ARBs, Diuretics, and Noise -- Plus New Guidelines for Children

Sunday, November 8, 2009

by Linda Brookes, MSc

Most of the news this month comes from the European Society of Cardiology conference that was held in Barcelona, Spain, August 29-September 2, 2009. Two Japanese trials investigated the benefits of angiotensin receptor blockers (ARBs), which appear to have benefit in angina and stroke, but not myocardial infarction. Is it because of their ability to lower blood pressure or is it the drug class itself that is responsible for these effects? The second trial --Valsartan Amlodipine Randomized Trial (VART) repeated the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, but this time with equal blood pressure lowering achieved for the ARB and the dihydropyridine calcium channel blocker (CCB); the results showed no difference in the cardiovascular endpoints. There was some speculation that the results provide further evidence that the renin-angiotensin system (RAS) has a larger role in vascular reactivity (angina, stroke) than in coronary disease where rupture of atheromas and thrombosis are major determinants, but the patient enrollments were different enough (younger, lower risk in VART) to make the comparison difficult. Further analysis of hypertension trials reporting a heart failure incidence looked at results in 217,387 patients and found that a diuretic (chlorthalidone preferred!) plus a RAS inhibitor are the best prevention. Although this appears to support the results of ALLHAT, the authors remain critical of that trial. Finally, the European Society of Hypertension (ESH) has formally published the new pediatric hypertension guidelines, first announced during the ESH conference in June, and in a wholly separate vein, a study has found that the higher the environmental noise in a child's living situation, the higher the mean blood pressure and the higher the risk fordisease later in life.

Valsartan Prevents Angina and Stroke but not Myocardial Infarction in High-Risk Japanese Hypertensive Patients

A large Japanese clinical study with valsartan in hypertensive patients has confirmed the efficacy of an ARB in lowering blood pressure and preventing stroke, but has failed to answer the lingering question about the efficacy of ARBs in preventing coronary events. The results of the KYOTO HEART study were presented by principal investigator Hiroaki Matsubara, MD (Kyoto Prefectural University School of Medicine) at the recent 2009 Congress of the European Society of Cardiology (ESC) in Barcelona, Spain[1] and published simultaneously in the European Heart Journal.[2] The study, which was carried out between January 2004 and January 2009, was funded by the Kyoto Prefectural University School of Medicine.

The study involved 3031 Japanese patients (43% women, mean age 66 years) with treated but uncontrolled hypertension (mean sitting systolic blood pressure [SBP] ≥ 140 mm Hg and/or diastolic blood pressure [DBP] ≥ 90 mmHg) and ≥ 1 additional risk factor. Following a prospective, randomized, open-label, blinded endpoints (PROBE) design, patients received either valsartan add-on or non-ARB treatment (conventional antihypertensive treatment other than ARBs or angiotensin converting enzyme [ACE] inhibitors) to reach the blood pressure goal of < 140/90 mm Hg or < 130/80 mm Hg in patients with diabetes mellitus or renal disease.[3] Valsartan was started at a dose of 40-80 mg and titrated to 100-160 mg as necessary to reach the target blood pressure (< 140/90 mm Hg or < 130/80 mm Hg in patients with renal disease).

The study was stopped early after a median follow-up of 3.27 years because of an unequivocal benefit seen with valsartan. During this time mean blood pressure was lowered from 157/88 mm Hg to 133/76 mm Hg. Compared with non-ARB treatment, valsartan add-on was associated with a 45% reduction in the primary endpoint of the trial, a composite of cardiovascular and cerebrovascular events (83 vs 155; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.42-0.72; P = .00001). This difference was mainly attributable to a 49% reduction in angina pectoris (P = .01 vs non-ARB) and a 45% reduction in stroke/transient ischemic attack (TIA) (P < .05 vs non-ARB). There were no significant differences in acute myocardial infarction (MI), heart failure, aortic dissection, and other endpoint components or in all-cause mortality or cardiovascular mortality. The incidence of new-onset diabetes was significantly lower with valsartan (P = .0282).

In the European Heart Journal, Prof. Matsubara and his colleagues speculated that the RAS has a larger role in the development of angina than in MI, in which rupture of atheromas and thrombosis are major determinants They suggested that sincevalsartan has been shown to have the highest selectivity for the angiotensin type 1 (AT1) receptor vs the AT2 receptor compared with other ARBs, AT2 receptor-mediated vascular protection via activation of bradykinin/NO system is more enhanced with valsartan treatment. They note that AT2 receptor is expressed in atherosclerotic lesions and that valsartan treatment effectively blocks coronary artery thickening and perivascular fibrosis.


Referring to this as the "ARB paradox" in Barcelona, ESC designated discussant, Frank Ruschitzka, MD (University Hospital, Zurich, Switzerland) called the results of the KYOTO HEART study "impressive, but almost too good to be true." Angina was a weak endpoint in the study, and he regarded it as being of minor value, particularly on the background of no benefit on MI. In an editorial in the European Heart Journal,[4] Dr Ruschitzka, along with coauthors Franz H. Messerli (St Luke's Roosevelt Hospital and Columbia University, New York) and Sripal Bangalore, MD (Brigham and Women's Hospital, Boston), described a meta-analysis that they carried out on 26 randomized non-heart failure trials of ARBs involving > 100,000 patients.[4] The analysis included the most recently reported trials, including TRANSCEND,[5] PRoFESS,[6] CASE-J,[7] HIJ-CREATE,[8] JIKEI,[9] as well as the KYOTO HEART study. Overall, they found a 13% reduction in the risk for stroke (P = .022) but a trend toward increased risk for MI (P = .06).

ARBs as a class have come of age and can be considered as preferred or baseline therapy in hypertension with regards to safety and efficacy, if efficacy is defined as blood pressure reduction, Dr Ruschitzka and his co-authors said. However, if efficacy is defined as a reduction in overall cardiovascular events and mortality, in view of the data in aggregate, ARBs should not be preferred, "or perhaps, not yet."

Effects of Valsartan and Amlodipine Differ in Japanese Hypertensive Patients in the Valsartan Amlodipine Randomized Trial

The results of another Japanese clinical trial involving valsartan in hypertensive patients, the Valsartan Amlodipine Randomized Trial (VART) were presented at ESC 2009 in Barcelona by Hiroya Narumi, MD (Chiba University Graduate School of Medicine, Chiba, Japan).[10] Similar to the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial,[11] VART compared valsartan with the CCB amlodipine, but following a PROBE design.[12]

VART was a multicenter trial involving a total of 1021 patients (mean age 60 years) enrolled at 92 medical facilities between June 2002 and March 2006. All patients were 30 years of age or older and newly diagnosed with hypertension (sitting SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg) or already being treated with antihypertensive drugs. Patients were followed until March 2008. After discontinuation of any previous antihypertensive therapy, patients initially received valsartan 80 mg/day or amlodipine 5 mg/day. These doses were increased to 160 mg and 10 mg, respectively, and alpha-blockers, beta-blockers, or diuretics were added if blood pressure was > 135/85 mm Hg. After registration, patients were followed up for 3 years for cardiovascular events (Primary endpoints), with use of echocardiography, laboratory tests, and blood pressure, plus 123I-metaiodobenzylguanidine (123I-MIBG) imaging (to depict myocardial sympathetic activity) for 1 year.

Blood pressure levels were controlled and remained equal in both treatment groups. At 36 months, mean blood pressure was 135 ± 13/80 ± 19 mm Hg in the patients on valsartan; and 135 ± 14/80 ± 10 mm Hg in the patients on amlodipine. There was no significant difference between the 2 treatment arms for the primary endpoint, a composite of all-cause death and cerebrovascular, cardiac, vascular, and renal events (HR, 1.0; 95% CI, 0.57-1.97; P = .943). Additionally there was no significant difference in the individual endpoints that made up the composite, including acute MI, stroke, and heart failure.

However, significant improvements were seen in a number of secondary endpoints. At 36 months, left ventricular mass index (LVMI) was decreased in both groups, but the percent change in the valsartan group was significantly greater compared with the amlodipine group (P < .05). Plasma norepinephrine was significantly decreased with valsartan (P = .00495), but there was no significant change with amlodipine. At 24 months, 123I-MIBG uptake, calculated as the heart/mediastinum ratio, was significantly increased in the valsartan group (P < .0001) but not in the amlodipine group. At 36 months, there was significant increase in the urinary albumin/creatinine ratio (UACR) in the amlodipine group (P < .0001), but not in the valsartan group. Diagnoses of new-onset diabetes mellitus were recorded in only 1.7% of the valsartan group vs 3.4% of the amlodipine group (odds ratio [OR] 0.47, 0.20-1.11), although the increase did not reach statistical significance in either group. Dr Narumi concluded that the results suggested that valsartan has more beneficial effects on the heart and kidney of Japanese hypertensive patients than amlodipine.


ESC session co-chair Roland E Schmieder, MD (University of Erlangen-Nuremberg, Germany) called the VART results "very important data," and asked why the striking differences seen in intermediate endpoints in the trial did not translate into a better prognosis. Dr Narumi suggested that the reasons might be that the VART patients were younger compared with those in other large-scale clinical trials such as VALUE (mean age 67 years),[11] and that the patients in other trials were at higher risk. For example, the percentage of patients with diabetes in VART (about 8%) was lower than in other trials. He also noted that most of the patients in VART (about 70%) were on monotherapy.

Diuretics Best for Prevention of Congestive Heart Failure in Hypertension

Diuretics are the most effective antihypertensive drugs for prevention of heart failure, closely followed by ARBs and ACE inhibitors, according to the results of a large network meta-analysis presented at ESC 2009.[13] Presenting the data in Barcelona, Sebastiano Sciarretta, MD (University of Rome "La Sapienza," Italy), said that their network meta-analysis, the largest ever performed in essential hypertension, showed that all antihypertensive strategies, with the exception of those based on alpha-blockers, were more effective than placebo in preventing heart failure. CCBs were significantly less effective than diuretics as first-line agents and they also tended to be inferior to RAS blockers and beta-blockers, with the differences being very close to statistical significance, Dr. Sciarretta reported.

Hypertension is a major risk factor for the development of heart failure. Estimates from the Framingham Heart Study indicate that persistent hypertension is the predominant contributory factor in 40% of men and 60% of women in whom heart failure develops. Despite all the evidence, however, heart failure is usually considered a "soft" endpoint in hypertension clinical trials and greater attention has been given to MI and stroke, Dr. Sciarretta noted. He and his colleagues recently showed in another meta-analysis of hypertension trials that the overall incidence of heart failure was comparable with other measured cardiovascular events, and not significantly different from that for stroke.[14]

"Since there was no conclusive evidence about the optimal antihypertensive therapy among different classes of drugs in heart failure prevention in hypertensive subjects," Dr. Sciarretta said, he and his colleagues carried out a network meta-analysis of recent trials in hypertension to investigate the most effective antihypertensive strategies in heart failure prevention. They used computerized searches of PubMed and Embase databases to find clinical studies published in peer-reviewed English-language journals between 1997 and December 2008. The investigators identified 25 trials involving patients with hypertension or at high cardiovascular risk with a predominant presence of hypertensive patients (> 65%), involving ≥ 200 subjects, with a duration of follow-up of ≥ 2 years that reported the absolute incidence of heart failure and other major cardiovascular events. Dr. Sciarretta explained that the Bayesian network meta-analysis that they performed is a more powerful meta-analytic technique that combines direct evidence provided by clinical trials with indirect evidence constructed from studies that have treatments in common.

The 25 trials identified involved a total of 217,387 subjects. Among these individuals, 40.3% were randomized to receive "traditional" antihypertensive therapy, including mostly diuretics and anti-adrenergic agents; 18.6% of patients were assigned to diuretic-based therapy, 4.1% patients to alpha-blockers, and 2.2% to beta-blockers. The remaining patients were treated with the "newer" antihypertensive drug classes, including CCBs, ACE-inhibitors, and ARBs. In addition, 7.1% of patients were randomized to receive placebo or the best standard treatment for their condition. The trials used different definitions of heart failure, which was most often a secondary endpoint.

A total of 8291 new heart failure cases occurred in the trials. All the antihypertensive therapies with the exception of those based on alpha-blockers were more effective in preventing heart failure onset compared with placebo. Diuretics were the most effective class of drugs (OR, 0.56; 95% CI, 0.44-0.69), followed by ARBs (OR, 0.67; 95% CI, 0.52-0.80) and ACE-inhibitors (OR, 0.67; 95% CI, 0.56-0.79). CCBs appeared to have the smallest effect (0.78; 0.62-0.92). From direct comparisons in trials, diuretics appeared to be significantly more effective than ACE inhibitors, CCBs, and beta-blockers; although more effective than ARBs, this difference was not significant.

Because the trials used different definitions of heart failure, the investigators performed 3 subanalyses. The first included only studies that did not enroll patients with heart failure at baseline; the second excluded the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) studies (because of criticism about the diagnosis of heart failure in this study); and the third excluded the ALLHAT studies and other trials that also included an endpoint of non-hospitalized heart failure. However, the results of these subanalyses did not differ from those of the main analysis, in that diuretics still appeared to be the most effective compared with the other drug classes and CCBs appeared to be less effective than the others.


Dr. Sciarretta noted that this meta-analysis was unable to reveal any information about the influence of differences in blood pressure, but he noted that previous landmark meta-analyses showed that heart failure prevention was independent of blood pressure reduction.[15,16] He suggested that the most effective first-line therapy for prevention of heart failure in hypertensive patients is a combination of a low-dose diuretic and a RAS inhibitor.

Commenting on the results of the analysis, ESC session co-chair, Prof. Schmieder pointed out that diuretics differ substantially with respect to the duration of effect on blood pressure and dosage. "We know well from hypertension trials like ALLHAT[17] that chlorthalidone has a long-lasting effect at low dose, and it has been said that we will never see that result with hydrochlorothiazide (HCTZ)," he said. He noted that chlorthalidone is not used as much in Europe as it is in the United States, and not at doses > 25 mg because of potential adverse metabolic effects.

European Society of Hypertension Issues First Pediatric Hypertension Guidelines

The European Society of Hypertension's guidelines for the management of hypertension in children and adolescents, first announced at the European Meeting on Hypertension in May, have been published as a position statement in the Journal of Hypertension.[17] The guidelines comprise recommendations for diagnosis and treatment of hypertension in patients aged ≤ 18 years, a group largely omitted from previous European hypertension guidelines.[18] The new guidelines are aimed primarily at pediatricians and general practitioners.

These guidelines were prepared by a Task Force chaired by Empar Lurbe, MD, PhD (Consorcio Hospital General, University of Valencia, Spain). They represent a consensus among specialists involved in the detection and control of high blood pressure in children and adolescents. They include:

  • Definition and classification of hypertension;
  • Diagnostic evaluation;
  • Preventative measures;
  • Evidence for therapeutic management;
  • Therapeutic strategies and approaches under special conditions;
  • Treatment of associated risk factors; and
  • Screening for secondary forms of hypertension.

In the definition and classification of hypertension, Prof. Lurbe and co-authors acknowledge that because of the large amount of data available, the 2004 US national guidelines on hypertension in children and adolescents remain "the study of reference." However, they point out that the data of the US Task Force do not refer to a European population and that at all ages, blood pressure values are several millimeters of mercury lower than those measured by the same auscultatory method in several European studies. Both reports define normal blood pressure in children as SBP and DBP less than 90th percentile for age, sex, and height, and hypertension as SBP and/or DBP persistently at the 95th percentile or higher, measured on ≥ 3 separate occasions with the auscultatory method. Children with average SBP or DBP 90th percentile or more but < 95th percentile are classified as having high-normal blood pressure; adolescents with blood pressure 120/80 mm Hg, even if less than 90th percentile, are also considered as having high-normal blood pressure.

Blood pressure targets are < 90th percentile for age, gender, and height. In children with chronic kidney disease, the target is blood pressure < 75th percentile in children without proteinuria and < 50th percentile in cases of proteinuria. Data from lifestyle intervention trials in children on which to base recommendations are limited at present, but most recommendations, including moderate to vigorous aerobic physical activity, are "obvious and common sense," the Task Force says. The decision to initiate antihypertensive treatment should not be taken on blood pressure levels alone, but should also consider the presence or absence of target organ damage, other risk factors, or diseases such as obesity, renal diseases, or diabetes mellitus.

Pharmacologic therapy should be initiated when patients have symptomatic hypertension, hypertensive target organ damage, secondary hypertension, or diabetes mellitus type 1 or 2 at the time of presentation. Although clinical studies are under way, there are currently limited data from trials of antihypertensive drugs in children and recommendations are based on a few industry-sponsored studies, and mostly on single-center case series, collective clinical experience, expert opinion, and extrapolation from data obtained in adults. Pediatric studies have been conducted with a limited number of beta-blockers, CCBs, ACE inhibitors, and ARBs, but only 1 very small study has been conducted on a diuretic (chlorthalidone, in 1984), the guidelines note. Recent European Union regulations have provided incentives for pharmaceutical companies to carry out pediatric studies of cardiovascular drugs, and this is expected to increase the availability of these medications authorized for children. For selecting combination therapy, the guidelines recommend following these choices presented in the 2007 ESH/ESC hypertension guidelines.

Finally, the Task Force calls attention to the burden of hypertension in children and adolescents, and its contribution to the current epidemic of cardiovascular disease.

"These guidelines should encourage public policy makers, to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents," the Task Force says.

Traffic Noise at Home May Affect Children's Blood Pressure

Data on the effects of exposure to road traffic noise on blood pressure in children are contradictory. The latest study, published in Science of the Total Environment,[21] appears to show small increases in SBP and DBP in children exposed to noise from busy streets at home. These increases were not clinically significant at the time, but they may predict rises in blood pressure later in life that might be damaging to health, the investigators believe.

Wolfgang Babisch, PhD (Federal Environment Agency), and colleagues in Berlin, Germany, investigated the effect of road traffic noise on a random sample of children aged 8-14 years from the German Environmental Survey for Children (GerES IV), carried out by the Agency between 2003 and 2006. The sample of 1048 children was representative of children in this age group living in Germany with respect to gender, community size, and geographic region. All the children had had a hearing test. Blood pressure was measured under standardized conditions at clinical study centers. During home visits, exposure to road traffic noise was determined by the parent's classification of the type of road in front of the children's room, and by orientating short-term noise measurements carried out during the day in front of the children's room window. The children and their parents were asked about leisure activities, housing conditions, and environmental factors. Blood pressure measurements were carried in ad hoc medical clinics so the resting blood pressure measurement reflected a chronic state of the children's circulatory system, which was not affected by the acute noise situation at home.

The lowest blood pressure readings were found in children whose room was facing a street with 'low traffic.' The highest readings were found in the group where the children's rooms were facing a street with a 'high or extremely high traffic' volume. After adjustment for age, gender, area, socioeconomic status, migrant status, agglomeration size, height, weight, and physical activity, higher blood pressure readings were found in the children exposed to noise in the highest categories. The difference between children who lived on a "busy traffic street" and an "extremely busy traffic street" and those living on a "low traffic street" was statistically significant for SBP (1.8 mm Hg, P = .036) but not for DBP (0.5 mm Hg). Short-term noise was associated with significant increases of 1.0 mm Hg (P = .004) in SBP and 0.6 mm Hg (P = .025) in DBP per 10 dB(A) increment of the noise level. The association between the noise level and SBP was 1.39 mm Hg per 10 dB(A) (P = .001)). No noise effects on heart rate were identified.

"J-shaped" associations were found when the presumably quietest category ("no street") was considered as the reference group. This group had a slightly higher SBP and DBP on average -- 0.6 and 0.5 mm Hg, respectively -- than the "low traffic" group. This may be due to road traffic in the distance when there was no street right in front of the children's bedroom, Dr Babisch and co-authors suggest. Although the 15-minute short-term noise measurements did not reveal a difference in the average equivalent sound pressure level between those groups, children from the "no street" group were slightly more annoyed by road traffic noise than the 'low traffic' group.

Dr. Babisch believes that the arteriosclerotic manifestations of increased blood pressure were unlikely to have been present in these children. "The effect may rather be due to sympathetic arousal, which is more pronounced in SBP," he suggests. The results confirm the findings of other studies where slightly higher blood pressure readings were found in children exposed to high noise levels at home or at school/day care centers.

With regard to possible health risks in later life, the findings in children are difficult to interpret, the researchers admit. "The effect may be of a temporary nature and may not be relevant to permanent health damage. On the other hand, there is evidence that during childhood and adulthood the blood pressure level at an early age is an important predictor of the blood pressure level at a later age," they say.


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