Benzodiazepine Consumption Is Associated With Lower Blood Pressure in Ambulatory Blood Pressure Monitoring (ABPM): Retrospective Analysis of 4938 ABPMs

Benzodiazepine Consumption Is Associated With Lower Blood Pressure in Ambulatory Blood Pressure... Abstract BACKGROUND The effect of chronic benzodiazepine use on blood pressure has not been documented. We aimed to evaluate whether regular benzodiazepine use can be associated to the results of ambulatory blood pressure monitoring (ABPM). METHODS A retrospective analysis of the ABPM database between 2009 and 2015 was performed. The study groups were divided according to benzodiazepine treatment at least 3 months before ABPM. Generalized estimating equation (GEE) model analysis was conducted to estimate the association between benzodiazepine treatment and ABPM test measurements. Multivariable COX regression survival analysis model for mortality and cardiovascular (CV) events was performed. RESULTS A total of 4,938 ABPM studies were included in final analysis, 670 ABPMs of benzodiazepine-treated patients, and 4,268 of untreated patients. The benzodiazepine-treated group was significantly older, with a predominance of female patients, comprised more diabetic patients and consumed more antihypertensive medications. Adjustment for age, gender, diabetes mellitus, and number of antihypertensive medications, showed an association between benzodiazepine treatment and significantly lower ABPM measurements. When the analysis was split into those ≥60 years old and the other <60 years old, regular benzodiazepine consumption was associated with lower ABPM measurements only among ≥60 years old. Multivariable Cox regression survival analysis showed that regular benzodiazepine consumption was not associated with increased mortality or CV events (mean follow-up period of 42.4 ± 19.8 and 42.1 ± 20.0 months, respectively). CONCLUSIONS Long-term use of benzodiazepines by ≥60 years old was independently associated with lower diastolic and systolic blood pressure in all parameters of ABPM, but not among younger patients. ambulatory blood pressure monitoring, benzodiazepines, blood pressure, hypertension Essential hypertension is characterized by an activation of the sympathetic nervous system, which contributes to blood pressure elevation.1 Furthermore, hypertension is positively associated with general anxiety and major depressive disorders.2,3 Benzodiazepines, due to their anxiolytic properties are prescribed to reduce anxiety and insomnia.4 They also decrease catecholamine uptake in certain areas of the brain, reduce the metabolism of serotonin in the cortex, and alter the availability of acetylcholine in the brain.5 As anxiolytic medication benzodiazepines were proved to assist in the management of acute blood pressure elevation (comparable to Captopril) in hypertensive patients without target organ damage,6,7 and a single dose of an anxiolytic during blood pressure elevations has been suggested as a measure that could prevent unnecessary visits to the emergency room.8 It also has been documented that administration of the benzodiazepine midazolam before dental treatment results in acute blood pressure reduction.9 While, the mentioned above studies evaluated short-term effect of benzodiazepine on blood pressure, the data about their long-term effect on blood pressure control is scarce. Ambulatory blood pressure monitoring (ABPM) is an important tool in the evaluation and follow-up of hypertensive patients. ABPM provides additional measurements than office or home BP measurement, including repeated measurements and BP measurements during sleep. It is also evident that ABPM compared to office and home BP is better predictor of cardiovascular (CV) outcome.10 In the current study, we aimed to evaluate whether regular benzodiazepine consumption (minimum of 3 months) is associated with difference in blood pressure measurements in ABPM. For this purpose, we examined the association between regular benzodiazepines utilization and ABPM: 24 hour, daytime, and nighttime systolic and diastolic blood pressure. PATIENTS AND METHODS Study population This is a retrospective population-based study. The study population comprised all patients that performed ABPM from 2009 to 2015 at Soroka University Medical Center (SUMC) and their health provider was Clalit Health Services (CHS). SUMC is the only medical center in its region and serves a population of approximately 700,000 as the primary hospital and nearly 1 million as a tertiary hospital. CHS is the largest health maintenance organization in the Negev region (insuring 70% of the adult population); therefore, CHS insured adults are a representative sample of the total Negev population. Sociodemographic data including: gender, age, clinical characteristics presenting comorbidities (diabetes, history of MI, hypertension, ischemic heart disease, and cerebrovascular disease) and laboratory data were derived from the CHS information system. As depicted in Supplementary Figure S1, 6,446 ABPM studies of 4,967 patients had data regarding demographics (age, gender) and medical history. We examined the association between benzodiazepine consumption and clinical outcomes of death and CV outcomes represented by a succeeding hospitalization with a primary diagnosis of acute coronary syndrome, stroke, or congestive heart failure. Hospitalizations accounted for occurred at SUMC, registered since the ABPM test date and up until the end of the study period. The study was approved by the ethics committee of our institution. Ambulatory blood pressure monitoring The ABPM was performed using Oscar 2 system (SunTech Medical) device. Blood pressure readings were obtained every 20 minutes during the day (06:00–22:00), and every 30 minutes at night (22:00–06:00). Only ABPM studies with at least 70% of measurements were included.11 A mean and SD were computed for systolic and diastolic blood pressure readings during the day (06:00–22:00), the night (22:00–06:00), and during 24-hour period. Six hundred and fifty-seven patients had more than 1 ABPM measurement included in the study analysis. Benzodiazepine treatment The study groups were divided according to benzodiazepine treatment during 3 months prior to an ABPM, based on the electronic medical records of benzodiazepines purchased. The benzodiazepine nontreated group comprised patients who did not purchase benzodiazepines prior to an ABPM measurement. The medications dispensing data used to identify prescription of benzodiazepine treatment were retrieved from the CHS computerized database. Since 1998, all pharmacy purchases covered by CHS have been computerized. Each record includes the name and defined daily dose of the drug purchased, the purchase date and the member’s national identification number enables follow up of all medical procedures and the purchase of medications per patient. The benzodiazepines included were both long acting: Lorazepam, Diazepam, Oxazepam, Clonazepam, and short acting: Brotizolam, Nitrazepam, Zolpidem, and Zopiclone. Statistical analysis Descriptive statistics included data summaries of main variables in the form of means and SDs for normally distributed quantitative variables, medians, ranges, and interquartile range for nonnormal distributed quantitative variables, and percentage of qualitative variables. Patient characteristics between the 2 benzodiazepine consumption groups were compared using independent Student’s t test for continuous variables and chi-square test for categorical variables. Number of antihypertensive medications utilized in the previous 6 months to an ABPM study was compared between the groups using Mann–Whitney test. The ABPM study measurements included 24 hour, daytime, and nighttime systolic blood pressure, diastolic blood pressure, and heart rate. Coefficient of variance was calculated in addition to mean with SD in order to address the fluctuation of blood pressure measurements. To account for multiple ABPM tests taken by the same patient we utilized generalized estimating equation (GEE) linear model with an identity link function to estimate the impact of benzodiazepine consumption on blood pressure measurements. Six hundred and fifty-seven patients, out of 4,105 (16%) contributed multiple ABPMs to the analysis. When identifying these patients in comparison with patients with no repeated measurements, it was found that repeated ABPM’s population were significantly older, had more diabetes mellitus, higher systolic measurements (but not diastolic), and utilized more BP medicine. These comorbidities were taken into account when we performed a multivariate analysis. Models were adjusted for age, gender, diabetes, and the number of blood pressure medications the patient had been using. We performed a stratified analysis to compare the magnitude of the effect among patients 60 years old and older vs. younger than 60.12 We examined the association between benzodiazepine consumption and clinical outcomes of death and CV outcomes in our study group (4,105 patients) represented by a succeeding hospitalization with a primary diagnosis of acute coronary syndrome, stroke, or congestive heart failure. We utilized Cox proportional hazard models for multivariate analysis of the association adjusted for age, gender, diabetes, and the number of blood pressure medications the patient had been using. In case more than 1 CV outcome occurred during follow-up, analysis took into consideration the chronologically first outcome. Survival analysis was performed using multivariable Cox regression survival analysis model for mortality and CV events in benzodiazepines treated vs. untreated patients, to analyze the association between benzodiazepine consumption, CV outcomes, and death over time. All statistical tests were performed at α = 0.05 (2-sided). The data were analyzed using IBM SPSS Statistics software (version 22). RESULTS Study population A total of 4,967 patients went through 6,446 ABPM studies during the study period (2009–2015). Among them, 5,214 studies fulfilled the criteria for ABPM study CHS patients that their ABPM included at least 70% valid measurements in 24 hours. Another 194 ABPM tests of patients who were treated with benzodiazepines for less than 3 months were excluded. The tests of 30 patients who moved from one study group to the other during the study period, including 82 tests, were also excluded. For the final analysis, 4,938 ABPM studies of 4,105 patients were included (Supplementary Figure S1). Clinical characteristics of patients: treated vs. untreated with benzodiazepines (Table 1). Table 1. Patients clinical characteristics of ABPM studies of benzodiazepine treated vs. untreated Variable  Benzodiazepine-treated (670 ABPMs’)  Benzodiazepine-untreated (4,268 ABPMs’)  P value  Age in years  67.3 ± 9.7  56.8 ± 15.07  <0.001  Male (%)  242 (36.1%)  2188 (51.3%)  <0.001  Diabetes mellitus, N (%)  151 (22.5%)  522 (12.2%)  <0.001  Smokers, N (%)  54 (8.1%)  163 (3.8%)  <0.001  LDL, mg/dl  93.7 ± 29.5  97.5 ± 30.7  0.024  Number of antihypertensive medications (median, IQR)  3.0 (1–4)  1 (0–3)  <0.001  24/h mean systolic/diastolic BP  135.6 ± 16/72.7 ± 9.6  135.9 ± 15.3/76.8 ± 10.2  0.609/<0.001  24/h SD systolic/diastolic variability  14.8 ± 3.8/10.2 ± 2.3  14.2 ± 3.8/10.6 ± 2.6  <0.001/<0.001  Daytime mean systolic/diastolic BP  138.24 ± 16.19/74.8 ± 10.1  138.7 ± 15.6/79 ± 10.7  0.416/<0.001  Daytime SD systolic/diastolic variability  13.58 ± 3.7/ 9.1 ± 2.4  12.8 ± 3.8/ 9.4 ± 2.6  <0.001/0.006  Nighttime mean systolic/ diastolic BP  127.8 ± 18.7/66.4 ± 10.2  127.26 ± 17.1/69.7 ± 10.6  0.581/<0.001  Nighttime SD systolic/diastolic variability  12.29 ± 4.3/8.7 ± 2.8  11.8 ± 4.3/9.2 ± 3.2  0.047/<0.001  Variable  Benzodiazepine-treated (670 ABPMs’)  Benzodiazepine-untreated (4,268 ABPMs’)  P value  Age in years  67.3 ± 9.7  56.8 ± 15.07  <0.001  Male (%)  242 (36.1%)  2188 (51.3%)  <0.001  Diabetes mellitus, N (%)  151 (22.5%)  522 (12.2%)  <0.001  Smokers, N (%)  54 (8.1%)  163 (3.8%)  <0.001  LDL, mg/dl  93.7 ± 29.5  97.5 ± 30.7  0.024  Number of antihypertensive medications (median, IQR)  3.0 (1–4)  1 (0–3)  <0.001  24/h mean systolic/diastolic BP  135.6 ± 16/72.7 ± 9.6  135.9 ± 15.3/76.8 ± 10.2  0.609/<0.001  24/h SD systolic/diastolic variability  14.8 ± 3.8/10.2 ± 2.3  14.2 ± 3.8/10.6 ± 2.6  <0.001/<0.001  Daytime mean systolic/diastolic BP  138.24 ± 16.19/74.8 ± 10.1  138.7 ± 15.6/79 ± 10.7  0.416/<0.001  Daytime SD systolic/diastolic variability  13.58 ± 3.7/ 9.1 ± 2.4  12.8 ± 3.8/ 9.4 ± 2.6  <0.001/0.006  Nighttime mean systolic/ diastolic BP  127.8 ± 18.7/66.4 ± 10.2  127.26 ± 17.1/69.7 ± 10.6  0.581/<0.001  Nighttime SD systolic/diastolic variability  12.29 ± 4.3/8.7 ± 2.8  11.8 ± 4.3/9.2 ± 3.2  0.047/<0.001  Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; IQR, interquartile range; LDL, low-density lipoprotein. View Large The ABPM studies included 670 studies that were of benzodiazepine-treated patients and 4,268 studies were of untreated patients. The total 4,105 patients that their ABPM studies were included were divided to: 524 patients in the benzodiazepines treated group; 3,581 patients in the untreated group. There was a significant difference between the groups in terms of demographics and CV risk factors. The benzodiazepine-treated patients were older (67.3 ± 9.7 vs. 56.8 ± 15.0, respectively, P < 0.001) and had a lower prevalence of male gender (242 (36.1%) vs. 2,188 (51.3%), respectively, P < 0.001). The benzodiazepines-treated group also had a higher prevalence of diabetes mellitus (151 (22.5%) vs. 522 (12.1%), respectively, P < 0.001) and utilized more antihypertensive medications in the 6 months previous to an ABPM study (3.0, interquartile range 1–4 vs. 1, interquartile range 0–3, respectively, P < 0.001). In ABPM measurement, there was no difference between the groups in systolic blood pressure measurements. While, the diastolic blood pressure in all ABPM measurements (24 hours, daytime, and night time) was significantly lower in the benzodiazepine-treated group compared to the untreated group. Association between long-term benzodiazepine use and changes in ABPM measurements: multivariate linear GEE regression analysis (Table 2). Table 2. Estimates of change in ABPM measurements associated with benzodiazepine use ABPM measurements  B*  95% Confidence interval for B    Lower bound  Upper bound  P value  24/h Systolic BP  −2.021  −3.255  −0.788  <0.001  24/h Systolic variability  0.447  0.118  0.775  0.008  24/h Diastolic BP  −3.121  −3.952  −2.291  <0.001  24/h Diastolic variability  −0.261  −0.464  −0.057  0.012  Daytime systolic BP  −2.091  −3.351  −0.831  <0.001  Daytime systolic variability  0.376  0.056  0.696  0.021  Daytime diastolic BP  −3.193  −4.063  −2.324  <0.001  Daytime diastolic variability  −0.231  −0.441  0.021  0.031  Nighttime systolic BP  −1.512  −2.941  −0.084  0.038  Nighttime systolic variability  0.220  −0.121  0.560  0.206  Nighttime diastolic BP  −2.63  −3.500  −1.759  <0.001  Nighttime diastolic variability  −0.383  −0.617  −0.149  0.001  ABPM measurements  B*  95% Confidence interval for B    Lower bound  Upper bound  P value  24/h Systolic BP  −2.021  −3.255  −0.788  <0.001  24/h Systolic variability  0.447  0.118  0.775  0.008  24/h Diastolic BP  −3.121  −3.952  −2.291  <0.001  24/h Diastolic variability  −0.261  −0.464  −0.057  0.012  Daytime systolic BP  −2.091  −3.351  −0.831  <0.001  Daytime systolic variability  0.376  0.056  0.696  0.021  Daytime diastolic BP  −3.193  −4.063  −2.324  <0.001  Daytime diastolic variability  −0.231  −0.441  0.021  0.031  Nighttime systolic BP  −1.512  −2.941  −0.084  0.038  Nighttime systolic variability  0.220  −0.121  0.560  0.206  Nighttime diastolic BP  −2.63  −3.500  −1.759  <0.001  Nighttime diastolic variability  −0.383  −0.617  −0.149  0.001  Results of multivariate linear GEE regression. Dependent variable; ABPM measurements, independent variables; benzodiazepine use, age, gender, diabetes mellitus, and number of antihypertensive medications. Abbreviations: ABPM, ambulatory blood pressure monitoring; B, changes in ABPM measurements are expressed as the B coefficient of the GEE model; BP, blood pressure; GEE, generalized estimating equation. *P value—BP measurements change in benzodiazepine treated vs. nontreated. View Large We found a significant association between benzodiazepine treatment and lower ABPM measurements (adjusted for age, gender, diabetes mellitus, and number of antihypertensive medications utilized). Benzodiazepine treatment was independently associated with significantly lower systolic blood pressure over 24 hours, during the daytime, and during the night [−2.0 mm Hg (confidence interval [CI] −3.2, −0.7); −2.09 mm Hg (CI −3.3, −0.8); and −1.5 mm Hg (CI −2.9, −0.08), respectively] as well as with significantly lower diastolic blood pressure over 24 hours, during the daytime, and during the night [−3.1 mm Hg (CI −3.9, −2.3); −3.1 mm Hg (CI −4.0, −2.3); and −2.6 mm Hg (CI −3.5, −1.7), respectively]. Benzodiazepines did not have a significant association with blood pressure variability, with the exception of the variability of diastolic blood pressure during the night [−0.2 mm Hg (CI −0.5, −0.004)]. The effect of long and short acting benzodiazepines was evaluated. Treatment with either long or short acting benzodiazepines was associated with systolic and diastolic blood pressure reduction during both daytime and night time (Supplementary Table S1). Association between benzodiazepine treatment ABPM measurements among age groups: multivariate linear GEE regression analysis (Table 3). Table 3. Estimates of change in ABPM measurements associated with benzodiazepine use, by age (cutoff of 60 years old)   Age groups (years)  B  95% Confidence interval for B    Lower bound  Upper bound  P value*  24/h Systolic BP  <60  −0.700  −3.290  1.891  0.596    ≥60  −2.595  −3.980  −1.211  <0.001  24/h Systolic variability  <60  −0.052  −0.655  0.552  0.867    ≥60  0.420  0.023  0.816  0.038  24/h Diastolic BP  <60  −0.193  −1.777  1.391  0.812    ≥60  −2.098  −2.944  −1.252  <0.001  24/h Diastolic variability  <60  −0.235  −0.682  0.211  0.301    ≥60  −0.033  −0.257  0.192  0.776  Daytime systolic BP  <60  −0.265  −2.985  2.454  0.848    ≥60  −2.603  −4.011  −1.196  <0.001  Daytime systolic variability  <60  −0.450  −1.109  0.210  0.181    ≥60  0.213  −0.147  0.572  0.246  Daytime diastolic BP  <60  −0.119  −1.786  1.548  0.889    ≥60  −2.090  −2.977  −1.204  <0.001  Daytime diastolic variability  <60  −0.384  −0.808  0.039  0.075    ≥60  −0.051  −0.296  0.194  0.685  Nighttime systolic BP  <60  −1.746  −4.784  1.293  0.260    ≥60  −2.110  −3.749  −0.470  0.012  Nighttime systolic variability  <60  −0.213  −0.862  0.436  0.520    ≥60  0.136  −0.258  0.530  0.499  Nighttime diastolic BP  <60  −0.882  −2.644  0.881  0.327    ≥60  −1.753  −2.695  −0.810  <0.001  Nighttime diastolic variability  <60  −0.590  −1.062  −0.117  0.014    ≥60  −0.268  −0.538  0.002  0.052    Age groups (years)  B  95% Confidence interval for B    Lower bound  Upper bound  P value*  24/h Systolic BP  <60  −0.700  −3.290  1.891  0.596    ≥60  −2.595  −3.980  −1.211  <0.001  24/h Systolic variability  <60  −0.052  −0.655  0.552  0.867    ≥60  0.420  0.023  0.816  0.038  24/h Diastolic BP  <60  −0.193  −1.777  1.391  0.812    ≥60  −2.098  −2.944  −1.252  <0.001  24/h Diastolic variability  <60  −0.235  −0.682  0.211  0.301    ≥60  −0.033  −0.257  0.192  0.776  Daytime systolic BP  <60  −0.265  −2.985  2.454  0.848    ≥60  −2.603  −4.011  −1.196  <0.001  Daytime systolic variability  <60  −0.450  −1.109  0.210  0.181    ≥60  0.213  −0.147  0.572  0.246  Daytime diastolic BP  <60  −0.119  −1.786  1.548  0.889    ≥60  −2.090  −2.977  −1.204  <0.001  Daytime diastolic variability  <60  −0.384  −0.808  0.039  0.075    ≥60  −0.051  −0.296  0.194  0.685  Nighttime systolic BP  <60  −1.746  −4.784  1.293  0.260    ≥60  −2.110  −3.749  −0.470  0.012  Nighttime systolic variability  <60  −0.213  −0.862  0.436  0.520    ≥60  0.136  −0.258  0.530  0.499  Nighttime diastolic BP  <60  −0.882  −2.644  0.881  0.327    ≥60  −1.753  −2.695  −0.810  <0.001  Nighttime diastolic variability  <60  −0.590  −1.062  −0.117  0.014    ≥60  −0.268  −0.538  0.002  0.052  Results of Multivariate linear GEE regression analysis. Dependent variable; ABPM measurements, Independent variables; benzodiazepine use, age, gender, diabetes mellitus, and number of antihypertensive medications. Abbreviations: ABPM, ambulatory blood pressure monitoring; B, changes in ABPM measurements are expressed as the B coefficient of the GEE model; BP, blood pressure; GEE, generalized estimating equation. *P value—blood pressure measurements change in benzodiazepine treated vs. nontreated. View Large We further stratified the population into 2 age groups by the age 60 years. In the benzodiazepine group, 81.5% were >60 years old and 18.5% were under 60 years old, while in the untreated group, 50.5% were >60 years old and 49.5% were under 60 years old. This analysis showed that regular benzodiazepine consumption was associated with lower ABPM measurements only in the elderly group (Table 3). Systolic blood pressure was lower over 24 hours, during the daytime, and at night [−2.5 mm Hg (CI −3.9, −1.2); −2.6 mm Hg (CI −4.0, −1.1); and −2.1 mm Hg (CI −3.7, −0.4), respectively]. Diastolic blood pressure was lower over 24 hours, during the daytime, and at night [−2.0 mm Hg (CI −2.9, −1.2); −2.0 mm Hg (CI −2.9, −1.2); and −1.7 mm Hg (CI −2.6, −0.8), respectively]. In the younger group (<60 y/o), regular benzodiazepine treatment was associated only with lower nighttime diastolic blood pressure variability [−0.5 mm Hg (CI −1.0, −0.1)]. Benzodiazepine treatment: mortality and CV outcomes (Table 4). Table 4. Multivariable COX regression analysis of factors associated with total mortality and cardiovascular eventsa   Total mortality (N = 138)  Cardiovascular event (N = 136)      95% CI  P value  HR  95% CI    Variable  HR  Lower  Upper  Lower  Upper  P value  Long-term Benz. consumption (yes/no)  1.256  0.840  1.878  0.266  1.013  0.660  1.553  0.954  Age (years)  1.066  1.047  1.087  <0.001  1.032  1.015  1.050  <0.001  Male gender  1.528  1.089  2.144  0.014  1.736  1.228  2.454  0.002  Diabetes mellitus  3.484  2.445  4.965  <0.001  4.925  3.439  7.052  <0.001  Number of antihypertensive medications  0.955  0.869  1.050  0.343  1.165  1.070  1.268  <0.001    Total mortality (N = 138)  Cardiovascular event (N = 136)      95% CI  P value  HR  95% CI    Variable  HR  Lower  Upper  Lower  Upper  P value  Long-term Benz. consumption (yes/no)  1.256  0.840  1.878  0.266  1.013  0.660  1.553  0.954  Age (years)  1.066  1.047  1.087  <0.001  1.032  1.015  1.050  <0.001  Male gender  1.528  1.089  2.144  0.014  1.736  1.228  2.454  0.002  Diabetes mellitus  3.484  2.445  4.965  <0.001  4.925  3.439  7.052  <0.001  Number of antihypertensive medications  0.955  0.869  1.050  0.343  1.165  1.070  1.268  <0.001  Abbreviations: CI, confidence interval; HR, hazard ratio. aCardiovascular events include: acute coronary syndrome (n = 86), cerebrovascular event (n = 39), and congestive heart failure (n = 11). View Large During the study period in our study group (4,105 patients) after mean follow-up period of 42.4 ± 19.8 months for, there were 138 deaths (mean follow-up 42.4 ± 19.8 months) and 136 cases of CV events (mean follow-up 42.1 ± 20.0 months; 86 cases of acute coronary syndrome, 39 cases of stroke, and 11 cases of congestive heart failure). Multivariable Cox regression analysis showed that regular benzodiazepine consumption was associated neither with change in mortality nor with adverse CV events. As expected, age, male gender, and diabetes mellitus were all significantly associated with both increased mortality and CV events. Antihypertensive treatment was associated with decreased total mortality. DISCUSSION In the current study, we found that in patients 60 years old and older regular consumption of benzodiazepines was significantly associated with lower systolic and diastolic blood pressure, while in the younger benzodiazepines did not have a significant association with blood pressure change. Liu et al. in their meta-analysis found that psychosocial stress was associated with an increased risk of hypertension (odds ratio = 2.40, 95% CI = 1.65–3.49), and hypertensive patients had a higher incidence of psychosocial stress compared to normotension patients (odds ratio = 2.69, 95% CI = 2.32–3.11).13 Furthermore, it is suspected that one of the mechanisms by which anxiety increases the risk for CV disease14 is through hypertension.15 This assumption is supported by an observational study showing that temporary increases in anxiety are associated with acute increases in ambulatory systolic blood pressure.16 In a systemic review of observational studies, Sparrenberger et al. found that chronic stress and particularly the nonadaptive response to stress are more likely causes of sustained elevation of blood pressure.17 An Israeli study showed that prolongation and suppression of feelings following conflicts in certain life situations was positively associated with the incidence of hypertension.18 Another study in different population showed that high sympathetic nervous activity during mental arithmetic predicts future blood pressure.19 This finding represents a quite convincing evidence that an abnormal reactivity to stress may be implicated in the development of future hypertension.20 The linking between anxiety and hypertension is even more profound as demonstrated by a study showing that high anxiety sensitivity was strongly associated with nonadherence to antihypertensive treatment.21 When benzodiazepines are administrated intravenous during anesthesia there is a significant decrease in systemic blood pressure.22,23 The benzodiazepines used for anesthesia cause transient depression of baroreflex function and a sustained decrease of sympathetic tone.24 Benzodiazepines act as positive allosteric modulators on the gamma aminobutyric acid (GABA)-A receptor. The GABA-A receptor is a ligand-gated chloride-selective ion channel.25 GABA is the most common neurotransmitter in the central nervous system, found in high concentrations in the cortex and limbic system. GABA is inhibitory in nature and thus reduces the excitability of neurons. GABA produces a calming effect on the brain.25 In animal model using spontaneously hypertensive rats that were fed with GABA-enriched fermented milk product, resulted in significant decrease of blood pressure 4–8 hours after administration.26 Another animal study showed the benzodiazepines have a peripheral vasodilatory direct effect on blood vessels. Midazolam-induced reversible, dose-dependent vasodilation in aortic rings from C57/BL6 mice that were precontracted with either potassium or phenylephrine.27 In the current study, we found the hypotensive effect of chronic benzodiazepines consumption was demonstrated in patients 60 years and older. Though, the lack of influence on blood pressure may be due to the fact that in the benzodiazepine group the prevalence of patients under 60 years old was less than 20%. Old age may lead to altered pharmacokinetics of sedative-anxiolytic drugs, causing higher plasma concentrations (relative to young individuals) after single or multiple doses.28 This might be one of the explanations for the significant hypotensive effect in older vs. younger patients in our study. Although, chronic benzodiazepines consumption by elderly patients might improve their blood pressure control one should also consider the hazard effect of benzodiazepines in this population. The American Geriatrics Society (AGS) placed benzodiazepines on a list of medications that should be avoided in patients over 65 years of age.29,30 It was also described that benzodiazepine use is associated with a considerable increase in all-cause mortality, showing that benzodiazepines treated dying at a 1.2- to 3.7-times higher rate per year compared with untreated individuals.31 Yet, it remains unclear whether this association is causal or whether benzodiazepine are being used more frequently by patients with eventually higher mortality rate.29 One of the most devastating morbidity in the elderly population is hip fracture. In the elderly, the incidence of hip fractures in benzodiazepine consumers individuals may be increased by 50% or more, particularly when other medications, such as antihypertensives and antidepressants, are co-prescribed.32,33 In our study, we did not find that benzodiazepines alter total or CV mortality probably due to short follow-up period. In conclusion, although there is a lot of evidence about the acute CV effect of benzodiazepines, to the best of our knowledge, the effect on blood pressure in chronic utilization was not described. We might suggest that although our study showed that chronic benzodiazepine consumption was associated with blood pressure reduction without increased mortality, caution is required in these groups of patients. Further prospective study is needed to evaluate the safety and efficacy of the combination between antihypertensive treatment and chronic benzodiazepinesine consumption. Future study should be focusing not only on CV morbidity and mortality, but also on recurrent falls, head trauma, hip fractures, and syncope. SUPPLEMENTARY MATERIAL Supplementary materials are available at American Journal of Hypertension online. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Esler M. The sympathetic system and hypertension. Am J Hypertens  2000; 13: 99S– 105S. Google Scholar CrossRef Search ADS PubMed  2. Carroll D, Phillips AC, Gale CR, Batty GD. Generalized anxiety and major depressive disorders, their comorbidity and hypertension in middle-aged men. Psychosom Med  2010; 72: 16– 19. Google Scholar CrossRef Search ADS PubMed  3. Ojike N, Sowers JR, Seixas A, Ravenell J, Rodriguez-Figueroa G, Awadallah M, Zizi F, Jean-Louis G, Ogedegbe O, McFarlane SI. Psychological distress and hypertension: results from the National Health Interview Survey for 2004-2013. Cardiorenal Med  2016; 6: 198– 208. Google Scholar CrossRef Search ADS PubMed  4. Lader M. Benzodiazepine harm: how can it be reduced? Br J Clin Pharmacol  2014; 77: 295– 301. Google Scholar CrossRef Search ADS PubMed  5. Robin C, Trieger N. Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature. Anesth Prog  2002; 49: 128– 132. Google Scholar PubMed  6. Grossman E, Nadler M, Sharabi Y, Thaler M, Shachar A, Shamiss A. Antianxiety treatment in patients with excessive hypertension. Am J Hypertens  2005; 18: 1174– 1177. Google Scholar CrossRef Search ADS PubMed  7. Yilmaz S, Pekdemir M, Tural U, Uygun M. Comparison of alprazolam versus captopril in high blood pressure: a randomized controlled trial. Blood Press  2011; 20: 239– 243. Google Scholar CrossRef Search ADS PubMed  8. Tandeter H. Hypothesis: a single dose of an anxiolitic may prevent unnecessary visits to the emergency room during blood pressure elevations. Med Hypotheses  2016; 88: 35– 37. Google Scholar CrossRef Search ADS PubMed  9. Watanabe Y, Higuchi H, Ishii-Maruhama M, Honda Y, Yabuki-Kawase A, Yamane-Hirano A, Tomoyasu Y, Maeda S, Miyawaki T. Effect of a low dose of midazolam on high blood pressure in dental patients: a randomised, double-blind, placebo-controlled, two-centre study. Br J Oral Maxillofac Surg  2016; 54: 443– 448. Google Scholar CrossRef Search ADS PubMed  10. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, Clement D, de la Sierra A, de Leeuw P, Dolan E, Fagard R, Graves J, Head GA, Imai Y, Kario K, Lurbe E, Mallion JM, Mancia G, Mengden T, Myers M, Ogedegbe G, Ohkubo T, Omboni S, Palatini P, Redon J, Ruilope LM, Shennan A, Staessen JA, vanMontfrans G, Verdecchia P, Waeber B, Wang J, Zanchetti A, Zhang Y; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens  2013; 31: 1731– 1768. Google Scholar CrossRef Search ADS PubMed  11. Parati G, Stergiou G, O’Brien E, Asmar R, Beilin L, Bilo G, Clement D, de la Sierra A, de Leeuw P, Dolan E, Fagard R, Graves J, Head GA, Imai Y, Kario K, Lurbe E, Mallion JM, Mancia G, Mengden T, Myers M, Ogedegbe G, Ohkubo T, Omboni S, Palatini P, Redon J, Ruilope LM, Shennan A, Staessen JA, vanMontfrans G, Verdecchia P, Waeber B, Wang J, Zanchetti A, Zhang Y; European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability. European Society of Hypertension practice guidelines for ambulatory blood pressure monitoring. J Hypertens  2014; 32: 1359– 1366. Google Scholar CrossRef Search ADS PubMed  12. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SCJr, Svetkey LP, Taler SJ, Townsend RR, Wright JTJr, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA  2014; 311: 507– 520. Google Scholar CrossRef Search ADS PubMed  13. Liu MY, Li N, Li WA, Khan H. Association between psychosocial stress and hypertension: a systematic review and meta-analysis. Neurol Res  2017; 39: 573– 580. Google Scholar CrossRef Search ADS PubMed  14. Roest AM, Martens EJ, de Jonge P, Denollet J. Anxiety and risk of incident coronary heart disease: a meta-analysis. J Am Coll Cardiol  2010; 56: 38– 46. Google Scholar CrossRef Search ADS PubMed  15. Paterniti S, Alpérovitch A, Ducimetière P, Dealberto MJ, Lépine JP, Bisserbe JC. Anxiety but not depression is associated with elevated blood pressure in a community group of French elderly. Psychosom Med  1999; 61: 77– 83. Google Scholar CrossRef Search ADS PubMed  16. Edmondson D, Arndt J, Alcántara C, Chaplin W, Schwartz JE. Self-esteem and the acute effect of anxiety on ambulatory blood pressure. Psychosom Med  2015; 77: 833– 841. Google Scholar CrossRef Search ADS PubMed  17. Sparrenberger F, Cichelero FT, Ascoli AM, Fonseca FP, Weiss G, Berwanger O, Fuchs SC, Moreira LB, Fuchs FD. Does psychosocial stress cause hypertension? A systematic review of observational studies. J Hum Hypertens  2009; 23: 12– 19. Google Scholar CrossRef Search ADS PubMed  18. Kahn HA, Medalie JH, Neufeld HN, Riss E, Goldbourt U. The incidence of hypertension and associated factors: the Israel Ischemic Heart Disease Study. Am Heart J  1972; 84: 171– 182. Google Scholar CrossRef Search ADS PubMed  19. Flaa A, Eide IK, Kjeldsen SE, Rostrup M. Sympathoadrenal stress reactivity is a predictor of future blood pressure: an 18-year follow-up study. Hypertension  2008; 52: 336– 341. Google Scholar CrossRef Search ADS PubMed  20. Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens  2010; 23: 1052– 1060. Google Scholar CrossRef Search ADS PubMed  21. Alcántara C, Edmondson D, Moise N, Oyola D, Hiti D, Kronish IM. Anxiety sensitivity and medication nonadherence in patients with uncontrolled hypertension. J Psychosom Res  2014; 77: 283– 286. Google Scholar CrossRef Search ADS PubMed  22. Samuelson PN, Reves JG, Kouchoukos NT, Smith LR, Dole KM. Hemodynamic responses to anesthetic induction with midazolam or diazepam in patients with ischemic heart disease. Anesth Analg  1981; 60: 802– 809. Google Scholar CrossRef Search ADS PubMed  23. Raza SM, Masters RW, Zsigmond EK. Comparison of the hemodynamic effects of midazolam and diazepam in patients with coronary occlusion. Int J Clin Pharmacol Ther Toxicol  1989; 27: 1– 6. Google Scholar PubMed  24. Marty J, Gauzit R, Lefevre P, Couderc E, Farinotti R, Henzel C, Desmonts JM. Effects of diazepam and midazolam on baroreflex control of heart rate and on sympathetic activity in humans. Anesth Analg  1986; 65: 113– 119. Google Scholar CrossRef Search ADS PubMed  25. Griffin CE3rd, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J  2013; 13: 214– 223. Google Scholar PubMed  26. Hayakawa K, Kimura M, Kasaha K, Matsumoto K, Sansawa H, Yamori Y. Effect of a gamma-aminobutyric acid-enriched dairy product on the blood pressure of spontaneously hypertensive and normotensive Wistar-Kyoto rats. Br J Nutr  2004; 92: 411– 417. Google Scholar CrossRef Search ADS PubMed  27. Colussi GL, Di Fabio A, Catena C, Chiuch A, Sechi LA. Involvement of endothelium-dependent and -independent mechanisms in midazolam-induced vasodilation. Hypertens Res  2011; 34: 929– 934. Google Scholar CrossRef Search ADS PubMed  28. Greenblatt DJ, Harmatz JS, Shader RI. Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part II). Clin Pharmacokinet  1991; 21: 262– 273. Google Scholar CrossRef Search ADS PubMed  29. Markota M, Rummans TA, Bostwick JM, Lapid MI. Benzodiazepine use in older adults: dangers, management, and alternative therapies, Mayo Clinic proceedings  2016; 91: 1632– 1639. Google Scholar CrossRef Search ADS PubMed  30. By the American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc  2015; 63: 2227– 2246. CrossRef Search ADS PubMed  31. Palmaro A, Dupouy J, Lapeyre-Mestre M. Benzodiazepines and risk of death: results from two large cohort studies in France and UK. Eur Neuropsychopharmacol  2015; 25: 1566– 1577. Google Scholar CrossRef Search ADS PubMed  32. Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA  1989; 262: 3303– 3307. Google Scholar CrossRef Search ADS PubMed  33. Ray WA, Griffin MR, Schaffner W, Baugh DK, Melton LJ3rd. Psychotropic drug use and the risk of hip fracture. N Engl J Med  1987; 316: 363– 369. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

Benzodiazepine Consumption Is Associated With Lower Blood Pressure in Ambulatory Blood Pressure Monitoring (ABPM): Retrospective Analysis of 4938 ABPMs

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Oxford University Press
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© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0895-7061
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1941-7225
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10.1093/ajh/hpx188
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Abstract

Abstract BACKGROUND The effect of chronic benzodiazepine use on blood pressure has not been documented. We aimed to evaluate whether regular benzodiazepine use can be associated to the results of ambulatory blood pressure monitoring (ABPM). METHODS A retrospective analysis of the ABPM database between 2009 and 2015 was performed. The study groups were divided according to benzodiazepine treatment at least 3 months before ABPM. Generalized estimating equation (GEE) model analysis was conducted to estimate the association between benzodiazepine treatment and ABPM test measurements. Multivariable COX regression survival analysis model for mortality and cardiovascular (CV) events was performed. RESULTS A total of 4,938 ABPM studies were included in final analysis, 670 ABPMs of benzodiazepine-treated patients, and 4,268 of untreated patients. The benzodiazepine-treated group was significantly older, with a predominance of female patients, comprised more diabetic patients and consumed more antihypertensive medications. Adjustment for age, gender, diabetes mellitus, and number of antihypertensive medications, showed an association between benzodiazepine treatment and significantly lower ABPM measurements. When the analysis was split into those ≥60 years old and the other <60 years old, regular benzodiazepine consumption was associated with lower ABPM measurements only among ≥60 years old. Multivariable Cox regression survival analysis showed that regular benzodiazepine consumption was not associated with increased mortality or CV events (mean follow-up period of 42.4 ± 19.8 and 42.1 ± 20.0 months, respectively). CONCLUSIONS Long-term use of benzodiazepines by ≥60 years old was independently associated with lower diastolic and systolic blood pressure in all parameters of ABPM, but not among younger patients. ambulatory blood pressure monitoring, benzodiazepines, blood pressure, hypertension Essential hypertension is characterized by an activation of the sympathetic nervous system, which contributes to blood pressure elevation.1 Furthermore, hypertension is positively associated with general anxiety and major depressive disorders.2,3 Benzodiazepines, due to their anxiolytic properties are prescribed to reduce anxiety and insomnia.4 They also decrease catecholamine uptake in certain areas of the brain, reduce the metabolism of serotonin in the cortex, and alter the availability of acetylcholine in the brain.5 As anxiolytic medication benzodiazepines were proved to assist in the management of acute blood pressure elevation (comparable to Captopril) in hypertensive patients without target organ damage,6,7 and a single dose of an anxiolytic during blood pressure elevations has been suggested as a measure that could prevent unnecessary visits to the emergency room.8 It also has been documented that administration of the benzodiazepine midazolam before dental treatment results in acute blood pressure reduction.9 While, the mentioned above studies evaluated short-term effect of benzodiazepine on blood pressure, the data about their long-term effect on blood pressure control is scarce. Ambulatory blood pressure monitoring (ABPM) is an important tool in the evaluation and follow-up of hypertensive patients. ABPM provides additional measurements than office or home BP measurement, including repeated measurements and BP measurements during sleep. It is also evident that ABPM compared to office and home BP is better predictor of cardiovascular (CV) outcome.10 In the current study, we aimed to evaluate whether regular benzodiazepine consumption (minimum of 3 months) is associated with difference in blood pressure measurements in ABPM. For this purpose, we examined the association between regular benzodiazepines utilization and ABPM: 24 hour, daytime, and nighttime systolic and diastolic blood pressure. PATIENTS AND METHODS Study population This is a retrospective population-based study. The study population comprised all patients that performed ABPM from 2009 to 2015 at Soroka University Medical Center (SUMC) and their health provider was Clalit Health Services (CHS). SUMC is the only medical center in its region and serves a population of approximately 700,000 as the primary hospital and nearly 1 million as a tertiary hospital. CHS is the largest health maintenance organization in the Negev region (insuring 70% of the adult population); therefore, CHS insured adults are a representative sample of the total Negev population. Sociodemographic data including: gender, age, clinical characteristics presenting comorbidities (diabetes, history of MI, hypertension, ischemic heart disease, and cerebrovascular disease) and laboratory data were derived from the CHS information system. As depicted in Supplementary Figure S1, 6,446 ABPM studies of 4,967 patients had data regarding demographics (age, gender) and medical history. We examined the association between benzodiazepine consumption and clinical outcomes of death and CV outcomes represented by a succeeding hospitalization with a primary diagnosis of acute coronary syndrome, stroke, or congestive heart failure. Hospitalizations accounted for occurred at SUMC, registered since the ABPM test date and up until the end of the study period. The study was approved by the ethics committee of our institution. Ambulatory blood pressure monitoring The ABPM was performed using Oscar 2 system (SunTech Medical) device. Blood pressure readings were obtained every 20 minutes during the day (06:00–22:00), and every 30 minutes at night (22:00–06:00). Only ABPM studies with at least 70% of measurements were included.11 A mean and SD were computed for systolic and diastolic blood pressure readings during the day (06:00–22:00), the night (22:00–06:00), and during 24-hour period. Six hundred and fifty-seven patients had more than 1 ABPM measurement included in the study analysis. Benzodiazepine treatment The study groups were divided according to benzodiazepine treatment during 3 months prior to an ABPM, based on the electronic medical records of benzodiazepines purchased. The benzodiazepine nontreated group comprised patients who did not purchase benzodiazepines prior to an ABPM measurement. The medications dispensing data used to identify prescription of benzodiazepine treatment were retrieved from the CHS computerized database. Since 1998, all pharmacy purchases covered by CHS have been computerized. Each record includes the name and defined daily dose of the drug purchased, the purchase date and the member’s national identification number enables follow up of all medical procedures and the purchase of medications per patient. The benzodiazepines included were both long acting: Lorazepam, Diazepam, Oxazepam, Clonazepam, and short acting: Brotizolam, Nitrazepam, Zolpidem, and Zopiclone. Statistical analysis Descriptive statistics included data summaries of main variables in the form of means and SDs for normally distributed quantitative variables, medians, ranges, and interquartile range for nonnormal distributed quantitative variables, and percentage of qualitative variables. Patient characteristics between the 2 benzodiazepine consumption groups were compared using independent Student’s t test for continuous variables and chi-square test for categorical variables. Number of antihypertensive medications utilized in the previous 6 months to an ABPM study was compared between the groups using Mann–Whitney test. The ABPM study measurements included 24 hour, daytime, and nighttime systolic blood pressure, diastolic blood pressure, and heart rate. Coefficient of variance was calculated in addition to mean with SD in order to address the fluctuation of blood pressure measurements. To account for multiple ABPM tests taken by the same patient we utilized generalized estimating equation (GEE) linear model with an identity link function to estimate the impact of benzodiazepine consumption on blood pressure measurements. Six hundred and fifty-seven patients, out of 4,105 (16%) contributed multiple ABPMs to the analysis. When identifying these patients in comparison with patients with no repeated measurements, it was found that repeated ABPM’s population were significantly older, had more diabetes mellitus, higher systolic measurements (but not diastolic), and utilized more BP medicine. These comorbidities were taken into account when we performed a multivariate analysis. Models were adjusted for age, gender, diabetes, and the number of blood pressure medications the patient had been using. We performed a stratified analysis to compare the magnitude of the effect among patients 60 years old and older vs. younger than 60.12 We examined the association between benzodiazepine consumption and clinical outcomes of death and CV outcomes in our study group (4,105 patients) represented by a succeeding hospitalization with a primary diagnosis of acute coronary syndrome, stroke, or congestive heart failure. We utilized Cox proportional hazard models for multivariate analysis of the association adjusted for age, gender, diabetes, and the number of blood pressure medications the patient had been using. In case more than 1 CV outcome occurred during follow-up, analysis took into consideration the chronologically first outcome. Survival analysis was performed using multivariable Cox regression survival analysis model for mortality and CV events in benzodiazepines treated vs. untreated patients, to analyze the association between benzodiazepine consumption, CV outcomes, and death over time. All statistical tests were performed at α = 0.05 (2-sided). The data were analyzed using IBM SPSS Statistics software (version 22). RESULTS Study population A total of 4,967 patients went through 6,446 ABPM studies during the study period (2009–2015). Among them, 5,214 studies fulfilled the criteria for ABPM study CHS patients that their ABPM included at least 70% valid measurements in 24 hours. Another 194 ABPM tests of patients who were treated with benzodiazepines for less than 3 months were excluded. The tests of 30 patients who moved from one study group to the other during the study period, including 82 tests, were also excluded. For the final analysis, 4,938 ABPM studies of 4,105 patients were included (Supplementary Figure S1). Clinical characteristics of patients: treated vs. untreated with benzodiazepines (Table 1). Table 1. Patients clinical characteristics of ABPM studies of benzodiazepine treated vs. untreated Variable  Benzodiazepine-treated (670 ABPMs’)  Benzodiazepine-untreated (4,268 ABPMs’)  P value  Age in years  67.3 ± 9.7  56.8 ± 15.07  <0.001  Male (%)  242 (36.1%)  2188 (51.3%)  <0.001  Diabetes mellitus, N (%)  151 (22.5%)  522 (12.2%)  <0.001  Smokers, N (%)  54 (8.1%)  163 (3.8%)  <0.001  LDL, mg/dl  93.7 ± 29.5  97.5 ± 30.7  0.024  Number of antihypertensive medications (median, IQR)  3.0 (1–4)  1 (0–3)  <0.001  24/h mean systolic/diastolic BP  135.6 ± 16/72.7 ± 9.6  135.9 ± 15.3/76.8 ± 10.2  0.609/<0.001  24/h SD systolic/diastolic variability  14.8 ± 3.8/10.2 ± 2.3  14.2 ± 3.8/10.6 ± 2.6  <0.001/<0.001  Daytime mean systolic/diastolic BP  138.24 ± 16.19/74.8 ± 10.1  138.7 ± 15.6/79 ± 10.7  0.416/<0.001  Daytime SD systolic/diastolic variability  13.58 ± 3.7/ 9.1 ± 2.4  12.8 ± 3.8/ 9.4 ± 2.6  <0.001/0.006  Nighttime mean systolic/ diastolic BP  127.8 ± 18.7/66.4 ± 10.2  127.26 ± 17.1/69.7 ± 10.6  0.581/<0.001  Nighttime SD systolic/diastolic variability  12.29 ± 4.3/8.7 ± 2.8  11.8 ± 4.3/9.2 ± 3.2  0.047/<0.001  Variable  Benzodiazepine-treated (670 ABPMs’)  Benzodiazepine-untreated (4,268 ABPMs’)  P value  Age in years  67.3 ± 9.7  56.8 ± 15.07  <0.001  Male (%)  242 (36.1%)  2188 (51.3%)  <0.001  Diabetes mellitus, N (%)  151 (22.5%)  522 (12.2%)  <0.001  Smokers, N (%)  54 (8.1%)  163 (3.8%)  <0.001  LDL, mg/dl  93.7 ± 29.5  97.5 ± 30.7  0.024  Number of antihypertensive medications (median, IQR)  3.0 (1–4)  1 (0–3)  <0.001  24/h mean systolic/diastolic BP  135.6 ± 16/72.7 ± 9.6  135.9 ± 15.3/76.8 ± 10.2  0.609/<0.001  24/h SD systolic/diastolic variability  14.8 ± 3.8/10.2 ± 2.3  14.2 ± 3.8/10.6 ± 2.6  <0.001/<0.001  Daytime mean systolic/diastolic BP  138.24 ± 16.19/74.8 ± 10.1  138.7 ± 15.6/79 ± 10.7  0.416/<0.001  Daytime SD systolic/diastolic variability  13.58 ± 3.7/ 9.1 ± 2.4  12.8 ± 3.8/ 9.4 ± 2.6  <0.001/0.006  Nighttime mean systolic/ diastolic BP  127.8 ± 18.7/66.4 ± 10.2  127.26 ± 17.1/69.7 ± 10.6  0.581/<0.001  Nighttime SD systolic/diastolic variability  12.29 ± 4.3/8.7 ± 2.8  11.8 ± 4.3/9.2 ± 3.2  0.047/<0.001  Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; IQR, interquartile range; LDL, low-density lipoprotein. View Large The ABPM studies included 670 studies that were of benzodiazepine-treated patients and 4,268 studies were of untreated patients. The total 4,105 patients that their ABPM studies were included were divided to: 524 patients in the benzodiazepines treated group; 3,581 patients in the untreated group. There was a significant difference between the groups in terms of demographics and CV risk factors. The benzodiazepine-treated patients were older (67.3 ± 9.7 vs. 56.8 ± 15.0, respectively, P < 0.001) and had a lower prevalence of male gender (242 (36.1%) vs. 2,188 (51.3%), respectively, P < 0.001). The benzodiazepines-treated group also had a higher prevalence of diabetes mellitus (151 (22.5%) vs. 522 (12.1%), respectively, P < 0.001) and utilized more antihypertensive medications in the 6 months previous to an ABPM study (3.0, interquartile range 1–4 vs. 1, interquartile range 0–3, respectively, P < 0.001). In ABPM measurement, there was no difference between the groups in systolic blood pressure measurements. While, the diastolic blood pressure in all ABPM measurements (24 hours, daytime, and night time) was significantly lower in the benzodiazepine-treated group compared to the untreated group. Association between long-term benzodiazepine use and changes in ABPM measurements: multivariate linear GEE regression analysis (Table 2). Table 2. Estimates of change in ABPM measurements associated with benzodiazepine use ABPM measurements  B*  95% Confidence interval for B    Lower bound  Upper bound  P value  24/h Systolic BP  −2.021  −3.255  −0.788  <0.001  24/h Systolic variability  0.447  0.118  0.775  0.008  24/h Diastolic BP  −3.121  −3.952  −2.291  <0.001  24/h Diastolic variability  −0.261  −0.464  −0.057  0.012  Daytime systolic BP  −2.091  −3.351  −0.831  <0.001  Daytime systolic variability  0.376  0.056  0.696  0.021  Daytime diastolic BP  −3.193  −4.063  −2.324  <0.001  Daytime diastolic variability  −0.231  −0.441  0.021  0.031  Nighttime systolic BP  −1.512  −2.941  −0.084  0.038  Nighttime systolic variability  0.220  −0.121  0.560  0.206  Nighttime diastolic BP  −2.63  −3.500  −1.759  <0.001  Nighttime diastolic variability  −0.383  −0.617  −0.149  0.001  ABPM measurements  B*  95% Confidence interval for B    Lower bound  Upper bound  P value  24/h Systolic BP  −2.021  −3.255  −0.788  <0.001  24/h Systolic variability  0.447  0.118  0.775  0.008  24/h Diastolic BP  −3.121  −3.952  −2.291  <0.001  24/h Diastolic variability  −0.261  −0.464  −0.057  0.012  Daytime systolic BP  −2.091  −3.351  −0.831  <0.001  Daytime systolic variability  0.376  0.056  0.696  0.021  Daytime diastolic BP  −3.193  −4.063  −2.324  <0.001  Daytime diastolic variability  −0.231  −0.441  0.021  0.031  Nighttime systolic BP  −1.512  −2.941  −0.084  0.038  Nighttime systolic variability  0.220  −0.121  0.560  0.206  Nighttime diastolic BP  −2.63  −3.500  −1.759  <0.001  Nighttime diastolic variability  −0.383  −0.617  −0.149  0.001  Results of multivariate linear GEE regression. Dependent variable; ABPM measurements, independent variables; benzodiazepine use, age, gender, diabetes mellitus, and number of antihypertensive medications. Abbreviations: ABPM, ambulatory blood pressure monitoring; B, changes in ABPM measurements are expressed as the B coefficient of the GEE model; BP, blood pressure; GEE, generalized estimating equation. *P value—BP measurements change in benzodiazepine treated vs. nontreated. View Large We found a significant association between benzodiazepine treatment and lower ABPM measurements (adjusted for age, gender, diabetes mellitus, and number of antihypertensive medications utilized). Benzodiazepine treatment was independently associated with significantly lower systolic blood pressure over 24 hours, during the daytime, and during the night [−2.0 mm Hg (confidence interval [CI] −3.2, −0.7); −2.09 mm Hg (CI −3.3, −0.8); and −1.5 mm Hg (CI −2.9, −0.08), respectively] as well as with significantly lower diastolic blood pressure over 24 hours, during the daytime, and during the night [−3.1 mm Hg (CI −3.9, −2.3); −3.1 mm Hg (CI −4.0, −2.3); and −2.6 mm Hg (CI −3.5, −1.7), respectively]. Benzodiazepines did not have a significant association with blood pressure variability, with the exception of the variability of diastolic blood pressure during the night [−0.2 mm Hg (CI −0.5, −0.004)]. The effect of long and short acting benzodiazepines was evaluated. Treatment with either long or short acting benzodiazepines was associated with systolic and diastolic blood pressure reduction during both daytime and night time (Supplementary Table S1). Association between benzodiazepine treatment ABPM measurements among age groups: multivariate linear GEE regression analysis (Table 3). Table 3. Estimates of change in ABPM measurements associated with benzodiazepine use, by age (cutoff of 60 years old)   Age groups (years)  B  95% Confidence interval for B    Lower bound  Upper bound  P value*  24/h Systolic BP  <60  −0.700  −3.290  1.891  0.596    ≥60  −2.595  −3.980  −1.211  <0.001  24/h Systolic variability  <60  −0.052  −0.655  0.552  0.867    ≥60  0.420  0.023  0.816  0.038  24/h Diastolic BP  <60  −0.193  −1.777  1.391  0.812    ≥60  −2.098  −2.944  −1.252  <0.001  24/h Diastolic variability  <60  −0.235  −0.682  0.211  0.301    ≥60  −0.033  −0.257  0.192  0.776  Daytime systolic BP  <60  −0.265  −2.985  2.454  0.848    ≥60  −2.603  −4.011  −1.196  <0.001  Daytime systolic variability  <60  −0.450  −1.109  0.210  0.181    ≥60  0.213  −0.147  0.572  0.246  Daytime diastolic BP  <60  −0.119  −1.786  1.548  0.889    ≥60  −2.090  −2.977  −1.204  <0.001  Daytime diastolic variability  <60  −0.384  −0.808  0.039  0.075    ≥60  −0.051  −0.296  0.194  0.685  Nighttime systolic BP  <60  −1.746  −4.784  1.293  0.260    ≥60  −2.110  −3.749  −0.470  0.012  Nighttime systolic variability  <60  −0.213  −0.862  0.436  0.520    ≥60  0.136  −0.258  0.530  0.499  Nighttime diastolic BP  <60  −0.882  −2.644  0.881  0.327    ≥60  −1.753  −2.695  −0.810  <0.001  Nighttime diastolic variability  <60  −0.590  −1.062  −0.117  0.014    ≥60  −0.268  −0.538  0.002  0.052    Age groups (years)  B  95% Confidence interval for B    Lower bound  Upper bound  P value*  24/h Systolic BP  <60  −0.700  −3.290  1.891  0.596    ≥60  −2.595  −3.980  −1.211  <0.001  24/h Systolic variability  <60  −0.052  −0.655  0.552  0.867    ≥60  0.420  0.023  0.816  0.038  24/h Diastolic BP  <60  −0.193  −1.777  1.391  0.812    ≥60  −2.098  −2.944  −1.252  <0.001  24/h Diastolic variability  <60  −0.235  −0.682  0.211  0.301    ≥60  −0.033  −0.257  0.192  0.776  Daytime systolic BP  <60  −0.265  −2.985  2.454  0.848    ≥60  −2.603  −4.011  −1.196  <0.001  Daytime systolic variability  <60  −0.450  −1.109  0.210  0.181    ≥60  0.213  −0.147  0.572  0.246  Daytime diastolic BP  <60  −0.119  −1.786  1.548  0.889    ≥60  −2.090  −2.977  −1.204  <0.001  Daytime diastolic variability  <60  −0.384  −0.808  0.039  0.075    ≥60  −0.051  −0.296  0.194  0.685  Nighttime systolic BP  <60  −1.746  −4.784  1.293  0.260    ≥60  −2.110  −3.749  −0.470  0.012  Nighttime systolic variability  <60  −0.213  −0.862  0.436  0.520    ≥60  0.136  −0.258  0.530  0.499  Nighttime diastolic BP  <60  −0.882  −2.644  0.881  0.327    ≥60  −1.753  −2.695  −0.810  <0.001  Nighttime diastolic variability  <60  −0.590  −1.062  −0.117  0.014    ≥60  −0.268  −0.538  0.002  0.052  Results of Multivariate linear GEE regression analysis. Dependent variable; ABPM measurements, Independent variables; benzodiazepine use, age, gender, diabetes mellitus, and number of antihypertensive medications. Abbreviations: ABPM, ambulatory blood pressure monitoring; B, changes in ABPM measurements are expressed as the B coefficient of the GEE model; BP, blood pressure; GEE, generalized estimating equation. *P value—blood pressure measurements change in benzodiazepine treated vs. nontreated. View Large We further stratified the population into 2 age groups by the age 60 years. In the benzodiazepine group, 81.5% were >60 years old and 18.5% were under 60 years old, while in the untreated group, 50.5% were >60 years old and 49.5% were under 60 years old. This analysis showed that regular benzodiazepine consumption was associated with lower ABPM measurements only in the elderly group (Table 3). Systolic blood pressure was lower over 24 hours, during the daytime, and at night [−2.5 mm Hg (CI −3.9, −1.2); −2.6 mm Hg (CI −4.0, −1.1); and −2.1 mm Hg (CI −3.7, −0.4), respectively]. Diastolic blood pressure was lower over 24 hours, during the daytime, and at night [−2.0 mm Hg (CI −2.9, −1.2); −2.0 mm Hg (CI −2.9, −1.2); and −1.7 mm Hg (CI −2.6, −0.8), respectively]. In the younger group (<60 y/o), regular benzodiazepine treatment was associated only with lower nighttime diastolic blood pressure variability [−0.5 mm Hg (CI −1.0, −0.1)]. Benzodiazepine treatment: mortality and CV outcomes (Table 4). Table 4. Multivariable COX regression analysis of factors associated with total mortality and cardiovascular eventsa   Total mortality (N = 138)  Cardiovascular event (N = 136)      95% CI  P value  HR  95% CI    Variable  HR  Lower  Upper  Lower  Upper  P value  Long-term Benz. consumption (yes/no)  1.256  0.840  1.878  0.266  1.013  0.660  1.553  0.954  Age (years)  1.066  1.047  1.087  <0.001  1.032  1.015  1.050  <0.001  Male gender  1.528  1.089  2.144  0.014  1.736  1.228  2.454  0.002  Diabetes mellitus  3.484  2.445  4.965  <0.001  4.925  3.439  7.052  <0.001  Number of antihypertensive medications  0.955  0.869  1.050  0.343  1.165  1.070  1.268  <0.001    Total mortality (N = 138)  Cardiovascular event (N = 136)      95% CI  P value  HR  95% CI    Variable  HR  Lower  Upper  Lower  Upper  P value  Long-term Benz. consumption (yes/no)  1.256  0.840  1.878  0.266  1.013  0.660  1.553  0.954  Age (years)  1.066  1.047  1.087  <0.001  1.032  1.015  1.050  <0.001  Male gender  1.528  1.089  2.144  0.014  1.736  1.228  2.454  0.002  Diabetes mellitus  3.484  2.445  4.965  <0.001  4.925  3.439  7.052  <0.001  Number of antihypertensive medications  0.955  0.869  1.050  0.343  1.165  1.070  1.268  <0.001  Abbreviations: CI, confidence interval; HR, hazard ratio. aCardiovascular events include: acute coronary syndrome (n = 86), cerebrovascular event (n = 39), and congestive heart failure (n = 11). View Large During the study period in our study group (4,105 patients) after mean follow-up period of 42.4 ± 19.8 months for, there were 138 deaths (mean follow-up 42.4 ± 19.8 months) and 136 cases of CV events (mean follow-up 42.1 ± 20.0 months; 86 cases of acute coronary syndrome, 39 cases of stroke, and 11 cases of congestive heart failure). Multivariable Cox regression analysis showed that regular benzodiazepine consumption was associated neither with change in mortality nor with adverse CV events. As expected, age, male gender, and diabetes mellitus were all significantly associated with both increased mortality and CV events. Antihypertensive treatment was associated with decreased total mortality. DISCUSSION In the current study, we found that in patients 60 years old and older regular consumption of benzodiazepines was significantly associated with lower systolic and diastolic blood pressure, while in the younger benzodiazepines did not have a significant association with blood pressure change. Liu et al. in their meta-analysis found that psychosocial stress was associated with an increased risk of hypertension (odds ratio = 2.40, 95% CI = 1.65–3.49), and hypertensive patients had a higher incidence of psychosocial stress compared to normotension patients (odds ratio = 2.69, 95% CI = 2.32–3.11).13 Furthermore, it is suspected that one of the mechanisms by which anxiety increases the risk for CV disease14 is through hypertension.15 This assumption is supported by an observational study showing that temporary increases in anxiety are associated with acute increases in ambulatory systolic blood pressure.16 In a systemic review of observational studies, Sparrenberger et al. found that chronic stress and particularly the nonadaptive response to stress are more likely causes of sustained elevation of blood pressure.17 An Israeli study showed that prolongation and suppression of feelings following conflicts in certain life situations was positively associated with the incidence of hypertension.18 Another study in different population showed that high sympathetic nervous activity during mental arithmetic predicts future blood pressure.19 This finding represents a quite convincing evidence that an abnormal reactivity to stress may be implicated in the development of future hypertension.20 The linking between anxiety and hypertension is even more profound as demonstrated by a study showing that high anxiety sensitivity was strongly associated with nonadherence to antihypertensive treatment.21 When benzodiazepines are administrated intravenous during anesthesia there is a significant decrease in systemic blood pressure.22,23 The benzodiazepines used for anesthesia cause transient depression of baroreflex function and a sustained decrease of sympathetic tone.24 Benzodiazepines act as positive allosteric modulators on the gamma aminobutyric acid (GABA)-A receptor. The GABA-A receptor is a ligand-gated chloride-selective ion channel.25 GABA is the most common neurotransmitter in the central nervous system, found in high concentrations in the cortex and limbic system. GABA is inhibitory in nature and thus reduces the excitability of neurons. GABA produces a calming effect on the brain.25 In animal model using spontaneously hypertensive rats that were fed with GABA-enriched fermented milk product, resulted in significant decrease of blood pressure 4–8 hours after administration.26 Another animal study showed the benzodiazepines have a peripheral vasodilatory direct effect on blood vessels. Midazolam-induced reversible, dose-dependent vasodilation in aortic rings from C57/BL6 mice that were precontracted with either potassium or phenylephrine.27 In the current study, we found the hypotensive effect of chronic benzodiazepines consumption was demonstrated in patients 60 years and older. Though, the lack of influence on blood pressure may be due to the fact that in the benzodiazepine group the prevalence of patients under 60 years old was less than 20%. Old age may lead to altered pharmacokinetics of sedative-anxiolytic drugs, causing higher plasma concentrations (relative to young individuals) after single or multiple doses.28 This might be one of the explanations for the significant hypotensive effect in older vs. younger patients in our study. Although, chronic benzodiazepines consumption by elderly patients might improve their blood pressure control one should also consider the hazard effect of benzodiazepines in this population. The American Geriatrics Society (AGS) placed benzodiazepines on a list of medications that should be avoided in patients over 65 years of age.29,30 It was also described that benzodiazepine use is associated with a considerable increase in all-cause mortality, showing that benzodiazepines treated dying at a 1.2- to 3.7-times higher rate per year compared with untreated individuals.31 Yet, it remains unclear whether this association is causal or whether benzodiazepine are being used more frequently by patients with eventually higher mortality rate.29 One of the most devastating morbidity in the elderly population is hip fracture. In the elderly, the incidence of hip fractures in benzodiazepine consumers individuals may be increased by 50% or more, particularly when other medications, such as antihypertensives and antidepressants, are co-prescribed.32,33 In our study, we did not find that benzodiazepines alter total or CV mortality probably due to short follow-up period. In conclusion, although there is a lot of evidence about the acute CV effect of benzodiazepines, to the best of our knowledge, the effect on blood pressure in chronic utilization was not described. We might suggest that although our study showed that chronic benzodiazepine consumption was associated with blood pressure reduction without increased mortality, caution is required in these groups of patients. Further prospective study is needed to evaluate the safety and efficacy of the combination between antihypertensive treatment and chronic benzodiazepinesine consumption. Future study should be focusing not only on CV morbidity and mortality, but also on recurrent falls, head trauma, hip fractures, and syncope. SUPPLEMENTARY MATERIAL Supplementary materials are available at American Journal of Hypertension online. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Esler M. The sympathetic system and hypertension. Am J Hypertens  2000; 13: 99S– 105S. 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American Journal of HypertensionOxford University Press

Published: Apr 1, 2018

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