New Recommendations for Hypertension Management Released.


New recommendations published online in the Journal of the American Medical AssociationExternal Link aim to provide guidance on the management of patients with hypertension. More specifically, the recommendations focus on when medication should be started in patients, the best choices for medications to begin treatment; and communicating achievable blood pressure goals to patients.

“Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults,” the report authors note.

The report, written by panel members appointed to the Eighth Joint National Committee, notes there is strong evidence to support treating hypertensive persons aged 60 years or older to a BP goal of less than 150/90 mm Hg and hypertensive persons 30 through 59 years of age to a diastolic goal of less than 90 mm Hg. However, given insufficient evidence in hypertensive persons younger than 60 years for a systolic goal, or in those younger than 30 years for a diastolic goal, the panel recommends a BP of less than 140/90 mm Hg for those groups. “The same thresholds and goals are recommended for hypertensive adults with diabetes or nondiabetic chronic kidney disease (CKD) as for the general hypertensive population younger than 60 years,” the report notes.

In general, the report authors note that the 140/90 mm Hg definition from Joint National Committee 7 “remains reasonable” and recommend that lifestyle interventions be used for everyone with blood pressures in this range. “For all persons with hypertension, the potential benefits of a healthy diet, weight control, and regular exercise cannot be overemphasized,” they said. “These lifestyle treatments have the potential to improve BP control and even reduce medication needs.”

Also in the report, the authors note there is moderate evidence to support initiating drug treatment with an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, or thiazide-type diuretic in the nonblack hypertensive population, including those with diabetes. In the black hypertensive population, including those with diabetes, a calcium channel blocker or thiazide-type diuretic is recommended as initial therapy. Additionally, there is moderate evidence to support initial or add-on antihypertensive therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in persons with CKD to improve kidney outcomes.

Moving forward, the authors point out that an algorithm included as part of the recommendations will facilitate implementation and be useful to busy clinicians. They also suggest that “the strong evidence base of this report be used to inform quality measures for the treatment of patients with hypertension.”

Practice guidelines are traditionally promulgated by the government or by learned medical professional societies. The JAMA paper is a report of a group experts in the field of hypertension, but it does not carry the endorsement of any organized body. Moving forward, these recommendations will be taken into account in the coming year as the ACC/AHA Task Force on Practice Guidelines moves forward with developing the collaborative model to update the national hypertension guidelines in partnership with the National Heart, Lung, and Blood Institute (NHLBI). According to the ACC and the American Heart Association (AHA), once a writing group is appointed, there will be an extensive science and evidence review process, followed by draft recommendations that will undergo a peer and stakeholder review. Once the review process is complete, the ACC/AHA and partnering organizations will publish the guidelines in 2015 for clinicians to follow as the national standard for hypertension prevention and treatment.

The ACC, AHA and the Centers for Disease Control and Prevention released a scientific advisory on the effective approach to hypertension in November that encourages use of enhanced, evidence-based, blood pressure treatment systems for providers, including standardization of protocols and algorithms, incentives for improved performance based on achieving and maintaining patients at blood pressure goals, and technology-facilitated clinical decision support and feedback.

Effects of a Fixed-Dose Combination Strategy on Adherence and Risk Factors in Patients With or at High Risk of CVD.


Importance   Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment.

Objective   To assess whether FDC delivery of aspirin, statin, and 2 blood pressure–lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C).

Design, Setting, and Participants   The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010–July 2011 in India and Europe. The trial follow-up concluded in July 2012.

Interventions   Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002).

Main Outcomes and Measures   Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline.

Results   At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (−2.6 mm Hg; 95% CI, −4.0 to −1.1 mm Hg; P < .001) and LDL-C (−4.2 mg/dL; 95% CI, −6.6 to −1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups.

Conclusions and Relevance   Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C.

 

Source: JAMA

Joint guideline contains new recommendations for diabetes, CVD.


New guidelines on diabetes, prediabetes and CVD unveiled at the ESC Congress 2013 recommend diagnosis using HbA1c, less-strict BP targets and optimal use of revascularization.

The guidelines were developed as a collaboration between the ESC and the European Association for the Study of Diabetes (EASD).

“The growing awareness of the strong biological relationship between diabetes and CVD rightly prompted these two large organizations to collaborate to generate guidelines relevant to their joint interests, the first of which were published in 2007,” the statement reads.

Among the notable updates is the recommendation to use HbA1c for the diagnosis of diabetes. If HbA1c is elevated, the patient is diagnosed with diabetes; if not elevated, patients with CVD should receive an oral glucose tolerance test.

“We have simplified diagnosis because many patients may be disclosed with HbA1c, limiting the numbers who need the lengthier test. But a normal HbA1c does not rule out diabetes in high-risk patients, who need to have an oral glucose tolerance test,” ESC chairperson Lars Rydén, MD, PhD, of the cardiology unit at Karolinska Institute, Sweden, stated in a press release.

The guidelines also simplify CV risk assessment and no longer advocate the use of risk engines. “Risk engines which accumulate risk factors and produce a low-, medium- or high-risk score are less useful for patients with diabetes,” EASD chairperson Peter J. Grant, MD, from the division of cardiovascular and diabetes research at University of Leeds, U.K., stated in the release.

Patients with diabetes are considered at high CV risk. Patients with diabetes and CVD, including MI, angina or peripheral vascular disease, are considered at very high risk for recurrent CVD, according to the release.

Recommendations on revascularization have also changed since the previous guidelines. Medical therapy is now recommended before intervention for patients with stable CAD and no complex coronary lesions. “In former days, we were quick to do coronary interventions, but based on new trial data we now do not advocate bypass surgery and coronaryangioplasty until medical therapy has been tried,” Rydén stated.

Another addition is the recommendation that patients with several or complex coronary artery stenoses should be offered bypass surgery before percutaneous coronary dilatation. This change was based on new trial data that show superior morbidity and mortality with bypass surgery as compared with coronary dilatation, according to the release.

The guidelines also individualize targets for BP and glycemic control. The general BP target for patients with diabetes is <140/85 mm Hg; in the 2007 version, the target was 130/80 mm Hg. In patients with diabetes and kidney disease, the target is <130/85 mm Hg. Stricter BP control is also urged for patients at risk for stroke. Younger patients with a recent diagnosis of diabetes and no CVD history have lower recommended glycemic control targets, while those who are older and have longstanding diabetes and CVD have more modest targets.

Other changes in the new guidelines include the prioritization of weight stabilization over reduction, recommendations against drugs to increase HDL levels and aspirin use in patients with diabetes and no CVD, and a new chapter on patient-centered care with emphasis on shared decision-making.

Source: Endocrine Today.

Low Diastolic BP Associated with Higher Mortality in Chronic Kidney Disease.


The association of blood pressure with mortality in chronic kidney disease seems to follow a J-shaped curve, especially with regard to diastolic pressure, according to an Annals of Internal Medicine study.
Researchers followed some 650,000 U.S. veterans with non-dialysis–dependent disease over a median of 6 years. After adjustment for such factors as age, diabetes, and cardiovascular disease, patients with blood pressure in the range of 130 to 159 mm Hg systolic and 70 to 89 diastolic had the lowest mortality risk. Even patients with “ideal” systolic blood pressure of less than 130 had increased mortality rates if their diastolic levels were under 70.
The association could be caused, the authors speculate, by lower coronary perfusion with decreased diastolic pressure. Editorialists (and the authors) emphasize the observational nature of the data, with the “attendant limitations,” and note the preponderance of male patients. “Translating these findings into practice is challenging,” they conclude.
Source: Annals of Internal Medicine article

 

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage.


BACKGROUND

Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known.

METHODS

We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician’s choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups.

RESULTS

Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively.

CONCLUSIONS

In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure.

Source: NEJM

 

Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial.


Background

Effective reduction of albuminuria and blood pressure in patients with type 2 diabetes who have nephropathy is seldom achieved with available treatments. We tested the effects of treatment of such patients with daglutril, a combined endothelin-converting enzyme and neutral endopeptidase inhibitor.

Methods

We did this randomised, crossover trial in two hospitals in Italy. Eligibility criteria were: age 18 years or older, urinary albumin excretion 20—999 μg/min, systolic blood pressure (BP) less than 140 mm Hg, and diastolic BP less than 90 mm Hg. Patients were randomly assigned (1:1) with a computer-generated randomised sequence to receive either daglutril (300 mg/day) then placebo for 8 weeks each or vice versa, with a 4-week washout period. Patients also took losartan throughout. Participants and investigators were masked to treatment allocation. The primary endpoint was 24-h urinary albumin excretion in the intention-to-treat population. Secondary endpoints were median office and ambulatory (24 h, daytime, and night-time) BP, renal haemodynamics and sieving function, and metabolic and laboratory test results. This study is registered with ClinicalTrials.gov, number NCT00160225.

Findings

We screened 58 patients, of whom 45 were enrolled (22 assigned to daglutril then placebo, 23 to placebo then daglutril; enrolment from May, 2005, to December, 2006) and 42 (20 vs 22) were included in the primary analysis. Daglutril did not significantly affect 24-h urinary albumin excretion compared with placebo (difference in change −7·6 μg/min, IQR −78·7 to 19·0; p=0·559). 34 patients had complete 24-h BP readings; compared with placebo, daglutril significantly reduced 24-h systolic (difference −5·2 mm Hg, SD 9·4; p=0·0013), diastolic (—2·5, 6·2; p=0·015), pulse (—3·0, 6·3; p=0·019), and mean (—3·1, 6·2; p=0·003) BP, as well as all night-time BP readings and daytime systolic, pulse, and mean BP, but not diastolic BP. Compared with placebo, daglutril also significantly reduced office systolic BP (—5·4, 15·4; p=0·028), but not diastolic (—1·8, 9·9; p=0·245), pulse (—3·1, 10·6; p=0·210), or mean (—2·1, 10·4; p=0·205) BP, and increased big endothelin serum concentration. Other secondary outcomes did not differ significantly between treatment periods. Three patients taking placebo and six patients taking daglutril had mild treatment-related adverse events—the most common was facial or peripheral oedema (in four patients taking daglutril).

Interpretation

Daglutril improved control of BP in hypertensive patients with type 2 diabetes and nephropathy and had an acceptable safety profile. Combined endothelin-converting enzyme and neutral endopeptidase inhibition could provide a new approach to hypertension in this high-risk population.

Discussion

8-week treatment with daglutril plus losartan and other antihypertensive drugs did not significantly affect urinary albumin excretion, nor renal haemodynamic measures or sieving function, but it did decrease ambulatory blood pressure in hypertensive patients with type 2 diabetes mellitus and albuminuria. Treatment was safe and well tolerated in all participants.

Because dietary salt intake and concomitant anti-hypertensive treatment were not systematically changed and 24-h urinary sodium excretion was stable during the study, we can reasonably exclude any confounding effect of intensified hypertension treatment or reduced sodium exposure. Moreover, we detected no substantial carry-over effect and the crossover design avoided confounding related to interpatient data heterogeneity. Thus, the reduction of blood pressure associated with daglutril seems to be a genuine treatment effect.

To the best of our knowledge, this study is the first randomised clinical trial reporting the beneficial effects of daglutril on arterial hypertension in patients with type 2 diabetes mellitus (panel). Hypertension affects most patients with diabetes and almost all of those with some renal involvement;13 systolic hypertension is almost always present. When combined with increased pulse pressure, it is almost always a result of increased vascular stiffness—a major risk factor for cardiovascular morbidity and mortality in this population.19 Systolic hypertension is often resistant to drug treatment,19 especially in patients with diabetes with renal involvement; in our study, systolic blood pressure averaged 140 mm Hg, despite background treatment with losartan, plus two or more antihypertensive drugs, and also a diuretic in most cases. This blood pressure exceeds the 130 mm Hg target that was recommended when the study was designed, but accords with the most recent guidelines,20 which recommend less stringent control of blood pressure in patients with diabetes.

Source: Lancet

 

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial.


Background

Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke.

Methods

In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130–149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306.

Findings

3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137–139) in the higher-target group and 127 mm Hg (95% CI 126–128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64–1·03, p=0·08), disabling or fatal stroke (0·81, 0·53–1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68–1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15–0·95, p=0·03). Treatment-related serious adverse events were infrequent.

Interpretation

Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial.

Funding

National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS)


Introduction

Hypertension is the most relevant and prevalent risk factor for stroke, particularly for stroke associated with cerebral small-vessel disease. Reduction in blood pressure is the most effective intervention to prevent stroke.12 and 3

Small subcortical brain infarcts, commonly known as lacunar strokes, comprise about 25% of ischaemic strokes.4 and 5 Most result from disease of the small penetrating arteries. Despite the frequency and importance of these strokes, randomised trials have not focused on prevention of recurrent stroke in patients with MRI-defined lacunar stroke. Whether there are optimum blood-pressure targets to prevent stroke recurrence in patients with cerebral small-artery disease is unknown.6

In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial we tested two interventions in patients with recent, symptomatic, MRI-confirmed lacunar stroke: two antiplatelet regimens and two target ranges of systolic blood pressure. The results of the antiplatelet component have been published previously.7 We present here the results of the blood-pressure component of the trial, in which we tested the hypothesis that assignment to a lower target range for systolic blood pressure would lessen the rate of stroke recurrence compared with a higher target range.

Methods

Patients

Details of the rationale, study design, and characteristics of the participants in SPS3 have been described elsewhere.8 and 9 Briefly, SPS3 was a randomised, multicentre, clinical trial undertaken in 81 centres in North America, Latin America, and Spain between March, 2003, and April, 2011. Eligible patients were aged 30 years or older, were normotensive or hypertensive, had had a recent (within 180 days), symptomatic, MRI-confirmed lacunar stroke, and were without surgically amenable ipsilateral carotid artery stenosis or high-risk cardioembolic sources. Main exclusion criteria included disabling stroke (modified Rankin score of 4 or higher), previous intracranial haemorrhage from non-traumatic causes, or cortical ischaemic stroke.7 and 8Participation required written informed consent and approval was provided by local ethics committees for human research.

Randomisation and masking

Patients were randomised, according to a two-by-two factorial design, to two blood-pressure-control groups with targets of 130–149 mm Hg or less than 130 mm Hg.10 Treatment was open label. To avoid lowering of blood pressure soon after an acute stroke, participants were randomised at least 2 weeks after the index stroke. Randomisation was stratified by clinical centre and baseline hypertensive status. The schedule was computer generated with a permuted-block design (variable block size). Treatment assignments were stored electronically on the study servers at the SPS3 statistical centre, University of Alabama at Birmingham, AL, USA, as well as locally for each study site on an SPS3-designated computer. Upon patients’ eligibility being established, study coordinators ransomised patients via their data entry systems.

Management of blood pressure

Baseline hypertensive status was determined by measurement of blood pressure taken at two consecutive visits before randomisation. Patients taking medications to control blood pressure were allowed to continue doing so. Blood pressure was measured three times at every visit and the average measurement was used to decide hypertensive status.8910 and 11 Patients were classified as being hypertensive if either or both of the following features were noted: average systolic blood pressure 140 mm Hg or higher or diastolic blood pressure 90 mm Hg or higher on two consecutive visits, and confirmed history of hypertension before the index stroke and taking antihypertensive medication at the time of visit. After randomisation, if patients had blood pressures outside the assigned target range, they were initially seen at least monthly for measurement of blood pressure and adjustment of medications. Patients whose blood pressure was in the relevant range for two consecutive visits were seen every 3 months. If at any point during the study a patient’s systolic blood pressure was outside the assigned target range, he or she was asked to return within 1 month.

All study sites were provided with automated Colin Press-Mate BP-8800C sphygmomanometers (Colin Medical Instruments, San Antonio, TX, USA).11 Blood-pressure management was overseen at each site by a physician with special expertise in blood-pressure control. If systolic blood pressure in patients assigned to the higher-target group (130–149 mm Hg) dropped to below the lower limit of the target range, the protocol required that patients taking antihypertensive medications stop taking them or have the doses reduced, unless prescribed for reasons other than blood pressure control; patients taking no antihypertensive medications continued to be followed up every 3 months. If systolic blood pressure increased to within the target range, patients were managed according to their originally assigned target. If patients or primary-care physicians refused to titrate blood pressure to the assigned target range per protocol, patients were classified as inactive. Patients whose blood pressure could not be kept within the assigned target range for medical reasons or because of intolerable side-effects of antihypertensive drugs after trying different agents were classified as failure to achieve assigned target. All participants were followed up to a common end-of-study date, irrespective of activity status.

Antihypertensive medications were prescribed by the local study physician and supplied via the study formularies. At least one drug from each of the major classes of antihypertensive medications was available. They were obtained and distributed to study centres by the Veterans Administration Cooperative Studies Program Clinical Research Coordinating Center, Drug Distribution Center, Albuquerque, NM, USA.

Statistical analysis

The primary endpoint was reduction in all stroke. Ischaemic stroke was clinically defined as a focal neurological deficit persisting for longer than 24 h, with an absence of haemorrhage confirmed by neuroimaging. Intracranial haemorrhages included intracerebral, subdural or epidural, and subarachnoid locations defined by neuroimaging. Disabling strokes were classified as those with modified Rankin scores of 3 or higher after 3–6 months. Strokes were deemed fatal if death occurred within 30 days or if death after 30 days could be attributed to the stroke. Secondary endpoints were reductions in acute myocardial infarction, defined by standard criteria (compatible clinical history with changes on ECG or in cardiac enzyme concentrations), need for acute admission to hospital for a major vascular event, and death, classified as vascular, non-vascular, or unknown. All reported efficacy outcomes were confirmed by a central adjudication committee that was unaware of treatment assignment. Safety outcomes were serious adverse events related to hypotension and blood-pressure management. The trial was monitored by an independent data and safety monitoring committee selected by the sponsor.

The initial sample size of 2500 patients was calculated assuming an average follow-up of 3 years, an estimated 3-year recurrent stroke rate of 21%, a 25% relative-risk reduction in stroke by intensive control of blood pressure, a type I error of α=0·05, and 90% power. Sample-size estimation was reassessed midway through the trial to check the power of the study on the basis of the observed overall event rate. This assessment resulted in the final sample size being increased from 2500 to 3000 patients.12

We did two prespecified subgroup analyses. The first was in patients who were hypertensive at baseline. Thus, we excluded from this analysis patients who were non-hypertensive at baseline (systolic blood pressure lower than 130 mm Hg without taking antihypertensive medications) and who received no antihypertensive therapy during the study unless blood pressure exceeded the assigned target range during follow-up. The second included data after censoring at 6 months of follow-up. This analysis was undertaken because the maximum separation of the baseline and achieved blood pressures requires an average of 6 months of medication titration. All participants who did not die or withdraw from the study during the first 6 months, irrespective of whether or not they had an event during this time, were included in this subgroup. We also assessed outcomes in various demographic and clinical subgroups.

We did standard time-to-event analyses of the primary endpoint with the log-rank test and used Cox’s proportional hazards models to compute hazard ratios (HRs) and 95% CIs in each treatment group. If multiple events of the same type occurred, time to event was calculated as time to first event. Data for patients with no events were censored at the end of study participation or death, whichever occurred first. The proportional hazards assumption was verified by assessment of the interaction between time and blood-pressure-intervention group, and we used Cox’s models to investigate whether the effect of intervention differed by specific subgroups. Odds ratios and 95% CIs were computed by logistic regression for orthostatic symptoms, as these were measured as whether or not the patient had at least one symptom during the follow-up period All analyses were based on the intention-to-treat principle and were done with SAS (version 9.2). The study is registered with ClinicalTrials.gov, number NCT00059306.

Role of the funding source

The sponsor of the study participated in study design, data collection, data analysis, data interpretation, and writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

3020 participants were enrolled from North America (n=1960 [65%]), Latin America (n=694 [23%]), and Spain (n=366 [12%]) and were followed up for a mean of 3·7 (range 0–8·6, SD 2·0) years (appendix p 1). Baseline characteristics did not differ substantially between target groups (table 1). The median time from qualifying stroke to randomisation was 62 days. Blood-pressure therapy was permanently discontinued in similar numbers of patients in the higher-target and lower-target groups (258 [17%] vs 240 [16%]). 90 (3%) participants were lost to follow-up and an additional 465 (15%) ended follow-up early for the following reasons: withdrawn consent (n=242), site closure (n=151), physician request (n=12), and other reasons (n=60).

Table 1. Patients’ characteristics

Higher-target group (n=1519) Lower-target group (n=1501)
Age (years) 63 (10·8) 63 (10·7)
Men 990 (65%) 912 (61%)
Blood pressure at entry (mm Hg)
Systolic 144 (19) 142 (19)
Diastolic 79 (11) 78 (10)
Body-mass index (kg/m2) 29·2 (7·5) 29·0 (6·1)
History of hypertension 1137 (75%) 1127 (75%)
Diabetes mellitus 553 (36%) 553 (37%)
Ischaemic heart disease 173 (11%) 144 (10%)
Previous clinical stroke or TIA 211 (14%) 237 (16%)
Current tobacco smoker 308 (20%) 309 (21%)
Qualifying event
Ischaemic stroke 1506 (99%) 1473 (98%)
TIA 13 (1%) 28 (2%)
Ethnic origin
White 760 (50%) 778 (52%)
Hispanic 468 (31%) 448 (30%)
Black 251 (17%) 241 (16%)
Other 40 (3%) 34 (2%)
Region
North America 987 (65%) 976 (65%)
Latin America 352 (23%) 342 (23%)
Spain 183 (12%) 183 (12%)
Number of antihypertensive medications at study entry 1·7 (1·2) 1·7 (1·2)
Mean number of antihypertensive medications at 1 year* 1·8 (1.4) 2·4 (1.3)
Types of antihypertensive medications at 1 year
Thiazides 576 (43%) 774 (58%)
ACE inhibitor/ARB 835 (63%) 1064 (80%)
Calcium-channel blockers 398 (30%) 571 (43%)
β blockers 333 (25%) 408 (31%)
Other 117 (9%) 146 (11%)
Mean number of antihypertensive medication at last visit 1·8 (1·4) 2·4 (1·4)
Types of antihypertensive medications at last visit§
Thiazides 569 (38%) 804 (54%)
ACE inhibitor/ARB 894 (60%) 1156 (78%)
Calcium-channel blockers 438 (39%) 637 (43%)
β blockers 424 (28%) 521 (35%)
Other 168 (11%) 204 (14%)
Statins used during follow-up 1248 (84%) 1254 (85%)

Data are mean (SD) or number (%). TIA=transient ischaemic attack. ACE=angiotensin-converting enzyme. ARB=antiotensin-II-receptor blocker.

*

Difference between groups p<0·0001.

Difference between groups p<0·0001 for all types, except β blockers (p=0·0008) and other (p=0·051).

Difference between groups p<0·0001.

§

Difference between groups p<0·0001 for all types, except other (p=0·042).

iscussion

Lowering of systolic blood pressure to a target of less than 130 mm Hg in patients with recent lacunar stroke resulted in non-significant reductions in all stroke, disabling or fatal stroke, and major vascular events, and a significant reduction in intracerebral stroke. These effects were associated with few serious side-effects, and were consistent across major subgroups, including patients with diabetes and Hispanic patients, and irrespective of blood pressure at study entry. Exclusion of normotensive patients at entry showed a reduction in the rate of recurrent stroke of 20% in the lower–target group, although this reduction was not significant. Blood-pressure lowering offered a similar effect on stroke recurrence irrespective of stroke subtype.

That lower is better is a general construct for chronic blood-pressure management after stroke, but optimum clinical practice requires that benefits and risks associated with specific targets be defined. The PROGRESS trial2 showed that lowering of blood pressure in stroke survivors was associated with a reduction of 28% in stroke recurrence. The mean achieved systolic blood pressure at the end of the study was 138 mm Hg, but the optimum target for blood-pressure control was not established. Similarly to the ACCORD trial,19 we explored the efficacy and safety of setting systolic-blood-pressure targets lower than 130 mm Hg, but our assessment was extended to patients with MRI-defined lacunar stroke attributed to small-vessel disease.

Our results are best viewed in the context of previous trials of long-term lowering of blood pressure in patients who have had brain ischaemia (table 5figure 4).1, 2, 3, 13, 14, 15, 16, 17 and 20 We tested target blood pressure rather than specific antihypertensive agents and explored effects in patients with well defined ischaemic-stroke subtypes. Although the magnitude of the reduction in rate was not significant, the findings are strongly supported by those of previous trials.1, 2 and 3

The trial protocol was based on the assigned target of systolic blood pressure being achieved and, therefore, we did not require specific antihypertensive agents to be used. Patients assigned to the lower-target group used an average of 2·4 antihypertensive medications and the distribution of medication categories differed from that in the higher-target group (table 1). The mean difference in systolic blood pressure at the end of the trial was 11 mm Hg. On the basis of previous studies, this difference should have resulted in about a 30% reduction in recurrent stroke. The observed reduction of 19% (95% CI −3 to 36), however, was smaller even than the hypothesised 25%. This finding could be due to chance or the specific population of patients assessed.2 and 21 The 95% CI for the 19% reduction does include the hypothesised 25% reduction, but it also spans zero and, therefore, is not significant. The rate of intracerebral haemorrhage was reduced by 63% in the lower-target group, which is consistent with the known sensitivity of this stroke subtype to strict blood-pressure control.14 This result indicates that the number needed to treat to prevent one intracerebral haemorrhage at 4 years (roughly the average follow-up in SPS3) would be 175.

The SPS3 trial had limitations. First, the observed rate of recurrent stroke was much lower than that anticipated. This low rate is similar to that seen in other trials that have assessed prevention of recurrent stroke.22, 23 and 24 It might, therefore, be the result of good blood-pressure control in both treatment groups, the frequent use of statins, and high adherence to antiplatelet therapy. Second, the assignment to blood-pressure targets was not masked, which could have potentially introduced bias. Stroke endpoints were, however, confirmed by a central adjudication committee that was unaware of patients’ group allocations, as is frequently done in large hypertension trials.25 Third, we tested treatment targets and not the effect of specific blood-pressure agents. Finally, some patients did not achieve blood pressures within the target ranges at any point during follow-up (70 [4·6%] in the higher-target group and 74 [4·9%] in the lower-target group). These proportions, however, are similar to those reported in other trials of blood-pressure targets and, therefore, probably reflect the clinical realities of blood-pressure management.19 and 25 An important strength of the SPS3 trial is that blood-pressure lowering was tested in a well defined and homogeneous cohort of stroke patients.

In conclusion, although our results do not show a significant reduction in the rate of recurrent stroke, the findings are congruent with those of previous trials of blood-pressure lowering after stroke and support a treatment target of less than 130 mm Hg systolic blood pressure for most patients with recent lacunar stroke (panel). As our study cohort comprised patients with recent lacunar strokes due mainly to cerebral small-vessel disease, whether our findings are applicable to patients with strokes from other mechanisms warrants additional research.

Panel. Research in context

Systematic review

We searched PubMed and Cochrane Library for randomised clinical trials of secondary stroke prevention with blood-pressure reduction as an intervention, published before April, 2013, in all languages. We used the search terms “blood pressure”, “reduction”, hypertension”, “secondary”, “stroke”, “prevention”, and “clinical trial”. Eight randomised clinical trials2, 13, 14, 15, 16, 17 and 18 and one pooled analysis1 were identified. Aggregate results showed consistently that reduced blood pressure in stroke survivors lessened the risk of stroke recurrence.

Interpretation

We assessed blood-pressure targets in survivors of MRI-defined lacunar stroke. A reduced rate of all stroke was observed in patients with a target systolic blood pressure lower than 130 mm Hg compared with a target of 130–149 mm Hg, but this difference was not significant. The intervention was safe and well tolerated. Interpreted in the context of previous randomised, controlled trials of blood-pressure lowering after stroke, our results suggest that management of systolic to levels lower than 130 mm Hg is likely to reduce the risk of recurrent stroke in patients with recent lacunar stroke.

Source: http://www.sciencedirect.com

 

Effect on blood pressure of combined inhibition of endothelin-converting enzyme and neutral endopeptidase with daglutril in patients with type 2 diabetes who have albuminuria: a randomised, crossover, double-blind, placebo-controlled trial.


Background

Effective reduction of albuminuria and blood pressure in patients with type 2 diabetes who have nephropathy is seldom achieved with available treatments. We tested the effects of treatment of such patients with daglutril, a combined endothelin-converting enzyme and neutral endopeptidase inhibitor.

Methods

We did this randomised, crossover trial in two hospitals in Italy. Eligibility criteria were: age 18 years or older, urinary albumin excretion 20—999 μg/min, systolic blood pressure (BP) less than 140 mm Hg, and diastolic BP less than 90 mm Hg. Patients were randomly assigned (1:1) with a computer-generated randomised sequence to receive either daglutril (300 mg/day) then placebo for 8 weeks each or vice versa, with a 4-week washout period. Patients also took losartan throughout. Participants and investigators were masked to treatment allocation. The primary endpoint was 24-h urinary albumin excretion in the intention-to-treat population. Secondary endpoints were median office and ambulatory (24 h, daytime, and night-time) BP, renal haemodynamics and sieving function, and metabolic and laboratory test results. This study is registered with ClinicalTrials.gov, number NCT00160225.

Findings

We screened 58 patients, of whom 45 were enrolled (22 assigned to daglutril then placebo, 23 to placebo then daglutril; enrolment from May, 2005, to December, 2006) and 42 (20 vs 22) were included in the primary analysis. Daglutril did not significantly affect 24-h urinary albumin excretion compared with placebo (difference in change −7·6 μg/min, IQR −78·7 to 19·0; p=0·559). 34 patients had complete 24-h BP readings; compared with placebo, daglutril significantly reduced 24-h systolic (difference −5·2 mm Hg, SD 9·4; p=0·0013), diastolic (—2·5, 6·2; p=0·015), pulse (—3·0, 6·3; p=0·019), and mean (—3·1, 6·2; p=0·003) BP, as well as all night-time BP readings and daytime systolic, pulse, and mean BP, but not diastolic BP. Compared with placebo, daglutril also significantly reduced office systolic BP (—5·4, 15·4; p=0·028), but not diastolic (—1·8, 9·9; p=0·245), pulse (—3·1, 10·6; p=0·210), or mean (—2·1, 10·4; p=0·205) BP, and increased big endothelin serum concentration. Other secondary outcomes did not differ significantly between treatment periods. Three patients taking placebo and six patients taking daglutril had mild treatment-related adverse events—the most common was facial or peripheral oedema (in four patients taking daglutril).

Interpretation

Daglutril improved control of BP in hypertensive patients with type 2 diabetes and nephropathy and had an acceptable safety profile. Combined endothelin-converting enzyme and neutral endopeptidase inhibition could provide a new approach to hypertension in this high-risk population.

Discussion

8-week treatment with daglutril plus losartan and other antihypertensive drugs did not significantly affect urinary albumin excretion, nor renal haemodynamic measures or sieving function, but it did decrease ambulatory blood pressure in hypertensive patients with type 2 diabetes mellitus and albuminuria. Treatment was safe and well tolerated in all participants.

Because dietary salt intake and concomitant anti-hypertensive treatment were not systematically changed and 24-h urinary sodium excretion was stable during the study, we can reasonably exclude any confounding effect of intensified hypertension treatment or reduced sodium exposure. Moreover, we detected no substantial carry-over effect and the crossover design avoided confounding related to interpatient data heterogeneity. Thus, the reduction of blood pressure associated with daglutril seems to be a genuine treatment effect.

To the best of our knowledge, this study is the first randomised clinical trial reporting the beneficial effects of daglutril on arterial hypertension in patients with type 2 diabetes mellitus (panel). Hypertension affects most patients with diabetes and almost all of those with some renal involvement;13 systolic hypertension is almost always present. When combined with increased pulse pressure, it is almost always a result of increased vascular stiffness—a major risk factor for cardiovascular morbidity and mortality in this population.19 Systolic hypertension is often resistant to drug treatment,19 especially in patients with diabetes with renal involvement; in our study, systolic blood pressure averaged 140 mm Hg, despite background treatment with losartan, plus two or more antihypertensive drugs, and also a diuretic in most cases. This blood pressure exceeds the 130 mm Hg target that was recommended when the study was designed, but accords with the most recent guidelines,20 which recommend less stringent control of blood pressure in patients with diabetes.

Thus, daglutril effectively improved both office and ambulatory systolic hypertension with much smaller effects on diastolic blood pressure. Reduction in systolic blood pressure is normally associated with a concomitant reduction in diastolic blood pressure, which can result in decreased left ventricular perfusion and a heightened risk of cardiovascular events—the so called J curve.21 Therefore, availability of a drug that can reduce systolic and pulse pressure with marginal effects on diastolic blood pressure might have major clinical implications. Indeed, a 10 mm Hg reduction in systolic blood pressure has been associated with a 22% reduction in coronary heart disease and 41% reduction in stroke.22 Whether the effect of daglutril observed in our study is a result of improved vascular stiffness should be investigated. The treatment effect of daglutril on ambulatory blood pressure was larger during night-time, and was achieved on top of full-dose losartan plus two or more additional hypotensive drugs in most patients. This might also have clinical implications, because night-time hypertension is a strong cardiovascular risk factor independent of trough, 24-h, or daytime blood pressure control, especially in patients with diabetes who have renal disease.23

We recorded a significant increase in office blood pressure, and a non-significant increase in other blood pressures, during placebo treatment, which might be a result of progression of renal disease with a consequent worsening of hypertension. Daglutril maintained all measures of office blood pressure and decreased ambulatory systolic and pulse blood pressure, an effect that translated into net differences compared with placebo that were larger for ambulatory than for office blood pressure.

The increase in serum concentrations of big EDN1 suggests that the treatment effect was mainly sustained by inhibition of endothelin-converting enzyme. In the vasculature, EDNRA and EDNRB are expressed on vascular smooth-muscle cells and mediate the vasoconstrictory effects of EDN1. ENDRB is also located on vascular endothelial cells, where its activation promotes vasodilation through release of nitric oxide and prostacyclin.10 In patients with mild-to-moderate hypertension without antihypertensive treatment, the mixed endothelin receptor antagonist bosentan has been reported to significantly reduce office and 24-h systolic and diastolic blood pressure compared with placebo, and to a similar extent as the angiotensin-converting enzyme inhibitor, enalapril.24 Furthermore, the selective EDNRA antagonist darusentan—when added to at least three other antihypertensive drugs—significantly reduced office and 24-h systolic and diastolic blood pressure in patients with treatment-resistant hypertension, and to a larger extent than had been shown for bosentan.25 Finally, avosentan—an EDNRA antagonist that is less selective than darusentan—improved albuminuria when given with angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers in patients with overt diabetic nephropathy, but had no antihypertensive effect.26 Theoretically, avoiding inhibition of EDNRB would be preferable, because it also mediates the clearance of circulating EDN1 in people, and in animal studies it has a role in regulation of natriuresis and diuresis. Thus, endothelin-converting enzyme inhibitors are promising new drugs—they will antagonise endothelin without affecting EDNRB-mediated clearance of EDN1.10

Blood pressure reduction during daglutril treatment was not associated with any significant change in 24-h albuminuria, renal haemodynamics, or albumin and IgG fractional clearances compared with placebo. One explanation could be that patients had increased bioavailability of pro-atrial natriuretic peptide secondary to inhibition of neutral endopeptidase, which could have increased glomerular permeability to plasma macromolecules.27 The consequent increase in albumin ultrafiltration might have offset the reduction in albuminuria expected from decreased kidney perfusion pressure and postglomerular vasodilatation from antagonism of endothelin.2829 Natriuretic peptides might also induce preglomerular vasodilatation that maintains glomerular perfusion and filtration despite reduced blood pressure.30 This hypothesis might explain why glomerular filtration rate and renal plasma flow were not reduced by daglutril treatment.

Our safety data compare favourably to the side-effects reported during treatment with endothelin receptor antagonists.24,25 Darusentan has been associated with a doubled incidence of fluid overload or oedema compared with placebo. Another study28 examining the effects of avosentan on progression of overt diabetic nephropathy had to be stopped prematurely because of an excess of fluid overload and congestive heart failure in the avosentan group. Kohan and colleagues29 reported that oedema occurred in up to 46% of patients receiving increasing doses of the highly selective EDNRA antagonist atrasentan. Notably, no angio-oedema occurred during our study, a finding of clinical relevance, because combined inhibition of angiotensin-converting enzyme and neutral endopeptidase has previously been associated with increased incidence of angio-oedema caused by decreased breakdown of bradykinin, leading to increased nitric oxide concentrations.31 Additional inhibition of endothelin-converting enzyme—as provided by daglutril—might alleviate this effect by reducing activation of EDNRB, thus decreasing production of nitric oxide.13

Further studies should be done to address whether higher doses of daglutril than were used in this study are needed to detect the antiproteinuric effects previously reported in animal studies and whether daglutril’s blood-pressure lowering effects apply to patients with non-diabetic nephropathies.14 The predominance of men in our study could be a result of the excess of men in the average population of patients with type 2 diabetes mellitus who have nephropathy and perhaps environmental factors that result in more men than women consenting to take part in the study. However, the large number of men does not affect the internal validity of the study and should not affect the generalisability of the findings to both sexes; no evidence exists of sex-specific effects of endothelin on hypertension, and previous studies25 of endothelin receptor antagonists showed the same antihypertensive effects in both men and women. Our results from autoregressive modelling18 provide additional evidence that daglutril has an antihypertensive effect—particularly on systolic blood pressure—throughout the whole 24-h observation period, independent of rhythmical (circadian) and non-rhythmical changes in blood pressure. Our sensitivity analyses confirmed the robustness of these results. The study design, measurement of 24-h blood pressure, and the gold-standard procedures used to measure albuminuria and renal haemodynamic and sieving function parameters are major strengths. Results of our per-protocol analyses of efficacy variables were similar to those of the modified intention-to-treat analyses, which confirmed the robustness of our findings. Long-term clinical trials are needed to test whether the blood-pressure lowering effect of daglutril provides consistent nephroprotection and cardioprotection in this high-risk population.

Soure: Lancet

Primary prevention of cardiovascular disease: new guidelines, technologies and therapies.


Abstract

  • A trend in primary prevention of cardiovascular disease (CVD) has been a move away from managing isolated risk factors, such as hypertension and dyslipidaemia, towards assessment and management of absolute CVD risk.
  • In Australian guidelines, absolute CVD risk is calculated as the probability of a stroke, transient ischaemic attack, myocardial infarction, angina, peripheral arterial disease or heart failure occurring within the next 5 years.
  • Absolute CVD risk should be regularly assessed in patients aged 45 years or older (35 years or older in Aboriginal and Torres Strait Islander people) using the Australian absolute CVD risk calculator (http://www.cvdcheck.org.au).
  • For patients currently taking a blood pressure (BP)-lowering or lipid-lowering agent, pretreatment values should be used to calculate risk.
  • Patients at high absolute risk of CVD (> 15% over 5 years) should be treated with both BP-lowering and lipid-lowering agents, unless contraindicated or clinically inappropriate.
  • For patients at moderate absolute risk of CVD (10%–15%) treatment with a BP-lowering and/or a lipid-lowering agent should be considered if the risk remains elevated after lifestyle interventions, BP is ≥ 160/100 mmHg, there is a family history of premature CVD, or the patient is of South Asian, Middle Eastern, Maori, Pacific Islander, Aboriginal or Torres Strait Islander ethnicity.
  • BP measurements taken using an oscillometric device can be used to approximate mean daytime ambulatory BP.
  • Conclusion
  • The move to an approach based on absolute risk for the primary prevention of CVD is likely to improve the effectiveness and cost-effectiveness of treatment, and the 2009 and 2012 NVDPA guidelines support this approach. The absolute risk approach targets the patients who are most likely to benefit from medication, and reduces the medicalisation of patients at low risk. The increasing availability of cardiovascular risk calculators, either on the internet or as standalone software, also removes one of the barriers to implementing the absolute risk approach. New technologies have varying evidence of utility, but oscillometric BP devices can be readily adopted. The role of coronary artery calcium scoring and other biomarkers in risk stratification is yet to be established.

Source: MJA

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage..


Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. Methods We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physician`s choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. Results Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. Conclusions In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure.

Source: NEJM