Systolic Blood Pressure and Outcomes in Stable Outpatients with Recent Symptomatic Artery Disease: A Population-Based Longitudinal Study

Objectives: The most appropriate targets for systolic blood pressure (SBP) levels to reduce cardiovascular morbidity and mortality in patients with symptomatic artery disease remain controversial. We compared the rate of subsequent ischemic events or death according to mean SBP levels during follow-up. Design: Prospective cohort study. FRENA is an ongoing registry of stable outpatients with symptomatic coronary (CAD), cerebrovascular (CVD) or peripheral artery disease (PAD). Setting: 24 Spanish hospitals. Participants: 4789 stable outpatients with vascular disease. Results: As of June 2017, 4789 patients had been enrolled in different Spanish centres. Of these, 1722 (36%) had CAD, 1383 (29%) CVD and 1684 (35%) PAD. Over a mean follow-up of 18 months, 136 patients suffered subsequent myocardial infarction, 125 had ischemic stroke, 74 underwent limb amputation, and 260 died. On multivariable analysis, CVD patients with mean SBP levels 130–140 mm Hg had a lower risk of mortality than those with levels <130 mm Hg (hazard ratio (HR): 0.39; 95% CI: 0.20–0.77), as did those with levels >140 mm Hg (HR: 0.46; 95% CI: 0.26–0.84). PAD patients with mean SBP levels >140 mm Hg had a lower risk for subsequent ischemic events (HR: 0.57; 95% CI: 0.39–0.83) and those with levels 130–140 mm Hg (HR: 0.47; 95% CI: 0.29–0.78) or >140 mm Hg (HR: 0.32; 95% CI: 0.21–0.50) had a lower risk of mortality. We found no differences in patients with CAD. Conclusions: In this real-world cohort of symptomatic arterial disease patients, most of whom are not eligible for clinical trials, the risk of subsequent events and death varies according to the levels of SBP and the location of previous events. Especially among patients with large artery atherosclerosis, PAD or CVD, SBP <130 mm Hg may result in increased mortality. Due to potential factors in this issue, Prospective, well designed studies are warranted to confirm these observational data.

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Workload-indexed blood pressure response is superior to peak systolic blood pressure in predicting all-cause mortality

European Journal of Preventive Cardiology ◽

10.1177/2047487319877268 ◽

2019 ◽

Vol 27 (9) ◽

pp. 978-987 ◽

Cited By ~ 4

Author(s):

Kristofer Hedman ◽

Nicholas Cauwenberghs ◽

Jeffrey W Christle ◽

Tatiana Kuznetsova ◽

Francois Haddad ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Systolic Blood Pressure ◽

Exercise Testing ◽

Lower Risk ◽

Metabolic Equivalents ◽

Risk Of Mortality ◽

Increased Risk ◽

All Cause Mortality ◽

Clinical Exercise Testing

Aims The association between peak systolic blood pressure (SBP) during exercise testing and outcome remains controversial, possibly due to the confounding effect of external workload (metabolic equivalents of task (METs)) on peak SBP as well as on survival. Indexing the increase in SBP to the increase in workload (SBP/MET-slope) could provide a more clinically relevant measure of the SBP response to exercise. We aimed to characterize the SBP/MET-slope in a large cohort referred for clinical exercise testing and to determine its relation to all-cause mortality. Methods and results Survival status for male Veterans who underwent a maximal treadmill exercise test between the years 1987 and 2007 were retrieved in 2018. We defined a subgroup of non-smoking 10-year survivors with fewer risk factors as a lower-risk reference group. Survival analyses for all-cause mortality were performed using Kaplan–Meier curves and Cox proportional hazard ratios (HRs (95% confidence interval)) adjusted for baseline age, test year, cardiovascular risk factors, medications and comorbidities. A total of 7542 subjects were followed over 18.4 (interquartile range 16.3) years. In lower-risk subjects ( n = 709), the median (95th percentile) of the SBP/MET-slope was 4.9 (10.0) mmHg/MET. Lower peak SBP (<210 mmHg) and higher SBP/MET-slope (>10 mmHg/MET) were both associated with 20% higher mortality (adjusted HRs 1.20 (1.08–1.32) and 1.20 (1.10–1.31), respectively). In subjects with high fitness, a SBP/MET-slope > 6.2 mmHg/MET was associated with a 27% higher risk of mortality (adjusted HR 1.27 (1.12–1.45)). Conclusion In contrast to peak SBP, having a higher SBP/MET-slope was associated with increased risk of mortality. This simple, novel metric can be considered in clinical exercise testing reports.

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Selective neuronal damage and blood pressure in atherosclerotic major cerebral artery disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-320326 ◽

2019 ◽

Vol 90 (9) ◽

pp. 975-980 ◽

Cited By ~ 1

Author(s):

Hiroshi Yamauchi ◽

Shinya Kagawa ◽

Masaaki Takahashi ◽

Kuninori Kusano ◽

Chio Okuyama

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Systolic Blood Pressure ◽

Cerebral Artery ◽

Neuronal Damage ◽

Benzodiazepine Receptors ◽

Benzodiazepine Receptor ◽

Artery Disease

ObjectiveIn patients with atherosclerotic major cerebral artery disease, low blood pressure might impair cerebral perfusion, thereby exacerbate the risk of selective neuronal damage. The purpose of this retrospective study was to determine whether low blood pressure at follow-up is associated with increased selective neuronal damage.MethodsWe retrospectively analysed data from 76 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery disease with no ischaemic episodes on a follow-up of 6 months or more. All patients had measurements of the distribution of central benzodiazepine receptors twice using positron emission tomography and 11C-flumazenil. Using three-dimensional stereotactic surface projections, we quantified abnormal decreases in the benzodiazepine receptors of the cerebral cortex within the middle cerebral artery distribution and correlated these changes in the benzodiazepine receptors index with blood pressure values at follow-up examinations.ResultsThe changes in the benzodiazepine receptor index during follow-up (mean 27±21 months) were negatively correlated with systolic blood pressure at follow-up. The relationship between changes in benzodiazepine receptor index and systolic blood pressure was different among patients with and without decreased cerebral blood flow at baseline (interaction, p<0.005). Larger increases in benzodiazepine receptor index (neuronal damage) were observed at lower systolic blood pressure levels in patients with decreased cerebral blood flow than in patients without such decreases.ConclusionIn patients without ischaemic stroke episodes at follow-up but with decreased cerebral blood flow due to arterial disease, low systolic blood pressure at follow-up may be associated with increased selective neuronal damage.

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Long-term hemodynamic changes and blood pressure in atherosclerotic major cerebral artery disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17727385 ◽

2017 ◽

Vol 39 (2) ◽

pp. 324-331 ◽

Cited By ~ 3

Author(s):

Hiroshi Yamauchi ◽

Shinya Kagawa ◽

Masaaki Takahashi ◽

Tatsuya Higashi

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Systolic Blood Pressure ◽

Cerebral Artery ◽

Internal Carotid ◽

Hemodynamic Improvement ◽

The Mean ◽

Artery Disease

In patients with major cerebral artery disease, lower blood pressure might reduce blood flow in the collateral pathways, thereby impairing the growth of cerebral collaterals, inhibiting hemodynamic improvement. We evaluated the hemodynamic status twice using positron emission tomography and 15O-gas, over time, in 89 medically treated patients with atherosclerotic internal carotid artery or middle cerebral artery disease that had no ischemic episodes during follow-up (mean, 28 ± 23 months). Changes in the mean hemispheric values of hemodynamic parameters in the territory of the diseased artery at follow-up were correlated with the mean blood pressure values at the baseline and follow-up examinations. There was a positive linear relationship between the degree of hemodynamic improvement and systolic blood pressure. Patients with low systolic blood pressure (<130 mmHg) ( n = 18) showed hemodynamic deterioration as indicated by significant decreases in cerebral blood flow, cerebral blood flow/cerebral blood volume ratio, and increases in oxygen extraction fraction during follow-up. In contrast, there were no significant changes in patients without low systolic blood pressure. In patients with atherosclerotic internal carotid artery or middle cerebral artery disease and no ischemic episodes of stroke during follow-up, lower systolic blood pressure was associated with lesser hemodynamic improvement.

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Abstract TP73: Lower Prehospital Blood Pressure Is Not Associated with Larger Infarct Volumes in Non-lacunar Ischemic Stroke Patients

Stroke ◽

10.1161/str.47.suppl_1.tp73 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Rahel T Zewude ◽

Laura C Gioia ◽

Mahesh Kate ◽

Kim Liss ◽

Brian Rowe ◽

...

Keyword(s):

Blood Pressure ◽

Ischemic Stroke ◽

Infarct Volume ◽

Cryptogenic Stroke ◽

Final Diagnosis ◽

Large Artery ◽

Stroke Etiology ◽

Artery Disease ◽

Suspected Stroke

Background: Although prehospital blood pressure (BP)-lowering trials in acute stroke have begun, concerns persist that hypotension may exacerbate hypoperfusion and increase infarct volumes, particularly in non-lacunar stroke. We tested the hypothesis that lower prehospital BP is associated with larger infarct volumes in non-lacunar ischemic stroke. Methods: We conducted a retrospective study of consecutive patients with suspected stroke transported by Emergency Medical Services (EMS) during an 18-month period. Serial prehospital BP data were obtained from a centralized EMS database. Hospital charts and neuroimaging were reviewed. Stroke etiology was classified using TOAST criteria. Infarct volumes were measured on follow-up MRI or CT using semi-automated thresholding planimetric techniques by two independent raters, blinded to prehospital BP. Results: Of a total 960 patients transported by EMS, 367 had a final diagnosis of ischemic stroke. Stroke etiology was large artery disease in 51 patients, cardioembolic in 140, lacunar in 44, other determined etiology in 22, and cryptogenic in 110 patients. Follow-up imaging was available in 315 patients (163 MR, 152 CT) at a median (IQR) 1(1) days. The overall median non-lacunar infarct volume was 16.5 (49.6) ml, median NIHSS was 7(10), and mean prehospital SBP was 153 ± 25 mmHg. Mean prehospital SBP was lower in patients with other determined etiology (133.2 ± 26.1 mmHg, p<0.01) than cardioembolic (150.9 ± 25.5 mmHg), large artery disease (157.1 ± 26.1 mmHg) and cryptogenic stroke (157.7 ± 22.9 mmHg). Median infarct volume was similar across categories of stroke etiology (large artery disease (16.3 (60.3) ml), cardioembolic (19.9 (76.2) ml), other determined etiology (23.9 (33.6) ml), and cryptogenic stroke (11.5 (35.9) ml), p=0.12). There was no correlation between mean prehospital SBP and mean infarct volume (r =-0.06, p=0.33). NIHSS score was correlated with mean infarct volume (r=0.6, p<0.001), but not mean prehospital SBP (r=-0.07, p=0.24). Conclusion: These data provide no evidence to suggest that lower prehospital BP is associated with larger infarct volumes in patients with non-lacunar ischemic stroke. The effect of BP reduction on infarct volumes should be assessed as part of randomized trials.

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Blood Pressure Increase and Microvascular Dysfunction Accelerate Arterial Stiffening in Children: Modulation by Physical Activity

Frontiers in Physiology ◽

10.3389/fphys.2020.613003 ◽

2020 ◽

Vol 11 ◽

Author(s):

Giulia Lona ◽

Christoph Hauser ◽

Sabrina Köchli ◽

Denis Infanger ◽

Katharina Endes ◽

...

Keyword(s):

Physical Activity ◽

Blood Pressure ◽

Microvascular Dysfunction ◽

Large Artery ◽

Clinical Trial Registration ◽

Oscillometric Device ◽

Artery Disease ◽

Cv Disease ◽

Arteriolar Narrowing

BackgroundAtherosclerotic remodeling starts early in life and can accelerate in the presence of cardiovascular risk (CV) factors. Regular physical activity (PA) can mitigate development of large and small artery disease during lifespan. We aimed to investigate the association of changes in body mass index (BMI), blood pressure (BP), PA behavior and retinal microvascular diameters with large artery pulse wave velocity (PWV) in prepubertal children over 4 years.MethodsThe school-based prospective cohort study included 262 children initially aged 6–8 years, assessing the above CV risk factors and retinal vessels by standardized procedures at baseline (2014) and follow-up (2018). PWV was assessed by an oscillometric device at follow-up.ResultsChildren with increased systolic BP over 4 years showed higher PWV at follow-up (β [95% CI] 0.006 [0.002 to 0.011] mmHg per unit, P = 0.002). In contrast, increased vigorous PA corresponded to a lower PWV at follow-up (β [95% CI] −0.009 [−0.018 to <0−0.001] 10 min/day per unit, P = 0.047). Progression of retinal arteriolar narrowing and venular widening were linked to a higher PWV after 4 years (β [95% CI] −0.014 [−0.023 to −0.004] 0.01 changes per unit, P = 0.003).ConclusionIncrease in systolic BP and progression of microvascular dysfunction were associated with higher PWV after 4 years. Children with increasing levels of vigorous PA were found to have lower PWV at follow-up. Habitual vigorous PA has the potential to decelerate the process of early vascular aging in children and may thus help counteract CV disease development later in life.Clinical Trial RegistrationClinicalTrials.gov, Identifier: NCT03085498.

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Long-term systolic blood pressure and all-cause mortality in heart failure with preserved ejection fraction: an analysis of the TOPCAT trial

European Heart Journal ◽

10.1093/ehjci/ehaa946.0983 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

P Huang ◽

C Liu

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Ejection Fraction ◽

Funding Source ◽

Preserved Ejection Fraction ◽

Risk Of Mortality ◽

All Cause Mortality ◽

History Of

Abstract Background Lower systolic blood pressure (SBP) at admission or discharge was associated with poor outcomes in patients with heart failure and preserved ejection fraction (HFpEF). However, the optimal long-term SBP for HFpEF was less clear. Purpose To examine the association of long-term SBP and all-cause mortality among patients with HFpEF. Methods We analyzed participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study. Participants had at least two SBP measurements of different times during the follow-up were included. Long-term SBP was defined as the average of all SBP measurements during the follow-up. We stratified participants into four groups according to long-term SBP: <120mmHg, ≥120mmHg and <130mmHg, ≥130mmHg and <140mmHg, ≥140mmHg. Multivariable adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality associated with SBP level. To assess for nonlinearity, we fitted restricted cubic spline models of long-term SBP. Sensitivity analyses were conducted by confining participants with history of hypertension or those with left ventricular ejection fraction≥50%. Results The 3338 participants had a mean (SD) age of 68.5 (9.6) years; 51.4% were women, and 89.3% were White. The median long-term SBP was 127.3 mmHg (IQR 121–134.2, range 77–180.7). Patients in the SBP of <120mmHg group were older age, less often female, less often current smoker, had higher estimated glomerular filtration rate, less often had history of hypertension, and more often had chronic obstructive pulmonary disease and atrial fibrillation. After multivariable adjustment, long-term SBP of 120–130mmHg and 130–140mmHg was associated with a lower risk of mortality during a mean follow-up of 3.3 years (HR 0.65, 95% CI: 0.49–0.85, P=0.001; HR 0.66, 95% CI 0.50–0.88, P=0.004, respectively); long-term SBP of <120mmHg had similar risk of mortality (HR 1.03, 95% CI: 0.78–1.36, P=0.836), compared with long-term SBP of ≥140mmHg. Findings from restricted cubic spline analysis demonstrate that there was J-shaped association between long-term SBP and all-cause mortality (P=0.02). These association was essentially unchanged in sensitivity analysis. Conclusions Among patients with HFpEF, long-term SBP showed a J-shaped pattern with all-cause mortality and a range of 120–140 mmHg was significantly associated with better outcomes. Future randomized controlled trials need to evaluate optimal long-term SBP goal in patients with HFpEF. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): China Postdoctoral Science Foundation Grant (2019M660229 and 2019TQ0380)

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Skin autofluorescence predicts new cardiovascular disease and mortality in people with type 2 diabetes

BMC Endocrine Disorders ◽

10.1186/s12902-020-00676-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Henderikus E. Boersma ◽

Robert P. van Waateringe ◽

Melanie M. van der Klauw ◽

Reindert Graaff ◽

Andrew D. Paterson ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Fasting Blood Glucose ◽

Multivariable Analysis ◽

Oral Glucose ◽

Skin Autofluorescence ◽

Z Score

Abstract Background Skin autofluorescence (SAF) is a non-invasive marker of tissue accumulation of advanced glycation endproducts (AGE). Recently, we demonstrated in the general population that elevated SAF levels predict the development of type 2 diabetes (T2D), cardiovascular disease (CVD) and mortality. We evaluated whether elevated SAF may predict the development of CVD and mortality in individuals with T2D. Methods We included 2349 people with T2D, available baseline SAF measurements (measured with the AGE reader) and follow-up data from the Lifelines Cohort Study. Of them, 2071 had no clinical CVD at baseline. 60% were already diagnosed with diabetes (median duration 5, IQR 2–9 years), while 40% were detected during the baseline examination by elevated fasting blood glucose ≥7.0 mmol/l) and/or HbA1c ≥6.5% (48 mmol/mol). Results Mean (±SD) age was 57 ± 12 yrs., BMI 30.2 ± 5.4 kg/m2. 11% of participants with known T2D were treated with diet, the others used oral glucose-lowering medication, with or without insulin; 6% was using insulin alone. Participants with known T2D had higher SAF than those with newly-detected T2D (SAF Z-score 0.56 ± 0.99 vs 0.34 ± 0.89 AU, p < 0.001), which reflects a longer duration of hyperglycaemia in the former group. Participants with existing CVD and T2D had the highest SAF Z-score: 0.78 ± 1.25 AU. During a median follow-up of 3.7 yrs., 195 (7.6%) developed an atherosclerotic CVD event, while 137 (5.4%) died. SAF was strongly associated with the combined outcome of a new CVD event or mortality (OR 2.59, 95% CI 2.10–3.20, p < 0.001), as well as incidence of CVD (OR 2.05, 95% CI 1.61–2.61, p < 0.001) and death (OR 2.98, 2.25–3.94, p < 0.001) as a single outcome. In multivariable analysis for the combined endpoint, SAF retained its significance when sex, systolic blood pressure, HbA1c, total cholesterol, eGFR, as well as antihypertensive and statin medication were included. In a similar multivariable model, SAF was independently associated with mortality as a single outcome, but not with incident CVD. Conclusions Measuring SAF can assist in prediction of incident cardiovascular disease and mortality in individuals with T2D. SAF showed a stronger association with future CVD events and mortality than cholesterol or blood pressure levels.

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Association between systolic blood pressure trajectories and hypertension risk at late adolescence: results from 10-year longitudinal follow-up in Chinese boys

BMJ Open ◽

10.1136/bmjopen-2020-042594 ◽

2021 ◽

Vol 11 (4) ◽

pp. e042594

Author(s):

Xijie Wang ◽

Bin Dong ◽

Sizhe Huang ◽

Zhaogeng Yang ◽

Jun Ma ◽

...

Keyword(s):

Blood Pressure ◽

Systolic Blood Pressure ◽

Late Adolescence ◽

Population Based ◽

Incidence Rates ◽

Hypertension Risk ◽

Logit Regression ◽

Binomial Regression ◽

Physical Examinations

ObjectiveTo identify various systolic blood pressure (SBP) trajectories in Chinese boys between 7 and 18 years of age, and to explore their high blood pressure (HBP) risk in their late adolescence years.Design and settingsA population-based cohort study in Guangdong, China.Participants4541 normal tensive boys who started primary school in 2005 in Zhongshan, Guangdong were included.OutcomesBlood pressure and relevant measurements were obtained by annual physical examinations between 2005 and 2016. HBP was defined by SBP or diastolic blood pressure ≥95th percentile for children under 13, and BP ≥130/80 mm Hg for children ≥13 years old. Logit regression for panel data and log-binomial regression model was used to estimate the risk of HBP among SBP trajectory groups.ResultsFour distinct SBP trajectory groups via group-based trajectory modelling: low stable (13.0%), low rising (42.4%), rising (37.4%) and high rising (7.3%). The overall incidence rates of HBP during the follow-up ranged from 40.24 (95% CI 36.68 to 44.19)/1000 person-years in the low stable group to 97.08 (95% CI 94.93 to 99.27)/1000 person-years in the high rising group. Compared with children with low stable SBP, those of other SBP trajectories suffered 3.05 (95% CI 2.64 to 3.46) to 4.64 (95% CI 4.18 to 5.09) times of higher risk of HBP in their late adolescence, regardless of their age, body mass index and BP level at baseline.ConclusionsSubgroups of SBP trajectories existed in Chinese boys, and are related to hypertension risk at late adolescence. Regular physical examinations could help identify those with higher risks at the beginning of pubertal growth.

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Hypertensive response in exercise - a tool to predict stroke risk?

European Journal of Preventive Cardiology ◽

10.1093/eurjpc/zwab061.225 ◽

2021 ◽

Vol 28 (Supplement_1) ◽

Author(s):

TE Graca Rodrigues ◽

N Cunha ◽

P Silverio-Antonio ◽

P Couto Pereira ◽

B Valente Silva ◽

...

Keyword(s):

Atrial Fibrillation ◽

Blood Pressure ◽

Systolic Blood Pressure ◽

Exercise Test ◽

Cardiovascular Events ◽

Protective Factor ◽

Independent Predictor ◽

Stress Test ◽

Coronary Syndrome

Abstract Funding Acknowledgements Type of funding sources: None. Introduction There is some evidence suggesting that exaggerated hypertensive response to exercise (HRE) may be associated with higher risk of future cardiovascular events, however the relationship between systolic blood pressure (SPB) during exercise test and stroke is not fully understood. Purpose To evaluate the ability to predict the risk of stroke in patients with HRE in exercise test. Methods Single-center retrospective study of consecutive patients submitted to exercise test from 2012 to 2015 with HRE to stress test. HRE was defined as a peak systolic blood pressure (PSBP) > 210 mmHg in men and > 190 mmHg in women, or a rise of the SBP of 60 mmHg in men or 50 mmHg in women or as a diastolic blood pressure > 90 mmHg or a rise of 10 mmHg. Patient’s demographics, baseline clinical characteristics, vital signs during the stress test and the occurrence of stroke during follow-up were analysed Results We included 458 patients with HRE (76% men, 57.5 ± 10.83 years). The most frequent comorbidities were hypertension (83%), dyslipidaemia (61%), previously known coronary disease (32%), diabetes (28%) and smoking (38%). Atrial fibrillation was present in 5.9% of patients. During a mean follow-up of 60 ± 2 months, the incidence of stroke was 2.1% (n = 8), all with ischemic origin. Considering the parameters analysed on exercise test, only PSBP demonstrated to be an independent predictor of stroke (HR 1.042, CI95% 1.002-1.084, p = 0.039,) with moderate ability to predict stroke (AUC 0.735, p = 0.0016) with a most discriminatory value of 203 mmHg (sensibility 56%, specify 67%). Regarding baseline characteristics, after age, sex and comorbidities adjustment, previously controlled hypertension was found to be an independent protective factor of stroke (OR 4.247, CI 95% 0.05-0.9, p = 0.036) and atrial fibrillation was an independent predictor of stroke occurrence (HR 8.1, CI95% 1.4-46.9, p = 0.018). Atrial fibrillation was also associated with hospitalization of cardiovascular cause and major cardiovascular events occurrence (mortality, coronary syndrome and stroke). Baseline SBP was associated with atrial fibrillation development (p = 0.008). Conclusion According to our results, PSBP during exercise test is an independent predictor of stroke occurrence and should be considered as a potencial additional tool to predict stroke occurrence, particularly in high risk patients. The identification of diagnosed hypertension as a protective factor of stroke may be explained by the cardioprotective effect of antihypertensive drugs.

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