Effect of gender on the prognostic value of dobutamine stress myocardial contrast echocardiography

Accepted Manuscript The impact of gender on the prognostic value of dobutamine stress myocardial contrast echocardiography Constantina Aggeli, Kali Polytarchou, Ioannis Felekos, Kostas Zisimos, Erifili Venieri, Athanasios Verveniotis, Dimitrios Varvarousis, Kostantinos Toutouzas, Eleutherios Tsiamis, Dimitrios Tousoulis PII:

S1109-9666(17)30007-6

DOI:

10.1016/j.hjc.2017.04.004

Reference:

HJC 163

To appear in:

Hellenic Journal of Cardiology

Received Date: 8 January 2017 Revised Date:

4 April 2017

Accepted Date: 12 April 2017

Please cite this article as: Aggeli C, Polytarchou K, Felekos I, Zisimos K, Venieri E, Verveniotis A, Varvarousis D, Toutouzas K, Tsiamis E, Tousoulis D, The impact of gender on the prognostic value of dobutamine stress myocardial contrast echocardiography, Hellenic Journal of Cardiology (2017), doi: 10.1016/j.hjc.2017.04.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT The impact of gender on the prognostic value of dobutamine stress myocardial contrast echocardiography Constantina Aggeli, Kali Polytarchou, Ioannis Felekos, Kostas Zisimos, Erifili

Eleutherios Tsiamis, Dimitrios Tousoulis

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Venieri, Athanasios Verveniotis, Dimitrios Varvarousis, Kostantinos Toutouzas,

Corresponding author: Kali Polytarchou, MD, MSc

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1st Cardiology Department, Hippokration Hospital, Athens Medical School, Greece

1st Cardiology Department, Hippokration Hospital,

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Athens Medical School, Greece

Vas. Sofias 114, Athens 11527, Greece Tel: 00306974433632

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e-mail: [email protected]

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fax: 210-7485039

ACCEPTED MANUSCRIPT Abstract Background: Dobutamine stress contrast echo (DSCE) has a well-established prognostic value in the context of coronary artery disease (CAD). However, data

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regarding its prognostic capability separately in men and women are scarce. The aim of the current study was to assess gender-related differences in the prognostic performance of DSCE.

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Methods: DSCE was performed in 2645 consecutive patients, who were classified in two groups depending on gender. Follow-up lasted 57.1±10.1 months. End points

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included all-cause mortality, cardiac death, late revascularization and hospitalizations. Survival analysis was performed comparing men and women.

Results: Out of 2645 patients (59.3±8.7 years), 69.1 % were men. DSCE was positive in 23.4% of male patients, while in females the respective percentage was 14.3%.

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There was statistically significant difference among the two groups with regards to end points occurrence (11.6% vs. 6.1%, p<0.05). Multivariate analysis revealed that DSCE response was the strongest predictor for adverse outcomes (Exp(B)=51.9,

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p<0.05) in both groups. The predictive model including DSCE results along with

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clinical data performed well without significant differences between males and females (C-index 0.93 vs. 0.87 respectively, p=NS). Conclusion: DSCE has a strong prognostic value for patients with known or suspected CAD, regardless of patient gender. This makes DSCE an attractive screening option for women, in whom CAD assessment can be challenging. Key words: stress echocardiography; women; gender; prognosis; coronary artery disease

ACCEPTED MANUSCRIPT Abbreviations: CVD: Cardiovascular Disease

DSCE: Dobutamine Stress Contrast Echocardiography MACE: Major Adverse Cardiovascular Events

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SCE: Stress Contrast Echocardiography

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CAD: Coronary Artery Disease

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SE: Stress Echocardiography

ACCEPTED MANUSCRIPT Introduction Despite therapeutic advances and greater awareness of the risk of cardiovascular disease (CVD) in women, outcomes and prognosis for women with

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CVD remain worse than those for men [1]. This disparity suggests that sex-related differences in disease presentation, mechanisms, risk factors, and treatment may affect prognosis [2]. Compared to men, non-invasive evaluation of coronary artery disease (CAD) in females remains challenging for several reasons: the lower single-

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vessel disease [3, 4], and less predictive and atypical symptoms [5]. These difficulties

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are even augmented in postmenopausal women in whom physiological and pathological changes occur, that have significant influence on cardiovascular risk factors partly due to estrogen deficiency [1, 2]. Notably, women with CAD have more adverse outcomes compared to men [1, 2]. Thus, accurate and early diagnostic

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assessment of CAD is crucial to improve prognosis in women. Dobutamine stress echo is a well-established clinical tool, both for the diagnostic and prognostic assessment of patients with known or suspected CAD [6-8].

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Its negative predictive value is high, thus allowing the assumption of favourable prognosis in patients with a negative for ischemia result [9-18]. However, studies

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focusing on women and especially on symptomatic postmenopausal patients are limited with a subsequent shortage of available evidence for contemporary noninvasive CAD tests such as dobutamine stress contrast echocardiography (DSCE). The aim of the current study was to assess gender-related differences in the prognostic performance of DSCE.

ACCEPTED MANUSCRIPT Materials and methods A total of 2645 patients, who were referred to our tertiary hospital for stress echocardiography (SE), were retrospectively studied, using the echo lab's electronic

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records. Clinical risk factors and the use of medications affecting the cardiovascular system were recorded at the time of DSCE, on the basis of the medical prescription and patient information. Diabetes mellitus was defined as a fasting plasma glucose level >125 mg/dl or the need for insulin or oral hypoglycemic agents.

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Hypercholesterolemia was defined as total cholesterol >200 mg/dl or treatment with

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lipid-lowering medications. Hypertension was defined as blood pressure >140/90 mmHg or use of antihypertensive medication.

Patients were stratified according to their gender in male and female. Mean follow-up lasted 57.1 ± 10 months and was obtained from reviews of patients’

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hospital charts, electronic records and from telephone interviews with patients. The primary end points of the study were major adverse cardiovascular events (MACE), as all-cause mortality, cardiovascular mortality, late revascularization (performed >3

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months after DSCE) and hospitalizations. Revascularization in a time interval less than three months was considered as therapeutic response to an abnormal test and thus

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it was excluded from study end-points. Cardiac death was defined as death associated with myocardial infarction, life-threatening arrhythmia, pulmonary edema, or sudden unexpected death occurring without another explanation. The study was approved by the institutional review board of Hippokration General Hospital. Dobutamine stress contrast echocardiography We used an accelerated dobutamine stress protocol, based on previous reports regarding the feasibility and safety of accelerated dobutamine protocols [19]. An

ACCEPTED MANUSCRIPT intravenous line was placed and dobutamine was infused in four 2-minute (instead of the conventional 3-minute) stages: 10–20–30–40 mcg/kg per minute. Atropine was administered at the end of the 8-minute period, as required (at a dose of 0.2– 1 mg) to achieve the age-adjusted target heart rate [0.95 x (220- age)], unless contraindicated

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(e.g., due to severe prostate enlargement, the presence of glaucoma, etc.). A shortacting beta-blocker (esmolol 20–40 mg) was administered upon test completion to all patients (except those with a known history of severe bronchospasm), in order to

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blockers at least 24 h prior to the stress test.

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accelerate normalisation of the heart rate. Patients were instructed to discontinue beta-

All studies were performed with a Philips iE33 ultrasound machine (Philips Medical Systems, Andover, Massachusetts, USA), equipped with a 2.5 MHZ S5-1 sector array transducer. Echo-contrast agent (sulphur hexafluoride micro bubbles; SonoVue, Bracco International BV, Milan, Italy) was administered to all patients at

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baseline and at peak stress, in order to improve left ventricular opacification. The contrast agent was administered by means of bolus injection of 0.3-0.5 ml, during the

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baseline and peak phases of the protocol (if a study was terminated prematurely, contrast was administered at that time). Segmental wall motion was assessed using

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left ventricle opacification settings (mechanical index 0.5). The stress protocol was terminated if: (1) the age-adjusted target heart rate

was achieved; (2) four or more contiguous segments showed signs of ischemia; (3) the patient reported intense chest pain; (4) the electrocardiogram showed ventricular tachycardia, ventricular bigeminy or trigeminy, or multiform premature ventricular complexes; Echocardiographic study interpretation

ACCEPTED MANUSCRIPT The left ventricle was divided into 17 segments, according to the American Society of Echocardiography recommendations [20]. Wall motion segmental score was graded as: 1-normokinetic, 2-mild hypokinetic, 3-severe hypokinetic, 4-akinetic and 5-dyskinetic. Any deterioration by one grade or more, from baseline to peak

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stress, was considered indicative of ischemia. The test was considered positive for ischemia, if new or worsening wall motion abnormalities appeared in two or more contiguous myocardial segments.

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Statistical analysis

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Continuous variables are expressed as mean ± SD and categorical variables as proportions. Two-tailed unpaired Student’s t tests were used for intergroup comparisons. Fisher’s exact and chi-square tests were used for comparisons of proportions. Kaplan-Meier curves were used to estimate the distribution of time to the

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end points. Annual event rates were obtained from Kaplan–Meier estimates. The association of selected variables with outcome was assessed with the Cox’s proportional hazards survival model using univariate and stepwise multivariate

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procedures. A significance of 0.05 was required for a variable to be included into the multivariate model, whereas 0.1 was the cut-off value for exclusion.

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Hazard ratios with the corresponding 95% confidence intervals of the combined end points of death, hospitalization and revascularization were estimated for each variable, including clinical and echocardiographic characteristics. To assess the value of DSCE result over clinical parameters for event prediction, DSCE result was sequentially included in multivariable models with relevant clinical predictors. Overall, chi-square tests were used to compare the prognostic value of the clinical model with model comprising DSCE parameters and C-statistics were used to compare model strengths. All tests of significance were 2-sided and a p value < 0.05

ACCEPTED MANUSCRIPT was considered significant. Data were analyzed using SPSS version 20.0 for Windows (SPSS, Inc., Chicago, Illinois). Results

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Demographic data Study population demographic characteristics are presented in detail in Table 1. Mean age was 58.8 ± 9.9 years, while baseline EF was 57.4 ± 5.6 %. As shown in

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the table, men have a significant higher rate of CAD and risk factors burden.

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However, female patients were older as compared to their male counterparts. Dobutamine stress contrast echo findings-adverse events

Dobutamine stress contrast echo was positive in 14.6% of male patients, while in females the respective percentage was 4%. Both male and female patients with

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positive DSCE had significantly more total adverse events compared to patients with normal DSCE (Figure 1). Table 2 illustrates that, during a mean follow up of 57.1 months, there was statistically significant difference among the two groups with

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regard to MACE occurrence (7.2% vs. 1.7%, p<0.0001). This difference was mainly

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driven by the higher late revascularization rates in men (4% vs 0.9%). Outcome prediction

Cox regression was performed to assess the impact of a number of factors on

MACE outcomes between male and female patients. The model contained nine independent clinical variables (diabetes, age, known CAD, the presence of symptoms, LVEF, hypertension, dyslipidemia, family history for cardiovascular disease and smoking) along with DSCE result. As shown by multivariate analysis in Table 3, the strongest predictors of MACE were the presence of CAD, symptoms and smoking in

ACCEPTED MANUSCRIPT men, while in women the major determinants were hypertension and CAD. In both groups the DSCE result was the major determinant of outcomes recording an odds ratio of 54 for male and 59.9 for female patients.

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Global chi-square of the full model for predicting outcome was 2280.2 (p < 0.0001) in men and 474.1 (p=0.0001) in women. Sequential Cox regression models were fit to test the incremental value of DSCE result on outcome prediction. With regards to male population chi-square increased by 554.3 (p<0.0001), while the

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respective increase in female population was 127.1 (p<0.0001). These data indicate

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that the model including DSCE results along with clinical data performed significantly better than the model with clinical data alone. There was no transgender difference in overall prognostic effect (C-index 0.933 for men vs 0.8670 for women, p=NS).

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Discussion

Echocardiography combined with physical or pharmacological stress is an effective and not gender-related tool for diagnostic purposes in women, having shown

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to provide significantly higher diagnostic accuracy when compared with exercise

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ECG testing [21, 22]. Despite this, little is known about the value of stress contrast echocardiography (SCE) in risk stratification of women with suspected or known CAD [23, 24].

In the present study we assessed the impact of gender in the prognostic value

of DSCE among patients with probable or known CAD. Our study confirmed the fact that DSCE has strong predictive value regarding survival and MACE [9-18]. The presence of ischemic response constituted the only independent negative prognostic factor, both in men and women. Strength of the study was the large number of the

ACCEPTED MANUSCRIPT study population. Furthermore, MACE rates in our study are in line with results of previous studies regarding stress imaging techniques [9-18, 25- 27]. DSCE is a method that combines the advantages of pharmaceutical stress echo

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with the administration of contrast agents resulting in increased sensitivity and specificity of the method. Moreover, the administration of echo-contrast agent is thought to increase the prognostic value of the method [28]. Our study demonstrated no gender-related difference regarding the prognostic value of DSCE. In contrast are

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the findings of another recent prospective randomized trial, which studied the impact

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of gender in the prognostic value of SCE when compared with conventional SE, without the administration of contrast agent [28]. In this study, men with abnormal SCE had a significantly worse prognosis than women, whereas no gender-related differences were observed in the group of patients with abnormal conventional SE. However, this finding can be attributed to the fact that, unlike our study, younger

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patients were included without known CAD and therefore pre-test probability was low. Previous studies investigating the prognostic value of exercise or

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pharmacological stress echocardiography without the administration of contrast agents, have also reported no differences between men and women, finding that

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comes in accordance with our results [23, 24, 29, 30]. Importantly, our study highlights the role of DSCE in risk stratification for

women. Women with a normal DSCE had <1% MACE, whereas a positive DSCE result was the strongest predictor of adverse events. Little data exist regarding the prognostic value of pharmaceutical stress echocardiography in women. Our findings correlate with the results of previous studies regarding early menopausal women and women without known CAD, who underwent exercise stress echocardiography [31, 32].

ACCEPTED MANUSCRIPT At this point some limitations of our study should be acknowledged. Our study is retrospective in design and DSCE inherently suffers from operator interpretation bias. Furthermore this study was a single center study and our result may not be easily extrapolated in a more generalized context. Data with regards to the intake of

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prognosis-modifying medication including beta-blockers, statins, aspirin and angiotensin converting enzyme-inhibitors are missing and their impact on our results cannot be assessed.

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In conclusion, DSCE plays an integral prognostic role regardless patient

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gender. This makes DSCE an indispensable clinical tool for the assessment of CAD in women, which may be extremely challenging. DSCE seems to be a reliable method with a strong predictive value for the overall survival and MACE of patients with

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possible CAD both in men and women.

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Conflict of Interest: None declared

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Women (N=817)

p value

415 (15.7%)

155 (5.9%)

0.03

Hypertension

877 (33.2%)

457 (17.3%)

<0.0001

Dyslipidaemia

703 (26.6%)

399 (15.1%)

<0.0001

Known CAD

523 (19.8%)

72 (2.7%)

<0.0001

Family history for CAD

346 (13.1%)

154 (5.8%)

<0.0001

Smoking

653 (24.7%)

195 (7.4%)

<0.0001

Age (years)

56.7 ± 10.8

59.8 ± 11.1

<0.0001

Symptoms

270 (10.2%)

155 (5.9%)

<0.0001

57.1 ± 5.8%

58.6 ± 4.2%

<0.0001

385 (14.6%)

105 (4%)

<0.0001

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Ischemic response

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Resting LVEF (%)

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Diabetes

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Men (N=1828)

Variable

Table 1: Study population demographic and echo data. CAD = coronary artery

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disease; LVEF = left ventricular ejection fraction

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Women (N=817)

p

Major adverse events

190 (7.2%)

45(1.7)

<0.0001

All-cause mortality

25 (0.9%)

20 (0.8%)

Cardiac death

15 (0.6%)

5 (0.2%)

Late revascularization

105 (4.0%)

25 (0.9%)

<0.0001

60 (2.3%)

0 (0%)

<0.0001

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Hospitalizations

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Men (N=1828)

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Table 2: Major adverse events in men and women. NS = non significant

NS

NS

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OR (95% CI)

p

Symptoms

1.8 (1.2 to 2.7)

0.004

Known CAD

2 (1.5 to 2.7)

<0.0001 0.2 (0.08 to 0.6)

Hypertension

LVEF

54 (31.8 to 91.7)

0.02

<0.0001 59.9 (27.3 to 131.3)

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Diabetes

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DSE Result

1.4 (1 to 1.9)

<0.0001

<0.0001

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Family Hx

0.003

0.2 (0.12 to 0.48)

Dyslipidaemia Smoking

p

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Age

OR (95% CI)

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Variable

Women

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Men

Table 3: Multivariate analysis of outcomes. OR = odds ratio; CI = confidence interval; CAD = coronary artery disease; DSE = dobutamine stress echo; LVEF = left ventricular ejection fraction

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Figure caption:

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Figure 1: Kaplan-Meier curves with regard to total adverse events in A) male and B)

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female patients. Log rank test comparisons are illustrated for each group.

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