ARBITER 6-HALTS: HDL Raising With Niacin Superior to Ezetimibe

by Michael O'Riordan

Technorati Tags: dislipidemia,ezetimibe,niacin

November 18, 2009 — Adding extended-release niacin (Niaspan, Abbott) to statin therapy results in a significant regression of atherosclerosis as measured by carotid intima-media thickness (IMT), whereas the addition of ezetimibe (Zetia, Merck/Schering-Plough) to statin therapy did not, according to an eagerly anticipated study [1].

The results, from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6: HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study, were presented at the American Heart Association 2009 Scientific Sessions and published simultaneously online in the New England Journal of Medicine.

"The proper framework of the ARBITER 6-HALTS study is to compare the effectiveness of two drugs," lead investigator Dr Allen Taylor (Medstar Research Institute, Washington, DC) told heartwire . "In this regard, the data are clear--niacin is clearly superior to ezetimibe. That's good news for patients, and it's also good news for doctors who need to know how different drugs compare against one another so they can practice evidence-based medicine."

Dr James Stein (University of Wisconsin, Madison), who was not part of the ARBITER 6-HALTS trial, told heartwire that while the study tells clinicians little, if anything, about ezetimibe, the results are good news for niacin.

"If you practice evidence-based medicine in 2009, after high-dose statin therapy, niacin is your number-two drug," he said. "The amount of evidence available for niacin, although it's less than for high-dose statins, dwarfs the evidence available for any of the prevention interventions that we currently have available. It certainly dwarfs the evidence available for ezetimibe and fibrates, and we really think that niacin should be the number-two drug for all patients who are taking a statin and that doctors should rarely be using ezetimibe these days."

Dr Steven Nissen (Cleveland Clinic, OH), also commenting on the results for heartwire , called ARBITER 6-HALTS a classic "comparative-effectiveness" study and said there have been calls in the US legislature for such trials for the past few years.

"Now, here it is," he said. "Niacin is a 50-year-old drug, and you can buy it over the counter at your local pharmacy. When you have an inexpensive therapy like this--there are issues about being able to tolerate high-dose niacin, but if you get patients to tolerate it--niacin looks to be a better strategy."

Significant Difference in IMT

The results of the ARBITER 6-HALTS study have been keenly awaited, but not because clinicians questioned the efficacy of niacin. Previous studies have shown that niacin, alone or in combination with other drugs, including simvastatin, was associated with plaque stabilization or a modest regression of atherosclerosis.

Instead, the ARBITER 6-HALTS study was anticipated because investigators compared two distinct lipid-modifying strategies in patients who had or who were at high risk for vascular disease but who had LDL-cholesterol levels <100 mg/dL and moderately low HDL-cholesterol levels (<50 mg/dL). Among the 363 patients enrolled in the study, half were randomized to a treatment that further reduced LDL-cholesterol levels with the addition of ezetimibe (10 mg/daily) to statin therapy, while the other half were randomized to HDL-raising therapy with extended-release niacin (2000 mg/daily).

Coupled with the unique treatment approaches, many wondered how ezetimibe would fare given its rash of negative press from recent clinical trials, among them the controversial ENHANCE study and the SEAS trial.

In ARBITER 6-HALTS, men and women with known vascular disease or coronary-disease risk equivalents treated with statins for at least three months prior to randomization were included in the study. At baseline, the mean LDL-cholesterol level was 84 mg/dL and 81 mg/dL in the niacin- and ezetimibe-treatment arms, respectively. After 14 months of treatment, mean HDL-cholesterol levels among the niacin-treated patients increased 18.4% to 50 mg/dL. In the ezetimibe arm, LDL-cholesterol levels further declined 19.2% to 66 mg/dL.

Compared with ezetimibe, treatment with niacin resulted in significantly larger changes in the mean and maximal carotid IMT over 14 months. From baseline, niacin resulted in a significant regression of mean and maximal carotid IMT when measured at eight months and 14 months, whereas there was no significant change in mean or maximal IMT among those treated with ezetimibe. Although not powered for clinical outcomes, there were more major cardiovascular events in the ezetimibe arm compared with those in the niacin arm (nine events vs two events, respectively; p=0.04).

Addressing the results, Taylor said the findings answer an important clinical question in secondary prevention. "If my patient is on a statin, then where do I go from here?" he said. "These results suggest that niacin is superior in a head-to-head trial with ezetimibe."

Stein, a researcher with experience in IMT studies, said the amount of regression with niacin is significant.

"The difference between niacin and ezetimibe in the IMT measurements is very large," he told heartwire . "The difference of 0.017 mm over 14 months is on the order of statin therapy vs placebo. It's essentially as effective as a statin and would be expected to translate into a large difference in cardiovascular events, which was observed in this study, although they occurred in a study that was short and small."

In a post hoc analysis exploring the relationship between changes in LDL-cholesterol levels and mean carotid IMT, investigators observed a "significant inverse relationship" between changes in LDL-cholesterol levels and mean carotid IMT in the ezetimibe arm, "such that a paradoxical increase in the carotid IMT was seen in patients with greater reductions in LDL cholesterol."

Taylor said his group performed the post hoc analysis based on the null effect with ezetimibe because they wanted to determine whether any patients, particularly those with the lowest on-treatment LDL-cholesterol levels, might have benefited from the LDL-cholesterol–lowering drug. The inverse relationship is counterintuitive, he acknowledged, and while it is only a weak to modest association, he said it raises some concerns about possible unintended biologic effects with the agent.

Relying on Surrogate End Points for Clinical Decisions

Speaking with heartwire , Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles) cautioned against making too much of the overall results, especially since ARBITER 6-HALTS was a small, short-duration, surrogate-end-point study that was prematurely stopped (40% of patients did not undergo the final IMT measurement at 14 months). He said that physicians should take these issues into account when interpreting the findings.

He expressed particular concern about the study's early termination, as did an editorial by Drs Roger Blumenthal and Erin Michos (Johns Hopkins University, Baltimore, MD) [2], saying there are only three reasons a trial should be stopped, and these are futility, unacceptable safety profile, or a large treatment effect where the ethical imperative is to protect the trial participants.

While the treatment effect between niacin and ezetimibe achieved statistical significance at the time of the interim analysis, he said that differences in carotid IMT do not justify early termination, because it is unclear what these differences actually mean. Although he also criticized the early termination of JUPITER, the rosuvastatin study, in 2008, that study was at least terminated early because of differences in hard clinical outcomes.

"I don't think we should be relying on surrogate-end-point studies to make clinical decisions," he said. Kaul noted that the use of carotid IMT remains controversial and that the United States Preventive Services Task Force recently concluded that the evidence available to assess benefits and harms using nontraditional risk factors, including carotid IMT, as a risk-prediction tool in asymptomatic men and women is insufficient. He said it is still unknown at this point if the difference in IMT outcomes between ezetimibe and niacin will translate into clinically relevant outcomes.

"The results of this study do not provide any new insights and are unlikely to change my practice of prescribing ezetimibe only as a third-choice agent after trying statins as first choice and niacin, fibrates, or resins as second choice," he said.

To heartwire , Taylor said the trial was stopped because of a precisely defined prespecified interim analysis showing niacin to be superior to ezetimibe. Nissen called the discussion about the early termination "insider baseball," saying that while it can be debated whether or not the study should have been stopped, he said, "No reasonable person is going to look at the results and believe that the early termination had any impact on what happened. There are points to be made, but the real question is which strategy is best, and this study provides a hands-down winner."

Strengths and Weaknesses

To heartwire , Stein said the fact that such a large difference was able to be shown in such a short period of time tells doctors that the treatment effect was large. Although they differ on the significance of the IMT findings, Stein and Kaul both said the post hoc findings should be regarded with caution given the potential for confounding in these analyses.

According to Stein, while some might see the study as an indictment of ezetimibe, ARBITER 6-HALTS "tells us nothing about ezetimibe's effectiveness, because there was no placebo arm, but instead tells us that niacin is more effective than ezetimibe for preventing the progression of carotid atherosclerosis." One could argue, he said (although he doesn't believe the argument), that the lack of progression in the ezetimibe arm means the much-maligned drug was "doing something."

"At the end of the day, ARBITER 6 is really just an IMT study that looks at different strategies of lowering LDL vs raising HDL cholesterol," Stein told heartwire . "But we have to remember that niacin does a lot more than raise HDL cholesterol--that's what makes the study a little more complicated than saying it is a direct comparison of LDL lowering vs HDL raising. Niacin raises HDL cholesterol, but it also lowers LDL cholesterol, lowers triglycerides, and makes LDL particles bigger, so it’s really a multiple lipoprotein intervention."

To heartwire , Taylor agreed, but said that clinicians primarily select niacin to raise HDL cholesterol and rarely use the drug to lower LDL cholesterol or triglyceride levels. Data from clinical trials, including HATS, show the benefit of niacin to be primarily from changes in HDL cholesterol, he said.

Dr Richard Karas (Tufts Medical Center, Boston, MA), who was also not part of the study, told heartwire that given the relationship between HDL cholesterol and the risk of cardiovascular events, the results are in line with what would be expected from a drug that increases HDL cholesterol approximately 20%. By increasing HDL cholesterol to 50 mg/dL, clinicians are able to significantly decrease the residual risk of patients treated with statins alone, whereas the extra boost from LDL lowering has little impact on that risk. Like Stein, he said that ARBITER 6-HALTS tells clinicians little about ezetimibe and that they must wait until outcomes studies are completed.

The Outcomes Studies

IMPROVE-IT, the large clinical-outcomes study with ezetimibe, is expected in 2012 but likely to be later, while SHARP, a study of ezetimibe in patients with renal failure, is also under way. The two much-anticipated outcome studies for niacin are AIM-HIGH, due out in 2011, and HPS2-THRIVE, which is expected to be completed in 2013.

As an aside, editorialists Drs John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) and Michel Bots (University Medical Center, Utrecht, the Netherlands) [3], as well as Nissen, raised concerns about whether IMPROVE-IT would ever reach completion. More than 5000 hard clinical end points are needed for the study to reach statistical significance, an unusually high number given that past studies, including JUPITER, required a few hundred events. Based on these concerns, many clinicians, among them Kaul and Nissen, reiterated their displeasure with an approval process that allowed ezetimibe to be on the market for more than a decade before any hard clinical end-point data are available.

Results Likely to Be Correct

In an editorial accompanying the published study, Kastelein and Bots write that the ARBITER findings are likely to be correct, although they, like others, suggest the magnitude of difference might be exaggerated because the trial was stopped early. Still, they argue in favor of a treatment approach with niacin.

"Together, the results available to date provide support for the concept that the use of statins to reduce LDL to target levels with the subsequent addition of a drug to raise HDL-cholesterol levels (niacin), rather than a drug to lower LDL-cholesterol levels (ezetimibe), is a more effective treatment for patients at high cardiovascular risk," they write.

In the second editorial, Blumenthal and Michos say there is substantial evidence for initial use of a statin in patients with an increased risk of vascular disease, but if the lipid goal can't be met with a statin alone, the choices of adjunctive therapy include a fibrate, niacin, a bile-acid sequestrant, n-3 fatty-acid supplements, or ezetimibe. For their money, though, they "support the use of niacin as the preferred adjunctive agent to be used in combination with the maximal dose of a potent statin in persons who have low levels of HDL cholesterol and established cardiovascular disease."

Abbott sponsored the ARBITER 6-HALTS study. Taylor reports receiving lecture fees from Abbott. Stein reports serving on the data monitoring committee for a nonniacin, Abbott-sponsored study, receiving a research grant from Siemens and SonoSite, and receiving royalties from the University of Wisconsin for carotid ultrasound and risk prediction not related to the ARBITER 6-HALTS study. Kastelein reports receiving consulting fees, lecture fees, and grant support from Merck and lecture fees from Schering-Plough. Bots reports lecture fees and grant support from AstraZeneca.

References

1. Taylor AJ, Villines TC, Stanck EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009; DOI:10.1056/NEJMoa907569. Available at: http://www.nejm.org.
2. Blumenthal RS, Michos ED. The HALTS trials--halting atherosclerosis or halted too early? N Engl J Med 2009; 361:2178-2180.
3. Kastelein JJ, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. N Engl J Med 2009; 361: 2180-2183.

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No Benefits of Aspirin for Primary Prevention in Diabetics, Meta-Analysis Suggests

by Shelley Wood

Technorati Tags: Aspirin,Diabetes,cardiovascular event

Another meta-analysis--this one focused on diabetics--is questioning the role of aspirin for the primary prevention of cardiovascular events [1]. Writing in a paper published online November 6, 2009 in BMJ, Dr Giogria De Berardis (Consorzio Mario Negri Sud, Maria Imbaro, Italy) and colleagues conclude that "a clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved."

We need to select very carefully the patients who are more likely to benefit.

De Berardis and colleagues point out that almost all of the major society guidelines recommend aspirin for primary prevention of cardiovascular events in people with diabetes, based on the evidence extrapolated from trials of high-risk patients. "Patients with diabetes have high cardiovascular risk, so it was supposed that aspirin was also effective in patients with diabetes," senior author Dr Antonio Nicolucci (Consorzio Mario Negri Sud) told heartwire . "But if we look at specific data coming from trials conducted in individuals with diabetes, quickly we realize that the evidence is not so strong."

Nicolucci, De Berardis, and their coinvestigators reviewed the literature for trials comparing aspirin with placebo or no aspirin in patients with diabetes and no known diagnosis of cardiovascular disease, ultimately identifying six eligible trials. When all of the data were combined, the authors found no statistically significant differences in the risk of major cardiovascular events, cardiovascular mortality, all-cause mortality, MI, or stroke, and "inconsistent" evidence of harm from aspirin use. In an analysis by sex, aspirin in men appeared to significantly reduce the risk of MI by 43%, but no significant reduction in MI was seen in women.

Effect of Aspirin Compared With Placebo or No Aspirin on Relative Risk of Clinical Events in Patients With Diabetes

End point	Relative risk	95% CI	p
Major cardiovascular events	0.90	0.81–1.00	0.06
MI	0.86	0.61–1.21	0.37
Stroke	0.83	0.60–1.14	0.25
Cardiovascular death	0.94	0.72–1.23	0.68
All-cause mortality	0.93	0.82–1.05	0.22
Any bleeding	2.50	0.76–8.21	NS

To heartwire , Nicolucci pointed to the meta-analysis [2] of aspirin for primary prevention published earlier this year in the Lancet by the AntithromboticTrialists' Collaboration and reported by heartwire --an update to their pivotal 2002 meta-analysis [3].

"It seems that not only in individuals with diabetes, but also in all other high-risk groups, the efficacy of aspirin for primary prevention is lower than expected. It doesn't mean that aspirin is not effective, it means that the efficacy is lower than expected, and that means we need to select very carefully the patients who are more likely to benefit."

Asked whether he thought guidelines should change, Nicolucci pointed out that guideline-writing committees are already softening their blanket recommendations.

"In the most recent guidelines from the Canadian Diabetes Association, for the first time they fully acknowledged the lack of definite data on the efficacy of aspirin, and they leave to the physician the decision of whether or not to use aspirin based on the characteristics of the individual patients. And the other [guideline groups] are starting to move from certainty to uncertainty as well."

Randomized Trial Results Needed

Two trials are currently trying to answer key questions about risk and benefit of aspirin for primary prevention in diabetic subjects: A Study of Cardiovascular Events in Diabetes (ASCEND) and the Aspirin and Simvastatin Combination for CardiovascularEvents Prevention Trial in Diabetes (ACCEPT-D).

In an accompanying editorial [4], Drs Richard Haynes, Louise Bowman, and Jane Armitage (Clinical Trial Service Unit, Oxford, UK) write that the evidence to date suggests "a modest but consistent reduction in the risk of vascular events with aspirin" but ongoing uncertainty as to whether these benefits are "clinically worthwhile" and outweigh the risks of bleeding.

Until clinical-trial results are in, they write, clinicians should use approaches "known to minimize cardiovascular risk (such as avoidance of smoking, [the use of] statins [and] ACE inhibitors, and good glucose control) before thinking about adding aspirin." Moreover, they note, "guidelines need to acknowledge the current equipoise and not recommend a treatment without supporting evidence, so that clinicians and their patients are fully aware of the evidence when making a decision."

To heartwire , Nicolucci points to another issue that warrants further exploration: whether there are specific characteristics of diabetic pathophysiology that make aspirin less likely to function as expected.

"There's strong basic research evidence suggesting that diabetes can represent a particular situation associated with poor response of platelets to aspirin, and there are many reasons for that," Nicolucci noted. "Diabetes is associated with hyperglycemia, hyperinsulinemia, insulin resistance, oxidative stress, and advanced glycation end products, and all these factors can be responsible for activation of platelets [via] different pathways that are not blocked by aspirin."

Nicolucci have disclosed no relevant financial relationships; he is principal investigator for ACCEPT-D. The editorialists having disclosed no relevant financial relationships; Armitage and Bowman are principal investigators for ASCEND.

References

1. De Berardis G, Sacco M, Strippoli GFM, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: Meta-analysis of randomised controlled trials.  BMJ 2009; DOI:10.1136/bmj.b4531. Available at: http://www.bmj.com.
2. Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849-1860.
3. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71-86.
4. Haynes R, Bowman L, Armitage J. Aspirin for primary prevention of vascular disease in people with diabetes. BMJ 2009; DOI:10.1136/bmj.b4596. Available at: http://www.bmj.com.

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Pericardial fat a better predictor of CHD than BMI

by Lisa Nainggolan

Technorati Tags: coronary heart disease,chest pain,Acute myocardial infarction,angina pectoris

Winston-Salem, NC- A new study has shown that fat around the heart—so-called pericardial fat—predicts coronary heart disease (CHD) independent of conventional risk factors [1].

In fact, pericardial fat may be a better predictor of an individual's future risk of CHD than either body-mass index (BMI) or waist circumference, say Dr Jingzhong Ding (Wake Forest University School of Medicine, Winston-Salem, NC) and colleagues in their paper in the September 2009 issue of the American Journal of Clinical Nutrition.

Ding told heartwire: "We and other groups have previously found in cross-sectional studies that pericardial fat is related to coronary artery disease. Our new study extends the findings to demonstrate that pericardial fat predicts the future development of clinical events of CHD and that this kind of prediction is beyond that conferred by conventional obesity measures—the first time this has been shown."

Inflammatory cytokines secreted by pericardial fat could be the culprits

Ding et al conducted a case-cohort study in 998 individuals randomly selected from the more than 6000 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), who had no history of CVD. The volume of pericardial fat was measured using cardiac CT scans performed at baseline in MESA.

Of the 998 individuals, 26 developed incident CHD during follow-up, from 2000 to 2005. Pericardial fat was positively correlated with both BMI (correlation coefficient=0.45; p<0.0001) and waist circumference (correlation coefficient=0.57; p<0.0001).

In unadjusted analyses, pericardial fat (relative hazard per one standard deviation increment 1.33), but not BMI (1.00), was associated with the risk of CHD. Waist circumference was marginally associated with CHD risk (1.14; p=0.1). The relation between pericardial fat and CHD remained significant after further adjustment for BMI and other cardiovascular disease risk factors (1.26).

"Our data support the idea that pericardial fat is a better predictor of incident CHD than are more general measures of adiposity (eg, BMI or waist circumference)," say Ding et al. "The present study extends the findings of other research in this field by relating pericardial fat to incident CHD in community-based adults without a history of CVD," they add.

Ding says he and his colleagues have a theory as to the possible mechanism underlying the link between pericardial fat and CHD. "The pericardial fat secretes many chemicals, such as inflammatory cytokines like IL-6," he noted. "We can postulate that direct secretion of such substances might lead to the development of atherosclerosis in the coronary arteries." Pericardial fat is also known to secrete such inflammatory cytokines at a higher rate than subcutaneous fat, he adds.

More research needed on pericardial fat

He told heartwire that much more research is needed on pericardial fat. In general, older people have been found to have more pericardial fat than younger ones, and the volume of pericardial fat does seem to correlate with BMI and other obesity measures, as shown in the current study. But slim people also have pericardial fat, he noted, and it is not known what amount is "normal," if any. Whether babies have pericardial fat present at birth, for example, is unclear. Nor is it known whether there is any kind of cutoff amount of this fat above which it becomes hazardous.

Future studies should also examine whether pericardial fat is the primary fat depot regarding the risk of developing CHD, after other regional fat depots are controlled for, say he and his colleagues. "If the hypothesis is confirmed, pericardial fat may serve as a more specific and sensitive marker of CHD than other fat measures."

However, they note that routine CT scans are not feasible for mass screenings at the present time, but the echocardiographic measurement of pericardial fat "has potential for CHD risk stratification."

"Ultimately, with a better understanding of the determinants of pericardial fat accumulation and the underlying mechanism of the link between pericardial fat and CHD, new therapeutic targets may be identified in the prevention of CHD," they conclude.

Source

1. Ding J, Hsu F-C, Harris TB, et al. The association of pericardial fat with incident coronary heart disease: the multi-ethnic study of atherosclerosis (MESA). Am J Clin Nutr 2009; 90:499-504.

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Drug-eluting stents for erectile dysfunction

by Shelley Wood

Technorati Tags: DES,Stents,Mandul,Erectile dysfunction,Disfungsi Ereksi

San Francisco, CA - Nine hospitals in the US are embarking on a stent trial that will no doubt perk the attention of interventionalists and patients alike. Amid all of the larger coronary stent trials making waves at TCT 2009 last week, Dr Jason H Rogers (UC Davis Medical Center, Sacramento, CA) got up and announced the launch of the ZEN trial, testing the use of a zotarolimus-eluting stent for the treatment of erectile dysfunction.

The trial, sponsored by Medtronic, is enrolling 50 men who've failed treatment with phosphodiesterase-5 (PDE-5) inhibitors and have angiographic evidence of internal pudendal artery disease amenable to percutaneous treatment.

Speaking with heartwire after TCT, Rogers reviewed the rationale for the trial. In four out of every five men with erectile dysfunction, he notes, the etiology is vasculogenic, and erectile dysfunction itself shares a host of risk factors with coronary artery disease, including age, diabetes, hypertension, dyslipidemia, and smoking.

"Up to 70% of men with coronary disease also have erectile dysfunction," Rogers said. "The development of erectile dysfunction predates the onset of symptomatic atherosclerotic disease by approximately 36 months, [yet] erectile dysfunction is not routinely screened by vascular specialists."

Correlation between vascular beds

Rogers and colleagues have already completed a pilot study, called the Pelvic Angiography in Non-Responders to PDE-5 Inhibitors (PANPI), which correlated angiographic evidence of coronary disease with pudendal arterial disease. In PANPI, 10 patients undergoing coronary angiography for CAD symptoms who also reported a poor response to PDE-5 inhibitors underwent a pelvic angiogram as well. Results showed that stenosis in the coronary arteries typically mirrored that of the pudendal artery, which ranged from a mean of 52% in the right internal pudendal artery to 60% in the left.

"We basically found a 100% correlation" between coronary artery disease and pudendal artery disease, Rogers told heartwire, "The pattern of disease is similar to that of the coronary arteries, and it appeared that it would be amenable to a stent."

Surprisingly—or not—men enrolled in PANPI were not overly interested in their coronary angiograms. "Despite the fact that we were diagnosing significant stenosis in the [left anterior descending] LAD, circumflex, and right coronary arteries, what they cared about was what the pudendal angiograms were showing," Rogers said.

Rogers noted that, to the best of his knowledge, there are no other studies looking at drug-eluting stents in the pudendal artery, although there were some early angioplasty studies that typically failed to demonstrate a long-term benefit due to problems of restenosis. Rogers would not reveal what stent is being used in ZEN, saying only that Medtronic was "leveraging technology in its inventory" and that this device was zotarolimus-eluting.

He also clarified: "This isn't stenting the penis," but rather the pudendal artery, which is located in the pelvis.

The ZEN trial represents a new opportunity for collaboration between urologists and cardiologists, Roger added—disciplines that have not interacted closely in the past. "A key message for cardiologists is that our practice is actually rich in patients with erectile dysfunction, and we don't do as good a job as we should at identifying people with erectile dysfunction," he told heartwire. "It's been shown that erectile dysfunction is a risk factor for CAD or CVD, and potentially, there may even be a therapy for this that cardiologists could deliver."

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Diuretics effective as second-line therapy for hypertension

by Lisa Nainggolan

Technorati Tags: hypertension,diuretics,hipertensi

Vancouver, BC - Diuretics, when given as second-line therapy to treat hypertension, reduce blood pressure to about the same extent as when they are used as first-line treatment, a new review shows.

The results also indicate that the BP-lowering effect of diuretics depends on the dose used but is independent of the type of first-line agent used; the latter being an unexpected finding, say Jenny MH Chen (University of British Columbia, Vancouver) and colleagues in a report published October 7, 2009 in the Cochrane Database of Systematic Reviews.

Hydrochlorothiazide (HCTZ) was the diuretic used in 92% of the studies included in this review, and it has recently been the subject of some criticism.

But Chen told heartwire she did not believe this to be warranted: "We believe that the recent criticism of HCTZ is misguided and not an accurate reflection of the evidence. Our review adds to the body of evidence demonstrating that HCTZ is indeed effective in lowering trough blood pressure; it can be given as a single daily pill and is an excellent drug choice for patients as the first or second drug."

Dr Franz Messerli (St Luke's Roosevelt Hospital, New York, NY), the lead author of a recent meta-analysis that concluded that HCTZ is a "paltry" antihypertensive at the usual doses prescribed (12.5-25 mg), told heartwire: "The meta-analysis of Chen et al is thorough and comprehensive, as one expects from this well-experienced team." But, he says, it is outcomes that are important, not merely lowering blood pressure, and there are no outcome data as yet for HCTZ 12.5 to 25 mg. "All outcome data with so-called 'thiazides' are based on chlorthalidone and indapamide."

Better information about BP-lowering effects of diuretics used second-line

Chen and colleagues say diuretics are widely prescribed for hypertension, not only as initial therapy but also as second-line treatment. This new analysis is the first to look at the additional reduction in BP with diuretics when given in combination with other antihypertensive drugs, they explain.

"It is possible for the effect of a diuretic as a second-line drug to be additive, subadditive, or synergistic," they observe. The aims of the review were to quantify the additional BP reduction achieved with a diuretic as a second drug vs placebo and to compare withdrawals due to adverse effects between a diuretic as a second drug and placebo.

"This review should be able to provide clinicians with better information about the magnitude of BP lowering when a diuretic is given as second-line therapy in the management of elevated blood pressure," they note.

There were 53 double-blind, randomized controlled trials evaluating a thiazide in 15 129 hypertensive patients (average baseline BP 156/101 mm Hg) included in the review. HCTZ was the thiazide used in 49 of the 53 (92%) included studies.

Thiazides as a second-line drug reduced BP by 6/3 mm Hg and 8/4 mm Hg at doses of one and two times the manufacturer's recommended starting dose, respectively. The antihypertensive effect was dose related and similar to that obtained when thiazides are used as a single agent.

Adding a thiazide diuretic as a second-line agent in combination resulted in greater reduction in BP compared with monotherapy without a thiazide.

Only three double-blind trials using loop diuretics were identified. This type of diuretic appeared to have a similar BP-lowering dose as thiazides at the recommended starting dose, the researchers say, although they acknowledge the evidence for this particular drug class is "weak." And due to wide confidence intervals, it was not possible to assess how loop diuretics compared with thiazides, they note.

Effect independent of first-line drug, or not?

Chen et al also showed that the BP-lowering effect of thiazides, particularly HCTZ, is independent of the type of first-line drug used, "a finding that was not expected," they say.

Based on the proposed mechanism of action, most doctors believe that adding a thiazide to an ACE inhibitor or an angiotensin receptor blocker (ARB) would have a greater effect than adding it to a calcium-channel blocker (CCB), they explain.

But Messerli says the claim that HCTZ's antihypertensive efficacy as an add-on was independent of the first-line drug used was "only true when 25 mg was given, whereas at lower doses (12.5 mg) the addition of HCTZ elicited a greater response in patients who were taking a renin angiotensin system (RAS) blocker [ACE inhibitor or ARB] than in those on a CCB. The authors shrug off these findings as being due to chance," he observes.

Unable to evaluate long-term side effects

Unfortunately, because of the short duration of trials and lack of reporting of adverse events, this review "does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug," Chen et al say. The trials were also carried out in predominantly white populations; therefore, further research of the BP-lowering effects of thiazides in people of other ethnicities is needed.

Chen commented to heartwire: "We agree that our data were not good at estimating side effects with long-term therapy. They did suggest that diuretics did not increase the rate of withdrawals due to adverse effects in the first three- to 12-week treatment period and thus appear well-tolerated at least for short-term therapy."

But, "Fortunately, there are also long-term trials showing the benefits of first-line thiazides in reducing mortality and morbidity, so we do not think our inability to estimate side effects is an important limitation," she added.

In conclusion, she told heartwire: "Thiazide diuretics are recommended as first-line agents in the treatment of hypertension" because "the evidence for the other classes of drugs such as beta blockers, ACE inhibitors, and CCBs, for example, is less robust."

However, Messerli begs to differ: "The authors get carried away by stating that thiazide diuretics are recommended as first-line agents because the evidence for other drug classes is less robust," but they "seem to forget that there are no outcome data for HCTZ in doses of 12.5 to 25 mg. Most important, we should remember that outcome data comparing combination therapy are scarce.

"The only convincing study is ACCOMPLISH, in which a fixed combination of amlodipine and benazepril was clearly superior to a fixed combination of benazepril and HCTZ with regard to morbidity and mortality. Since BP was lowered to the same extent in both treatment arms, this would indicate that antihypertensive effect per se is of limited value when assessing combination therapy," he concludes.

Source

1. Chen JMH, Heran BS, Wright JM, et al. Blood pressure lowering efficacy of diuretics as second-line therapy for primary hypertension. Cochrane Database Syst Rev 2009; 4:CD007187.

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

by Linda Brookes, MSc

Technorati Tags: Hypertension,Angiotensin Reseptor blockers (ARBs),myocardial infarction,valsartan,amloipine

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.

Comment

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.

Comment

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.

Comment

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.

References

1. Matsubara H. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events (KYOTO Heart Study). Presented at ESC 2009, August 29-September 2, 2009, Barcelona, Spain.
2. Sawada T, Yamada H, Dahlöf B, Matsubara H; the KYOTO HEART Study Group. Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study. Eur Heart J. Published online ahead of print August 31, 2009.
3. Sawada T, Takahashi T, Yamada H, et al; the KYOTO HEART Study Group. Rationale and design of the KYOTO HEART study: effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high risk of cardiovascular events. J Hum Hypertens. 2009;23:188-195. Abstract
4. Messerli FH, Bangalore S, Ruschitzka F. Angiotensin receptor blockers: baseline therapy in hypertension? Eur Heart J. Published online before print, August 31, 2009.
5. The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators.Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174-1183. Abstract
6. Yusuf S, Diener HC, Sacco RL, et al; PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359:1225-1237. Abstract
7. Ogihara T, Nakao K, Fukui T, et al. Effects of candesartan compared with amlodipine in hypertensive patients with high cardiovascular risks: candesartan antihypertensive survival evaluation in Japan trial. Hypertension. 2008;51:393-398. Abstract
8. Kasanuki H, Hagiwara N, Hosoda S,et al. Angiotensin II receptor blocker based vs. non-angiotensin II receptor blocker-based therapy in patients with angiographically documented coronary artery disease and hypertension: the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (HIJ-CREATE). Eur Heart J. 2009;30:1203-1212.
9. Mochizuki S, Dahlöf B, Shimizu M, et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet. 2007;369:1431-1439. Abstract
10. Narumi H, Takano H, Shindo S, et al. Effects of valsartan and amlodipine on cardio-renal protection in Japanese hypertensive patients: Valsartan Amlodipine Randomized Trial (VART). Eur Heart J. 2009;30:861. Abstract: 5001
11. Julius S, Kjeldsen SE, Weber M, et al; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:2022-2031. Abstract
12. Nakayama K, Kuwabara Y, Daimon M, et al. Valsartan Amlodipine Randomized Trial (VART): design, methods, and preliminary results. Hypertens Res. 2008;31:21-28. Abstract
13. Sciarretta S, Palano F, Paneni F, et al. Prevention of congestive heart failure in hypertension: a bayesian network meta-analysis involving more than 210.000 subjects. Eur Heart J. 2009;30:861. Abstract: 5002
14. Tocci G, Sciarretta S, Volpe M. Development of heart failure in recent hypertension trials. J Hypertens. 2008;26:1477-1486. Abstract
15. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289:2534-2544. Abstract
16. Blood Pressure Lowering Treatment Trialists' Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-958. Abstract
17. Davis BR, Piller LB, Cutler JA, et al. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006;113:2201-2210. Abstract
18. Lurbe E; Cifkova R; Kennedy JK, et al. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. Journal of Hypertens. 2009;27:1719-1742.
19. Mancia G, De Backer G, Dominiczak A, et al; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187. Abstract
20. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 2004;114:555–576.
21. Babisch W, Neuhauser H, Thamm M, Seiwert M. Blood pressure of 8-14 year old children in relation to traffic noise at home -- Results of the German Environmental Survey for Children (GerES IV). Sci Total Environ. Published online ahead of print September 1.

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