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

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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
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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.
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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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Bedtime Aspirin Lowers Ambulatory Blood Pressure

By Will Boggs, MD

Technorati Tags: Aspirin,anti platelet,salisilat,ASA,coronary heart disease,hypertension

NEW YORK (Reuters Health) Aug 12 - Aspirin taken at bedtime reduces ambulatory blood pressure in patients with prehypertension, according to a report in the August issue of the American Journal of Hypertension.

"Bedtime ingestion of low-dose aspirin could provide a cost-effective approach for blood pressure control in subjects with prehypertension, thus delaying the actual development of hypertension and the need for costly pharmacologic treatment," Dr. Ramon C. Hermida from University of Vigo, Spain, told Reuters Health in an email.

Dr. Hermida and colleagues investigated the influence of aspirin on ambulatory blood pressure in patients who received aspirin at different times of the day according to their rest-activity cycle and who were evaluated by 48-hour ambulatory blood pressure monitoring before and after 3 months of pharmacologic intervention.

Blood pressure did not change after nonpharmacological intervention or after administration of aspirin upon awakening, the researchers note.

In contrast, the authors report, systolic blood pressure decreased by 6 mm Hg and diastolic blood pressure decreased by 3 mm Hg in patients who took 100 mg aspirin at bedtime.

Nearly three quarters (71%) of the patients who took aspirin at bedtime experienced at least a 3 mm Hg reduction in 24-hour systolic blood pressure, but only 6% showed an increase in blood pressure after treatment.

Heart rate was unchanged in all treatment groups.

"Aspirin given at the end of the activity cycle, but not upon awakening, could thus target the nocturnal peak of plasma renin activity, while enhancing the nocturnal trough in the production of nitric oxide," the investigators suggest.

"Thus," they continue, "the enhanced reduction in plasma renin activity, beneficial impact on endothelial function and blocking of alpha- and beta-adrenergic receptors associated (with) bedtime administration of low-dose aspirin could explain the impact of this intervention on blood pressure here documented in subjects with high-normal blood pressure."

"We are currently developing a new multicenter prospective trial with awakening versus bedtime administration of low-dose aspirin for primary prevention of cardiovascular events in subjects with impaired fasting glucose or diabetes," Dr. Hermida explained. "The study will involve 3200 subjects who will be followed for over 5 years."

Reference

Am J Hypertens 2009;22:896-903.

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New ASCOT Analysis: Beta Blockers Not Beneficial in Hypertensives With Tachycardia

by Lisa Nainggolan

Technorati Tags: beta blocker,hypertension,amlodipine,CCB,atenolol

September 24, 2009 — A new analysis of the Anglo-Scandinavian Cardiac Outcomes Trial--Blood Pressure Lowering Arm (ASCOT-BPLA) shows that the amlodipine (Norvasc, Pfizer)-based arm of the study remained superior to the beta-blocker arm, even when resting heart rate was taken into account [1].

The study was published in the September 22, 2009 issue of the Journal of the American College of Cardiology.

The findings mean that "there is no reason to believe that beta blockers should be used earlier on in the treatment of hypertension on the basis of heart rate," lead author Dr Neil R Poulter (Imperial College London, UK) told heartwire . He said many cardiologists have had "a hindbrain belief" that "if there is a touch of tachycardia, beta blockers are the right drugs to use in hypertension management." But prior to this analysis, there had been no data from randomized controlled trials available to assess the impact of this advice on patient outcomes, he noted.

"We thought, if it's true that a touch of tachycardia should push you toward beta blockers, we'd be able to see that in ASCOT," Poulter added. Noting that the ASCOT-BPLA study–-reported in 2005--confirmed the superiority of an amlodipine-based regimen over an atenolol-based regimen, "we looked to see whether, if you started with tachycardia, was that still the case?" he noted. "The bottom line is, yes, it is. Pulse rate should not be the determinant of what drugs you use in hypertension."

These findings "reinforce the UK guidelines that state that, in primary prevention, beta blockers should be kept to a much later stage of intervention," Poulter says.

No Attenuation of Amlodipine Superiority on Basis of Heart Rate

The ASCOT trial enrolled 19 257 hypertensive patients with at least three other cardiovascular risk factors from 650 general practices in the UK, Ireland, and the Nordic countries. The results showed that an antihypertensive strategy based on amlodipine, with perindopril added as required, significantly reduced all-cause mortality and other cardiovascular end points, including stroke, compared with an atenolol-based strategy, with the diuretic bendroflumethiazide added as required.

In this new subgroup analysis, patients with atrial fibrillation or taking rate-limiting antihypertensive drugs at baseline were excluded. The potential attenuation of the treatment effect with higher baseline heart rate on total cardiovascular events and procedures (TCVP) was assessed via an interaction term. Secondary analyses evaluated coronary and stroke outcomes.

There were 12 759 of the ASCOT patients included and 1966 total cardiovascular events and procedures. At the final visit, mean heart-rate reduction from baseline was 12.0 and 1.3 beats per minute in the atenolol- and amlodipine-based groups, respectively. There was a reduction in total cardiovascular events and procedures in those allocated to amlodipine-based therapy compared with those on atenolol-based therapy (unadjusted hazard ratio 0.81; p<0.001).

This benefit was unattenuated at higher heart rates (interaction p value=0.82). Similar results were obtained for coronary and total stroke outcomes.

"These analyses provide no evidence that atenolol-based therapy is superior to amlodipine-based therapy for patients with hypertension uncomplicated by coronary heart disease across the wide range of baseline heart rates observed in the ASCOT database," say Poulter et al.

"Pending further information--which could perhaps be gleaned from other studies such as [Losartan Intervention for Endpoint Reduction in Hypertension] LIFE--beta-blocker–based therapies are not appropriate to select as initial therapy for hypertension on the basis of a higher heart rate unless congestive heart failure and/or symptomatic ischemic heart disease coexist," they conclude.

Results Apply to All Beta Blockers, Until Further Notice

Poulter added to heartwire that "some cardiologists will say that if we hadn’t used atenolol the results would have been different: 'If you'd used my favorite "olol," ' for example, and I say, 'Prove it!' "

He believes that beta blockers "are not all the same, they do have different effects on all sorts of things," but "there is no evidence of heterogeneity in terms of cardiovascular outcomes," he maintains.

"Until further notice, beta blockers should not come up the pecking order on the basis of pulse rate."

Poulter has served as a consultant to and received travel expenses, payment for speaking at meetings, or funding for research from one or more pharmaceutical companies marketing BP-lowering or lipid-lowering drugs. Poulter has also previously received financial support from Pfizer to cover administrative and staffing costs of the ASCOT study and travel or accommodation expenses or both incurred by attending relevant meetings. Disclosures for the coauthors are listed in the paper.

References

1. Poulter NR, Dobson JE, Sever PS, et al. Baseline heart rate, antihypertensive treatment, and prevention of cardiovascular outcomes in ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). J Am Coll Cardiol 2009; 54:1154-1161.

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Rethinking Hypertension in the 21st Century: An Overview of the Expanded Definition and Classification of Hypertension

by Thomas D. Giles, MD

Technorati Tags: hipertension,cardiovascular disease,chest pain,angina

Introduction

As epidemiologic and clinical data regarding the relationship between blood pressure (BP) and the risk for cardiovascular disease (CVD) have accumulated, a pronounced shift has taken place in how the disease of hypertension is viewed and defined. Cardiovascular (CV) risk has been found to be elevated at BP levels previously considered normal; in some cases, sporadic elevations in BP levels may be physiologically benign and not associated with additional CVD risk.^[1-3] As a consequence, many hypertension experts consider elevated BP at its core a disease marker, rather than a cause of hypertension. Moreover, elevated BP, as 1 marker of CVD, frequently coexists with other equally compelling disease markers.^[2] Elevated BP should not, therefore, be viewed or treated in isolation, but considered in the context of whole patient care, which takes into account the presence of other risk factors and disease markers for CVD to achieve a more comprehensive, or global, assessment of CV risk.

With these points in mind, in 2005, the Hypertension Writing Group (HWG), a national group of hypertension specialists, proposed a new definition of hypertension as "a progressive cardiovascular syndrome, the early markers of which may be present even before BP elevations are observed."^[4] The stated goal of the new definition was to identify individuals at risk for CVD at an earlier point in the disease process, as well as to avoid labeling persons as hypertensive who are at low risk for CVD.^[4] Viewed from this perspective, the HWG believed that threshold-based classification systems of hypertension, such as that endorsed in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7),^[5] while serving as tools to identify patients across a broad range of CVD risk, may lead to underestimation or overestimation of clinical risk within individual patients. In either case, the presence or absence of other disease markers or risk factors, the coexistence of target-organ damage, or both can be used to risk-stratify patients with hypertension more accurately.

To simplify risk stratification and align it more closely with clinical practice, the HWG proposed classifying all patients as either normal or hypertensive (eliminating the prehypertension category proposed in JNC 7), with hypertension classified into stage 1, stage 2, or stage 3.^[4] Because the CV syndrome represented by hypertension may be present even when BP falls within the normal category by conventional standards, the risk categories created by the HWG focus not on BP levels per se, but on the presence of deleterious BP patterns or the presence of CVD. Stages of hypertension are further categorized based on the presence of risk factors for early, advanced, or progressive CVD, as well as by other CVD markers (classified as BP, cardiac, vascular, renal, and retinal changes) and target-organ damage (classified as cardiac, vascular, renal, and cerebrovascular).^[4]

Beyond the goal of providing a more clinically relevant assessment of global CV risk in clinical practice, this paradigm shift served to focus attention on the enormous unmet need regarding prevention and optimal treatment of hypertension across a spectrum of fields, from basic research and drug development to patient education and clinical management.^[4] Two critical areas of research in particular -- the development of specific and sensitive cost-effective tests that can detect early CVD markers in the clinical setting, and the development of strategies to slow or prevent the onset of target-organ damage or overt CVD by treating early vascular derangements -- may benefit from being examined within the context of the categories for hypertension.

Recently, the HWG further refined and updated the definition and classification of hypertension.^[6] This article reviews the revised definition and classification scheme and the implications for clinical practice. As the authors stressed, however, while definitions of disease are useful for detection, management, research, and education, definitions alone do not constitute recommendations for treatment. In the latter case, the initiation of treatment should be individualized and guided by CV risk, rather than BP thresholds.^[1]

Blood Pressure as a Biomarker for Hypertension

The concept of elevated BP as a disease marker for hypertension, rather than its cause, is supported by multiple lines of evidence suggesting that the risk for renovascular and CV sequelae may be higher than expected in the presence of normal or near-normal BP in some patients, or, conversely, lower than expected in the presence of above-normal BP in others. This view is based, in part, on the physiologically dynamic nature of BP, in which tissue perfusion is matched with metabolic demands in a complex, ever-changing manner that depends on the coordinated activity of numerous mechanisms involved in hemostasis, including the sympathetic nervous system, the renin-angiotensin system, and the vasodilatory system (eg, prostaglandins and nitric oxide).^[4] According to this perspective, optimal BP can vary among individuals and within the same person, depending on hemodynamic circumstances. Sporadic BP elevations may occur in individuals who have no evidence of early CVD.^[2] Conversely, because adverse CV and renal outcomes increase across all BP values, hypertension-related morbidity and mortality can occur even at BP levels considered normal by conventional standards. The significant proportions of myocardial infarctions and strokes that occur in patients who have only slight BP elevation, or even normal BP, adds weight to this argument.^[7]

Perhaps the most convincing evidence against using BP thresholds to define hypertension is that there is no threshold of BP above 115/70 mm Hg that identifies CV risk -- that is, risk is linear and doubles for each 20/10 mm Hg increase in BP.^[2] As a consequence of the dynamic nature of BP, it may be more clinically relevant to use BP patterns, rather than discrete BP thresholds as measured in the clinic, when assessing CV risk in an individual patient. Thus, the HWG places particular attention on ambulatory BP and the contribution of systolic BP (SBP) and pulse pressure (the difference between SBP and diastolic BP [DBP]) to risk, because these are widely considered to be more accurate markers of CV risk than is office DBP, particularly in older patients.^[5,8]

The Interrelationship of High Blood Pressure and Other Cardiovascular Risk Factors

Another key principle endorsed by the HWG is that of the interrelationship between elevated BP and other CV risk factors. Even in patients with frank elevations in BP, risk stratification based on BP levels alone often underestimates CV risk. This is because above-optimal BP levels rarely occur in isolation, and patients seen in clinical practice frequently have multiple CVD markers or risk factors (eg, overweight, insulin resistance, dyslipidemia) that point to greater overall risk.^[1,9-13] What is particularly significant, from the perspective of defining hypertension beyond BP thresholds, is that many of these disease processes are intimately interrelated and interact via common pathobiologic processes involving oxidative stress and endothelial dysfunction (Figure).^[14] Moreover, the presence of risk factors and disease markers defines the earliest stage in this CVD continuum, well before overt CVD and target-organ damage can be measured in the clinic.^[14] From this perspective, above-optimal BP (a risk factor) is not necessarily synonymous with hypertension (a disease representative of progressive CVD and tissue injury).^[6]

Figure. Cardiovascular and renal pathophysiologic continuum. CV = cardiovascular; MI = myocardial infarction; CHF = congestive heart failure; ESRD = end-stage renal disease. Adapted from Dzau VJ, et al.^[14]

Another consequence of the CV and renal pathophysiologic continuum is that the complex interplay of risk factors and disease markers frequently may manifest as a dramatically higher CV risk than would be expected, based on thresholds for each individual risk factor alone. This is highlighted by the particularly deleterious condition known as the cardiometabolic syndrome, in which individual risk factors combine to increase CV risk synergistically, rather than additively.^[12,15] Ultimately, a more clinically meaningful assessment of CV risk can be obtained by global assessment of a patient's risk, rather than focusing solely on whether a patient has crossed a particular BP threshold.

Taken together, this evidence suggests that it may be more useful to view BP as 1, but not the only, biomarker for the disease hypertension, and to view above-optimal levels of BP in an individual patient as those that, when sustained, cause damage to the vasculature.^[6] This forms the basis of the revised definition of hypertension, as shown in Table 1.

Table 1. Revised Definition of Hypertension From Hypertension Writing Group 2009

• Hypertension is a progressive CV syndrome arising from complex and interrelated etiologies

• Early markers of the syndrome are often present before BP elevation is sustained; therefore, hypertension cannot be classified solely by discreet BP thresholds

• Progression is strongly associated with functional and structural cardiac and vascular abnormalities that damage the heart, kidneys, brain, vasculature, and other organs, and lead to premature morbidity and death

• Reduction of elevated BP generally confers a reduction in the risk for CV events. Note that HWG separates elevated BP (one manifestation of the disease) from hypertension (the disease)

BP = blood pressure; CV = cardiovascular
From Giles T, et al.^[6]

Because hypertension is defined by as "a progressive cardiovascular syndrome," it is clinically helpful to categorize, or stage, patients (Table 2), with each stage characterized by the cumulative presence or absence of markers of hypertensive CVD and evidence of target-organ damage. This provides a snapshot of the extent to which the disease has advanced at a particular time.^[6]

Table 2. Revised Definition and Classification of Hypertension From Hypertension Writing Group 2009

Classification	Normal	Stage 1 Hypertension	Stage 2 Hypertension	Stage 3 Hypertension
Descriptive category	Normal BP or rare BP elevations AND no identifiable CVD	Occasional or intermittent BP elevations OR early CVD	Sustained BP elevations OR progressive CVD	Marked and sustained BP elevations OR advanced CVD
Cardiovascular risk factors (see Table 3)	None or few	Several risk factors present	Many risk factors present	Many risk factors present
Early disease markers (see Table 4)	None	Usually present	Overtly present	Overtly present with progression
Target-organ disease (see Table 5)	None	None	Early signs present	Overtly present with or without CVD events

BP = blood pressure; CVD = cardiovascular disease
From Giles T, et al.^[6]

In the broadest sense, individuals are classified as either normal or hypertensive based on their CV status (ie, the absence or presence of identifiable CVD), regardless of their BP pattern. The stages within the hypertension category are further refined, based on BP patterns or the extent of CVD (early, advanced, or progressive). Each hypertension stage is further characterized by the cumulative presence or absence of risk factors for CVD (Table 3);markers of hypertensive CVD, such as microalbuminuria or mild left ventricular hypertrophy (Table 4); and evidence of target-organ damage, such as frank albuminuria or moderate-to-severe left ventricular hypertrophy (Table 5).^[6] The occurrence of a major cardiac event clearly places the progression of hypertensive CVD at a more advanced stage.^[6]

Table 3. Cardiovascular Risk Factors

Increasing age

Elevated BPa

High heart rate

Overweight/obesity

− Increased BMI

− Central obesity

− Increased abdominal circumference

− Increased abdominal adiposity (waist-to-hip ratio)a

Dyslipidemia

− Elevated LDL or non-HDLb cholesterol

− Low HDL cholesterola

− Elevated triglyceridesa

Elevated blood glucose, insulin resistance, or diabetes mellitusa

Chronic kidney disease

Smoking

Family history of premature CVD (age < 50 yr in men, < 60 yr in women)

Sedentary lifestyle

Psychosocial stressors

Elevated hs-CRP

BMI = body mass index; BP = blood pressure; CVD = cardiovascular disease; HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein
^aComponents of the metabolic syndrome
^bNon-HDL cholesterol = total cholesterol minus HDL cholesterol

Table 4. Early Markers of Hypertensive Cardiovascular Disease

System	Physiologic Alteration
Blood pressure
	Loss of nocturnal BP dipping
	Exaggerated BP responses to exercise or mental stress
	Salt sensitivity
	Widened pulse pressure
Cardiac
	Left ventricular hypertrophy (mild)
	Increased atrial filling pressure
	Decreased diastolic relaxation
	Increased natriuretic peptide
Renal
	Microalbuminuria (urinary albumin excretion of 30-300 mg/day)a
	Reduced estimated GFR (60-90 mL/min)
Cerebrovascular
	Stroke
	Transient ischemic attack
	Decreased cognitive function
	Dementia
	Loss of vision

BP = blood pressure; GFR = glomerular filtration rate
^aAlso a marker of microcirculatory disease

Table 5. Hypertensive Target-Organ Damage and Overt Cardiovascular Disease

System	Evidence of Target-organ Damage and Cardiovascular Disease
Cardiac
	Left ventricular hypertrophy (moderate to severe)
	Systolic or diastolic cardiac dysfunction
	Symptomatic heart failure
	Myocardial infarction
	Angina pectoris
	Ischemic heart disease or prior revascularization
Vascular
	Peripheral arterial disease
	Carotid arterial disease
	Aortic aneurysm
Renal
	Albuminuria (urinary albumin excretion > 300 mg/day)
	Chronic kidney disease (estimated GFR < 60 mL/min) or ESRD
Cerebrovascular
	Stroke
	Transient ischemic attack
	Decreased cognitive function
	Dementia
	Loss of vision

ESRD = end-stage renal disease; GFR = glomerular filtration rate

Clinical Characteristics and Practical Implications of the Proposed Hypertension Categories

A practical clinical interpretation of the revised hypertension categories is shown in Table 6.

Table 6. Clinical Characterization, BP Patterns, and Practical Implications of the Hypertension Algorithm

Hypertension Category	Clinical Characterization	BP Pattern	Practical Implications
Normal	Optimal BP levels	Resting BP levels usually < 120/80 mm Hg	Includes some patients identified as having prehypertension (based on JNC 7 criteria)
	No identifiable early markers of CVD	Occasional BP elevations, even to ≥ 140/90 mm Hg, may occur
Stage 1	Early CVD markers present	BP levels > 115/75 mm Hg	Earliest identifiable stage of hypertensive disease
	Frequently 1 or more CVD risk factors present	BP may be frankly elevated, particularly with environmental stress	Includes individuals with prehypertension (based on JNC 7 criteria) who also have CVD risk factors or early disease markers
	No evidence of target-organ damage
Stage 2	Diffuse disease markers present OR evidence (limited) of early target-organ damage	Sustained resting BP frequently ≥ 140/90 mm Hg, with much higher elevations induced by physiologic or psychologic stressors	Equivalent to JNC 7 stage 1 hypertension
			Indicates progressive disease
			Risk factors, if not attenuated, continue to contribute to progressive target-organ disease
Stage 3	Overt CVD present	Sustained resting BP levels ≥ 140/90 mm Hg usual (untreated or inadequately treated)	Equivalent to JNC 7 stage 2 hypertension
		Marked BP elevations to levels > 160/100 mm Hg not uncommon (untreated or inadequately treated)	Includes all individuals with clinical evidence of overt target-organ damage or CVD, or who have sustained a CVD event, regardless of BP levels

BP = blood pressure; CVD = cardiovascular disease; JNC 7 = Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure

In the algorithm, individuals with optimal levels of BP and no identifiable early markers of CVD are categorized as normal. These individuals usually have resting BP levels of 120/80 mm Hg or lower, but BP may be elevated occasionally, even to levels of 140/90 mm Hg or higher.^[6] Given the limits of clinic BP measurements, home BP determinations or 24-hour ambulatory BP recordings may be helpful in identifying patients with more than occasional BP elevations, who may be categorized more appropriately as having stage 1 hypertension.^[16]Because the HWG algorithm does not recognize a prehypertension category, some individuals designated as having prehypertension according to the JNC 7 classification may be considered normal in the paradigm.

The earliest identifiable stage of hypertensive disease, stage 1 hypertension, is characterized by the presence of early CVD markers. Although BP levels are higher than 115/75 mm Hg and may be frankly elevated in patients at this stage, abnormal BP patterns -- including loss of nocturnal dipping, exaggerated responses to exercise or mental stress, and widened pulse pressure -- may provide clearer evidence of the presence of early hypertensive disease.^[4] Although patients should have more than 1 CV risk factor to be included in this category, they should not have any evidence of target-organ damage.

In contrast to stage 1, stage 2 hypertension is characterized by diffuse disease markers and evidence of progressive disease as a consequence of persistent functional and structural changes in BP control mechanisms and in the heart and vasculature. Although patients at this stage frequently have sustained elevations in resting BP levels of 140/90 mm Hg or higher -- with much higher elevations induced by physiologic or psychologic stress -- it is important to recognize that any individual with numerous disease markers or limited evidence of early target-organ damage, such as left ventricular hypertrophy, fits into this category, regardless of BP levels. Methods of detecting or measuring some of the early target-organ damage characteristic of this stage of hypertension are currently limited to specialized or research settings, and further evaluation is needed to determine their potential utility and cost-effectiveness in clinical settings.^[6] Nonetheless, aggressive management of CV risk factors that are identified in patients at this stage may help attenuate the progression of target-organ damage.

Finally, stage 3 hypertension is an advanced stage of the hypertensive continuum, characterized by the presence of overt CVD. Overt hypertensive target-organ disease is often pervasive, and CVD events may have already occurred. If inadequately treated or left untreated, individuals at this stage usually have sustained resting BP levels of 140/90 mm Hg or higher, although marked elevations to levels higher than 160/100 mm Hg are not uncommon.^[6] Regardless of BP levels, however, all individuals with clinical evidence of overt target-organ damage or CVD, as well as those who have already sustained CVD events, are included in this category. Reaching this phase means that damage to target organs, as well as overt cardiorenal disease, has already occurred. As a consequence, CV risk factor modification and treatment of target-organ disease and all identified CVD should be vigorous and sustained.^[6]

Strategies for and the Clinical Implications of Treating Patients Along a Continuum of Global Cardiovascular Risk

The paradigm shift in viewing elevated BP as a marker for hypertension and hypertension as a progressive CVD syndrome has important implications for treating patients in the clinical setting. The risk-based approach proposed by the HWG will lead to reclassifying patients who were previously designated prehypertensive (based on JNC 7 criteria) to either HWG normal or stage 1 hypertension.^[4] In terms of treatment, lowering BP remains an important goal of antihypertensive therapy, yet ultimately the overarching objective is to prevent CV complications.^[9] Treatment of other CV risk factors is therefore equally important. Moreover, CV risk factors, including elevated BP, are not only precipitators, but also continuous pathogenic components at every stage of progression of CVD.^[9] Clinical strategies, therefore, need to focus on detecting and treating patients at risk at every stage along the continuum, from preventing target-organ damage and interrupting CVD progression in patients with early-stage hypertension, to making aggressive efforts to slow further disease progression and avoid CV events in patients with late-stage hypertension.

Evidence for the benefit of antihypertensive treatment in early-stage hypertension (HWG stage 1 or JNC 7 prehypertension category) has only recently become available. The Trial of Preventing Hypertension (TROPHY) study has shown that antihypertensive therapy may help prevent the development of elevated BP levels among individuals with BP lower than 140/90 mm Hg who are at high risk for frank hypertension (due to the presence of multiple CV risk factors).^[17] In line with the HWG paradigm, patients in this study had high-normal SBP/DBP levels of 130-139/85-89 mm Hg at baseline, yet had a strikingly high rate of CV risk factors other than elevated BP.^[17] Among the TROPHY patients, 96% had at least 1 additional CV risk factor, includingvarious measures of dyslipidemia, insulin resistance, and obesity, as well as elevatedhematocrit and heart rate; 81% had 2 or more additional risk factors; and33% had 4 or more additional risk factors. The most prevalent risk factor in thecohort as being overweight.^[2,17] Patients were randomized to receive treatment with the angiotensin receptor blocker candesartan or placebo for 2 years, followed by an additional 2 years of placebo-only therapy; all patients were instructed to make changes in lifestyle to reduce BP throughout the trial.^[17] After 2 years, hypertension haddeveloped in 154 patients in the placebo group and 53 patients in the angiotensin receptor blockergroup, representing a significant 63% relative risk reduction with pharmacotherapy (P < .001). After 4 years, hypertension had developed in 240 patients assigned to placeboand 208 patients assigned to active treatment (relative risk reduction, 15.6%;P < .007). Serious adverse events occurred in 3.5% of patients who received active treatment and in 5.9% of those who received placebo. As the authors noted, the absolute difference between active treatment and placebo at 2 years in TROPHY, 26.8%, is much higher than the 8% absolute difference observed in the Trials of Hypertension Prevention,^[18] the only trial of lifestyle modification with a similar duration, suggesting that drug therapy plus lifestyle modification is more effective than lifestyle modification alone in early hypertension.^[17]

The benefit of treatment with antihypertensive agents in patients classified as normotensive by conventional standards also is supported by the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).^[19] In this study, antihypertensive treatment in subjects without elevated BP (mean BP, 136/79 mm Hg) but with a history of target-organ damage -- in this case, a history of transient ischemic attacks or stroke -- was associated with a significant 27% reduction in the relative risk for stroke compared with placebo (P < .01), similar to the 32% reduction observed in patients designated as hypertensive.^[19] Moreover, intensive BP reduction with combination therapy was associated with better outcomes than less-intensive BP reduction with single-agent therapy, regardless of hypertension status. Because individuals similar to those considered normotensive in PROGRESS would be classified as having stage 2 hypertension (based on the presence of target-organ damage) in the HWG paradigm, results of this study highlight the importance of considering comprehensive risk factor assessment, including the presence of target-organ damage, when defining and staging patients with hypertension.

Whether all individuals with early-stage hypertension, as defined by the HWG, should be treated with antihypertensive therapy requires further study. As the group emphasized in their 2005 report, characterizing hypertension as a complex CV disorder associated with, but not exclusively defined by, high BP is best viewed as a transitional strategy that is intended to generate further clinical research into improved strategies for detecting, treating, and possibly preventing the disease.^[4]

Summary

The key points advanced by the HWG in their updated hypertension position paper are that BP serves as a biomarker for the disease hypertension and, as such, elevated BP is not synonymous with hypertension. Some individuals may exhibit elevated BP in the absence of hypertension, whereas other individuals with the same levels of BP might be classified into different stages of hypertension.^[6] Therefore, for purposes of calculating total CV risk and staging patients as normal or hypertensive, BP should be evaluated in the context of other CV risk factors and disease markers. Ultimately, it is hoped that the risk-based approach to defining and staging hypertension, as proposed by the HWG, will lead to earlier identification of individuals with hypertensive CVD. Preliminary data, such as that described by the TROPHY Investigators, suggest that lowering BP with pharmacologic therapy can prevent or delay the progression of hypertensive CVD even at early stages (ie, HWG stage 1 hypertension/JNC 7 prehypertension). Additional research is necessary to confirm these findings and identify cost-effective methods to detect and measure early CVD markers in clinical practice.

This activity is supported by an independent educational grant from Pfizer.

This article is a CME certified activity. To earn credit for this activity visit:
http://cme.staging.medscape.com/viewarticle/708548

References

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2. Giles TD. Assessment of global risk: a foundation for a new, better definition of hypertension. J Clin Hypertens (Greenwich). 2006;8:5-14.
3. Khosia N, Black HR. Expanding the definition of hypertension to incorporate global cardiovascular risk. Curr Hypertens Rep. 2006;8:384-390.
4. Giles TD, Berk BC, Black HR, et al. Expanding the definition and classification of hypertension. J Clin Hypertens (Greenwich). 2005;7:505-512.
5. Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.
6. Giles TD, on behalf of the Hypertension Writing Group. Definition and classification of hypertension: an update. J Clin Hypertens (Greenwich). In press.
7. Sierra C, de la Sierra A. Early detection and management of the high-risk patient with elevated blood pressure. Vasc Health Risk Manag. 2008:4;289-296.
8. Franklin SS, Khan SA, Wong ND, et al. Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circulation. 1999;100:354-360.
9. Basile J. Management of global risk across the continuum of hypertensive heart disease. J Clin Hypertens (Greenwich). 2006;8:21-30.
10. Khot UN, Khot MB, Bajzer CT. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003;290:898-904.
11. Neaton JD, Wentworth D; the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Arch Intern Med. 1992;152:56-64.
12. Meigs JB, D'Agostino RB Sr, Wilson PW, et al. Risk variable clustering in the insulin resistance syndrome: the Framingham Offspring Study. Diabetes. 1997;46:1594-1600.
13. Gregg EW, Cheng YJ, Cadwell BL, et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA. 2005;293:1868-1874.
14. Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: Part I: pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006;114:2850-2870.
15. Hoerger TJ, Ahmann AJ. The impact of diabetes and associated cardiometabolic risk factors on members: strategies for optimizing outcomes. J Manag Care Pharm. 2008;14:S2-S14.
16. Pickering TG, White WB; American Society of Hypertension Writing Group. ASH position paper: home and ambulatory blood pressure monitoring. When and how to use self (home) and ambulatory blood pressure monitoring. J Clin Hypertens (Greenwich). 2008;10:850-855.
17. Julius S, Nesbitt SD, Egan BM, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354:1685-1697.
18. The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II. Arch Intern Med. 1997;157:657-667.
19. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033-1041.

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How to shave 10 years off your life: Have high cholesterol, be hypertensive, and smoke

Technorati Tags: Hypertension,Prevention,Dyslipidemia,Statin,Aspirin

by Lisa Nainggolan

Oxford, UK - A new analysis from the British Whitehall study looking at male civil servants has found that a single measurement of three cardiovascular risk factors in middle age—smoking, high blood pressure, and high cholesterol—predicted a threefold higher rate of vascular mortality compared with none of the risk factors [1]. The researchers also showed a twofold higher rate of nonvascular mortality and an almost 10-year shorter life expectancy from age 50 in those with the risk factors.

Dr Robert Clarke (University of Oxford, UK) and colleagues report their findings online September 17, 2009 in BMJ. And when they used more extreme categorization of risk factors, including body-mass index (BMI), diabetes mellitus/glucose intolerance, and employment grade, life expectancy differed by up to 15 years.

Clarke says there has been uncertainty about the limits of life expectancy and the relevance of cardiovascular risk factors for its prediction. "What is unique about this study is the prolonged follow-up; it enables us to put a figure on the life-limiting effects of these risk factors," he told heartwire.

The study shows concordance with recent findings from the Physicians' Health Study in the US [2] and "provides a stark illustration of the importance of these risk factors to reduce life expectancy," he adds. The findings also provide support for public-health policies aimed at achieving modest changes in major risk factors throughout the population to achieve improvements, he notes.

"This is a metric that is readily understood by patients. It's repackaging these old risk factors to give them a bit more quantitative importance. We have all these new factors, like CRP, when in fact these old risk factors explain much of the difference in life expectancy," he stresses.

All three risk factors associated with 10 to 15 years lower life expectancy

Data were collected from 18 863 men aged 40 to 69 who were working in the civil service in London when they were first examined in 1967-1970. They completed questionnaires and had a medical exam, including measurement of blood pressure, cholesterol, glucose concentrations, and height and weight, and answered questions about medical history, smoking habits, employment grades, and marital status.

People were divided into two groups based on the three main CV risk factors: current smoker (yes/no); baseline BP ("high"=systolic BP >140 mm Hg or "low"; and baseline cholesterol ("high"=cholesterol >5.0 mmol/L or "low"). In addition, a risk score was computed from these factors. The men were followed for 38 years: 13 501 died, and 4811 were reexamined in 1997.

At entry, 42% of the men were current smokers, 39% had high blood pressure, and 51% had high cholesterol. At the reexamination, about two-thirds of the previously "current" smokers had quit smoking shortly after entry, and the mean differences in levels of those with high and low levels of BP and cholesterol were attenuated by two-thirds.

Despite this, compared with men without any baseline risk factors, the presence of all three risk factors at entry was associated with a 10-year shorter life expectancy from age 50 (23.7 vs 33.3 years). And compared with men in the lowest 5% of the risk score based on smoking, diabetes, employment grade, and continuous levels of BP, cholesterol concentration, and BMI, men in the highest 5% had a 15-year shorter life expectancy from age 50 (20.2 vs 35.4 years).

Prospective study, with large sample size and long follow-up

The study has several strengths in addition to the prolonged follow-up, say Clarke et al, including a prospective design, large sample size, availability of repeat measurements between middle and old age, a large number or deaths, and virtually complete mortality follow-up.

Limitations include the fact that total cholesterol concentrations were employed rather than cholesterol fractions or apolipoproteins, which are much stronger predictors of vascular mortality than total cholesterol, they note. Also, the effects of BP and cholesterol on mortality might have been slightly underestimated because of increased use of aspirin, statins, and BP-lowering drugs during follow-up (in 1997, around a third of survey participants were taking aspirin and/or antihypertensives, although only 2% were taking statins).

"Continued public-health strategies to lower mean levels of the three main cardiovascular risk factors, together with more intensive medical treatment for 'high-risk' subgroups, including use of medication to lower blood pressure and cholesterol concentration, which have proven efficacy, could result in further improvements in life expectancy," they conclude.

Sources

Clarke R, Emberson J, Fletcher A, et al. Life expectancy in relation to cardiovascular risk factors: 38-yar follow-up of 19 000 men in the Whitehall study. BMJ 2009; DOI:10.1136/bmj.b3513. Available at: http://www.bmj.com.

Yates LB, Djoussé L, Kurth T, et al. Exceptional longevity in men: modifiable risk factors associated with survival and function up to age 90 years. Arch Intern Med 2009; 168: 284-290.

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Do ACE inhibitors increase mortality in CABG patients?

by Shelley Wood

Bristol, UK - Authors of a large, observational study say preoperative use of ACE inhibitors may double the risk of dying after CABG surgery [1]. Dr Antonio Miceli (University of Bristol, UK) and colleagues say their findings support a strategy of stopping ACE inhibitors presurgery and then restarting them postoperatively. But not everyone agrees with the results of the new analysis: commenting on the study for heartwire, Dr Harold Lazar (Boston University School of Medicine, MA) argued that there are some patients in whom ACE inhibitors should not be stopped, particularly patients with hypertension and/or diabetes, who have had a recent MI.

The study will be published in an upcoming issue of the Journal of the American College of Cardiology and was published online August 13, 2009.

Miceli et al's research adds a generous dollop of data to an already confusing mélange of studies supporting or rejecting a role for ACE inhibitors in CABG patients. As Miceli et al explain, ACE inhibitors lower blood pressure and have antiatherosclerotic, antithrombotic, and anti-inflammatory effects—all of which paved the way for recommendations to use them in patients with coronary artery disease. But their effect when used preoperatively in CABG patients "is still controversial," they note.

To gauge these effects, Miceli and colleagues reviewed data on preoperative ACE-inhibitor use among more than 10 000 patients who had CABG surgery between April 1996 and May 2008 at the Bristol Heart Institute, UK. In all, 3052 were taking ACE inhibitors prior to their surgery and were matched with a control group using propensity scores.

Miceli et al report that the mortality rate in the ACE-inhibitor group was nearly double that of patients not taking ACE inhibitors: 1.3% vs 0.7%. As well, new-onset atrial fibrillation, renal dysfunction, and use of inotropic support were all higher among patients taking ACE inhibitors preoperatively. Use of ACE inhibitors remained an independent predictor of mortality after multivariate analysis.

Postoperative outcomes

Outcome	ACE inhibitors (%)	Control (%)	Odds ratio (95% CI)	p
Mortality	1.3	0.7	2.0 (1.17-3.42)	0.013
Atrial fibrillation	25	20	1.34 (1.18-1.51)	<0.0001
Renal dysfunction	7.1	5.4	1.36 (1.1-1.67)	0.006
Use of inotropic support	45.9	41.1	1.22 (1.1-1.36)	<0.0001

The authors note that their findings on the link between preoperative ACE-inhibitor use and need for inotropic support largely reflect earlier studies, while the findings regarding kidney disease, atrial fibrillation, and mortality are at odds with at least some of the published literature. The different findings are partially explained by the fact that the current study includes a larger sample size than most of the prior studies and was restricted to patients undergoing CABG, the authors write.

Asked to review the paper for heartwire, Lazar took issue what he identified as a number of limitations of the study (many of which were also acknowledged by Miceli et al in their paper). Lazar pointed to the shortcomings of a propensity analysis, when a randomized clinical trial is the only way to properly address the safety of ACE inhibitors in the setting of CABG. He also questioned the 12-year duration of the study, noting that the kinds of patients being treated for CABG changed substantially over the study period. He also pointed to "missing information" in the paper, such as that regarding dose, type, and duration of ACE-inhibitor therapy; indications for, dose, type, and duration of inotropic support; details on atrial fibrillation and its management in the study cohort; and a breakdown of the cause of death reported in the study. "Were these cardiac deaths, or were they other things that ACE inhibitors have no effect on?" Lazar asked.

Overall, Lazar concluded, "the results are very soft. . . . The use of ACE inhibitors in this study was associated with a higher incidence of death; however, although this may be true statistically, clinically I don't think we're talking about a real, significant end point."

Even the mortality difference between the two groups—a difference of 0.6%—"that's really splitting hairs," he said.

"In my own practice, for an elective operation, we will ask the patient to stop the ACE inhibitor 48 hours before the surgery, and if it's an in-house patient and we can stop it safely, again we'll stop ACE inhibitors 48 hours beforehand. However, in those patients who have had a recent MI with hypertension and those who are diabetic, we will keep the ACE inhibitor going right up to the time of surgery. We will also lower the dose sometimes as well. We feel that gives us the protection of the ACE inhibitor but minimizes the vasodilatation associated with the drug."

But the authors stand by their findings, insisting the best strategy is to stop the ACE inhibitors two days prior to surgery and restart them after the patient is stable again postsurgery. Speaking with heartwire, senior author on the study, Dr Massimo Caputo (University of Bristol), agreed that survival after CABG is higher now than ever before, "so the fact that we found a statistically significant difference in mortality is quite astonishing," he said. But he agrees, in terms of clinical impact, that the adverse effects of ACE inhibitors are even more important for atrial fibrillation and renal dysfunction, "where there is a much clearer difference between the groups."

"Our goal was not to say that ACE inhibitors are bad or should not be used. We're just saying that in the perioperative period, you should stop ACE inhibitors two to five days before and restart them probably two days postoperatively, to reduce the risk of the complications we saw."

And while a large, prospective, randomized trial would be ideal, Caputo said his study fills an important gap and "used the best possible data, to determine the best possible therapy for our patients."

Source

1. Miceli A, Capoun R, Fino C, et al. Effects of angiotensin-converting enzyme inhibitor therapy on clinical outcome in patients undergoing coronary artery bypass grafting. J Am Coll Cardiol 2009; DOIi:10.1016/j.jacc.2009.07.008. Available at: http://content.onlinejacc.org.

Technorati Tags: ACE inhibitors,CABG,hypertension,CAD

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