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Presentation, delay, and contraindication to thrombolytic treatment in females and males with myocardial infarction

      Abstract

      Background

      This study seeks to explore gender-relevant factors of medical history, sociodemographics, symptom presentation, and delay on thrombolysis administration (or recorded contraindication) in a sample of men and women with confirmed myocardial infarction (MI).

      Methods

      Cross-sectional examination of self and nurse-report data collected in the coronary care unit (CCU) from 12 hospitals across south-central Ontario, Canada. A total of 482 MI patients (347 males, 135 females; 63% response rate) were recruited.

      Main findings

      There was no gender difference in the report of chest pain (χ2(1) = 3.78, p = .052), or in prehospital delay time (median = 96.5 minutes). Thrombolysis was administered in 158 males (68.4%) and 50 females (50.0%) without reported contraindication. Females (median = 27 minutes) had a significantly longer interval between diagnostic electrocardiogram (ECG) and administration of a thrombolytic than males (median = 22, U = 3,056). No contraindication was indicated for not administering a thrombolytic (i.e., too late, risk of bleed) in approximately 40% of females. In accordance with clinical practice guidelines, thrombolysis was more often administered in participants with a shorter time interval between symptom onset and hospital arrival. For females, thrombolysis was more often administered in younger participants (Kruskal Wallis = 5.88).

      Conclusions

      Reducing gender, age, and socioeconomic disparities in access to thrombolysis treatment is imperative. Hospital delays with female cardiac patients may be precluding thrombolysis administration.

      Keywords

      Introduction

      C urrent American College of Cardiology/American Heart Association guidelines recommend that thrombolytic therapy be administered to all patients regardless of age, gender, or race who have symptoms suggestive of myocardial infarction (MI) and who present to the hospital within 12 hours of symptom onset, have diagnostic changes on their 12-lead electrocardiogram (ECG) (ST-segment elevation or bundle-branch block), and have no contraindications (
      • Ryan T.J
      • Anderson J.L
      • Antman E.M
      • Braniff B.A
      • Brooks N.H
      • Califf R.M
      • et al.
      ACC/AHA guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).
      ). Unfortunately, this therapy has been underused, particularly among females (
      • Barron H.V
      • Bowlby L.F
      • Breen T
      Use of reperfusion therapy for acute myocardial infarction in the united states: Data from the national registry of myocardial infarction 2.
      ,

      Cundiff, D. K. (2002). Thrombolysis for acute myocardial infarction: Drug review. Medscape General Medicine. Available: www.medscape.com/viewarticle/414942

      ,
      • Kudenchuk P
      • Maynard C
      • Martin J
      • Wirkus M
      • Weaver W.D
      Comparison of presentation, treatment, and outcome of acute myocardial infarction in males versus females.
      ). Gender-relevant factors that may affect thrombolysis administration include age, medical history, symptom presentation, and delay (
      Fibrinolytic Therapy Trialists' (FTT) Collaborative GroupFibrinolytic Therapy Trialists' (FTT) Collaborative Group
      Indications for fibrinolytic therapy in suspected acute myocardial infarction Collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients.
      ).
      In particular, underuse of thrombolysis in females has been reported in several large studies, even after adjustment for patient age and other clinical variables (
      • Barron H.V
      • Bowlby L.F
      • Breen T
      Use of reperfusion therapy for acute myocardial infarction in the united states: Data from the national registry of myocardial infarction 2.
      ,
      • Bell D.B
      • Nappi J
      Myocardial infarction in women: A critical appraisal of gender differences in outcomes.
      ,
      • Weitzman S
      • Cooper L
      • Chambless L
      • Rosamond W
      • Clegg L
      • Marcucci G
      • et al.
      Gender, racial, and geographic differences in the performance of cardiac diagnostic and therapeutic procedures for hospitalized acute myocardial infarction in four states.
      ). A decade-long examination of thrombolysis treatment showed that 60% of eligible females received thrombolysis compared with nearly 80% of eligible males (
      • Spencer F
      • Scleparis G
      • Goldberg R.J
      • Yarzebski J
      • Lessard D
      • Gore J.M
      Decade-long trends (1986 to 1997) in the medical treatment of patients with acute myocardial infarction: A community-wide perspective.
      ). However, females do not differ significantly from males with regard to early infarct-related artery patency rates, reocclusion after thrombolytic therapy, or ventricular functional response to injury or reperfusion (
      • Woodfield S.L
      • Lundergan C.F
      • Reiner J.S
      • Thompson M.A
      • Rohrbeck S.C
      • Deychack Y
      • et al.
      Gender and acute myocardial infarction: Is there a different response to thrombolysis.
      ). While conflicting evidence exists (

      Cundiff, D. K. (2002). Thrombolysis for acute myocardial infarction: Drug review. Medscape General Medicine. Available: www.medscape.com/viewarticle/414942

      ), large randomized clinical trials document that thrombolysis after acute myocardial infarction reduces mortality rates among females and males (although females have higher mortality rates in both the treatment and placebo groups;
      ISIS-3
      A randomised comparison of streptokinase vs. tissue plasminogen activator vs. alteplase and of aspirin plus heparin vs. aspirin along among 41,299 cases of suspected acute myocardial infarction.
      ,
      • Weaver W.D
      • White H.D
      • Wilcox R.G
      • Aylward P.E
      • Morris D
      • Guerci A
      • et al.
      Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy.
      .

      Objectives

      The purpose of this study was to explore the constellation of gender-relevant factors in contraindication of thrombolysis administration. We will investigate differences in the administration of thrombolysis, nonadministration with legitimate contraindication recorded, and nonadministration without recorded contraindication in female and male MI patients based on both prehospital and hospital delay, and other pertinent gender differences. Based on

      Kaplan, K., Fitzpatrick, P., Cox, C., Shammas, N., & Marder, V. J. Use of thrombolytic therapy for acute myocardial infarction: Effects of gender and age on treatment rates. Journal of Thrombosis & Thrombolysis, 13, 21–26

      , we postulate that after taking into account recorded contraindications, delay, and symptom presentation, a bias in thrombolytic administration based on gender and age will persist.

      Materials and methods

      Participants

      Nine hundred fifty-four consecutive patients who were diagnosed with MI in twelve coronary care units (CCUs) across south-central Ontario, Canada, were approached for the study. After taking into account patient ineligibility based on illness severity (n = 107), confusion (n = 44), low English language proficiency (n = 132), unconsciousness (n = 4), and refusal, we had 482 consenting participants (response rate 63%). Of the patients approached, participants were significantly younger than those who refused or were ineligible to participate (t (948) = −10.51, p < .001). Significantly more males agreed to participate than females (χ2 (1) = 19.00, p < .001), and more married and fewer widowed individuals agreed to participate (χ2 (1) = 19.12, p < .001).
      Four hundred eighty-two patients (347 males, 135 females) consented to participate in the study (see Table 1). Their ages ranged from 31 to 93 years with a mean age of 61.9 ± 12.22 years. Seventy-six percent of the participants (n = 364) were married, 31.3% had some postsecondary education (n = 146), and 45% had a family income over $50,000 CAD (i.e., approximately $32,000 USD; n = 183) annually. Family income was scored with four response categories: 68 participants (16.7%) reported an annual family income under $25,000 CAD, 155 (38.2%) reported a family income from $25,001 to $50,000, 87 (21.4%) reported a family income from $50,001 to $75,000, and 96 (23.6%) reported over $75,000 annually (some participants declined to report their family income). With regard to disease severity, 368 (80.2%) had a Killip class score of 1. Over 80% of participants (n = 391) were recruited from a nonteaching hospital.
      Table 1Sociodemographic and clinical characteristics stratified by gender
      VariableFemales (n = 135)Males (n = 347)Test statistic
      Age (mean; SD)66.29 (12.33)59.21 (11.61)t (480) = −5.91
      p < .001.
      Marital status (% married)71 (53.0%)293 (85.0%)χ2 = 58.08
      p < .01.
      Education (% <high school)103 (78.6%)218 (64.9%)χ2 = 8.29
      p < .05.
      PMH
      Past medical history.
      myocardial infarction
      41 (31.8%)104 (31.5%)χ2 = .003
      PMH congestive heart failure5 (3.9%)8 (2.4%)χ2 = .71
      PMH diabetes mellitus32 (26.7%)67 (21.3%)χ2 = 1.44
      PMH cigarette smoking47 (37.3%)140 (41.7%)χ2 = .73
      Admission systolic blood pressureχ2 = 4.37
      <10010 (7.7%)12 (3.6%)
      101–13045 (34.6%)127 (37.9%)
      131–16053 (40.8%)128 (38.2%)
      161–19018 (13.8%)57 (17.0%)
      >1904 (3.1%)11 (3.3%)
      Admission heart rate (beats/min)χ2 = 2.75
      <8068 (53.5%)205 (61.9%)
      80–10044 (34.6%)96 (29.0%)
      >10015 (11.8%)30 (9.1%)
      Admission Killip classχ2 = 11.66
      p < .05.
      188 (69.8%)280 (84.1%)
      2, 3, or 438 (30.2%)53 (15.9%)
      ST elevation
      Normal9 (7.8%)35 (10.8%)
      No ST elevation37 (31.9%)85 (26.2%)
      LBBB9 (7.8%)4 (1.2%)
      Inferior ST elevation32 (27.6%)94 (29.0%)
      Anterior ST elevation25 (21.6%)88 (27.2%)
      Paced01 (0.3%)
      Other ST elevation4 (3.4%)17 (5.2%)
      Note. All variables except age, history of diabetes and smoking, marital status, and education are nurse-reported. Due to the nature of nurse-report data from 12 sites there is some missing data, and thus valid percentages are reported.
      a Past medical history.
      b p < .05.
      c p < .01.
      d p < .001.

      Measures

      The self-report survey consisted of questions about sociodemographics, cardiac symptomatology, medical history, delay, and tests and treatments in checklist format. The sociodemographic data included age, gender, marital status, education, income, and living situation. Items regarding delay asked about waiting before taking action, and length of delay.
      Survey data were linked with prospectively and contemporaneously collected clinical data compiled by CCU nurses. This included past medical history, admitting and confirmed diagnosis (based on ECG), presentation profile, documentation about thrombolysis (including whether it was administered, and reason for nonadministration), time of initiation of thrombolysis, and thrombolytic agent used. It also recorded time interval from symptom onset to hospital arrival, from hospital arrival to ECG, from diagnostic ECG to administration of thrombolysis, and an adjusted time interval from hospital arrival through to thrombolytic administration.

      Design and procedure

      This is a cross-sectional piece of a longitudinal study, linking MI patient self-reported and nurse-reported data from the CCU. Participants were recruited in the CCU by a research nurse on the second to fifth day of hospitalization. Inclusion criteria consisted of patients who were diagnosed with a confirmed MI and who were 18 years of age or older. Exclusion criteria consisted of patients who were too ill or confused to give informed consent to participate, or unable to read or speak English. Those who met study criteria and agreed to participate signed a consent form and were provided with a self-report questionnaire. Consent was also obtained to link participant's self-report questionnaire data with their nurse-recorded clinical data.

      Statistical analyses

      Data were cleaned and screened to evaluate statistical assumptions (
      • Tabachnick B.G
      • Fidell L.S
      Using multivariate statistics.
      ). Statistical analyses were performed with SPSS 11.0. A descriptive examination of the variables was performed. Gender differences in the variables of interest were tested using Pearson's χ2 analyses and t-tests as appropriate. Mann-Whitney U and Games-Howell were used where the assumption of homogeneity of variance was violated. A Kruskal-Wallis one-way analysis of variance was used to test for significant differences in family income, age, delay in symptom onset to hospital arrival, and delay from hospital arrival to diagnostic ECG in minutes based on thrombolysis administration (i.e., thrombolysis administered, thrombolysis not administered with contraindication indicated, thrombolysis not administered with no contraindication indicated). This analysis was run separately for males and females.

      Results

      Gender differences in baseline characteristics of sample

      Characteristics of the sample relevant to practice guidelines (
      • Ryan T.J
      • Anderson J.L
      • Antman E.M
      • Braniff B.A
      • Brooks N.H
      • Califf R.M
      • et al.
      ACC/AHA guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).
      ) are presented in Table 1. Where sample sizes were large enough, Pearson's χ2 or Student's t-test were used to test for significant differences by gender. Females participants were significantly older, were less likely to be married, and less likely to have postsecondary education than males. There were no significant gender differences in admission heart rate or systolic blood pressure; however, females were 1.27 times more likely to have a Killip class (
      • Killip T
      • Kimball J.T
      Treatment of myocardial infarction in a coronary care unit: A two year experience with 250 patients.
      ) above one, indicating greater disease severity.

      Symptom presentation

      Symptoms that prompted the patient to seek hospital care are presented in Table 2. Participants reported up to 23 symptoms, with a mean of 6.13 (SD = 4.24). Chest pain was experienced by approximately 68% of male and female participants. The most frequent symptoms reported were chest pain behind the breast bone, sweating, shortness of breath, and chest pain in the left arm. Gender differences in all 25 symptoms were tested using Pearson's χ2 with a Bonferonni adjustment (.05/25 = .002). There were no significant gender differences in any of the most frequently reported cardiac symptoms. Where gender differences did occur, symptoms experienced in the 30 days before the coronary event were more prevalent in females (e.g., pain/pressure in the right side of their back, vomiting) than males. This is likely due to the fact that women (mean = 7.44, SD = 4.62) reported significantly more symptoms than males (mean = 5.62, SD = 3.98; t(480) = −4.33, p < .001).
      Table 2Self-reported cardiac symptom presentation by gender
      SymptomFemales (n = 135)Males (n = 347)χ2 (1)
      Chest pain behind breast bone87 (65.4%)238 (69.0%)0.56
      Sweating75 (56.4%)169 (49.0%)2.11
      Shortness of breath67 (50.4%)139 (40.3%)3.98
      Chest pain into left arm67 (50.4%)150 (43.5%)1.84
      Weakness58 (43.6%)116 (33.6%)4.14
      Nausea57 (42.9%)100 (29.0%)8.37
      Anxiety48 (36.1%)103 (29.9%)1.73
      Chest pain into neck47 (35.3%)71 (20.6%)11.24
      p < .002.
      Fatigue46 (34.6%)102 (29.6%)1.13
      Funny feeling in chest43 (32.3%)88 (25.5%)2.25
      Dizziness40 (30.1%)69 (20.0%)5.54
      Pain in left side of back37 (27.8%)53 (15.4%)9.75
      p < .002.
      Chest pain into jaw37 (27.8%)47 (13.6%)13.36
      p < .001.
      Faint feeling37 (27.8%)53 (15.4%)9.75
      p < .002.
      Feeling ill36 (27.1%)79 (22.9%)0.91
      Vomiting34 (25.6%)40 (11.6%)14.32
      p < .001.
      Indigestion32 (24.1%)66 (19.1%)1.43
      Light-headedness31 (23.3%)44 (12.8%)8.08
      Numbness/tingling31 (23.3%)58 (16.8%)2.67
      Pain in right side of back30 (22.6%)37 (10.7%)11.15
      p < .002.
      Losing energy20 (15.0%)55 (15.9%)0.06
      Pain in abdomen13 (9.8%)18 (5.2%)3.29
      Pain in left arm, no chest pain14 (10.5%)25 (7.2%)1.38
      Pain in jaw, no chest pain10 (7.5%)10 (2.9%)5.11
      Fainting8 (6.0%)19 (5.5%)0.05
      a p < .002.
      b p < .001.

      Stages of delay

      Prehospital delay

      In terms of self-reports, once symptoms began 105 (77.8%) females and 293 (84.4%) males delayed before taking action, but this gender difference in delay did not reach statistical significance (χ2 (1) = 3.00, p = .08). Delay was also recorded in the CCU by nurses (see Table 3). The nurse-recorded time interval between symptom onset and hospital arrival ranged from 0 to 899.0 minutes, with a median of 96.5 minutes (interquartile range = 135.75), or approximately 1.5 hours. There was no gender difference in nurse-reported delay time from onset of symptoms to hospital arrival (p = .52).
      Table 3Nurse-recorded median number of minutes delay in cardiac care by gender
      VariableFemales (n = 135)Males (n = 347)Mann-Whitney U
      Mann-Whitney U used to test for significant gender differences due to the heterogeneity of variance in time delay.
      Symptom onset to arrival110.092.57450.5
      Arrival to first ECG10.57.09365.5
      Diagnostic ECG to thrombolysis27.022.03056.0
      p < .05.
      Delay to order thrombolysis12.09.03016.5
      Arrival to thrombolysis43.537.53111.5
      Adjusted arrival to thrombolysis
      The nurse-recorded adjusted arrival to thrombolysis figures provide an accurate method to assess time-to-treatment for those patients whose first ECG may not have been the diagnostic ECG.
      38.530.02711.0
      p < .01.
      a Mann-Whitney U used to test for significant gender differences due to the heterogeneity of variance in time delay.
      b The nurse-recorded adjusted arrival to thrombolysis figures provide an accurate method to assess time-to-treatment for those patients whose first ECG may not have been the diagnostic ECG.
      c p < .05.
      d p < .01.

      Hospital delay

      The nurse-recorded time from hospital arrival to the first ECG ranged from 0 to 270 minutes, with a median of 8 minutes (interquartile range = 9.0; trend toward longer delay among women, p = .06). The time from the diagnostic ECG to the administration of the thrombolytic drug ranged from 0 to 254 minutes, with median of 24 minutes (interquartile range = 22.25). There was a significantly longer delay for female patients from diagnostic ECG to thrombolysis administration (p = .034). The time required to order the thrombolytic ranged from 0 to 54 minutes, with a median of 10 minutes (interquartile range = 13.25).
      The overall time from hospital arrival to thrombolytic administration ranged from 0 to 960 minutes, with a median of 38.5 minutes (interquartile range = 42.5). The nurse-recorded adjusted arrival to thrombolysis figures provide an accurate method to assess time-to-treatment for those patients whose first ECG may not have been the diagnostic ECG. The adjusted arrival to drug time ranged from a minimum of 0 minutes to a maximum of 436 minutes. The median number of minutes was 33 (interquartile range = 26.0), with women waiting significantly longer than men (p = .005).

      Thrombolysis

      Two hundred eight participants (44.1%) were thrombolyzed. Patient contraindications to thrombolysis are presented in Table 4. Of the patients for whom there were no contraindications to thrombolysis (i.e., diagnostic ECG, arrived without delay, no risk of bleeding; n = 331), thrombolytic was given on admission to 208 patients (62.8%), but not to 123 patients (37.2%). There was a significant gender difference in administration of thrombolysis among those patients with an MI who were eligible for such treatment (χ2 (1) = 10.12, p = .001). Fifty females (50.0%) and 158 males (68.4%) received this treatment. There was also a significant gender difference in reasons that thrombolysis was not administered, χ2 (6) = 40.98, p < .001. Females were less likely to receive the drug, and at the same time less likely to have a recorded explanation for contraindication than males.
      Table 4Frequency of nurse-reported thrombolysis administration and contraindication by gender
      ReasonFemale (%) (n = 135)Male (%) (n = 347)
      Thrombolysis administered50 (37.9%)158 (46.5%)
      Thrombolysis not administered
      ECG not diagnostic20 (15.2%)62 (18.2%)
      Too late8 (6.1%)43 (12.6%)
      Risk intracranial bleed1 (0.8%)3 (0.9%)
      Risk bleed in other site2 (1.5%)0 (0%)
      Risk—other1 (0.8%)1 (0.3%)
      No reason given50 (37.9%)73 (21.5%)
      Note: There were no data available for three females and seven males.
      Two Kruskal-Wallis one-way ANOVAs were performed examining thrombolysis: whether it was administered, not administered with recorded contraindication, or not administered without recorded contraindication (see Table 5). One was performed using the male sample, the other with the female sample. Independent variables were fourfold: age, family income, symptom onset to arrival time, and time from hospital arrival to diagnostic ECG. Tests of homogeneity of variance revealed that age (Levene's statistic = .82, p = .44) and family income (Levene's statistic = .68, p = .51) met this assumption; however, onset to arrival time (Levene's statistic = 31.96, p < .001) and hospital arrival to ECG time (Levene's statistic = 3.39, p = .04) did not. Therefore, where Kruskal-Wallis was significant, post-hoc LSD tests were used where assumptions were met and Games-Howell was used where assumptions were violated.
      Table 5Median age, family income, and prehospital and hospital delay in minutes based on gender, and nurse recording regarding thrombolysis administration
      Independent VariableTlysis AdministeredTlysis Not Administered No Contraindication RecordedTlysis Not Administered Contraindication Recorded
      Males
      Age55.560.060.5
      Family income
      Family income is scored from 1 to 4 with higher scores denoting higher annual family income.
      ,
      Denotes significant difference based on Kruskal-Wallis one-way analysis of variance.
      3.0
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      3.02.0
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      Onset—arrival time
      Denotes significant difference based on Kruskal-Wallis one-way analysis of variance.
      81.0
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      176.0245.5
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      Arrival—ECG time
      Denotes significant difference based on Kruskal-Wallis one-way analysis of variance.
      7.013.018.5
      Females
      Age
      Denotes significant difference based on Kruskal-Wallis one-way analysis of variance.
      65.0
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      69.5
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      66.0
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      Family income2.01.01.0
      Onset—arrival time
      Denotes significant difference based on Kruskal-Wallis one-way analysis of variance.
      105.0
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      89.5245.0
      Denotes significant difference in post-hoc LSD or Games-Howell tests.
      Arrival—ECG time
      Denotes significant difference based on Kruskal-Wallis one-way analysis of variance.
      11.0
      Games-Howell, p = .083.
      18.013.0
      Games-Howell, p = .083.
      a Family income is scored from 1 to 4 with higher scores denoting higher annual family income.
      b Denotes significant difference based on Kruskal-Wallis one-way analysis of variance.
      c Denotes significant difference in post-hoc LSD or Games-Howell tests.
      d Games-Howell, p = .083.
      Among males, there was a significant difference in thrombolysis administration based on family income (χ2 (2) = 7.30, p = .03), onset to arrival time (χ2 (2) = 17.72, p < .001), and arrival to ECG time (χ2 (2) = 39.90, p < .001). Post-hoc LSD tests revealed that male MI patients who received thrombolysis had significantly higher family income than those who did not receive thrombolysis due to a legitimate contraindication (p = .006), and Games-Howell revealed that males who received thrombolysis had significantly shorter delay from onset to arrival than patients with a legitimate contraindication (p < .001). For females, there was a significant difference in thrombolysis administration based on age (χ2 (2) = 5.88, p = .05), symptom onset to hospital arrival time (χ2 (2) = 9.58, p = .01), and arrival to ECG time (χ2 (2) = 7.85, p = .02). Post-hoc LSD tests revealed that female MI patients who received thrombolysis were significantly younger than those who did not receive thrombolysis due to a legitimate contraindication (p = .02), and younger than those for whom there was no contraindication provided for nonadministration (p = .04). Based on Games-Howell, females who received thrombolysis had significant shorter delay from onset to arrival than patients with a legitimate contraindication (p = .01).

      Discussion

      This study explored gender differences relevant to the administration of thrombolysis. The baseline characteristics of the sample were similar to those presented in the literature. There were no significant gender differences in heart rate or systolic blood pressure on admission, but females were older, less educated, and more likely to have a higher Killip class than males. In regard to symptom presentation, there were no gender differences in typical cardiac symptoms including chest pain. Contrary to the literature, there was no significant gender difference in prehospital delay assessed via self-report or nurse-report, but there was a significantly longer hospital delay for female patients from the diagnostic ECG to thrombolysis. Upon arrival to the hospital, 68% of eligible males and 50% of eligible females received thrombolysis. For approximately 40% of females, there was no contraindication recorded regarding why they did not receive such treatment.

      Symptom presentation

      The pervasive stereotype of ischemic heart disease (IHD) as a predominantly male disorder that presents with chest pain and incapacitating symptoms effectively discounts the experience in females. Females are more likely to experience symptoms that do not fit the established patterns for MIs (
      • Miller C.L
      Cue sensitivity in women with cardiac disease.
      ,
      • Milner K.A
      • Funk M
      • Richards S
      • Wilmes R.M
      • Vaccarino V
      • Krumholz H.M
      Gender differences in symptom presentation associated with coronary heart disease.
      ). Despite the fact that chest pain is the most common presentation, there is still a large contingent of females who present with symptoms that can be confused or misinterpreted. Indigestion, nausea, vomiting, shortness of breath, fatigue, and edema are not uncommon in females. If any of these occur without chest pain they can easily be interpreted as a cold, flu, or other common ailments, and appropriate investigations not undertaken.
      In this sample, approximately 68% of participants reported chest pain, and there was no significant gender difference in prevalence of this symptom. However, females reported a significantly greater number of nonchest pain symptoms such as vomiting, feeling faint, pain radiating into the neck, and radiating into the left side of the back, which is consistent with other studies (
      • Milner K.A
      • Funk M
      • Richards S
      • Wilmes R.M
      • Vaccarino V
      • Krumholz H.M
      Gender differences in symptom presentation associated with coronary heart disease.
      ). The reasons for gender differences in cardiac symptom prevalence are unknown, but polysymptomatic presentation may obscure the underlying cardiac etiology for patients and physicians.
      Females may delay help-seeking because their cardiac symptoms do not match expected male symptoms such as central chest pain, radiating arm or shoulder pain, and collapse (
      • Finnegan J.R
      • Meischke H
      • Zapka J.G
      • Leviton L.C
      • Meshack A
      • Benjamin-Barner R
      • et al.
      Patient delay in seeking care for heart attack symptoms: Findings from focus groups conducted in five U.S. regions.
      ,
      • van Tiel D
      • van Vliet K.P
      • Moerman C.J
      Sex differences in illness beliefs and illness behaviour in patients with suspected coronary artery disease.
      ). Vague and less typical symptoms may be experienced by females, and this incongruence can lead to delay in seeking treatment, diagnosis, and underuse of effective therapies (
      • Horne R
      • James D
      • Petrie K.J
      • Weinman J
      • Vincent R
      Patients' interpretation of symptoms as a cause of delay in reaching hospital during acute myocardial infarction.
      ,
      • Miller C.L
      Cue sensitivity in women with cardiac disease.
      ).

      Delay

      Thrombolysis is more effective the earlier it is administered. Prehospital delay time is defined as the amount of time between the first awareness of symptoms and arrival at hospital (
      • Dracup K
      • Moser D.K
      • Eisenberg M
      • Meischke H
      • Alonzo A.A
      • Braslow A
      Causes of delay in seeking treatment for heart attack symptoms.
      ). Given the importance of reperfusion therapy for MI, the interval from the onset of symptoms to the initiation of treatment is also critical. The hospital action phase, more popularly known as “door-to-needle time,” encompasses the interval from the patient's arrival at the hospital to receiving definitive care, such as thrombolysis.
      We found no gender differences in prehospital delay. This may be related to the typical symptomatology reported by both males and females, which lead them to identify and label their symptoms as cardiac in nature. The median prehospital delay time varies in the literature from 2 to 6.5 hours (
      • Dracup K
      • Moser D.K
      • Eisenberg M
      • Meischke H
      • Alonzo A.A
      • Braslow A
      Causes of delay in seeking treatment for heart attack symptoms.
      ). The median prehospital delay in this sample was over 1.5 hours, which is comparable to the Western Washington thrombolytic therapy trials (
      • Maynard C
      • Althouse R
      • Olsufka M
      • Ritchie J.L
      • Davis K.B
      • Kennedy J.W
      Early versus late hospital arrival for acute myocardial infarction in the Western Washington thrombolytic therapy trials.
      ), and the 2.2 hours median delay reported by Horne et al. (2000). The median adjusted door-to-needle time was 33 minutes, significantly shorter for males than females in bivariate analyses. The literature reports a hospital action phase delay time of 60 to 90 minutes (
      • Barakat K
      • Wilkinson P
      • Suliman A
      • Ranjadayalan K
      • Timmis A
      Acute myocardial infarction in women: Contribution of treatment variables to adverse outcome.
      ), which is consistent with our unadjusted door-to-needle time. These median delay times are well under the 12 hours (e.g., 720 minutes) recommended to ensure the efficacy to thrombolysis.

      Thrombolytic treatment

      Thrombolysis was administered in 62.8% of eligible participants. For over 30% of participants who appeared eligible for thrombolysis, however, there was no contraindication recorded. The analyses of variance showed that the delay from symptom onset to arrival at the hospital, and from arrival at the hospital to ECG was significantly related to administration of thrombolysis in both women and men, which is consistent with clinical practice guidelines. However, some troubling findings emerged. Among women, older age was significantly related to a lack of recorded contraindication for thrombolytic administration. Clinical practice guidelines indicate the use of thrombolysis regardless of age (
      • Ryan T.J
      • Anderson J.L
      • Antman E.M
      • Braniff B.A
      • Brooks N.H
      • Califf R.M
      • et al.
      ACC/AHA guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).
      ). However, females are more often older than males at the time of an MI (
      • Hochman J.S
      • McCabe C.H
      • Stone P.H
      • Becker R.C
      • Cannon C.P
      • DeFeo-Fraulini T
      • et al.
      Outcome and profile of women and men presenting with acute coronary syndromes: A report from TIMI IIIB.
      ,
      • Malacrida R
      • Genoni M
      • Peitro Mannioni A
      • Spataro V
      • Parish S
      • Palmer A
      • et al.
      A comparison of the early outcome of acute myocardial infarction in women and men.
      ,
      • Woodfield S.L
      • Lundergan C.F
      • Reiner J.S
      • Thompson M.A
      • Rohrbeck S.C
      • Deychack Y
      • et al.
      Gender and acute myocardial infarction: Is there a different response to thrombolysis.
      ), and the literature suggests that patients who are older are less likely to receive thrombolytic therapy (
      • Spencer F
      • Scleparis G
      • Goldberg R.J
      • Yarzebski J
      • Lessard D
      • Gore J.M
      Decade-long trends (1986 to 1997) in the medical treatment of patients with acute myocardial infarction: A community-wide perspective.
      ). Promotion activities to increase awareness of the benefits of thrombolysis in older female cardiac patients should be pursued.
      Among men, there was a significant difference in thrombolytic administration based on family income. Clearly, despite the universal healthcare system (i.e., single-payer) in which this study was conducted, unexplained inequalities in health care remain. These findings could be due to a third variable, considering that low-income patients are often in poorer health than high-income patients. In this sample, potential alternative explanations for underuse of thrombolysis could be related to comorbidity, subtle or overt classism, ageism, or sexism, level of literacy, knowledge, or disease severity, but cannot be explained by out-of-pocket costs, differences in health insurance coverage, symptom presentation, or delay in reaching medical care. Other research in the region demonstrates that patients of low socioeconomic status have less access to angiography and revascularization (
      • Alter D.A
      • Naylor C.D
      • Austin P
      • Tu J.V
      Effects of socioeconomic status on access to invasive cardiac procedures and on mortality after acute myocardial infarction.
      ), supporting our findings.

      Study limitations

      Caution is warranted when interpreting these results considering our 63% response rate, that there were some significant differences in our sample participants when compared to nonparticipants, and the significant gender differences among participants. Moreover, due to the nature of collecting nurse-report data across 12 sites, some medical data were missing. This study was conducted in an English-speaking Canadian population, thus these results may not be generalizable to other populations or health care systems. Finally, where there was no documented contraindication for thrombolytic administration, this could merely represent a nursing error or records error. Future research is warranted to investigate the relationship between patient characteristics and divergence from clinical practice guidelines, which may include interviewing emergency room personnel and treating physicians.

      Conclusion

      Contrary to other reports, there were no significant gender differences in prehospital delay among patients hospitalized for an MI, but longer hospital delays for women patients were evident. Nor were there significant gender differences in presentation with chest pain, although women presented with more symptoms overall than men. Analysis of nurse-reports failed to reveal a recorded contraindication for thrombolysis more frequently in females compared to males. Overall, women were less likely to receive a thrombolytic than men, and this is clearly multifactorial. Our results show that this could be explained by the longer delay from diagnostic ECG to thrombolytic administration, or older age. Clinical practice guidelines promote thrombolytic administration regardless of age, and the gender difference in hospital delay is disconcerting. In summary, the gap in ischemic coronary care appears to be multifactorial, consisting in gender, age, and socioeconomic issues, differences in risk factors (i.e., severity, comorbidity), as well as hospital delay. Prehospital delay and presentation of chest pain may not play as large a role in gender differences as previously suspected.

      Acknowledgements

      We gratefully acknowledge Eli-Lilly Canada for funding the UHN-Eli Lilly Women's Health Fellowship which supported Dr. Grace, the Heart and Stroke Foundation of Ontario for a research grant to investigate gender differences in CCU patients to Drs. Stewart and Abbey, and the Samuel Lunenfeld Foundation which funded pilot work by Drs. Stewart and Abbey. We also acknowledge Linda Green and the CCU staff nurses for their diligence in recruitment and data collection.

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      Biography

      Dr. Grace is a CIHR post-doctoral fellow with the University Health Network Women's Health Program where she primarily investigates gender differences in cardiac services, particularly referral processes to cardiac rehabilitation.
      Dr. Abbey is a psychiatrist and research scientist with the University Health Network, with research interests in organ transplantation, cardiovascular disease, and mindfulness-based meditation.
      Ms. Bisaillon is the Director for the Neuroscience/Muskulosketal Health System at Trillium Health Centre, and is currently working on issues related to acute spine and stroke care.
      Dr. Shnek is a health psychologist with extensive experience in the areas of promoting healthy lifestyles and helping people cope with chronic illness.
      Dr. Irvine is an associate professor in the Department of Psychology at York University and a research scientist with the University Health Network Behavioural and Health Sciences Division, with research interests in behavioral aspects of cardiovascular disease.
      Dr. Stewart is Professor and Chair of Women's Health at University of Toronto and University Health Network where she directs the Women's Health Program. She is interested in many aspects of Women's Health including equity, services, and adjustment to medical illnesses.