Prognostic Implications of Orthostatic Hypotension in Elective Coronary Artery Bypass Grafting

Introduction

The fall in blood pressure (BP) on standing is called orthostatic hypotension (OH) when it meets generally accepted criteria [1]. If present, it is considered to be a major sign of an autonomic disorder [2]. The definition of classic OH is a sustained decrease in systolic BP of at least 20 mmHg and/or a decrease in diastolic BP of at least 10 mmHg or a decrease in systolic BP to <90 within 3 min. of active standing or upright tilt [1].

OH may be neurogenic or non-neurogenic. Neurogenic OH is caused by primary or secondary autonomic nervous system disease, often presenting as an inadequate release of norepinephrine while standing and/or baroreceptor dysfunction [3]. Non-neurogenic OH is caused by reduced cardiac output and/or impaired vasoconstriction without an obvious autonomic nervous system abnormality [2]. Pharmacological therapy may cause OH as an unwanted effect [4]. Treatment with beta-blockers, vasodilators, tricyclic antidepressants, diuretics, or chemotherapeutic agents, coupled with a reduction in circulating blood volume, venous pooling, and inotropic or chronotropic heart failure, can induce OH. Conversely, administration of midodrine and fludrocortisone may mitigate the decline in BP upon standing [3,4].

The multiplicity of causes of OH contributes to the high variability of results of the orthostatic test [3,4]. The prevalence of OH in the general population increases with age; it is ~5% in patients of 50 years, reaches 30% in those >70 years, and even more in older patients with heart failure [3–6].

OH has been reported to have a negative effect on long-term prognosis in many previous studies. However, surprisingly, in heart failure patients, OH was not a prognostic factor for one-year mortality [3,6–12]. Similarly, among oncological patients and in coronary artery disease (CAD) OH was not associated with worse mortality [13,14]. Following cardiac surgery, OH was found in up to 40% of patients [15], probably as an effect of prolonged bed rest post-procedure and dehydration. Less is known about the prevalence and importance of OH in patients presenting for CABG [16]. This study aimed to assess the incidence of a positive orthostatic test and its relationship with long-term mortality among patients with documented advanced CAD and a high risk of adverse events when undergoing elective cardiac surgery.

Material and Methods

PATIENTS:

The study was conducted in patients admitted to the Department of Cardiac Surgery for elective isolated CABG between 08.2013–04.2016 in a single university medical center. Patients who were admitted to hospital for planned CABG in the coming days were invited by the first author to participate in this study after full explanation. The exclusion criteria included bedridden patients or those who, due to comorbidities, could not independently adopt a standing position. The study was approved by the Bioethics Committee (509/2013). Each patient provided written consent to participate in the study.

A structured questionnaire was used to collect clinical data concerning diabetes, previous myocardial infarction, arterial hypertension, smoking, family history of premature cardiovascular disorders, syncopal history, cardiovascular drugs, the presence of symptoms such as fatigue, unsteady gait, dizziness, excessive sweating, and falls. Complete filling of all fields in the structured questionnaire was required.

Furthermore, cardiac and renal function parameters were noted from medical records (ejection fraction of the left ventricle (EF) and creatinine clearance respectively).

ORTHOSTATIC TESTING (ACTIVE STAND):

Orthostatic testing was performed on the day of hospital admission after a 30-min. supine rest in a quiet room. In that day patient had taken routine treatment. The test was conducted by a nurse. The patient did not use a mobile phone and no medical interviews were conducted during this time. The BP was measured on the left upper arm using an automatic sphygmomanometer (OMRON M HEM-7223-E, Japan). The first measurement was performed at the end of the 30-min. supine resting period. Then, using the same device, BP measurements were taken at 3 min. after the upright position was adopted.

A positive orthostatic test was defined as a significant decrease of systolic BP of 20 mmHg or more and/or a decrease of 10 mmHg more in diastolic BP, or a decrease in systolic BP to <90 mmHg, after 3 min of standing. Patients were divided according to the orthostatic test results into patients with OH (OH+) and patients without OH (OH−).

SURVIVAL DATA:

Survival data were obtained from the Polish Ministry of Digitalization on 31 August 2024.

STATISTICAL ANALYSIS:

Statistical 13.3 software (TIBCO Software, Inc., Palo Alto, CA, USA) was used to perform the analysis. The continuous variables were presented as medians and interquartile ranges (IQR) and compared using the Mann-Whitney U test. The discrete variables are presented as numbers and percentages and compared using the chi-square test, with Yates correction when necessary. Kaplan-Meier curves were created to present the survival in OH+ and OH− patients.

The proportional hazards Cox regression analysis was performed to identify factors related to long-term survival. First, univariate analyses were performed. Variables with at least P<0.15 significance were used to build the multivariable analysis.

The survival analysis was performed with the Cox proportional hazard analysis Statistica.pl module. In the assumptions of the model, the reliability of Efron was selected. In next step, the model was created, considering all effects and using the backward method. Then, Cox regression assumptions were assessed by analyzing Martingale-based residuals for survival models and Schoenfeld residuals over time. The correlation of residuals and time was examined using the Spearman’s correlation. In case of finding a variable that violates the assumptions of the Cox proportional hazard regression, the variable was excluded from the model.

The proportional hazard assumptions were checked with the module of proportional hazards.

In case of finding a variable that violated the assumptions of the Cox proportional hazards regression, that variable was excluded from the model. Further, the logistic regression analysis of the survival data cut-off the shortness observation duration were also performed.

Results

DEMOGRAPHICS:

In the study, 392 patients were included, with a median age of 66 (61–74) years. There were 99 females with a median age of 70 (76–77) and 293 males with a median age of 65 (60–72) years (Table 1). Of these, 80 met the diagnostic criteria of OH.

The size of the study group required for 80% statistical power was calculated using statistica.pl software based on the following assumptions. First, according to the literature, the expected 10-year mortality rate in patients treated with CABG varies from 15% to as high as 50%, depending on age and comorbid conditions [17–19]. For the purposes of our study, we assumed that the 10-year mortality rate would be 36%. Second, OH is considered to be associated with increased mortality. The ARIC Study found that mortality in middle-aged adults was 4 times higher in patients with OH compared to those without it [20]. We presume that the increased mortality due to OH will be 50%. Using mortality rates of 36% for the OH− group and 54% for the OH+ group, along with a two-sided alpha level of 0.05 and a power (beta) of 0.80, we calculated that the total sample sizes should be at least 292 patients in the OH− group and 73 patients in the OH+ group.

Patients with OH did not differ from those without OH regarding age. The proportion of patients over 75 was similar in the groups. In the OH− group, men were significantly more numerous.

ORTHOSTATIC TEST:

Data on systolic BP and diastolic BP at baseline, and after 3 min of standing, in the total group and in patients with and without OH are provided in Table 2. Supine systolic BP and diastolic BP were significantly higher in the OH+ group compared with the OH− group. There were no significant differences in systolic BP and diastolic BP between the 2 groups after 3 min of standing.

The OH+ and OH− patients did not differ regarding comorbidities, smoking, family history of premature cardiovascular disorders, renal failure, and systolic heart failure, syncopal history, or cardiovascular drugs (Table 3).

Similarly, there were no significant differences between patient groups regarding self-reported prevalence of symptoms that could be manifestations of OH. The frequency of these symptoms is presented in the Table 4.

FOLLOW-UP:

Survival data were obtained from all patients in the study group. The median time from enrolment to 31 August 2024 was 9.7 (9.0–10.5) years. The survival of patients with OH+I and OH− regarding the time of inclusion in the study are presented in Figure 1.

In the total cohort, the median follow-up period was 3243.0 days, ranging from 4 to 4025.0 days (IQR: to 2571.5 to 3588.0 days). In the OH+ group, the median follow-up was 3399.5 days, ranging from 23 to 4025 days (IQR: 2929.5 to 3649.0 days). The OH− group had a median follow-up of 2625 days, ranging from 4 to 4018 days (IQR: 2425.5 to 3556.0 days).

SHORT AND LONG-TERM SURVIVAL:

No significant differences were observed between the groups at 30 days, 1 year, and at the end of follow-up (Table 5).

The survival data of OH− and OH+ patients are presented using Kaplan-Meier curves in Figure 2.

Factors related to long-term mortality identified in the backward stepwise regression analysis included age, male sex, heart failure, and renal failure. The presence of OH was not associated with long-term mortality in patients undergoing elective CABG (Table 6). Independent variables in the final stepwise regression model were uncorrelated with each other. The Cox proportional hazards regression analysis revealed that the variables were not correlated, but the assumption of proportionality was violated for the heart failure variable, which was therefore excluded from the analysis. The results of logistic regression analysis at the data cut-off on the shortest observation period from enrolment to 31 August 2024 in the study group are presented in Table 7.

Discussion

LIMITATIONS:

There are several important limitations in this study. The first limitation is that there were no pre-operative catecholamine measurements. Increased catecholamine levels may indicate non-neurogenic hypotension, whereas increased catecholamines levels are associated with neurogenic OH, which can have adverse long-term effects on mortality [35]. The second limitation is lack of data regarding fragility and postoperative conditions. The third limitation is that this is a single-center study, and we recognize that expansion to multiple centers is required for validation of our findings. The results of the study concern only orthostatic tests performed before CABG and do not apply to other situations.

Conclusions

The prevalence of orthostatic hypotension in patients undergoing cardiac surgery is about 20%.

A positive orthostatic hypotension test result prior to planned coronary artery bypass grafting is not an independent risk factor for long-term mortality.