCI non-acute | 59 | 0.72 (0.67–0.76) | 0.71 (0.67–0.76) | 0.92 (0.87–0.98) |
| Outcome measure | Observation time (days) | Women vs. men hazard ratio (95% confidence interval) | ||
|---|---|---|---|---|
| Model 1a | Model 2b | Model 3c | ||
| Revascularization | 60 | 0.68 (0.66–0.71) | 0.69 (0.66–0.71) | 0.91 (0.87–0.95) |
| CABG | 60 | 0.59 (0.53–0.65) | 0.55 (0.50–0.62) | 0.83 (0.74–0.93) |
| PCI | 60 | 0.74 (0.71–0.77) | 0.75 (0.72–0.78) | 0.93 (0.89–0.97) |
| PCI acute | 1 | 0.76 (0.72–0.80) | 0.79 (0.75–0.83) | 0.93 (0.89–0.98) |
| PCI non-acute | 59 | 0.72 (0.67–0.76) | 0.71 (0.67–0.76) | 0.92 (0.87–0.98) |
CAG, coronary angiography; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft.
aUnadjusted.
bAdjusted for age group, year of admission, previous revascularization, and comorbidity (all as categorical variables).
cAdjusted for coronary artery disease and the variables in model 2.
When investigating PCI and CABG separately, the HRs showed a similar pattern, with CABG having the largest difference between sexes (Table 4). Time from admission to invasive treatment with PCI was similar in men and women. Restricting the analyses to patients with confirmed MI yielded similar results (data not shown).
Discussion
We demonstrated, at a nationwide level, that significantly fewer women with ACS are revascularized even after correcting for baseline differences and differences in mortality after ACS. A less aggressive invasive diagnostic approach in women accounted for much of the difference in invasive treatment. Furthermore, the difference in invasive treatment of women was to some extent explained by less severe CAD. Importantly, the results did not differ when restricting the analysis to the 83% of the patients with confirmed MI.
The result of the propensity score matched subpopulation was in accordance with our findings on the whole population.
The Danish recommendations for the treatment of ACS follow the European guidelines, and during the study period there were no differences in the recommendations for women and men. These recommendations were clear, despite controversies existing with respect to the benefit of invasive treatment in women.15,16
The gender difference in the rate of CAG could not be explained by other variables available in our study. The difference between men and women was present, in both the acute phase and the non-acute phase of ACS, although a larger difference was present in the acute phase. We can only speculate as to the reasons, but a different symptom presentation in women31 and a higher proportion of ST-elevation MI in men14 could contribute to the observed difference. Data on these matters are not currently available in the registries.
The gender difference in rate of invasive revascularization among patients examined with CAG could largely be explained by differences in the extent of CAD found at the CAG. Nevertheless, a significant difference still persisted between the sexes, when taking this information into account.
Differences in the size of coronary arteries, where smaller diameter vessels in women could lead to technical difficulties in the procedures might explain some of the difference.
Our findings are in accordance with previous findings of a gender bias in the invasive treatment of ACS.6,7,10,13,14 We found differences, however, in both the CAG and revascularization rates. Even after taking the differences in the number of affected vessels into account the differences persisted both in PCI and CABG rates, something not previously shown.
Strengths and limitations
The contemporary data and the completeness of the registries give valuable information on the management strategies of ACS in the present clinical setting, and the findings point towards areas needing our attention. This study was based on complete and nationwide data. The data covered the entire population of Denmark, independent of race, socioeconomic status, age or participation in health-insurance programmes. Therefore, the risk of selection-bias was minimized, and the study included citizens both in and outside the labour market. Reporting to the Danish Heart Registry was mandatory by a directive issued by the Danish Board of Health for all hospitals performing the procedures, both public and private, which strengthens the completeness of the data. The patients had a length of stay of at least 1 day and left with a discharge diagnosis of ACS, thus adding to the validity of the diagnosis. No gender differences were observed in the number of excluded patients.
The main limitation was inherent in the observational nature of the study. Other limitations to our analysis that warrant consideration were the differences between men and women in the clinical presentation of ACS on which we had little information.32 We had no information on key clinical variables, such as ECG changes on presentation, elevation in biomarkers, and medication before and after the event. The diagnosis of UAP had not been validated in the registries to the same extent as the MI diagnosis, but we found that patients with UAP underwent similar diagnostic investigations as did patients with MI. The sensitivity analysis of data from only MI patients yielded the same overall results.
Conclusion and implications
Our study showed that the gender differences in invasive treatment after ACS can be attributed to two things: women were less likely to undergo CAG because of factors associated with gender independently of age and comorbidity, and differences in coronary artery disease account for most, but not all, of the differences in revascularization rate between men and women who had a CAG. Hence, gender is an issue in the choice of strategy, mostly in the choice of performing the CAG and, to a minor degree, in the subsequent execution of mechanical revascularization.
Thus, more focus on the sex as an independent issue in the invasive treatment of ACS is warranted, and in particular we recommend that registries closely follow the pattern of angiography and revascularization.
Funding
This work was supported by The Danish Heart Foundation [07-10-R61-A1656-B728-22426F].
Conflict of interest: none declared.
Acknowledgement
We thank the contributors to The Danish Heart Registry for the work put into its continuous operation.
Comments
We read with interest the manuscript of Hvelplund A, et al about the gender differences in the management of patients with acute coronary syndrome in Denmark [1]. For this purpose, authors identified all patients admitted to Danish hospitals with acute coronary syndrome in 2005-07 (9561 women and 16406 men). Authors found that significantly less women underwent coronary angiography than men (64% versus 78%, P <0.05; hazard ratio 0.68; 95% CI 0.65-0.70, P <0.0001). Moreover, percutaneous revascularization was also less likely performed in women compared with men. Previous studies in different European countries have shown that women are somewhat less intensively treated, especially regarding invasive procedures [2]. This situation may be even worse since patients included in these studies had a diagnosis of acute coronary syndrome. As atypical chest pain is more frequent in women than in men, many women are not correctly diagnosed of myocardial infarction, or when they are diagnosed, sometimes it is too late and may not benefit from revascularization [3]. Unfortunately, these differences do not only occur in acute setting, but they remain during the follow-up. Thus, when compared gender differences in patients with chronic ischemic heart disease, women appear to be undertreated and underdiagnosed, what may in part explain the poorer risk factors control rates observed in this population [4]. Despite cardiovascular disease is the most important cause of death among women, it seems that many physicians and patients do not actually realize about the coronary risk in women, particularly in those with a history of myocardial infarction [5]. Although this could be at least partially due to confidence in the well-known cardioprotective effect of female hormones, the fact is that physicians do not adequately diagnose and treat women with cardiovascular disease. It is very likely that this undertreatment may have an important role in the cardiovascular prognosis of women. All these data emphasize the need for ongoing medical education to improve the recognition and management of both acute and chronic coronary heart disease in women, with the goal of reducing overall cardiovascular risk.
References
1. Hvelplund A, Galatius S, Madsen M, Rasmussen JN, Rasmussen S, Madsen JK, Sand NP, Tilsted HH, Thayssen P, Sindby E, Hojbjerg S, Abildstrom SZ. Women with acute coronary syndrome are less invasively examined and subsequently less treated than men. Eur Heart J. 2010;31:684-690.
2. Alfredsson J, Stenestrand U, Wallentin L, Swahn E. Gender differences in management and outcome in non-ST-elevation acute coronary syndrome. Heart. 2007;93:1357-1362.
3. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernandez-Aviles F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598-1660.
4. Barrios V, Escobar C, Bertomeu V, Murga N, de Pablo C, Calderon A. Sex differences in the hypertensive population with chronic ischemic heart disease. J Clin Hypertens (Greenwich). 2008;10:779-786.
5. Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, Ganiats TG, Gomes AS, Gornik HL, Gracia C, Gulati M, Haan CK, Judelson DR, Keenan N, Kelepouris E, Michos ED, Newby LK, Oparil S, Ouyang P, Oz MC, Petitti D, Pinn VW, Redberg RF, Scott R, Sherif K, Smith SC Jr, Sopko G, Steinhorn RH, Stone NJ, Taubert KA, Todd BA, Urbina E, Wenger NK. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481-1501.
Conflict of Interest:
None declared