Linda Brookes, MSc 

Medscape Cardiology.  2006;10(1) ?2006 Medscape

Introduction

New data on the first entirely new class of antihypertensive treatment in 10 years were presented at the American Society of Hypertension Annual Meeting this month. Also, there was more argument from the ALLHAT investigators about diuretics, hypertension, and heart failure, followed by a contradictory report that a history of arterial hypertension does not affect mortality in patients who are hospitalized with congestive heart failure. A very interesting analysis of ethnic differences in susceptibility to adverse drug reactions to antihypertensive drugs was followed by the perhaps surprising finding that there is no relation between reduction in blood pressure and reduction in levels of C-reactive protein. Finally, new US guidelines for primary prevention of ischemic stroke stress blood pressure reduction and a brief clarification about caffeine in children, which raises blood pressure but lowers heart rate during exercise.

New Data on First-in-Class Oral Renin Inhibitor, Aliskiren, Revealed at American Society of Hypertension Meeting

It has long been thought that one of the most effective classes of cardiovascular drugs are those that inhibit the activities of the renin-angiotensin-aldosterone system (RAAS). Originally, this meant angiotensin-converting enzyme (ACE) inhibitors, targeting the rate-limiting enzyme in the conversion of angiotensin I to angiotensin II. Later, angiotensin II type 1 receptor blockers (ARBs) were introduced, developed on the premise that they would provide more specific inhibition of the RAAS. Now comes news of the latest class of RAAS inhibitors, aimed specifically at reducing plasma renin activity, which tends to be increased by both ACE inhibitors and ARBs.

Clinical data on aliskiren, the first in a new class of orally active renin inhibitors, were presented on May 17, 2005 at the 21st Annual Scientific Meeting of the American Society of Hypertension (ASH 2006) in New York, NY (see "Related Links" for Medscape Cardiology's ASH conference coverage). The latest findings demonstrate the safety and efficacy of the drug either as monotherapy or coadministered with the diuretic hydrochlorothiazide (HCTZ). The phase 3 data, which were more detailed than any previous data released about the drug, also showed that aliskiren provides effective 24-hour blood pressure control both alone and in combination with the diuretic. Phase 3 clinical trials with aliskiren have been ongoing in Europe, the United States, and Japan.

The data presented at ASH included a study led by Jerry Mitchell, MD (Texas Center for Drug Development, Houston, Texas), in which mean 24-hour ambulatory systolic and diastolic blood pressures (SBP and DBP) were measured in 216 patients with mild-to-moderate hypertension (mean sitting DBP ≥ 95 mm Hg and < 110 mm Hg) who had been randomized to receive once-daily aliskiren 150 mg, 300 mg, or 600 mg or placebo.^[1] The patients, who were part of a larger cohort participating in an 8-week trial, underwent 24-hour ambulatory blood pressure monitoring at baseline and at the end of the study.

All 3 doses of aliskiren significantly reduced 24-hour mean ambulatory SBP and DBP compared with placebo. The antihypertensive effect was maintained throughout the 24 hours following dosing. Of note, the normal, early-morning blood pressure surge was reduced by aliskiren compared with placebo. "Sustained, smooth 24-hour control is important, because blood pressure fluctuates and surges in the early morning are associated with a marked increase in cardiovascular events," said Dr Mitchell. By helping control blood pressure around the clock and preventing blood pressure surges, "aliskiren may lower the risks for heart attacks and strokes." Aliskiren also has the potential to provide optimized end-organ protection, he suggested.

Another study, led by James R. Herron, MD (Herron Medical Center, Chicago, Illinois), demonstrated that when patients discontinued aliskiren there were no rebound increases in blood pressure or plasma renin activity (PRA).^[2] Blood pressure and PRA remained suppressed for 2 weeks, suggesting that the sustained effect of aliskiren may be clinically beneficial in patients with poor compliance.

Combination Therapy With Diuretic

Two studies of aliskiren in combination with HCTZ were presented at the meeting. In an 8-week, double-blind trial involving 2776 patients with mild-to-moderate hypertension, researchers led by Alberto Villamil, MD (Fundapres, Buenos Aires, Argentina), found that aliskiren alone at a dose of 75 mg, 150 mg, or 300 mg provided significant dose-dependent reductions in mean sitting SBP and DBP compared with placebo.^[3] In combination with HCTZ 6.25 mg, 12.5 mg, or 25 mg, aliskiren provided significant additional blood pressure reductions. The greatest mean reduction was seen with aliskiren 300 mg/HCTZ 25 mg.

All active treatments were well tolerated, and the overall incidence of adverse events was similar in placebo and all mono/combination therapy groups. In combination therapy, aliskiren also prevented the reactive rise in PRA induced by HCTZ, suggesting that aliskiren may be a useful adjunct to diuretic treatment by improving end-organ protection, the researchers noted.^[4]

Renoprotection

Potential renoprotective effects of aliskiren were reported from a study in rats.^[5] The renal localization and long renal residence time of the drug may have implications for its mechanism of action and could lead to long-lasting inhibition of local generation of angiotensin II, researchers speculated. Aliskiren was detected 3 weeks after washout in the animals, suggesting that long-term renoprotective effects could be derived at the tissue level. The researchers suggested that this could also explain the clinical findings of sustained blood pressure lowering following withdrawal of aliskiren.

Development News

Aliskiren is being developed by Novartis (Basel, Switzerland) in conjunction with Speedel (Basel and Bridgewater, New Jersey). The first regulatory submission for aliskiren was made in the United States at the beginning of 2006, and on April 20, Novartis announced that the New Drug Application (NDA) for aliskiren as a treatment for high blood pressure had been accepted for review by the US Food and Drug Administration (FDA). A European regulatory submission is planned for late 2006. If approved, aliskiren is expected to be marketed under the trade name Rasilez.

Novartis plans to start a clinical outcomes program with aliskiren in 2007. Two studies will define the role of direct renin inhibition in primary and secondary prevention. AVIATOR (Aliskiren in VIsceral obesity AT risk patients Outcomes Research), a prehypertension study in approximately 15,000 high-risk patients, will determine whether aliskiren delays the time to a first major cardiovascular event. ALTITUDE (ALiskiren Trial in Type 2 Diabetic nEphrophathy) is a type 2 diabetes outcomes study that will be carried out in approximately 6000 subjects to determine whether aliskiren delays time to diabetic complications in patients with diabetes mellitus and nephropathy. First data from these studies are expected to be available in 2011.

Aliskiren is likely to become the first truly new treatment approach available for hypertension in over 10 years. Earlier development of renin inhibitors in hypertension by a number of pharmaceutical companies was stopped in the mid-1990s, apparently for commercial reasons that are based on the success of ARBs. Early renin inhibitors also had problems of potency, bioavailability, duration of action, and costs of synthesis. Programs to develop renin inhibitors were reactivated when these problems had been overcome. Speedel, which carried out a number of phase 1 and 2 clinical trials with aliskiren, has several other renin inhibitors currently in development, including one (SPP635) in phase 1.

ALLHAT Investigators Again Claim That Diuretics Are Superior to Other Drug Classes for Heart Failure Prevention

A new analysis of data from ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) -- the largest hypertension trial ever conducted -- claims that diuretics are more effective than calcium channel blockers or, at least in the short term, more effective than ACE inhibitors in preventing heart failure (HF), according to the ALLHAT investigators led by Barry R. Davis, MD, PhD (University of Texas School of Public Health, Houston, Texas).

The ALLHAT clinical trial studied patients aged ≥ 55 years with stage I hypertension and ≥ 1 risk factor for heart disease.^[6] Patients who had been hospitalized or treated for HF or had a left ventricular (LV) ejection fraction < 35% were excluded from the study. A total of 33,357 patients were randomly assigned to treatment with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine), or an ACE inhibitor (lisinopril). Goal blood pressure was < 140/90 mm Hg, which was achieved by uptitration of whichever of the 3 step 1 drugs that the patient was on, followed by addition of an open-label drug of the physician's choice (step 2, not including one of the step 1 drug classes), and finally the addition of study-supplied drugs for step 3, as necessary. HF was a prespecified secondary outcome of the study. The study was supported by the National Heart, Lung, and Blood Institute and Pfizer, with contributions of study medications from Pfizer (New York, NY), AstraZeneca (Wilmington, Delaware), and Bristol-Myers Squibb (New York, NY).

The ALLHAT investigators have faced some criticism about the HF endpoint in their study, and mounted a vigorous defense against commentators who called it "a soft endpoint.^[7]" They conducted several HF validity studies, the largest of which, the ALLHAT Heart Failure Validation Substudy, reported confirmation of 70% to 84% of the investigator-assigned HF diagnoses in each treatment group.^[8]

As reported in the May 9, 2006 issue of Circulation,^[9] over a mean follow-up of 4.9 years, 1773 ALLHAT patients developed HF, which was defined for this analysis as hospitalization for HF or fatal HF. These patients were older, more likely to be male, diabetic, current smokers, or taking antihypertensive medications before study entry. They also had higher body mass indexes, higher SBP, lower DBP, and higher heart rate, and were more likely to have a history of coronary heart disease (CHD) and evidence of LV hypertrophy.

Overall, the chlorthalidone group had a lower incidence of HF than the lisinopril or amlodipine groups, with a relative risk (RR) for amlodipine of 1.35 (95% confidence interval [CI] 1.21-1.50, P < .001) and for lisinopril 1.11 (95% CI 0.99-1.24, P = .09). The difference in risk was highest in the first year of treatment, when HF incidence in the amlodipine and lisinopril groups was double that in the chlorthalidone group (amlodipine RR 2.22, 95% CI 1.69-2.91, P < .001; lisinopril RR 2.08, 95% CI 1.58-2.74, P < .001). After the first year, however, there was no difference between the risk with lisinopril and that with chlorthalidone, whereas the risk remained higher with amlodipine (RR 1.22, 95% CI 1.08-1.38, P = .001).

These results were not affected by age, race, sex, or diabetes status, nor could they be explained by prior use of specific antihypertensive medications, concomitant use of open-label blood pressure-lowering drugs, or differences in follow-up blood pressure, said the investigators. One possible explanation for the differing results over time could be that diuretics have an immediate effect on HF prevention because they decrease fluid overload volume, whereas ACE inhibitors affect remodeling of the heart, which long term may have a more beneficial effect on preventing HF, Dr. Davis suggested. Another explanation might be the addition of step-up drugs, which made the treatment regimens more similar.

Dr. Davis emphasized the need to treat hypertension to prevent HF. "Over 90% of people who develop heart failure first had high blood pressure," he said. "Although not as well recognized as its effects on stroke and heart attack, one of the benefits of treating high blood pressure is that it helps prevent heart failure. Among patients in the ALLHAT study, there was a 5% death rate overall over 2 and a half years, but it was 2 times higher in those who had been hospitalized for heart failure," he noted.

Critique

In an accompanying editorial,^[10] Salim Yusuf, MBBS, DPhil (McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada) points out that both the primary outcomes (fatal CHD and nonfatal myocardial infarction [MI]) and the most important secondary outcome (total mortality) were similar across the 3 treatment groups. So from a purist's point of view, he says, this makes interpretation of secondary outcomes "challenging." However, he believes that these analyses may be valid if they achieve an extreme probability value, and in this context, the comparison between chlorthalidone and amlodipine is valid, but not that between chlorthalidone and lisinopril. In addition, the post hoc subdivision by time (< 1 year vs later) was "methodologically suspect," "not supported by other data," and "not particularly persuasive," Dr. Yusuf concluded. What really matters, he said, is not which single drug to use, but which combination of drugs to use. His preference in most patients is a combination of a diuretic and an ACE inhibitor, given the results of various trials of diuretics in hypertension and the special benefits of ACE inhibitors in patients with HF, post MI, and in other high-risk patients.

History of Arterial Hypertension Does Not Affect Mortality in Patients Hospitalized With Congestive Heart Failure (CHF)

Perhaps as further proof that the complex condition known as "hypertension" is still not completely understood, another report this month finds that a history of hypertension has no bearing on heart failure risk -- in direct contradistinction to Dr. Davis' statement in the previous section that "Over 90% of people who develop heart failure first had high blood pressure." Thus, according to Danish researchers reporting in Heart Online,^[11] although arterial hypertension is an important risk factor in the general population and probably in patients with CHD, it does not seem to play a major role in patients with moderate-to-severe CHF, regardless of the underlying cause of LV failure.

On the basis of previous observations in patients with LV systolic dysfunction after acute MI, Finn Gustafsson, MD, PhD (Rigshospitalet, Copenhagen, Denmark), and other members of the DIAMOND (Danish Investigations Of Arrhythmia And Mortality On Dofetilide)-CHF study group hypothesized that a history of hypertension in CHF patients would be associated with decreased survival.

To test this hypothesis, Dr. Gustafsson and his colleagues analyzed the 5491 patients hospitalized with new or worsening CHF who were entered into the DIAMOND study between 1993 and 1996. The DIAMOND study was a multicenter, randomized controlled trial of the efficacy of the class III antiarrhythmic agent dofetilide on mortality in CHF patients. Forty percent of the patients had significant LV systolic dysfunction and 57% had ischemic heart disease. A total of 1333 (29%) of the patients had a history of hypertension. More women than men had a history of hypertension, and preserved LV systolic function was more common among patients with a history of hypertension.

During follow-up, which ranged from 5 to 8 years, 3955 (72%) patients died. No association was found between a history of hypertension and increased risk for death (hazard ratio 0.99, with a very narrow CI of 0.92-1.07). Adjustment for other risk factors did not alter this result. The hazard ratio was similar in patients with and without a history of ischemic heart disease, nor was there any effect of hypertension in patients with depressed or preserved LV systolic function.

The finding that a history of arterial hypertension did not affect mortality in patients hospitalized with CHF agrees with a number of previous reports, although some smaller studies have reported an association. However, regardless of their documented difference with the ALLHAT group's apparent correlation of hypertension and HF, Dr. Gustafsson's group agrees with the admonition that this "should not displace emphasis from the fact that hypertension is a major risk factor for developing CHF, which may be prevented by adequate blood pressure control in the population."

Ethnic Differences in Susceptibility to Adverse Drug Reactions to Antihypertensive Drugs

Ethnicity may predict differences in susceptibility to adverse drug reactions (ADRs) to cardiovascular drugs, according to a review of published data carried out by UK researchers. In particular, the data show that ACE inhibitors are associated with a higher incidence of angioedema in black patients and cough in East Asian and black patients, compared with white patients. The results of this review are published in the May 20 issue of the BMJ.^[12]

Researchers from West Midlands Centre for Adverse Drug Reaction Reporting at the City Hospital in Birmingham and the University of Birmingham (Birmingham, United Kingdom), searched the scientific literature through March 2005 and identified and analyzed the results of 24 studies that included at least 2 ethnic groups and ≥ 1 ADR to cardiovascular drugs.

Pooled analysis of unadjusted data from 4 studies that reported angioedema due to ACE inhibitors showed that black patients had 3 times the relative risk for angioedema (RR 3.0; 95% CI 2.5-3.7) compared with nonblack patients. Pooled analysis of the data from 3 studies, with the random effects model, found a nonsignificant RR of 1.1 (95% CI 0.5-2.3) for cough due to ACE inhibitors in black compared with nonblack patients. The pooled RR of cough calculated from data from 2 studies comparing East Asian (Chinese, Korean, or Japanese) patients showed an RR of 2.7 (95% CI 1.6-4.5) compared with white patients.

Other studies that described ADRs associated with the use of other antihypertensive drugs included a small clinical trial that reported significantly more depression with HCTZ in black patients than in white patients. A prospective study, using a different measure, described a subtle difference in depression scores between black and white patients treated with antihypertensive drugs. A small randomized controlled trial noted that 17% of black patients reported headache compared with only 2% in nonblack patients (P < .05). A retrospective analysis of medical records found that 26% of East Asian patients (Chinese, Japanese, Filipino, Korean, and other) reported adverse effects associated with antihypertensive drugs, compared with 13% of white patients (P < .002).

The UK investigators also looked at reports of ADRs associated with oral anticoagulants, antiarrhythmic agents, and simvastatin in different ethnic groups. They concluded that patients from different ethnic groups have different risks for important ADRs to cardiovascular drugs. "These findings may help doctors present more accurate and relevant data to their patients when prescribing cardiovascular therapy," they proposed. They suggested that these ethnic differences may act as a marker for "potentially important genetic or environmental factors that can influence the balance between benefit and harm and help to direct future research." The investigators call for recruitment of more people from different ethnic groups into clinical trials and for pharmaceutical companies to routinely report data on ethnicity in analyses of clinical trial data. In order to achieve greater consistency and improved comparison between studies, however, reports must describe how ethnicity was classified and how it is relevant to the study, the UK researchers advised.

Val-MARC Results Show No Relation Between Reduction in Blood Pressure and Reduction in Levels of C-Reactive Protein

A trial investigating the relation between blood pressure lowering with an ARB, with or without a diuretic, and changes in levels of high-sensitivity C-reactive protein (hsCRP) in hypertensive patients has reached the surprising conclusion that there is minimal or no correlation between change in blood pressure and hsCRP reduction. The results of the Val-MARC (Valsartan-Managing blood pressure Aggressively and evaluating Reductions in hsCRP) trial showed that combination therapy with valsartan plus HCTZ was superior to valsartan monotherapy in terms of absolute blood pressure reduction, but that only valsartan alone significantly reduced levels of the inflammatory biomarker. "This is almost prima facie evidence that these 2 phenomena are quite independent of each other," said the trial's lead investigator, Paul M. Ridker, MD, MPH (Center for Cardiovascular Disease Prevention, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts), who presented the results at the ASH meeting.^[13] The study has also been published online and will appear in the July print issue of Hypertension.^[14] The study was funded by Novartis.

The Val-MARC trial was based on the known association between increased levels of hsCRP and hypertension and on angiotensin's role as a potent proinflammatory mediator. Between January 2004 and June 2005, 1668 patients with stage II hypertension (SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg) were randomized to valsartan 160 mg or valsartan 160 plus HCTZ 12.5 mg. At 2 weeks, the dose of valsartan was increased to 320 mg, and if blood pressure remained uncontrolled at 6 weeks, physicians were allowed to add HCTZ 12.5 mg in both groups until week 12.

Dr. Ridker and his colleagues were not surprised that combination therapy was "clearly superior" to monotherapy in lowering blood pressure (-25 mm Hg vs -18 mm Hg, respectively; P < .001), with 48% on combination therapy vs 32% on monotherapy weeks (P < .001) reaching goal (< 140/90 mm Hg) at 6 weeks. However, only valsartan monotherapy reduced levels of hsCRP. The median change in hsCRP in the valsartan group was -0.12 mg/L, whereas it was +0.05 mg/L in the valsartan plus HCTZ group, a net difference of 13.3% (P < .001). These results were consistent across all major subgroups analyzed, including sex and ethnicity. The change in hsCRP did not differ by use or nonuse of concomitant medications, including aspirin, hormone replacement therapy, and statins, although a number of clinical trials have shown that statins reduce hsCRP levels. Subgroup analysis by blood pressure reduction (>/< 20 mm Hg) did not affect the hsCRP results.

Previous studies have suggested that angiotensin blockade may have clinically relevant anti-inflammatory effects. The Val-MARC data suggest that angiotensin blockade with valsartan monotherapy may lower inflammation in a manner that is independent of blood pressure reduction, Dr. Ridker proposed. "Whether this translates to a net clinical advantage will require well-designed prospective trials of hypertension treatment that specifically target those with an enhanced innate immune response," he said. "This will be true for both treatment and prevention trials of hypertension," he added. Additional studies will be needed to discover whether thiazide-type diuretics, such as HCTZ, have adverse effects on hsCRP when given alone, he noted.

New US Guidelines for Primary Prevention of Ischemic Stroke Stress Reduction of Blood Pressure

Actual blood pressure reduction is generally more important than which specific antihypertensive agent is used for primary prevention of stroke, according to new guidelines issued by the American Heart Association (AHA) and its division, the American Stroke Association (ASA), and published in both the rapid-access online issue of Stroke and in the June printed issue.^[15] The new guidelines are a complete revision of the last AHA/ASA statement, published in 2001,^[16] say the authors, led by Larry B. Goldstein, MD, Professor of Medicine (neurology) and Director of the Duke Center for Cerebrovascular Disease at Duke University Medical Center in Durham, North Carolina. The guidelines are endorsed by the American Academy of Neurology.

Antihypertensive agents, such as thiazide-type diuretics, ACE inhibitors, ARBs, beta blockers, and calcium channel blockers have all been shown to reduce the risk for stroke in patients with hypertension, but no specific antihypertensive drug classes have been shown to offer special protection against stroke, the guidelines state. They follow the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)^[17] in advising that most people need ≥ 2 antihypertensive agents to control their blood pressure. People with blood pressure levels below drug treatment thresholds should reduce their risk for stroke by adopting "nondrug or lifestyle approaches."

The new guidelines note that the risk for stroke increases as blood pressure rises, and a significantly high proportion of the US population has uncontrolled hypertension, particularly among minority groups and the elderly. "Programs to improve treatment compliance need to be developed and supported," the guidelines say. They recommend that people be screened for hypertension at least every 2 years (more often in minority populations and the elderly) and that management, including lifestyle modification, dietary changes, and drug treatment, follow the JNC 7 recommendations.

The AHA/ASA guidelines also review and make recommendations for other "well-documented and modifiable risk factors," including exposure to cigarette smoke, diabetes, atrial fibrillation, and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. "Less well-documented or potentially modifiable risk factors" include the metabolic syndrome, alcohol abuse, drug abuse, oral contraceptive use, sleep-disordered breathing, migraine headache, hyperhomocysteinemia, elevated lipoprotein(a), elevated lipoprotein-associated phospholipase, hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are also reviewed.

Stroke is the third leading cause of death and a major source of disability in the United States. Approximately 700,000 people each year in the United States have a stroke, resulting in nearly 158,000 deaths. From 1993 to 2003, the stroke death rate fell 18.5%, but the actual number of stroke deaths declined only 0.7%, according to 2006 AHA/ASA statistics. "Stroke remains a major public health problem. Its human and economic toll is staggering," Dr. Goldstein said. "Stroke can be prevented and we are learning more about ways of accomplishing that."

Caffeine Raises Blood Pressure, Lowers Heart Rate in Children During Exercise

A recent US study reported that high caffeine intake in adolescents, who usually consume it in soft drinks, was resulting in a significant increase in blood pressure and the risk for hypertension.^[18] Now, however, according to new research from Harding University in Searcy, Arkansas, it appears that although caffeine elevates blood pressure and lowers heart rate in children during exercise, it does not affect overall metabolic rate. The study is the first to investigate the effects of caffeine, given in a carbonated drink, on both cardiovascular and metabolic responses to exercise in healthy boys and girls. Although the physical effects of caffeine have been studied for years, few studies have addressed the effects of caffeine in young children. Soft drink consumption by children and adolescents has been increasing, and although the exact amount of caffeine that they consume is unknown, "it is evident that children are consuming a substantial amount," researchers say.

In the study, published in the March issue of Medicine & Science in Sports & Exercise, by the American College of Sports Medicine (Indianapolis, Indiana),^[19] 52 healthy children aged 7-9 years (26 boys and 26 girls) were entered into a double-blind, randomized, double-blind, crossover study. Twice on 4 separate days they were each given a placebo drink (a mixture of Sprite, cherry syrup, and water) or a caffeinated drink (the placebo with 5 mg/kg body mass with anhydrous caffeine dissolved in it). One hour after resting, each child rode a stationary bicycle ergometer while blood pressure, heart rate, and oxygen consumption were measured.

The results showed that caffeine significantly increased both resting and exercise blood pressure and significantly reduced heart rate in boys and girls given a moderate to high dose of caffeine 1 hour before exercise. The caffeine did not affect metabolism (measured as oxygen consumption and respiratory exchange ratio), nor were significant differences found between boys and girls. "We expected the increase in blood pressure," Dr. Turley said, "but the decrease in heart rate was surprising." He suspects that it was due to the body's response to try to maintain a normal blood pressure. He noted that the heart rate effect, unlike the blood pressure effect, does not agree with adult studies, adding that comparing the data from this study with adult literature should be done with caution until studies have been carried out with the same methodologies.

Dr. Turley is concerned about the long-term effects of caffeine in children. "Long-term caffeine intake has been associated with increased blood pressure in adolescents that increases the risk of hypertension," he said. "Although this study describes only an acute affect, the length of which is unknown, repeated exposure over days or weeks could contribute to possible long-term increases. Thus, exposure to caffeine in young children should at best be limited, at least in children who are borderline hypertensive."

Mitchell J, Oh B, Herron J, et al. Once-daily aliskiren provides effective, smooth 24-hour control in patients with hypertension. J Clin Hypertens. 2006;8(supplA):A93. Abstract P-209. Herron J, Mitchell J, Oh B, et al. The novel renin inhibitor aliskiren is not associated with rebound effects of blood pressure or plasma renin activity following treatment withdrawal. J Clin Hypertens. 2006;8(supplA):A86. Abstract P-193. Villamil A, Chrysant SG, Calhoun D, et al. The novel oral renin inhibitor aliskiren provides effective blood pressure control in patients with hypertension when used alone or in combination with hydrochlorothiazide. J Clin Hypertens. 2006;8(supplA):A101. Abstract P-230. Calhoun D, Chrysant S, Villamil A, et al. The novel renin inhibitor aliskiren decreases plasma renin activity (PRA) and neutralizes hydrochlorothiazide-induced activation in hypertensive patients. J Clin Hypertens. 2006;8(supplA):A77. Abstract P-168. Feldman DL, Persohn E, Schutz H, et al. Renal localization of the renin inhibitor aliskiren. J Clin Hypertens. 2006;8(supplA):A80. Abstract P-178. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:1981-1997. Davis BR, Furberg CD, Wright JT Jr, Cutler JA, Whelton P; ALLHAT Collaborative Research Group. ALLHAT: setting the record straight. Ann Intern Med. 2004;141:39-46. Abstract Einhorn P, Davis B, Piller L, et al; ALLHAT Collaborative Research Group. Review of heart failure events in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT): ALLHAT Heart Failure Validation Study. Circulation. 2003;108(supplIV):IV-399. Abstract. Davis BR, Piller LB, Cutler JA, et al; Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) Collaborative Research Group. The 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 Yusuf S. Preventing vascular events due to elevated blood pressure. Circulation. 2006;113:2166-2168. Abstract Gustafsson F, Torp-Pedersen C, Seibaek MB, Burchardt H, Nielsen OW, Kober L. A history of arterial hypertension does not affect mortality in patients hospitalized with congestive heart failure. Heart. 2006 Apr 18; [Epub ahead of print]. McDowell SE, Coleman JJ, Ferner RE. Systematic review and meta-analysis of ethnic differences in risks of adverse reactions to drugs used in cardiovascular medicine. BMJ. 2006;332:1177-1181. Abstract Ridker PM, Danielson E, Rifai N, Glynn R; Val-MARC Investigators. Valsartan, blood pressure reduction, and C-reactive protein: primary report of the Val-MARC trial. Program and abstracts of the 21st Annual Scientific Meeting and Exposition of the Annual Society of Hypertension; May 16-20, 2006; New York, NY. Late breaking clinical trials. Ridker PM, Danielson E, Rifai N, Glynn R; Val-MARC Investigators. Valsartan, blood pressure reduction, and C-reactive protein: primary report of the Val-MARC trial. Hypertension. 2006;48:1-7. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Stroke. 2006 May 4; [Epub ahead of print]. Available at: http://stroke.ahajournals.org/ Accessed May 25, 2006. Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Stroke. 2001;32:280-299. Abstract Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252. Abstract Turley KR, Gerst JW. Effects of caffeine on physiological responses to exercise in young boys and girls. Med Sci Sports Exerc. 2006;38:520-526. Abstract Savoca MR, Evans CD, Wilson ME, et al. The association of caffeinated beverages with blood pressure in adolescents. Arch Pediatr Adolesc Med. 2004;158:473-477. Abstract

Funding Information

Supported by an independent educational grant from Pfizer.