Blood Pressure Lowering Treatment Research Articles

P114 SHORT-TERM EFFECTS OF BLOOD PRESSURE LOWERING DRUGS ON CARDIOVASCULAR EVENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMISED, PLACEBO-CONTROLLED, DOUBLED-BLIND TRIALS

Background and Objective: There remains uncertainty about the short-term effects of blood pressure (BP) lowering drugs on cardiovascular events. This meta-analysis of double-blind, short-term randomised trials, evaluated the effect of BP-lowering drugs on cardiovascular events compared to placebo. Methods: A systematic search was performed in the following databases: MEDLINE, Cochrane Central Register of Controlled Trials, and Epistemonikos. Trials satisfying the following criteria were included: (i) randomized, double-blind placebo-controlled trials of 2-26 weeks published in English language; (ii) adults (age ≥18 years) with hypertension (BP ≥140/90 mmHg) or taking BP-lowering drugs; (iii) intervention: oral fixed dose of BP-lowering drug(s) as either monotherapy or combination therapy from five major classes (angiotensin converting enzyme, angiotensin-II receptor blockers, calcium channel blockers, beta-blockers, and diuretics); (iv) placebo comparator; (v) reported data on cardiovascular events; (vi). The primary outcome was major adverse cardiovascular events (MACE), defined as stroke, transient ischaemic attack (TIA), myocardial infarction, heart failure, angina or coronary revascularisation. Results: 451 trials (93121 participants [mean age 54yrs, 56% males, mean follow-up 8 weeks] were included. There was no effect of the intervention compared to placebo on MACE (0.19% versus 0.43%; relative risk [RR] 0.89, 95% CI 0.69-1.14, p=0.35). There was a significant reduction in stroke (0.01% versus 0.05%; RR 0.37 [0.19-0.72]; p<0.001) and TIA (0.001% versus 0.01%; RR 0.26 [0.08-0.82]; p=0.02). Subgroup analysis suggested combination therapy provided the most benefit in stroke reduction (RR 0.21 [0.04-1.01], p=0.05), but benefits were observed across all anti-hypertensive groups for TIA outcomes. There were no between group differences in all-cause or cardiovascular mortality, myocardial infarction, heart failure hospitalization, angina or coronary secularization. Conclusions: This meta-analysis of placebo-controlled RCTs demonstrated reduced stroke and TIA events with BP-lowering drugs even at short-term follow up. These findings suggest BP lowering treatment should be initiated as soon as possible in at risk individuals because even 8 weeks of treatment can significantly reduce the risk of stroke/TIA.

IMPROVEMENT OF RENAL HAEMODYNAMICS AND ECHOCARDIOGRAPHIC PARAMETERS IN PHARMACOLOGICAL CONTROLLED HYPERTENSIVES

Objective: A study was carried out to evaluate the influence of blood pressure lowering treatment with combined doses of olmesartan plus amplodipina compared with those of either drug at a single dose level. Design and method: By double-blind, three-way crossover study (balanced Latin square design) in 102 subjects (mean age 51.9 +/- 7.42 years) with essential hypertension we used Olmesartan 40 mg plus Amplodine 5 mg compared with those of either drug at a single and higher dose level (40 or 10 mg daily, respectively). Left ventricular mass and function were evaluated by M-B mode echocardiography, renal function by glomerular filtration rate (GFR) and by serum and 24-h urinary Na+ and K+ during wash-out period and after 24 weeks of treatment. Results: The supine blood pressure for subjects given placebo was 171/103 mmHg. After 24 weeks of treatment, systolic and diastolic supine blood pressure were significantly lower with 40 mg iolmesartan plus 5 mg amplodipine (134/84 mmHg) than with 10 mg amplodipine (137/84 mmHg) or with 40 mg olmesartan (144/85 mmHg). Left ventricular posterior wall and septal thickness were significantly and similarly reduced in all groups. Left ventricular systolic and diastolic end diameters were not significantly changed. Left ventricular mass (LVM) was significantly reduced in Olmesartan plus Amplodipine group and Olmesartan group. GFR was not significantly altered. The 24-h urinary Na+ significantly increased with olmesartan, more so than amplodipine. The combination was tolerated better than either monotherapy. We observed no clinically significant changes in laboratory variables including blood lipoproteins. Conclusions: The combination of olmesartan plus amplodipina reduced blood pressure more effectively and was better tolerated than other drug alone. All three groups showed similar changes in echocardiographic indices and no change in renal function.

ACUTE EXERCISE-INDUCED INFLAMMATORY AND THROMBOTIC RESPONSE IN HYPERTENSIVE PATIENTS

Objective: Vigorous physical activity may acutely trigger the onset of an acute coronary syndrome especially in sedentary persons with established cardiovascular risk factors such as arterial hypertension. The rupture of an inflamed coronary plaque and the activation of the coagulation cascade are the main underlying mechanisms. The present study aimed to determine the effect of acute exercise on the inflammatory and thrombotic response in patients with arterial hypertension as compared to normotensive peers. Design and method: After excluding patients with any inflammatory or/and coronary artery disease, a total of 60 non-treated hypertensive patients and 65 normotensive individuals underwent a maximal treadmill exercise testing. Blood samples were drawn at rest and immediately after peak exercise. High-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), white blood cell (WBC), interleukin-6 (IL-6), and total fibrinogen (TF) levels, as well as plasminogen activator inhibitor-1 (PAI-1) activity were measured. Results: All biomarkers increased with exercise, except PAI-1, which decreased (P<0.05 for the change between resting and peak exercise for all biomarkers). The normotensive group had less marked (P<0.05) exercise-induced changes than the hypertensive group in hsCRP (7.7 vs. 8.6%), SAA (5.6 vs. 11.9%), WBC (45.0 vs. 51.7%), and PAI-1 (-17.3 vs. -20.1%) and a similar (P=NS) change in IL-6 (23.8 vs. 23.0%) and TF (8.5 vs. 8.5%). Conclusions: In conclusion, the acute exercise-induced inflammatory and thrombotic response seems to be more pronounced in non-treated hypertensive patients than in normotensive controls. The effect of blood-pressure lowering treatment on the exercise-induced acute phase response remains to be elucidated.

Effects of an Early Intensive Blood Pressure-lowering Strategy Using Remifentanil and Dexmedetomidine in Patients with Spontaneous Intracerebral Hemorrhage: A Multicenter, Prospective, Superiority, Randomized Controlled Trial.

Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes. A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management.

Baseline high sensitivity C-Reactive Protein predicts incident cardiovascular events and all-cause mortality in the ASCOT Study at 20-years

Abstract Introduction The prediction of future cardiovascular events in those at greatest risk is essential to optimise preventative therapies appropriately and effectively. The value of high sensitivity C-reactive Protein (hsCRP) has been questioned in this regard, and recent studies have suggested the utility of this widely assessed biomarker for predicting future mortality in those presenting with suspected myocardial infarction (MI), however the relationship in stable patients is still debated. Purpose To investigate the role of baseline hsCRP for predicting long-term incident cardiovascular events in hypertensive patients in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), with follow-up extending to 20-years. Methods This ASCOT legacy study reports events after 20-years of the UK participants in the original ASCOT trial. ASCOT was a multicentre randomised trial, randomising patients with hypertension into amlodipine-based or atenolol-based blood pressure-lowering (BPL) treatment. In addition, those with total cholesterol &amp;lt;6.5 mmol/L and no previous lipid-lowering treatment underwent further randomisation to either atorvastatin or placebo as part of the lipid-lowering (LL) arm of ASCOT. We examined outcomes related to hsCRP levels in the LL arm, dichotomously (&amp;lt; or &amp;gt; 2mg/L), in tertiles or continuously, adjusting in Model 1 (age, sex, socio-economic status [years of education] and ethnicity) and Model 2 (Model 1 plus current smoker, body mass index, baseline systolic blood pressure, creatinine, diabetes, history of vascular diseases, history of antihypertensive medication and allocation to BPL and LL). All-cause mortality, non-fatal and fatal MI, total coronary events and procedures and total cardiovascular events were assessed. Results 5,294 participants were included in the final cohort, after exclusion of 3,286 participants in the LL arm (n=8,580) without hsCRP data. There were no substantial differences in baseline characteristics between treatment allocation arms (non-randomised, placebo or atorvastatin). The highest tertile of hsCRP (median [IQR], 6.41 [4.81-10.44]) strongly related to all-cause mortality, withstanding adjustment in both Model 1 (HR 95% CI, 1.38 [1.27-1.53]; p&amp;lt;0.001; p&amp;lt;0.001 for interaction) and Model 2 (HR 1.25 [1.10-1.42]; p&amp;lt;0.001; p&amp;lt;0.001 for interaction). Moreover, the highest hsCRP tertile also related to fatal and non-fatal MI (Model 2 – HR 1.32 [1.05-1.67]; p=0.020; p=0.019 for interaction); total coronary events and procedures (Model 2 – HR 1.27 [1.09-1.47]; p=0.002; p=0.003 for interaction); and total cardiovascular events (Model 2 – HR 1.22 [1.08-1.37]; p=0.001; p=0.001 for interaction). Conclusions This study demonstrates that one hsCRP reading at baseline independently predicts cardiovascular events and all-cause mortality at very long-term follow-up in patients at high-risk for these events, and may help stratify patients into higher risk categories for intensive preventative strategies.

Orthostatic hypotension and orthostatic hypertension are both associated with lower cognitive function: The S.AGES cohort.

Blood pressure (BP) postural changes, both orthostatic hypotension (OHYPO) and orthostatic hypertension (OHYPER) are common in older adults. Few studies have investigated their association with cognition, particularly for OHYPER, an emerging cardiovascular risk factor. We aimed to assess the association between OHYPO, OHYPER and cognition in non-institutionalized older subjects. The S.AGES (Sujets ÂGES, Aged Subjects) cohort followed every 6 months for 3 years non-institutionalized subjects aged ≥65 years without dementia at inclusion, in France. OHYPO and OHYPER were respectively defined as a fall or an increase of ≥20 mmHg in systolic BP and/or ≥10 mmHg in diastolic BP after standing from a sitting position. Cognition was assessed using the Mini-Mental State Examination (MMSE). Linear mixed models were used for the analyses. Among the 3170 subjects included (mean age 78 years, 56% women), 209 (6.5%) had OHYPO and 226 (7.1%) had OHYPER at baseline. After adjustment for demographics, cardiovascular risk factors and disease, seated SBP/DBP and BP lowering treatment, mean MMSE was 0.52 point lower in participants with OHYPER compared to those with normal BP postural changes (β adjusted [95% CI] = -0.52 [-0.96; -0.09], p = 0.02) and 0.50 point lower in participants with OHYPO compared to those with normal BP postural changes (β adjusted [95% CI] = -0.50 [-0.95; -0.06], p = 0.03). Sensitivity analyses showed a dose-response relationship between OHYPO and cognition. Although the absolute differences in MMSE were small, both OHYPO and OHYPER were associated with lower cognition. Orthostatic BP measurements could help identify patients with risk of cognitive impairment. Further studies are needed to assess whether controlling orthostatic BP could be a promising interventional target in preserving cognition among older adults.

BLOOD PRESSURE LOWERING TREATMENT AND BASELINE CARDIOVASCULAR RISK IN PRIMARY PREVENTION: SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED TRIALS

Objective: Blood pressure (BP) lowering is accompanied by reduced cardiovascular (CV) outcomes and death in hypertensive patients. No data are available for the effect of BP lowering in trials stratified according to baseline CV risk according to the SCORE-2 system. Design and method: A systematic review was conducted to identify randomized trials in electronic databases (Pubmed and CENTRAL, years: 1966 to 11/2022) for the effect of BP-lowering treatment against placebo, no treatment or less intense BP reduction on fatal or non-fatal CV outcomes. Selected studies reported outcomes in patients without a history of previous CV disease. In each study, we calculated baseline cardiovascular risk using SCORE-2. Risk ratios (RR) were calculated together with their 95% confidence interval (CI) under the random-effects model. Results: We studied 12 trials with low-to-moderate CV risk, n = 21,192 patients; 13 trials with high risk, n = 66,886; and 29 trials with very high risk, n = 79,061. For a standard SBP/DBP reduction of 10/5 mmHg, the relative risk of the combined outcome of major CV events (i.e., myocardial infarction, stroke, and heart failure) was decreased by 27% (95% CI, 22-35%) in the category of very high-risk patients, and by 10% in the category of high-risk patients (p value for interaction = 0.020). Also, the relative risk reduction of the combined outcome was progressively greater the higher the baseline CV risk (p trend = 0.006). The risk reduction of CV death showed a significant trend from lower to higher baseline CV risk (p trend = 0.036). CV death showed a significant reduction in the high-risk group compared to the low-moderate risk group (p = 0.005), and in the very high-risk group compared to the low-moderate risk group (p = 0.001). Conclusions: The greatest outcome benefit from BP lowering treatment in primary is observed in patients at higher baseline cardiovascular risk, as calculated by the SCORE-2.

GASTROINTESTINAL ANGIONEUROTIC EDEMA AS A CONSEQUENCE OF ANGIOTENSIN – CONVERTING ENZYME INHIBITOR TREATMENT

Objective: To report a case of unusual severe adverse reaction to an angiotensin-converting enzyme inhibitor (ACEI). Design and method: A 33-year-old male with a history of hypertension for 10 years, asthma, and atopy was admitted to a local emergency department due to diffuse abdominal pain with vomiting and diarrhea for about 3 days. A few days earlier, the patient had blood pressure (BP) lowering treatment modified due to suboptimal BP control, with introduction of perindopril. The first ACEI dose was followed by lower abdominal pain, urge to have bowel movement, and difficulty passing stool. 24 hours later, the next dose was followed by severe, gradually increasing, diffuse abdominal pain, nausea, vomiting, and diar-rhea. With signs of peritonitis present on admission, a surgeon suspected an acute abdomen and or-dered abdominal computed tomography (CT) due to unclear etiology. CT showed diffuse infiltrates within the small intestine and its mesentery, with free abdominal fluid but no perforation. The patient was not operated and seen by an internist who suspected gastrointestinal angioneurotic edema related to ACEI. On admission to the medical unit, the patient was moderately unwell, conscious, with BP 185/110 mmHg, HR 128 bpm, SaO2 99% on room air, and no fever. Abdomen examination showed reduced bowel sounds, abdominal guarding, tenderness on palpation, especially in the mid-abdomen, and rebound tenderness. Laboratory tests showed elevated WBC (16,800/mm3) and CRP (19 mg/L). Results: Perindopril was withdrawn, the patient received antihistamines, analgesics, and intravenous fluids, with improvement of the patient's condition and reduction of pain and inflammation markers. Follow-up abdominal CT after 5 days showed resolution of small intestinal edematous lesions. The patient was discharged home in good condition, without abdominal pain, and with good BP control. The final diag-nosis was gastrointestinal angioneurotic edema associated with ACEI treatment. Conclusions: One condition may mimic another and thus unclear clinical presentations require cautious diagnostic and therapeutic decisions. In the presented case, angioneurotic edema following introduction of perin-dopril was unusually located in the gastrointestinal tract and its manifestations imitated an acute abdo-men.

BASELINE DATA OF A 3-YEAR RANDOMIZED CONTROLLED TRIAL ASSESSING THE EFFECTS OF THE REDUCTION OF ANTIHYPERTENSIVE TREATMENT IN NURSING HOME RESIDENTS &gt;80 YO. THE RETREAT FRAIL TRIAL

Objective: Although the benefits of blood pressure (BP) lowering treatments in patients over 80 years with preserved functional status have been shown, the benefits in treated hypertensive patients of this age-group with several co-morbidities and loss of functionality, remain controversial: data from observational studies show rather inverse relationships between BP and prognosis, whereas there is a total lack of interventional trials in these subjects. Design and method: RETREAT FRAIL is a multicenter randomized controlled trial aiming to evaluate the effect of the step-down of antihypertensive medications on all-cause mortality (mean follow-up, 36 months) in nursing home (NHs) residents over 80 years, treated with &gt;1 antihypertensive drug and presenting an SBP&lt;130 mmHg. The only clinical exclusion criterion was an estimated life expectancy &lt;3 months. Enrolled patients were randomized into one of the 2 groups: treatment step-down or control group. In both groups, the follow-up is performed in the NHs every 2 months, including a comprehensive geriatric assessment every 6 months. Results: Between April 2019 and July 2022, 1048 patients (842 women), mean age 90±5, from 108 NHs were randomized (528 step-down and 520 controls). They were receiving at mean 9.4±3.4 different medications including 2.5±0.7 antihypertensive medications. Mean SBP: 118±11mmHg, DBP: 65±10 mmHg and HR: 71±12 bpm. Based on ADL, MMSE, and mobility criteria, 52% had severe loss of autonomy, 32 % partial loss of functionality and autonomy and 16% had preserved autonomy and functionality. No differences were observed for all these parameters between the 2 randomization groups. The 3-year follow-up of this trial will be completed June 2024. Conclusions: Despite the difficulties in NHs dramatically aggravated during the COVID-19 pandemic, we were able to complete the enrolment of the residents and to respect the follow-up protocol. RETREAT FRAIL will be the first randomized trial to provide information concerning the long-term effects of a progressive standardized down-titration of the BP lowering treatment in very old frail patient i.e. those who have so far been completely excluded from clinical trials.

Trends in prevalence, treatment and control of hypertension in 38,825 adults over 36 years in Tromsø prospective study.

Serial blood pressure surveys in cohort studies can inform public health policies to control blood pressure for prevention of cardiovascular diseases. Mean levels of systolic blood pressure (SBP) were collected in six sequential surveys, involving 38,825 individuals aged 30-79 years (51% female), between 1979 and 2015 in the Tromsø Study in Norway. Mean levels of SBP, prevalence of hypertension and use of blood pressure-lowering treatment were estimated by age, sex and calendar year of survey. Age-specific mean levels of SBP in each decade of age increased by 20-25 mmHg in men and 30-35 mmHg in women and the prevalence of hypertension increased from 25% to 75% among adults aged 30-79 years. Among successive cohorts of adults aged 40-49 years at the time of the six surveys between 1979 and 2015, the mean levels of SBP declined by about 10 mmHg and the prevalence of hypertension declined from 46% to 25% in men and from 30% to 14% in women. The proportion of individuals with hypertension who were treated increased sixfold (from 7% to 42%) between 1979 and 2015, and the proportion of adults with hypertension that were successfully controlled also increased sixfold from 10% to 60% between 1979 and 2015. Although this study demonstrated a halving in the age-specific prevalence of hypertension in men and women and a sixfold increase in treatment and control of hypertension, the burden of hypertension remains high among older people in Norway.

Hypertension in pregnancy: challenges in the management

Pregnancy is a cardiovascular and metabolic challenge to the human female body.During pregnancy, systemic vascular resistance and blood pressure decrease, whereas cardiac output and blood volume increase to safeguard an adequate circulation in the utero-placental arterial bed.Hypertensive disorders of pregnancy affect approximately from 5 to 10% of all pregnant women, and are the main contributors of maternal and neonatal morbidity and mortality worldwide. Hypertension in pregnancy includes a wide spectrum of conditions, including pre-eclampsia and eclampsia, pre-eclampsia superimposed on chronic hypertension, chronic hypertension, and gestational hypertension. Endothelial dysfunction, oxidative stress and an exaggerated inflammatory response are features related to hypertensive disorders. To reduce the risk of maternal and foetal complications due to haemodynamic maladaptation, the current management includes rest at home or in the hospital, closes monitoring of maternal and foetal signs and symptoms, early start of antihypertensive therapy, and timely delivery regarding maternal and foetal survival chances. Thresholds to initiate blood pressure lowering treatment during pregnancy are 160 mmHg systole or 110 mmHg diastole. Below these thresholds, treatment must be individualized because current evidence does not support aggressive medical interventions. Alpha-methyldopa and dihydropyridine calcium channel blockers are among the recommended antihypertensives. The major goal is to prevent maternal complications without compromising uteroplacental perfusion and fetal circulation. Before an antihypertensive agent is prescribed, the potential risk to the fetus from intrauterine drug exposure should be carefully reviewed. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 186

Prediction of the 10-year risk of atherosclerotic cardiovascular disease in the Korean population.

Proper risk assessment is important for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, no validated risk prediction tools are currently in use in Korea. This study sought to develop a 10-year risk prediction model for incident ASCVD. Using the National Sample Cohort of Korea, 325,934 subjects aged 20-80 years without previous ASCVD were enrolled. ASCVD was defined as a composite of cardiovascular death, myocardial infarction, and stroke. The Korean atherosclerotic cardiovas cular disease risk prediction (K-CVD) model was developed separately for men and women using the development dataset and validated in the validation dataset. Furthermore, the model performance was compared with the Framingham risk score (FRS) and pooled cohort equation (PCE). Over 10 years of follow-up, 4,367 ASCVD events occurred in the overall population. The predictors of ASCVD included in the model were age, smoking status, diabetes, systolic blood pressure, lipid profiles, urine protein, and lipid-lowering and blood pressure-lowering treatment. The K-CVD model had good discrimination and strong calibration in the validation dataset (time-dependent area under the curve=0.846; 95% confidence interval, 0.828 to 0.864; calibration χ2=4.73, goodness-of-fit p=0.32). Compared with our model, both FRS and PCE showed worse calibration, overestimating ASCVD risk in the Korean population. Through a nationwide cohort, we developed a model for 10-year ASCVD risk prediction in a contemporary Korean population. The K-CVD model showed excellent discrimination and calibration in Koreans. This population-based risk prediction tool would help to appropriately identify high-risk individuals and provide preventive interventions in the Korean population.

Causal inference with recurrent and competing events.

Many research questions concern treatment effects on outcomes that can recur several times in the same individual. For example, medical researchers are interested in treatment effects on hospitalizations in heart failure patients and sports injuries in athletes. Competing events, such as death, complicate causal inference in studies of recurrent events because once a competing event occurs, an individual cannot have more recurrent events. Several statistical estimands have been studied in recurrent event settings, with and without competing events. However, the causal interpretations of these estimands, and the conditions that are required to identify these estimands from observed data, have yet to be formalized. Here we use a formal framework for causal inference to formulate several causal estimands in recurrent event settings, with and without competing events. When competing events exist, we clarify when commonly used classical statistical estimands can be interpreted as causal quantities from the causal mediation literature, such as (controlled) direct effects and total effects. Furthermore, we show that recent results on interventionist mediation estimands allow us to define new causal estimands with recurrent and competing events that may be of particular clinical relevance in many subject matter settings. We use causal directed acyclic graphs and single world intervention graphs to illustrate how to reason about identification conditions for the various causal estimands based on subject matter knowledge. Furthermore, using results on counting processes, we show that our causal estimands and their identification conditions, which are articulated in discrete time, converge to classical continuous time counterparts in the limit of fine discretizations of time. We propose estimators and establish their consistency for the various identifying functionals. Finally, we use the proposed estimators to compute the effect of blood pressure lowering treatment on the recurrence of acute kidney injury using data from the Systolic Blood Pressure Intervention Trial.

Effects of intensive blood pressure lowering on cerebral ischaemia in thrombolysed patients: insights from the ENCHANTED trial.

Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130-140mm Hg within 1h; maintained for 72h) or guideline-recommended (systolic target <180mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30,2018. All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24-36h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24-36h. Mean achieved systolic blood pressures over 1-24h were 141mm Hg and 149mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24-36h (0.3 [IQR 0.0-16.6] in the intensive group and 0.9 [0.0-12.5] in the guideline group; log Δmean-0.17, 95% CI-0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Intensive blood pressure lowering treatment to a systolic target <140mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Optimizing cardiovascular risk assessment and registration in a developing cardiovascular learning health care system: Women benefit most.

Since 2015 we organized a uniform, structured collection of a fixed set of cardiovascular risk factors according the (inter)national guidelines on cardiovascular risk management. We evaluated the current state of a developing cardiovascular towards learning healthcare system-the Utrecht Cardiovascular Cohort Cardiovascular Risk Management (UCC-CVRM)-and its potential effect on guideline adherence in cardiovascular risk management. We conducted a before-after study comparing data from patients included in UCC-CVRM (2015-2018) and patients treated in our center before UCC-CVRM (2013-2015) who would have been eligible for UCC-CVRM using the Utrecht Patient Oriented Database (UPOD). Proportions of cardiovascular risk factor measurement before and after UCC-CVRM initiation were compared, as were proportions of patients that required (change of) blood pressure, lipid, or blood glucose lowering treatment. We estimated the likelihood to miss patients with hypertension, dyslipidemia, and elevated HbA1c before UCC-CVRM for the whole cohort and stratified for sex. In the present study, patients included up to October 2018 (n = 1904) were matched with 7195 UPOD patients with similar age, sex, department of referral and diagnose description. Completeness of risk factor measurement increased, ranging from 0% -77% before to 82%-94% after UCC-CVRM initiation. Before UCC-CVRM, we found more unmeasured risk factors in women compared to men. This sex-gap resolved in UCC-CVRM. The likelihood to miss hypertension, dyslipidemia, and elevated HbA1c was reduced by 67%, 75% and 90%, respectively, after UCC-CVRM initiation. A finding more pronounced in women compared to men. In conclusion, a systematic registration of the cardiovascular risk profile substantially improves guideline adherent assessment and decreases the risk of missing patients with elevated levels with an indication for treatment. The sex-gap disappeared after UCC-CVRM initiation. Thus, an LHS approach contributes to a more inclusive insight into quality of care and prevention of cardiovascular disease (progression).

Genetically Predicted Differences in Systolic Blood Pressure and Risk of Cardiovascular and Noncardiovascular Diseases: A Mendelian Randomization Study in Chinese Adults.

Mendelian randomization studies of systolic blood pressure (SBP) can assess the shape and strength of the associations of genetically predicted differences in SBP with major disease outcomes and are less constrained by biases in observational analyses. This study aimed to compare the associations of usual and genetically predicted SBP with major cardiovascular disease (CVD) outcomes, overall and by levels of SBP, age, and sex. The China Kadoorie Biobank involved a 12-year follow-up of a prospective study of 489 495 adults aged 40 to 79 years with no prior CVD and 86 060 with genetic data. Outcomes included major vascular events (59 490/23 151 in observational/genetic analyses), and its components (ischemic stroke [n=39 513/12 043], intracerebral hemorrhage [7336/5243], and major coronary events [7871/4187]). Genetically predicted SBP used 460 variants obtained from European ancestry genome-wide studies. Cox regression estimated adjusted hazard ratios for incident CVD outcomes down to usual SBP levels of 120 mm Hg. Both observational and genetic analyses demonstrated log-linear positive associations of SBP with major vascular event and other major CVD types in the range of 120 to 170 mm Hg. Consistent with the observational analyses, the hazard ratios per 10 mm Hg higher genetically predicted SBP were 2-fold greater for intracerebral hemorrhage (1.71 [95% CI, 1.58-1.87]) than for ischemic stroke (1.37 [1.30-1.45]) or major coronary event (1.29 [1.18-1.42]). Genetic analyses also demonstrated 2-fold greater hazard ratios for major vascular event in younger (1.69 [95% CI, 1.54-1.86]) than in older people (1.28 [1.18-1.38]). The findings provide support for initiation of blood pressure-lowering treatment at younger ages and below the conventional cut-offs for hypertension to maximize CVD prevention, albeit the absolute risks of CVD are far greater in older people.

S-10-2: OPTIMAL BLOOD PRESSURE TARGET TO PREVENT SEVERE HYPERTENSION IN PREGNANCY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective: Severe hypertension in pregnancy is a hypertensive crisis that requires urgent and intensive care due to its high maternal and fetal mortality. However, there still remain some discrepancies between guidelines in a target blood pressure to prevent severe hypertension in pregnancy. This study aimed to find the optimal blood pressure (BP) levels to prevent severe hypertension in pregnant women with nonsevere hypertension. Design and method: We searched Ovid MEDLINE and the Cochrane Library to identify all randomized controlled trials, which compared effects of antihypertensive drugs and placebo/no treatment or more intensive and less intensive BP-lowering treatments on adverse maternal and fetal pregnancy outcomes among pregnant women with nonsevere hypertension. A random effects model meta-analysis was performed to estimate the pooled risk ratio (RR) and 95% confidence interval (CI) for the outcomes. Results: Forty RCTs with 6355 patients were included in this study. BP lowering treatment significantly prevented severe hypertension (RR, 0.46; 95% CI, 0.37 to 0.56), preeclampsia (RR, 0.82; 95% CI, 0.69 to 0.98), severe preeclampsia (RR, 0.38; 95% CI, 0.17 to 0.84), placental abruption (RR, 0.52; 95% CI, 0.32 to 0.86), and preterm birth (before 37 weeks; RR, 0.81; 95% CI, 0.71 to 0.93), while the risk of small for gestational age infants was increased (RR, 1.25; 95% CI, 1.02 to 1.54). An achieved systolic blood pressure (SBP) of lower than 130 mmHg reduced the risk of severe hypertension to nearly one-third compared with an achieved SBP of 140 mmHg or higher, with a significant interaction of the BP levels achieved with BP lowering therapy. There was no significant interaction between BP lowering treatment and the subtypes of hypertensive disorders of pregnancy, including gestational hypertension, preeclampsia, and chronic hypertension. Conclusions: BP lowering treatment aimed at a SBP of lower than 130 mmHg and accompanied by careful monitoring of fetal growth might be recommended to prevent severe hypertension among pregnant women with nonsevere hypertension.

DB-2-3: ANTIHYPERTENSIVE STRATEGIES IN END-OF LIFE OLD PATIENTS (PRO/CON SESSION)

High blood pressure (BP) especially systolic BP is very common in older persons and is associated with considerable morbidity and mortality. Evidence from a limited number of clinical studies indicates that people 80+ y.o. can get significant benefits from BP lowering treatments and that targeting SBP &lt; 140 mmHg reduces morbidity and mortality. However, these clinical studies excluded patients with high frailty and severe alteration of functionality/autonomy. Indeed, in subjects with this clinical profiles, observational data indicate that low SBP is associated with higher morbidity and mortality particularly in those with antihypertensive medication and multiple other drug regimens. These observations made in very altered or end-of-life patients by several clinical research groups should be taken into account by the clinicians, and therefore deprescription i.e. reduction of the antihypertensive treatment, should be considered in presence of very low SBP levels (&lt;130mmHg). However, this approach should be viewed with great caution: firstly, observational studies provide weak evidence and therefore further data are needed from controlled clinical trials in very old patients with the health condition and of autonomy status described above, i.e. people who have been systematically excluded from clinical trials so far. Second, deprescribing should be done gradually, taking into account comorbidities and patient preferences. Finally, in these patients, emphasis should be given to the quality of life and symptoms relief when choosing therapeutic strategies. Collaboration between hypertension specialists, geriatricians and clinical pharmacists is a key issue in this perspective.

DB-2-2: STARTING ANTIHYPERTENSIVE TREATMENT WITH COMBINATION THERAPY: CON SIDE OF THE ARGUMENT

The 2018 ESC/ESH and the 2020 ISH guidelines for the management of hypertension proposed that initial combination therapy with two antihypertensive agents in a single-pill combination (SPC) is preferred in most patients in need of blood-pressure (BP) lowering treatment and should replace the long-standing concept of starting treatment with a single agent, rotating through antihypertensive drug classes, and next moving towards combining drug classes. The 2019 Japanese guidelines took a more balanced approach in formulating their recommendation for the use of SPCs. The Japanese document states that when a systolic/diastolic BP decrease of 20/10 mmHg is targeted, combination therapy is an option to be considered in starting treatment. However, the Japanese guideline also recommended that if a drug shows only a weak depressor effect or is poorly tolerated, it must be replaced by another agent with a different mechanism of action, implying that starting with SPCs is not mandatory. By moving SPCs forward as the initial BP lowering strategy, the ESC/ESH and ISH guideline committees overlooked several vested principles in hypertension management: (i) understanding the pathophysiology of hypertension; (ii) prioritizing evidence from randomized clinical trials above observational studies and expert opinion; and (iii) giving consideration to the cost-effectiveness of antihypertensive drug treatment and the sustainability of health care. This article addresses these points. Sources of information included: (i) guidelines issued by European, American, International, British and Japanese Expert Committees, published between 1999 and 2020; (ii) a PubMed search with as terms in the abstract or title hypertension combined with fixed combination OR hypertension combined with single and costs; (iii) the placebo-controlled trials of antihypertensive drug treatment; (iv) three randomized controlled trials of usual versus intensive BP control; and (v) the retail costs of antihypertensive drugs. We propose that starting antihypertensive therapy in treatment-naive hypertensive patients might be based on a few simple principles. First, use antihypertensive drugs with different modes of action. Second, use antihypertensive agents with a long duration of action based on their molecular structure, so-called forgiving drugs, rather than extended-release dosage formulations. Third, titrate each drug to the highest dose that does not produce adverse effects. Fourth, include a thiazide in the drug combination. Finally, once the right combination has been found by rotating through and combining drug classes as well as the timing of dosing, stimulate adherence by reducing the pill load by prescribing of SPCs including 2 or 3 antihypertensive agents in adjustable doses.

S-02-4: BLOOD PRESSURE, ANTIHYPERTENSIVES AND DEMENTIA, AN INDIVIDUAL PATIENT DATA META-ANALYSIS

Background: A large number of observational studies show links between hypertension or higher blood pressure (BP) in mid-life and an increased risk of later dementia. In late life, the evidence is more mixed with some studies indicating higher BP is associated with higher dementia risk and some finding U-shaped associations between BP and incident dementia in older age. The clinical trials of antihypertensives to lower BP have shown largely negative results when examining the relationship between antihypertensive use and incident dementia. However, the trials were designed to examine cardiovascular endpoints and several stopped early for cardiovascular benefit thus limiting their statistical power and ability to accrue dementia outcomes. To overcome some of these limitations a pooled individual patient data meta-analysis of five seminal double-blind placebo-controlled randomised trials was undertaken to better define the effects of BP lowering treatment for the prevention of dementia. Methods: The double-blind placebo-controlled randomised antihypertensive trials; Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), Hypertension in the Very Elderly Trial (HYVET), Perindopril Protection Against Recurrent Stroke Study (PROGRESS), Systolic Hypertension in the Elderly Program (SHEP), and SYSTolic Hypertension in EURope Trial (SYST-EUR) were merged into a single database. Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, baseline Mini-Mental State Exam (MMSE) score and presence of prior stroke. Results: All trials were balanced across randomised groups. The combined sample was n = 28,008 recruited from 20 countries. Mean baseline age was 69.1 (Standard Deviation 9.3). Median follow-up 4.3 years. Incident dementia occurred in 2.9% and 3.3% of those in active and placebo groups, respectively. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age, sex, baseline systolic BP, baseline MMSE or prior stroke. Discussion: This is the first single-stage individual patient data meta-analysis from double-blind placebo-controlled clinical trials. It provides high-quality evidence to support the benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential benefit from antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia.