Blood Pressure Lowering Therapy Research Articles

Stroke : Highlights of Selected Articles

<i>Stroke</i> : Highlights of Selected Articles

Benefit of Blood Pressure Control in Diabetic Patients.

The coexistence of arterial hypertension and diabetes represents a devastating partnership for cardiovascular health. Thus, blood pressure and blood glucose control are essential therapeutic goals to reduce cardiovascular risk and other diabetes-related endpoints in these patients. The major benefit of blood pressure lowering in diabetes comes from a marked reduction of cardiovascular and renal endpoints. New target blood pressure values to achieve maximum cardiovascular and renal protection will be discussed. In addition to the reduction of macrovascular endpoints, blood pressure lowering therapy in diabetic patients has also been discussed to improve microvascular diseases during diabetes, in particular microalbuminuria or diabetic retinopathy. However, current clinical trial evidence is less robust than for macrovascular disease. Clinical studies showed controversial results, and will be discussed. Finally, new data from the ADVANCE-ON study about the long-term, sustained benefit of blood pressure lowering in hypertensive, diabetic patients has been recently published, and will be evaluated in the context of previous evidence. In summary, the present article will discuss selected new topics in the field of hypertension and diabetes focusing on the benefits achieved by blood pressure lowering in these patients.

Effects of an Antihypertensive Combination Based on the Long-Acting Calcium Channel Blocker Benidipineon Vascular and Renal Events

Background: The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared three regimens based on the calcium channel blocker (CCB) benidipine.Hypertensive outpatients between the ages of 40–85 years who did not achieve the target blood pressure (<140/90 mmHg) with 4 mg/day of benidipine received an additional angiotensin receptor blocker (ARB), β-blocker, or thiazide. The analysis included 3,293 patients who received an ARB (n = 1,110), β-blocker (n = 1,089), or thiazide (n = 1,094) in addition to benidipine and were followed for a median of 3.61 years. The COPE trial demonstrated a significantly higher incidence of hard cardiovascular composite endpoints and of fatal or non-fatal strokes in the benidipine-β-blocker group than in the benidipine-thiazide group (P = 0.0201, P = 0.0109, respectively). Objective and Methods: In this pre-specified sub-analysis, we further evaluated treatment effects of the three benidipine-based regimens on vascular and renal events. Results: We observed a total of 10 vascular events(0.8 per 1,000 person-years) including 9 cases ofperipheral artery disease (0.8 per 1,000 person-years) and 1 aortic dissection (0.1 per 1,000 person-years). We also observed a total of 7 renal events (0.6 per 1,000 person-years).Few differences were observed among the three treatment groups regarding vascular and renal events (vascular events, P = 0.29; renal events, P = 0.16, Log-rank test). Conclusions: This sub-analysis of the COPE trial demonstrated that blood pressure-lowering therapy with benidipine combined with an ARB, β-blocker, or thiazide diuretic was similarly effective in the prevention of vascular and renal events in hypertensive outpatients.

Abstracts From the 36th Annual Scientific Meeting of the HBPRCA

### CONTRIBUTION OF THE AREA POSTREMA TO THE INCREASED CARDIAC SYMPATHETIC NERVE ACTIVITY IN OVINE HEART FAILURE Abukar Y, Ramchandra R, May CN The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia Background : Heart failure (HF) is associated with an increase in cardiac sympathetic nerve activity (CSNA), which is directly linked to mortality in HF patients. The mechanisms responsible for the elevated CSNA remain unclear. Previous studies indicate that the area postrema (AP), a circumventricular organ in the brainstem, plays a role in the control of sympathetic nerve activity. We hypothesized that the elevated CSNA in HF is mediated by the AP and lesioning this region would reduce the increased CSNA in sheep with HF. Aims : To determine the effect of sham lesion or lesion of the AP on CSNA and hemodynamics in conscious sheep with HF. Methods : Studies were conducted in 2 groups of sheep with pacing-induced HF: sham (n=6) and AP lesion (n=6) sheep. Mean arterial blood pressure (MAP), heart rate (HR) and CSNA were recorded simultaneously in conscious sheep at least 4 days after surgery. Results : Heart failure was associated with a significant decrease in ejection fraction (from 74±2 % to 38±1 %; P<0.001), which was similar in both groups. There was a significant reduction in CSNA burst incidence in the AP lesion group compared with the sham group (45±10 and 89±3 bursts/100 heartbeats, respectively; P<0.01). Conclusions : In sheep with HF, the group with lesion of the AP had a significantly lower CSNA compared with the sham group. These data suggest that the AP plays a role in setting the detrimental high levels of CSNA in HF. ### G PROTEIN-COUPLED ESTROGEN RECEPTOR SIGNALING IMPROVES STROKE OUTCOME IN FEMALE MICE Broughton BRS, Jansen GL, Sobey CG Department of Pharmacology, Monash University, Clayton, Victoria, Australia Background: Estrogen has been assumed to provide neuroprotection following stroke entirely via classical estrogen receptors. Interestingly, there is recent evidence that activation of a novel G …

Effects of blood pressure reduction in mild hypertension: a systematic review and meta-analysis.

Effects of blood pressure reduction in persons with grade 1 hypertension are unclear. To investigate whether pharmacologic blood pressure reduction prevents cardiovascular events and deaths in persons with grade 1 hypertension. Trials included in the BPLTTC (Blood Pressure Lowering Treatment Trialists' Collaboration) and trials identified from a previous review and electronic database searches. Patients without cardiovascular disease with blood pressures in the grade 1 hypertension range (140 to 159/90 to 99 mm Hg) who were randomly assigned to an active (antihypertensive drug or more intensive regimen) or control (placebo or less intensive regimen) blood pressure-lowering regimen. Individual-patient data from BPLTTC trials and aggregate data from other trials were extracted. Risk of bias was assessed for all trials. Individual-patient data involved 10 comparisons from trials where most patients had diabetes, and aggregate data involved 3 comparisons from trials of patients without diabetes. The average blood pressure reduction was about 3.6/2.4 mm Hg. Over 5 years, odds ratios were 0.86 (95% CI, 0.74 to 1.01) for total cardiovascular events, 0.72 (CI, 0.55 to 0.94) for strokes, 0.91 (CI, 0.74 to 1.12) for coronary events, 0.80 (CI, 0.57 to 1.12) for heart failure, 0.75 (CI, 0.57 to 0.98) for cardiovascular deaths, and 0.78 (CI, 0.67 to 0.92) for total deaths. Results were similar in secondary analyses. Withdrawal from treatment due to adverse effects was more common in the active groups. Blood pressure reductions and numbers of events were small. Blood pressure-lowering therapy is likely to prevent stroke and death in patients with uncomplicated grade 1 hypertension. Swedish Heart-Lung Foundation, Swedish Research Council, Australian Research Council, and National Health and Medical Research Council of Australia.

Predicting the effects of blood pressure-lowering treatment on major cardiovascular events for individual patients with type 2 diabetes mellitus: results from Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation.

Blood pressure-lowering treatment reduces cardiovascular risk in patients with diabetes mellitus, but the effect varies between individuals. We sought to identify which patients benefit most from such treatment in a large clinical trial in type 2 diabetes mellitus. In Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) participants (n=11 140), we estimated the individual patient 5-year absolute risk of major adverse cardiovascular events with and without treatment by perindopril-indapamide (4/1.25 mg). The difference between treated and untreated risk is the estimated individual patient's absolute risk reduction (ARR). Predictions were based on a Cox proportional hazards model inclusive of demographic and clinical characteristics together with the observed relative treatment effect. The group-level effect of selectively treating patients with an estimated ARR above a range of decision thresholds was compared with treating everyone or those with a blood pressure >140/90 mm Hg using net benefit analysis. In ADVANCE, there was wide variation in treatment effects across individual patients. According to the algorithm, 43% of patients had a large predicted 5-year ARR of ≥1% (number-needed-to-treat [NNT5] ≤100) and 40% had an intermediate predicted ARR of 0.5% to 1% (NNT5=100-`200). The proportion of patients with a small ARR of ≤0.5% (NNT5≥200) was 17%. Provided that one is prepared to treat at most 200 patients for 5 years to prevent 1 adverse outcome, prediction-based treatment yielded the highest net benefit. In conclusion, a multivariable treatment algorithm can identify those individuals who benefit most from blood pressure-lowering therapy in terms of ARR of major adverse cardiovascular events and may be used to guide treatment decisions in individual patients with diabetes. http://www.clinicaltrials.gov. Unique identifier: NCT00145925.

Reversibility of left ventricular mechanical dysfunction in patients with hypertensive heart disease.

Prior studies indicate that hypertension is associated with mechanical systolic dysfunction, even in the presence of a normal ejection fraction, but whether this cardiac dysfunction may be ameliorated by antihypertensive treatment is unknown. To test the hypothesis that mechanical systolic dysfunction in hypertension may respond to blood pressure-lowering therapy, we studied 182 patients with uncontrolled hypertension who underwent a 24-week trial of intensive versus standard antihypertensive therapy (titrated to a goal SBP <130 versus <140 mmHg) and had both baseline and follow-up echocardiography. We examined changes in left ventricular systolic function, reflected by systolic global longitudinal strain (GLS), in the entire cohort and in the subset of patients with systolic dysfunction at baseline (defined as GLS >-15%). Despite all patients having a preserved left ventricular ejection fraction (≥50%), almost a third (32%) had mechanical systolic dysfunction at baseline. In the total sample, GLS significantly improved in response to antihypertensive therapy (-16.8 ± 3.8 to -18.7 ± 3.4%; P < 0.0001), and this improvement was especially evident in patients with baseline dysfunction (13.1 ± 2.2 to -17.0 ± 2.9%; P < 0.0001). Improvement in GLS was associated with lower BMI (P = 0.015) and was greater in women than in men (P = 0.003). Although uncorrelated with blood pressure change, GLS improvement was related to having received high doses of antihypertensive therapy during the study (P = 0.040). In patients with hypertensive heart disease and normal left ventricular ejection fraction, abnormalities in left ventricular mechanical systolic function can be ameliorated in the setting of targeted antihypertensive treatment.

Strengthening Cardiovascular Disease Prevention in Remote Indigenous Communities in Australia's Northern Territory

In 2012 the Northern Territory Department of Health commenced the Chronic Conditions Management Model - strengthening cardiovascular disease prevention in remote Indigenous communities. Interventions included providing regular functional reporting and decision support to frontline primary health care teams. Longitudinal (three monthly) clinical audits of cardiac prevention services were undertaken between 2012 and 2014. Our primary outcome was population coverage of cardiovascular risk assessment for Indigenous clients aged 20 years and older. Secondary outcomes for those identified at high risk were (i) assessment of modifiable cardiac risk factors, (ii) prescription of risk lowering medications, and (iii) the proportion of high risk clients achieving clinical targets for risk reduction. As of August 2014, 7266 clients have had their cardiovascular risk assessed, improving population coverage from 23% in mid June 2012 to 58.5%. For 2586 high risk clients, 1728 (67%) and 1416 (55%) were prescribed blood pressure and lipid lowering therapy and for those clinically re-assessed, 1366 (57%) and 989 (40%) were achieving clinical targets for risk reduction for blood pressure and lipids respectively. Functional reporting and decision support was associated with improvement in cardiovascular risk assessment coverage and a sustained proportion of high risk clients achieving clinical targets for cardiovascular risk reduction. Further intervention-based research is required to close the gap between identification of risk and risk reduction.

Amino-terminal-pro-B-type natriuretic peptide levels and low diastolic blood pressure: potential relevance to the diastolic J-curve.

There is debate whether the J-curve relationship between cardiac event risk and DBP is because of inherent cardiac risk or is a consequence of blood pressure (BP) lowering therapy. We examined the association between the cardiovascular risk marker amino-terminal-pro-B-type natriuretic peptide (NT-proBNP) and DBP in 1781 women and 2211 men aged at least 60 years with one or more cardiovascular risk factors; exclusion criteria were known heart failure or cardiac abnormality on a cardiac imaging study. The lowest median serum NT-proBNP levels were for DBP 85-89 mmHg for both women and men. DBP less than 70 mmHg in women and less than 80 mmHg in men was associated with higher NT-proBNP levels than the levels at DBP 85-89 mmHg, and this relationship was present for those with SBP equal to or less than 140 and SBP greater than 140 mmHg. In conditional logistic regression models, the association of elevated NT-proBNP levels with low DBP in women was no longer statistically significant after adjustment for age, ischaemic heart disease (IHD), pulse rate, atrial fibrillation, haemoglobin and glomerular filtration rate, whereas the association in men was no longer statistically significant after adjustment for age and IHD. By contrast, the association between elevated NT-proBNP levels and low DBP remained statistically significant after adjustment for the number of antihypertensive drug classes alone or together with all antihypertensive drugs, including β-blocker therapy. There was a J-curve relationship between the cardiovascular risk marker NT-proBNP and DBP that was explained by the clinical variables and not by the BP-lowering therapy.

Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes

BackgroundIn the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up.MethodsWe invited surviving participants, who had previously been assigned to perindopril–indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events.ResultsThe baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure–lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure–lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.ConclusionsThe benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure–lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.)

Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data

We aimed to investigate whether the benefits of blood pressure-lowering drugs are proportional to baseline cardiovascular risk, to establish whether absolute risk could be used to inform treatment decisions for blood pressure-lowering therapy, as is recommended for lipid-lowering therapy. This meta-analysis included individual participant data from trials that randomly assigned patients to either blood pressure-lowering drugs or placebo, or to more intensive or less intensive blood pressure-lowering regimens. The primary outcome was total major cardiovascular events, consisting of stroke, heart attack, heart failure, or cardiovascular death. Participants were separated into four categories of baseline 5-year major cardiovascular risk using a risk prediction equation developed from the placebo groups of the included trials (<11%, 11-15%, 15-21%, >21%). 11 trials and 26 randomised groups met the inclusion criteria, and included 67,475 individuals, of whom 51,917 had available data for the calculation of the risk equations. 4167 (8%) had a cardiovascular event during a median of 4·0 years (IQR 3·4-4·4) of follow-up. The mean estimated baseline levels of 5-year cardiovascular risk for each of the four risk groups were 6·0% (SD 2·0), 12·1% (1·5), 17·7% (1·7), and 26·8% (5·4). In each consecutive higher risk group, blood pressure-lowering treatment reduced the risk of cardiovascular events relatively by 18% (95% CI 7-27), 15% (4-25), 13% (2-22), and 15% (5-24), respectively (p=0·30 for trend). However, in absolute terms, treating 1000 patients in each group with blood pressure-lowering treatment for 5 years would prevent 14 (95% CI 8-21), 20 (8-31), 24 (8-40), and 38 (16-61) cardiovascular events, respectively (p=0·04 for trend). Lowering blood pressure provides similar relative protection at all levels of baseline cardiovascular risk, but progressively greater absolute risk reductions as baseline risk increases. These results support the use of predicted baseline cardiovascular disease risk equations to inform blood pressure-lowering treatment decisions. None.

High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis

ObjectivesNon-adherence to therapy is an important cause of suboptimal blood pressure control but few practical tools exist to accurately and routinely detect it. We used a simple urine-based assay to...

Poststroke Cognitive Decline Not Reduced by Aggressive Blood Pressure Lowering or Dual Antiplatelet Therapy

Poststroke Cognitive Decline Not Reduced by Aggressive Blood Pressure Lowering or Dual Antiplatelet Therapy

Personalized cardiovascular disease prevention by applying individualized prediction of treatment effects

Large-scale randomized clinical trials have established the efficacy of cholesterol-lowering, blood pressure-lowering, and anti-platelet therapy to prevent cardiovascular diseases. A challenge for clinicians is to apply group-level evidence from these trials to individual patients. Trials typically report a single treatment effect estimate which is the average effect of all participants, comprising patients who respond poorly, intermediately, and well. Clinicians would preferably make patient-tailored treatment decisions. Therefore, one would require an estimate of an individual patient's response to therapy. Although not yet widely recognized, trials contain this type of information. In this paper, we show how available information from landmark trials can be translated to an individual 'treatment score' through the use of multivariable therapeutic prediction models. These models provide an individual estimate of the absolute risk reduction in cardiovascular events given the specific combination of multiple clinical characteristics of a patient under care. Based on this individualized treatment estimate and metrics such as the individual number-needed-to-treat, clinicians together with their patients can decide whether drug treatment or what treatment intensity is worthwhile. Selective treatment of those who can anticipate the greatest benefit and the least harm on an individualized basis could reduce the number of unnecessary treatments and healthcare costs beyond that currently achievable by subgroup analyses based on single patient characteristics.

Abstract 180: The Relation of Timing and Degree of Blood Pressure Control with Hematoma Growth - Secondary Analysis of The Interact2 Trial

Background: Acute blood pressure (BP) lowering therapy has shown clinical benefit in patients with acute intracerebral hemorrhage (ICH), but the effect of timing and degree of BP control on ICH growth has received less study. Methods: Among the INTERACT2 participants (N=2839) with acute ICH allocated either to intensive BP lowering therapy (IT, systolic target &lt;140mmHg) or standard BP treatment (ST), CT brain imaging at baseline and 24 hours were centrally analysed in a subset of 491 (34%) in the IT and 473 (34%) in the ST groups. Results: Absolute mean ICH growth was lower in patients reaching BP target in &lt;1h from randomization (1.7ml), as compared to those reaching target in 1-6h (4.2ml), and &gt;6h (4.6ml, p=0.04). Hematoma growth was particularly high (14.4ml, 95%CI:10.0-18.8) in patients admitted with systolic BP&gt;160mmHg who achieved &lt;10mmHg systolic BP lowering over 24h, as compared to those achieving 10-20mmHg (3.7ml, 95%CI:0.3-7.1) or 20-30mmHg BP reduction (2.7ml, 95%CI:1.1-4.3); p&lt;0.01). Patients maintaining target BP at 0-2 measurements over 24h had higher absolute volume increase (3.6ml; 95%CI:1.8-5.4) as compared to those who maintained target BP over 3-4 (1.6ml, 95%CI:-0.3-3.5), or 5-8 measurements (0.4ml, 95%CI:-1.7-2.4; p=0.01). Conclusion: These findings suggest that early and sustained BP control have favorable effects on hematoma growth. This reinforces the principle for patients with acute ICH to receive BP lowering therapy as early as possible and to achieve a lower level of systolic BP for the most favorable outcome.

Abstract W P167: Lacunar Infarction and Hypertensive Intracerebral Hemorrhage-Similarities and Differences of Two Different Clinical Entities of Cerebral Small-Vessel Disease

Introduction: Lacunar infarction (Lac) and hypertensive intracerebral hemorrhage (ICH) are known as cerebral small-vessel disease in which hypertension plays a pivotal role in the development of pathology. However, it is unclear why some patients suffer from cerebral infarction and others bleed. We compared the background of these two groups, and examined differences and similarities between them. Methods: Between February 2008 and January 2013, 1149 patients were admitted to our institution within 1 week after the onset of stroke. A database was prospectively constructed with this consecutive patients’ cohort and data were analyzed retrospectively. Among the patients, 138 had Lac and 109 had ICH. Results: Age, sex, and BMI were not different between the groups. Medication prior to the onset of stroke was more common in Lac than in ICH (77.5% vs. 55.1%; p&lt;0.001). The frequency of antiplatelet therapy, blood pressure-lowering therapy, and lipid-lowering therapy was not different between the groups. Treatment for diabetes mellitus (DM) was significantly more frequent in Lac than in ICH (29.0% vs. 8.3%; p&lt;0.001). Calcification of the aortic arch was significantly more common in Lac than in ICH (62.2% vs. 43.3%; p=0.009). Smoking, past history of stroke, and familial history of stroke were not different between the groups. Left-sided stroke was significantly more common in Lac than in ICH (63.8% vs. 50.4%; p=0.004). On admission, triglycerides, total cholesterol (Chol), HDL-Chol, LDL-Chol, total protein, serum albumin, and blood sugar levels were not different between the groups. HbA1c levels on admission were significantly higher in Lac than in ICH (6.4+/-1.3% vs. 5.9+/-1.0%; p=0.004). Conclusions: Lac and ICH have similar backgrounds. However, left-sided stroke, calcification of the aortic arch, and a medical history of DM are more common in Lac than in ICH patients. HbA1c values on admission are higher in Lac than in ICH patients. This suggests that there are subgroups of Lac in which the pathological process is different from that in ICH. Therefore, endothelial damage induced by DM may play a role in some patients with Lac, and left-sided propensity and a tendency for aortic arch calcification suggest that some aortogenic embolisms may be diagnosed as Lac.

Overview of cardiovascular risk factors in diabetic patients: focus on hypoglycemia, dyslipidemia, body weight and cardiovascular disease

The incidence of type 2 diabetes mellitus continues to grow rapidly, paralleling the overweight and obesity epidemic. Diabetes has long been related to a significant increase in cardiovascular risk profile. Epidemiological studies have documented a 2 to 4-fold increase in cardiovascular mortality and morbidity. Type 2 diabetes is linked to the metabolic syndrome, a cluster of several metabolic risk factors (such as obesity, hypertension and dyslipidemia). Although improved glycemic control has repeatedly been shown to reduce microvascular diabetic complications, uncertainty remains regarding whether any particular glucose-lowering strategy, or specific therapeutic agent, is safe from a cardiovascular standpoint or can actually lower cardiovascular risk. Thus, there remains a strong clinical need for antihyperglycemic drugs that can improve glycemic control without increasing cardiovascular events, which seems to be strictly related to hypoglycemia. The differences between extra-glycemic effects of antidiabetic drugs currently available should be carefully evaluated, thus improving the achievement of therapeutic goals as suggested by national and international guidelines. An ef fective treatment of the concomitant cardiovascular risk factors through cholesterol- and blood pressure-lowering therapies and a weight-control therapeutic approach should also be considered.

Prevention of Decline in Cognition after Stroke Trial (PODCAST): a study protocol for a factorial randomised controlled trial of intensive versus guideline lowering of blood pressure and lipids.

BackgroundStroke is a common cause of cognitive impairment and dementia. However, effective strategies for reducing the risk of post-stroke dementia remain undefined. Potential strategies include intensive lowering of blood pressure and/or lipids.Methods/DesignDesign: multi-centre prospective randomised open-label blinded-endpoint controlled partial-factorial phase IV trial in secondary and primary care.Participants: 100 participants from 30 UK Stroke Research Network sites who are post- ischemic stroke or intracerebral haemorrhage by three to seven months.Interventions - all patients (1:1): intensive versus guideline blood pressure lowering (target systolic < 125 mmHg versus < 140 mmHg).Interventions - ischemic stroke (1:1): intensive versus guideline lipid lowering (target low density lipoprotein-cholesterol (LDL-c) < 1.4 mmol/l versus < 3 mmol/l).Hypotheses: does ‘intensive’ blood pressure lowering therapy and/or ‘intensive’ lipid control reduce cognitive decline and dementia in people with ischemic stroke; and does ‘intensive’ blood pressure lowering therapy reduce cognitive decline and dementia in patients with hemorrhagic stroke.Primary outcome: Addenbrooke’s Cognitive Examination-Revised.Secondary outcomes: feasibility of recruitment and retention of participants, tolerability and safety of the interventions, achieving and maintaining the blood pressure and lipid targets, maintaining differences in systolic blood pressure (> 10 mmHg) and low density lipoprotein-cholesterol (> 1 mmol/l) between the treatment groups, and performing clinic and telephone follow-up of cognition measures.Randomisation: using stratification, minimization and simple randomization.Blinding: participants receive open-label management. Cognition is assessed both unblinded (in clinic) and blinded (by telephone) to treatment. Adjudication of events (dementia, vascular, serious adverse events) is blinded to management.DiscussionThe PODCAST trial is ongoing with 78 patients recruited to date from 22 sites. Outcomes of cognitive impairment and dementia are accruing.Trial registrationISRCTN85562386

Effects of a benidipine-based combination therapy on the risk of stroke according to stroke subtype: the COPE trial

The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine-based therapies when combined with an angiotensin receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke.

Letter by Aries et al Regarding Article, “Autoregulation of Cerebral Blood Flow is Preserved in Primary Intracerebral Hemorrhage”

To the Editor: With interest, we read the recent article of Gould et al1 about computed tomography (CT) perfusion studies in primary intracranial hemorrhage (ICH) patients. In this subanalysis of the Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trail (ICH ADAPT), 20 patients each of whom had 2 CT perfusion scans were selected. Of these, 69% received active blood pressure (BP) lowering therapy in a broad time window after ictus (1.5–72.2 hours).2 After reading the article, certain important issues, unfortunately, remain unclear. First, from the methods section, it is difficult to comprehend how the 20 …