Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudies.

BACKGROUND: In the PATHWAY-2 study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension. METHODS: PATHWAY-2 was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1); assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2); and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2 trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081. FINDINGS: Of the 314 patients in PATHWAY-2, 269 participated in one or more of the three substudies: 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001). INTERPRETATION: Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension. FUNDING: British Heart Foundation and UK National Institute for Health Research.

Contrasting mortality risks among subgroups of treated hypertensive patients developing new-onset diabetes.

AIMS: Hypertension and diabetes mellitus (DM) frequently cluster together and synergistically increase cardiovascular risk. Among those who develop DM during treatment for hypertension (new-onset diabetes, NOD), it is unclear whether NOD reflects a separate entity associated with increased risk or merely reflects accelerated presentation of DM. METHODS AND RESULTS: We analysed data on 15 089 hypertensive patients attending the Glasgow Blood Pressure Clinic. The date at first hospital encounter either with diagnosis of diabetes or prescription of anti-hyperglycaemic medication were considered as the onset of diabetes. Cox proportional hazard models (including propensity score matching) were employed to study associations between diabetes status, early and late NOD (diagnosis <10 years or >10 years from first clinic visit) and cause-specific mortality. There were 2516 patients (16.7%) with DM, of whom 1862 (12.3%) had NOD [early NOD = 705 (4.6%); late NOD = 1157 (7.6%)]. The incidence rate of NOD was 8.2 per 1000 person-years. The total time at risk was 239 929 person-years [median survival: 28.1 years (inter-quartile range: 16.2-39.9)]. Compared with non-diabetic individuals, prevalent DM [hazard ratio (HR) = 1.8, 95% confidence interval (CI): 1.4-2.2] and time varying NOD status (HR: 1.09, 95% CI: 1.06-1.17) were associated with increased adjusted all-cause mortality. Early NOD (HR: 1.39, 95% CI: 1.2-1.6) was associated with increased in mortality risk, but not late NOD (HR: 0.92, 95% CI: 0.83-1.01). Results were consistent in the propensity score matched analyses. CONCLUSION: Although 1-in-8 hypertensive patients develop NOD, mortality is increased only in the 1-in-20 who develop early NOD. Further studies are warranted to determine if early identification of such individuals should provide an alert for intensification of therapeutic interventions.

Acetaminophen use and risk of myocardial infarction and stroke in a hypertensive cohort.

Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and that acetaminophen causes a modest blood pressure rise. There are no randomized trials or studies using verified prescription data of this relationship. We aimed to assess the relationship between verified acetaminophen prescription data and risk of myocardial infarction or stroke in patients with hypertension. We performed a retrospective data analysis using information contained within the UK Clinical Research Practice Datalink. Multivariable Cox proportional hazard models were used to estimate hazard ratios for myocardial infarction (primary end point), stroke, and any cardiovascular event (secondary end points) associated with acetaminophen use during a 10-year period. Acetaminophen exposure was a time-dependent variable. A propensity-matched design was also used to reduce potential for confounding. We included 24,496 hypertensive individuals aged ≥ 65 years. Of these, 10,878 were acetaminophen-exposed and 13,618 were not. There was no relationship between risk of myocardial infarction, stroke, or any cardiovascular event and acetaminophen exposure on adjusted analysis (hazard ratio, 0.98; 95% confidence interval, 0.76-1.27; hazard ratio, 1.09; 95% confidence interval, 0.86-1.38; and hazard ratio, 1.17; 95% confidence interval, 0.99-1.37; respectively). Results in the propensity-matched sample (n=4000 per group) and when men and women were analyzed separately were similar. High-frequency users (defined as receiving a prescription for >75% of months) were also not at increased risk. After allowance for potentially confounding variables, the use of acetaminophen was not associated with an increased risk of myocardial infarction or stroke in a large cohort of hypertensive patients.

Long-term and ultra long-term blood pressure variability during follow-up and mortality in 14,522 patients with hypertension.

Recent evidence indicates that long-term visit-to-visit blood pressure variability (BPV) may be an independent cardiovascular risk predictor. The implication of this variability in hypertension clinical practice is unclear. BPV as average real variability (ARV) was calculated in 14,522 treated patients with hypertension in 4 time frames: year 1 (Y1), years 2 to 5 (Y2-5), years 5 to 10 (Y5-10), and years >10 (Y10+) from first clinic visit. Cox proportional hazards models for cause-specific mortality were used in each time frame separately for long-term BPV, across time frames based on ultra long-term BPV, and within each time frame stratified by mean BP. ARV in systolic blood pressure (SBP), termed ARV(SBP), was higher in Y1 (21.3±11.9 mm Hg) in contrast to Y2-5 (17.7±9.9 mm Hg), Y5-10 (17.4±9.6 mm Hg), and Y10+ (16.8±8.5 mm Hg). In all time frames, ARV(SBP) was higher in women (P<0.01) and in older age (P<0.001), chronic kidney disease (P<0.01), and prevalent cardiovascular disease (P<0.01). Higher long-term and ultra long-term BPV values were associated with increased mortality (all-cause, cardiovascular, and noncardiovascular mortality; P for trend, <0.001). This relationship was also evident in subgroups with mean SBP<140 mm Hg in all time frames. Monitoring BPV in clinical practice may facilitate risk reduction strategies by identifying treated hypertensive individuals at high risk, especially those with BP within the normal range.

Serum chloride is an independent predictor of mortality in hypertensive patients.

Chloride (Cl-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary Cl- intake increases blood pressure, yet paradoxically, higher serum Cl- appears associated with lower mortality and cardiovascular risk. This implies that serum Cl- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12,968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl- was an independent predictor of mortality. To distinguish the effect of Cl- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+ /HCO3- and Cl- levels. Generalized estimating equation was used to determine the effect of baseline Cl- on follow-up blood pressure. The total time at risk was 19,7101 person-years. The lowest quintile of serum Cl- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+ , and HCO3- levels. The group with Na+ > 135 and Cl- > 100 had the best survival, and compared with this group, the Na+ >135 and Cl- <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.

Noninvasive cardiac event monitoring to detect atrial fibrillation after ischemic stroke: a randomized, controlled trial.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) elevates risk of recurrent stroke but is incompletely identified by standard investigation after stroke, though detection rates correlate with monitoring duration. We hypothesized that 7 days of noninvasive cardiac-event monitoring early after stroke would accelerate detection of AF and thus uptake of effective therapy. METHODS: We performed a pragmatic randomized trial with objective outcome assessment among patients presenting in sinus rhythm with no AF history, within 7 days of ischemic stroke symptom onset. Patients were randomized to standard practice investigations (SP) to detect AF, or SP plus additional monitoring (SP-AM). AM comprised 7 days of noninvasive cardiac-event monitoring reported by an accredited cardiac electrocardiology laboratory. Primary outcome was detection of AF at 14 days. RESULTS: One-hundred patients were enrolled from 2 centers. Within 14 days of stroke, sustained paroxysms of AF were detected in 18% of patients undergoing SP-AM versus 2% undergoing SP (P<0.05). Paroxysms of any-duration were detected in 44% of patients undergoing SP-AM versus 4% undergoing SP (P<0.001). These differences persisted at 90 days. Anticoagulant therapy was commenced within 14 days in 16% of SP-AM patients versus none randomized to SP (P<0.01). This difference persisted to 90 days (22% versus 6%; P<0.05). CONCLUSIONS: Routine noninvasive cardiac-event monitoring after acute stroke enhances detection of paroxysmal AF and early anticoagulation. Extended monitoring should be offered to all eligible patients soon after acute stroke. Guidelines on investigation for AF in stroke patients could be strengthened. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com/isrctn/. Unique identifier: ISRCTN97412358.

Blood pressure response to patterns of weather fluctuations and effect on mortality.

Very few studies have looked at longitudinal intraindividual blood pressure responses to weather conditions. There are no data to suggest that specific response to changes in weather will have an impact on survival. We analyzed >169 000 clinic visits of 16 010 Glasgow Blood Pressure Clinic patients with hypertension. Each clinic visit was mapped to the mean West of Scotland monthly weather (temperature, sunshine, rainfall) data. Percentage change in blood pressure was calculated between pairs of consecutive clinic visits, where the weather alternated between 2 extreme quartiles (Q(1)-Q(4) or Q(4)-Q(1)) or remained in the same quartile (Q(n)-Q(n)) of each weather parameter. Subjects were also categorized into 2 groups depending on whether their blood pressure response in Q(1)-Q(4) or Q(4)-Q(1) were concordant or discordant to Q(n)-Q(n). Generalized estimating equations and Cox proportional hazards model were used to model the effect on longitudinal blood pressure and mortality, respectively. Q(n)-Q(n) showed a mean 2% drop in blood pressure consistently, whereas Q(4)-Q(1) showed a mean 2.1% and 1.6% rise in systolic and diastolic blood pressure, respectively. However, Q(1)-Q(4) did not show significant changes in blood pressure. Temperature-sensitive subjects had significantly higher mortality (1.35 [95% confidence interval, 1.06-1.71]; P=0.01) and higher follow-up systolic blood pressure (1.85 [95% confidence interval, 0.24-3.46]; P=0.02) compared with temperature-nonsensitive subjects. Blood pressure response to temperature may be one of the underlying mechanisms that determine long-term blood pressure variability. Knowing a patient's blood pressure response to weather can help reduce unnecessary antihypertensive treatment modification, which may in turn increase blood pressure variability and, thus, risk.

Acetaminophen use and change in blood pressure in a hypertensive population.

OBJECTIVE: Recent data suggest that self-reported acetaminophen use is associated with increased risk of cardiovascular events and a rise in arterial blood pressure (BP). We investigated the association between acetaminophen use and BP in a large cohort of patients with hypertension using verified prescription data. METHODS: We extracted data from the UK General Practice Research Database for all hypertensive patients aged 65 years or older who were prescribed acetaminophen and had BP measured both before and during acetaminophen treatment. Patients were grouped according to whether their antihypertensive treatment remained unchanged or not during the study period. The change in SBP and DBP during acetaminophen use was determined and compared with the change in BP in a group of nonacetaminophen-exposed people identified using propensity matching. RESULTS: A total of 2754 acetaminophen-exposed individuals were included. BP rose slightly during the period of acetaminophen treatment wherein antihypertensive treatment was unchanged [change in SBP 1.6 [95% confidence interval (CI) 0.7-2.5) mmHg and change in DBP 0.5 (95% CI 0.1-1.0) mmHg)]. BP fell when new antihypertensive medications were prescribed. These BP changes were no different to those seen in matched nonacetaminophen-exposed individuals [between-group difference wherein antihypertensive treatment was unchanged was 0.6 (95% CI -0.6 to 1.9) mmHg and 0.5 (-0.1 to 1.1) mmHg for change in SBP and DBP, respectively]. CONCLUSION: We found no evidence of a sustained rise in blood pressure caused by acetaminophen treatment in a large population of patients with treated hypertension.

Cardiovascular outcomes in hypertensive patients: comparing single-agent therapy with combination therapy.

OBJECTIVES: To determine whether blood pressure (BP) control in hypertensive patients achieved with combination drug therapy provides the same cardiovascular benefits as with single-agent therapy. BACKGROUND: Drug combinations, most often including hydrochlorothiazide (HCTZ), are now recommended for routine BP management, but their effects on cardiovascular event rates have not been compared with effective monotherapy. METHODS: We conducted retrospective analyses of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) data. VALUE compared cardiovascular event rates of valsartan and amlodipine. Patients with BPs not controlled (<140/90  mmHg) by the single agents had HCTZ and, if required, additional drugs of different classes, added. Using data pooled from the two treatment arms, we have now divided patients into those controlled on monotherapy and those controlled or not controlled by combination therapy. The primary study endpoint was first occurrence of cardiovascular death or nonfatal myocardial infarction or stroke. Comparisons between groups were by Cox regression, adjusted for on-treatment BP, age, prior cardiovascular events and left ventricular hypertrophy; the comparison between the monotherapy and combination therapy controlled groups was based on events occurring after 3 months by when the decision to use monotherapy or combination therapy was made. RESULTS: The primary endpoint occurred in 505 of 5924 (8.5%) monotherapy and 511 of 4621 (11.1%) combination therapy controlled patients: hazard ratio was 0.80 [95% confidence interval (CI) 0.70-0.90]. If these two groups were matched for baseline BPs and all events included from study baseline, the hazard ratio was 0.76 (95% CI 0.67-0.86). The difference between combination controlled and uncontrolled [434 of 3390 (12.8%)] groups was not significant [hazard ratio 0.90 (95% CI 0.80-1.03], nor when they were matched for baseline BPs [hazard ratio 0.95 (95% CI 0.81-1.11)]. CONCLUSION: Independent of prior cardiovascular history or baseline BP, hypertensive patients requiring combination therapy, which includes a thiazide diuretic for BP control, have a poorer cardiovascular prognosis than those controlled by monotherapy and only a nonsignificantly lower event rate than noncontrolled patients.

Hematocrit predicts long-term mortality in a nonlinear and sex-specific manner in hypertensive adults.

Hematocrit has been inconsistently reported to be a risk marker of cardiovascular morbidity and mortality. The Glasgow Blood Pressure Clinic Study cohort included 10951 hypertensive patients, who had hematocrit measured at their initial clinic visit and followed for ≤35 years. Cox proportional hazards models were used to estimate hazard ratios for all-cause, cardiovascular, ischemic heart disease, stroke, and noncardiovascular mortality. There were 3484 deaths over a follow-up period of 173245 person-years. Hematocrit was higher in men (median, 0.44; interquartile range, 0.42-0.47) than in women (median, 0.41; interquartile range, 0.38-0.43). The lowest risk for all-cause mortality was seen in quartile 2 for men (range, 0.421-0.440) and women (range, 0.381-0.400). Compared with quartile 2, the adjusted hazard ratios for quartiles 1, 3, and 4 were, respectively, 1.11 (range, 0.97-1.28), 1.19 (range, 1.04-1.37), and 1.22 (range, 1.06-1.39) in men and 1.17 (range, 1.01-1.36), 0.97 (range, 0.83-1.13), and 1.19 (range, 1.04-1.37) in women. Men showed a J-shaped pattern for cardiovascular mortality and a linear pattern for noncardiovascular mortality in cause-specific analysis, whereas in women a U-shaped pattern was observed for noncardiovascular mortality only. Higher baseline hematocrit was associated with higher on-treatment blood pressure during follow-up. Baseline hematocrit did not affect the time to reach target blood pressure. The increased risk of death attributed to higher hematocrit was seen in men and women irrespective of their achievement of target blood pressure, indicating that the risk is independent of the effect of hematocrit on blood pressure. Hypertensive patients with hematocrit levels outside of the sex-specific reference ranges identified in this study should be targeted for more aggressive blood pressure and cardiovascular risk reduction treatment.

Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension.

A high heart rate (HR) predicts future cardiovascular events. We explored the predictive value of HR in patients with high-risk hypertension and examined whether blood pressure reduction modifies this association. The participants were 15,193 patients with hypertension enrolled in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial and followed up for 5 years. The HR was assessed from electrocardiographic recordings obtained annually throughout the study period. The primary end point was the interval to cardiac events. After adjustment for confounders, the hazard ratio of the composite cardiac primary end point for a 10-beats/min of the baseline HR increment was 1.16 (95% confidence interval 1.12 to 1.20). Compared to the lowest HR quintile, the adjusted hazard ratio in the highest quintile was 1.73 (95% confidence interval 1.46 to 2.04). Compared to the pooled lower quintiles of baseline HR, the annual incidence of primary end point in the top baseline quintile was greater in each of the 5 study years (all p <0.05). The adjusted hazard ratio for the primary end point in the highest in-trial HR heart rate quintile versus the lowest quintile was 1.53 (95% confidence interval 1.26 to 1.85). The incidence of primary end points in the highest in-trial HR group compared to the pooled 4 lower quintiles was 53% greater in patients with well-controlled blood pressure (p <0.001) and 34% greater in those with uncontrolled blood pressure (p = 0.002). In conclusion, an increased HR is a long-term predictor of cardiovascular events in patients with high-risk hypertension. This effect was not modified by good blood pressure control. It is not yet known whether a therapeutic reduction of HR would improve cardiovascular prognosis.

Direct-acting vasodilators.

KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Hydralazine and minoxidil act by dilating resistance arterioles, thus reducing peripheral resistance, with no dilating effect on the venous side of the circulation. • There is a baroreflex-mediated venoconstriction, resulting in an increase in venous return to the heart, along with a direct catecholamine-mediated positive inotropic and chronotropic stimulation of the heart. • Hydralazine therapy is usually combined with a sympathetic inhibitor to prevent expression of this reflex, as well as with a diuretic agent to prevent sodium retention caused by reduction in renal perfusion pressure. • Hydralazine is indicated in the long-term therapy of essential hypertension, in the short-term therapy of pregnancy-induced hypertension and eclampsia, and in the therapy of hypertensive crisis. • Adverse effects include the anticipated tachycardia, fluid retention, and headache, caused by the vasodilation, especially in the early days of therapy, but may frequently be prevented by the concomitant use of a ß-blocker. • As with other drugs that are N-acetylated, there is a low risk of lupus-like syndrome with high doses and long-term use. • Because of the severity of adverse effects with minoxidil, its usage is limited to persons with severe hypertension unresponsive to other treatments. • Hirsutism, a common side effect of minoxidil, is particularly bothersome in women and reverses in a few months after discontinuation. • Sodium nitroprusside is used in the intensive care setting to lower pressure in hypertensive crisis or to treat severe left ventricular failure, particularly valuable when elevated pressure or severe left ventricular failure threatens the patient's survival. • Although nitrates have not achieved widespread use as antihypertensive agents, they are effective in producing sustained blood pressure (BP) reductions when added to other antihypertensive regimens.

Long-term outcome following attendance at a transient ischemic attack clinic.

BACKGROUND AND PURPOSE: Many patients who attend transient ischemic attack clinics have a noncerebrovascular diagnosis. The long-term outcomes in this group are not well described. We evaluated these in a cohort referred to a transient ischemic attack clinic with a suspected transient ischemic attack. METHODS: Patients were clinically classified as having stroke or a transient ischemic attack or a noncerebrovascular diagnosis (nontransient ischemic attack). Follow-up was via electronic record linkage. The primary endpoint was cardiovascular death or a major cardiovascular event. Secondary outcomes included incident neurological disease (excluding stroke or transient ischemic attack) and the need for permanent pacemaker insertion. Outcomes in the transient ischemic attack and nontransient ischemic attack cohorts were compared using Cox's proportional hazards models. Mortality outcomes were further compared with those in a contemporary control group of individuals with hypertension. RESULTS: Of the 3533 patients who attended the transient ischemic attack clinic, 53.5% had a transient ischemic attack. Of these, 769 (40.7%) suffered a cardiovascular endpoint, compared with 458 (27.9%) with a nontransient ischemic attack (hazard ratio 1.53, 95% confidence interval 1.36-1.72). The risk remained higher but was attenuated following adjustment (hazard ratio 1.21, 95% confidence interval 1.05-1.41). Cardiovascular mortality in both groups was higher than that in hypertensive controls. The risk of a subsequent nonstroke neurological event was higher in those without a transient ischemic attack. CONCLUSIONS: Patients without a transient ischemic attack referred to a transient ischemic attack clinic have a high risk of future vascular events that exceeds risk in a cohort with hypertension. All patients attending transient ischemic attack clinics should undergo assessment of their cardiovascular risk and the use of methods to reduce this risk should be explored.

A double-blind, randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism.

BACKGROUND: Eplerenone is claimed to be a more selective blocker of the mineralocorticoid receptor than spironolactone being associated with fewer antiandrogenic side-effects. We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism. METHODS: The study was multicentre, randomized, double-blind, active-controlled, and parallel group design. Following a single-blind, placebo run-in period, patients were randomized 1: 1 to a 16-week double-blind, treatment period of spironolactone (75-225 mg once daily) or eplerenone (100-300 mg once daily) using a titration-to-effect design. To be randomized, patients had to meet biochemical criteria for primary aldosteronism and have a seated DBP at least 90 mmHg and less than 120 mmHg and SBP less than 200 mmHg. The primary efficacy endpoint was the antihypertensive effect of eplerenone versus spironolactone to establish noninferiority of eplerenone in the mean change from baseline in seated DBP. RESULTS: Changes from baseline in DBP were less on eplerenone (-5.6 ± 1.3 SE mmHg) than spironolactone (-12.5 ± 1.3 SE mmHg) [difference, -6.9 mmHg (-10.6, -3.3); P<0.001]. Although there were no significant differences between eplerenone and spironolactone in the overall incidence of adverse events, more patients randomized to spironolactone developed male gynaecomastia (21.2 versus 4.5%; P=0.033) and female mastodynia (21.1 versus 0.0%; P=0.026). CONCLUSION: The antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism.

Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial.

BACKGROUND: Short-term studies have suggested that the use of initial combination therapy for the control of blood pressure improves early effectiveness. We tested whether a combination of aliskiren and amlodipine is superior to each monotherapy in early control of blood pressure without excess of adverse events, and if initial control by monotherapy impairs subsequent control by combination therapy. METHODS: We did a double-blind, randomised, parallel-group, superiority trial at 146 primary and secondary care sites in ten countries, with enrolment from Nov 28, 2008, to July 15, 2009. Patients eligible for enrolment had essential hypertension, were aged 18 years or older, and had systolic blood pressure between 150 and 180 mm Hg. Patients were randomly assigned (1:1:2) to treatment with 150 mg aliskiren plus placebo, 5 mg amlodipine plus placebo, or 150 mg aliskiren plus 5 mg amlodipine. Random assignment was through a central interactive voice response system and treatment allocation was masked from the patients. From 16-32 weeks, all patients received combination therapy with 300 mg aliskiren plus 10 mg amlodipine. Our primary endpoints, assessed on an intention-to-treat basis (ie, in patients who received the allocated treatment), were the adjusted mean reduction in systolic blood pressure from baseline over 8 to 24 weeks, and then the final reduction at 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862. FINDINGS: 318 patients were randomly assigned to aliskiren, 316 to amlodipine, and 620 to aliskiren plus amlodipine. 315 patients initially allocated to aliskiren, 315 allocated to amlodipine, and 617 allocated to aliskiren plus amlodipine were available for analysis. Patients given initial combination therapy had a 6·5 mm Hg (95% CI 5·3 to 7·7) greater reduction in mean systolic blood pressure than the monotherapy groups (p<0·0001). At 24 weeks, when all patients were on combination treatment, the difference was 1·4 mm Hg (95% CI -0·05 to 2·9; p=0·059). Adverse events caused withdrawal of 85 patients (14%) from the initial aliskiren plus amlodipine group, 45 (14%) from the aliskiren group, and 58 (18%) from the amlodipine group. Adverse events were peripheral oedema, hypotension, or orthostatic hypotension. INTERPRETATION: We believe that routine initial reduction in blood pressure (>150 mm Hg) with a combination such as aliskiren plus amlodipine can be recommended. FUNDING: Novartis Pharma AG.

Resting heart rate pattern during follow-up and mortality in hypertensive patients.

There is a linear relationship between resting heart rate (HR) and mortality in normotensive and untreated hypertensive individuals. However, it is not clear whether HR is a marker of increased risk in hypertensive patients on treatment. We investigated the relationship between HR and mortality in patients with hypertension. We analyzed baseline HR, final HR, and HR change during follow-up in patients attending the Glasgow Blood Pressure Clinic. Using a threshold of 80 bpm, we classified patients into those who had a consistently high (high-high) or low (low-low) HR or patients whose HR increased (low-high) or decreased (high-low) over time. Survival analysis was carried out using Cox proportional hazards models adjusted for age, sex, body mass index, smoking, rate-limiting therapy, systolic blood pressure, and serum cholesterol. For each beat of HR change there was a 1% change in mortality risk. The highest risk of an all-cause event was associated with patients who had increased their HR by >or=5 bpm at the end of follow-up (1.51 [95% CI: 1.03 to 2.20]; P=0.035). Compared with low-low patients, high-high patients had a 78% increase in the risk of all-cause mortality (HR: 1.78 [95% CI: 1.31 to 2.41]; P<0.001). Cardiovascular mortality showed a similar pattern of results. Rate-limiting therapy did not have an independent effect on outcomes in this analysis. Change in HR achieved during follow-up of hypertensive patients is a better predictor of risk than baseline or final HR. After correction for rate-limiting therapy, HR remained a significant independent risk factor.

Does the ratio of serum aldosterone to plasma renin activity predict the efficacy of diuretics in hypertension? Results of RENALDO.

OBJECTIVES: We hypothesized that the aldosterone: renin ratio (ARR) predicts the antihypertensive response to mineralocorticoid receptor antagonist, spironolactone (SPIRO), when compared with bendroflumethiazide (BFZ). METHODS: We conducted a randomized, crossover, trial on hypertensive patients with either high ARR (HARR defined as >750 and plasma aldosterone >250 pmol/l) or low ARR (LARR defined as <300 and plasma renin activity <10 ng/ml per h). Each group took SPIRO 50 mg once daily for 12 weeks and BFZ 2.5 mg once daily for 12 weeks in random order separated by 2-week washout. Patients with mean 24-h systolic ambulatory blood pressure (SABP) at least 140 mmHg were included. Primary endpoint was difference in SABP between SPIRO and BFZ in patients with HARR compared with those with LARR. RESULTS: One hundred and eleven patients (60 HARR and 51 LARR) completed the study. SABP at 12 weeks in the HARR group was 129.4 mmHg on SPIRO and 134.4 mmHg on BFZ [difference -5.01; 95% confidence interval (CI) -7.51, -2.52; P < 0.0002]. In the LARR group, SABP was 129.7 mmHg on SPIRO and 133.1 mmHg on BFZ [difference -3.43 (95% CI -6.18, -0.68) P < 0.01]. Difference between groups (HARR vs. LARR) was -1.58 mmHg (95% CI 5.25, -2.08; not significant, P = 0.394). In a secondary analysis of the overall study population of 111 patients, SABP reduction with SPIRO 50 mg was superior to BFZ 2.5 mg [SPIRO -14.8 mmHg, BFZ -10.5 mmHg, difference -4.29 mmHg (95% CI -6.12, -2.46)]. Results were similar for secondary endpoints. Plasma renin activity or aldosterone did not predict blood pressure response to SPIRO. Results were independent of concomitant angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use. CONCLUSION: The ARR did not predict the blood pressure response to SPIRO. SPIRO 50 mg was significantly more effective than BFZ 2.5 mg in lowering SABP irrespective of baseline ARR, plasma renin activity or aldosterone.