New Treatment Recommendations, Plus a New Dietary Supplement, a New Drug, a New Gene Locus, and Pfizer/National Medical Association on Race

August 19, 2003

Introduction

Treatment recommendations -- More hypertension-related recommendations were published in the United States in July. The latest are by the US Preventive Services Task Force, a nongovernment body that "strongly urges" clinicians to screen everyone aged 18 years or older for hypertension. The Task Force has not issued any guideline for children and adolescents because of conflicting evidence, but evidence from a recently published study carried out in The Netherlands, where school-age children are routinely screened, seems to indicate that cardiovascular risk can be assessed in adolescents by blood pressure measurement.

Diet -- From a study designed to clarify the effect of dietary potassium on blood pressure, British researchers suggest that low-level potassium supplementation can significantly lower blood pressure in people on normal diets.

Drugs -- In the world of pharmaceuticals, encouraging news comes from international investigators in diabetes, who had already shown that the alpha-glucosidase inhibitor acarbose could reduce the risk of diabetes in patients with impaired glucose tolerance and now report that acarbose also reduces the risk of cardiovascular disease and hypertension in these patients. The furthest in clinical development of a new class of antihypertensive agents known as advanced glycation end-product (AGE) crosslink breakers may progress to phase 3, although some results in phase 2 trials are disappointing.

Genes -- The worldwide search for "the hypertension gene" continues, but the latest report from the United Kingdom only adds to the list of chromosome regions that may contain specific genes or variants.

Race -- Finally, racial differences in the prevalence and treatment of hypertension in the United States are highlighted in a joint report from the National Medical Association and Pfizer Inc, based on national databases, including the latest National Health and Nutrition Examination Survey (NHANES).

US Task Force Recommends Blood Pressure Screening for Everyone Aged 18 Years or Over

The US Preventive Services Task Force (USPSTF), an independent panel of private sector experts in prevention and primary care sponsored by the Agency for Healthcare Research and Quality (AHRQ), has issued its latest recommendations on screening for high blood pressure,[1] an update from those made in 1996.[2] Its main recommendation is that clinicians screen all adults aged 18 or older for high blood pressure. This extends the recommendation made in 1996, which was for screening in adults aged 21 or over. The latest recommendation is based on "good evidence that early detection and treatment of high blood pressure can significantly reduce the risk of cardiovascular disease." The USPSTF concluded that "the benefits of screening for, and treating, high blood pressure in adults substantially outweigh the harms." In children and adolescents, the USPSTF found the evidence insufficient to recommend for or against screening for blood pressure to reduce the risk of cardiovascular disease.

The USPSTF based its conclusions on an AHRQ-sponsored report prepared by a team led by Stacey Sheridan, MD, MPH (University of North Carolina at Chapel Hill). The team identified new evidence related to the detection and treatment of hypertension from searches of MEDLINE, DARE, and the COCHRANE Collaboration Library, recent systematic reviews, and the 1996 Guide to Preventive Services. The USPSTF recommendations are independent of the US government. The report notes that despite clear evidence supporting screening and the widespread use of clinical blood pressure measurement, identification and treatment of hypertension remain suboptimal for the US population as a whole, and that "substantial progress in organization and access to care" will be required to approach the NHANES III "Healthy People 2010" goals (to increase the proportion of adults who have their blood pressure measured to 95% and those with controlled hypertension to 50%).[3]

High Blood Pressure in Adolescence Increases Cardiovascular Risk

In apparent synchrony with the new USPSTF recommendations comes a call for blood pressure screening in adolescents, following a Dutch study published in the July issue of The American Journal of Hypertension.[4] Researchers from Utrecht report that high blood pressure in adolescence and a relative increase in blood pressure through adulthood are associated with increased carotid intima media thickness (CIMT), a measure of subclinical atherosclerosis. Lydia E. Vos, MD, and colleagues investigated a community-based sample of 750 adults aged 27-30 years who had had at least 1 blood pressure measurement recorded at a mean age of 13 years. (Almost all children in The Netherlands are screened regularly as part of the Municipal Health Service, starting at age 4 weeks until they leave secondary school at age 16-19.) All subjects answered a questionnaire on risk factors, had a fasting blood sample drawn, and underwent ultrasound examination of both carotid arteries for measurement of CIMT.

In adolescence, each standard deviation increase in systolic blood pressure (SBP) was found to be associated with an increase of 7.5 micrometers in CIMT. Similar relations were found for pulse pressure and mean arterial pressure (MAP). After adjustment for sex, age, and BMI and young adulthood and adult blood pressure, the correlation with pulse pressure remained significant. Subjects with the highest SBP and pulse pressure from adolescence through young adulthood had the greatest increase in CIMT.

The investigators suggest that their finding of a 7.5-mu increase in CIMT is equivalent to a relative increase of 1.9% risk of coronary heart disease. They believe that their results "strengthen the notion that the process of increasing cardiovascular risk is already initiated at adolescence."

Reaction to the study comes from American Journal of Hypertension editor, Michael Weber, MD (SUNY Downstate College of Medicine, Brooklyn, New York), who has stated that parents should ensure that their adolescent children have their blood pressure checked regularly.

Addition of Low-Dose Potassium to Diet Lowers Blood Pressure

A sustained low-dose addition of potassium (KCl) to a normal diet can significantly lower blood pressure, UK researchers report in the July issue of the British Journal of Nutrition.[5] Professor Donald J. Naismith, MD, and Alessandro Braschi, PhD (King's College London) conducted a trial in which 69 healthy volunteers were randomized to receive either 24 mmol KCl/day or placebo for 6 weeks. KCl was administered as 1 slow-release tablet containing 8 mmol KCL taken 3 times daily with meals. This daily dose of potassium is equivalent to the content of 5 portions of fresh fruits and vegetables. At the end of the 6-week intervention, the 30 subjects who took potassium showed significant decreases in SBP and DBP (7.60 and 6.46 mm Hg, respectively) and thus in MAP (7.01 mm Hg), the primary outcome of the study, compared with the group given placebo. The changes in blood pressure occurred gradually over the study.

The benefits of potassium on blood pressure have been known for some time, but to date studies to define the optimal dose have been inconclusive or conflicting. Professor Naismith and Dr. Braschi believe that their study highlights the importance of an adequate intake of potassium and that diet supplementation with potassium or fortification of processed foods may offer an inexpensive and safe preventive measure where increased consumption of fruits and vegetables is unrealistic because of their relatively high cost.

Antidiabetes Drug Reduces Risk of Cardiovascular Disease and Hypertension

In 2002, the results of the international Study to Prevent Noninsulin-Dependent Diabetes Mellitus (STOP-NIDDM) showed that reducing postprandial glucose levels in patients with impaired glucose tolerance (IGT) with the alpha-glucosidase inhibitor acarbose could reduce the risk of diabetes.[6] In the July 23/30 issue of JAMA,[7] the STOP-NIDDM trial investigators reported that acarbose was also associated with a significant reduction in the risk of cardiovascular disease and hypertension in these patients. Out of a total of 1429 patients with IGT randomized to either acarbose 100 mg 3 times daily or placebo, 1368 were available for a modified intent-to-treat analysis. Those who received acarbose showed a 49% relative risk reduction in the development of cardiovascular events, of which the major reduction was in the risk of MI. Acarbose was also associated with a 34% risk reduction in new cases of hypertension. These reductions associated with acarbose treatment remained significant after adjustment for major risk factors.

While acknowledging limitations in their interpretation of these data -- including modification of the intent-to-treat population through dropouts, the small numbers of events, and the fact that the STOP-NIDDM trial was powered for incidence of diabetes, not cardiovascular disease -- the investigators believe that their observations are statistically and clinically significant. They are hypothesis generating, however, and will need to be confirmed.

New Class of Antihypertensive Agents Continues in Development

The most advanced compound in development among a new class of antihypertensive drugs known as AGE crosslink breakers has failed to lower blood pressure as expected in phase 2 trials.[8] ALT-711, under development by Alteon (New Jersey), was evaluated in a total of 768 patients in 2 phase 2b trials, the Systolic and Pulse Pressure Hemodynamic Improvement by Restoring Elasticity (SAPPHIRE) and the Systolic Hypertension Interaction with Left VEntricular Remodeling (SILVER).

All patients had elevated SBP (> 150 mm Hg), with or without enlargement of the left ventricle, and were maintained on background hypertension medication as well as receiving ALT-711 or placebo over 6 months. ALT-711 did not demonstrate statistical significance compared with placebo against the prespecified primary endpoint of reduction of SBP by office cuff pressure measurement at the highest of 4 dose levels (210 mg/day). In the SAPPHIRE intent-to treat-population, however, lower doses of ALT-711 resulted in a 2- to 3-mm Hg greater reduction in SBP compared with placebo. In the patients who completed the study, this effect at lower doses was amplified to a 4-mm Hg difference.

According to George L. Bakris, MD (Rush-Presbyterian St Luke's Medical Center, Chicago, Illinois), lead investigator on the SAPPHIRE and SILVER trials, if confirmed in further studies, such an effect "would be an important addition to the treatment of this patient population."

ALT-711 was reported to be safe and well tolerated in both trials, and additional phase 2 studies of ALT-711 are being planned on the basis of its activity at lower doses. If the results are positive, phase 3 trials in systolic hypertension will begin in 2005, according to Alteon.

ALT-711 chemically reverses the crosslinks between protein-glucose complexes (AGEs) that lead to increased stiffness of tissues, impairing the normal function of organs that depend on flexibility, such as blood vessels and cardiac muscle. ALT-711 was previously shown to improve total arterial compliance in older adults with vascular stiffening, suggesting that it might be a novel therapeutic approach for this abnormality, which occurs with aging, diabetes, and isolated systolic hypertension.[9] It was also reported to be effective in diastolic heart failure, in the Distensibility, Improvement and Remodeling in Diastolic Heart Failure (DIAMOND) trial, earlier this year.[10]

UK Researchers Identify New Chromosomal Region Associated With Blood Pressure

Although around 40% of blood pressure variability is thought to be genetically determined, attempts to identify the genes underlying this trait have had only limited success. A wide range of chromosome regions that may contain relevant genes has been identified, but to date, no specific genes or variants. In the latest study to be published,[11] the Medical Research Council BRItish Genetics of HyperTension (BRIGHT) study used genome-wide screening of DNA from 2010 affected sibling pairs from 1599 severely hypertensive families. All participants were white and had hypertension diagnosed before age 60 years. A locus near one end of chromosome 6q was identified by linkage analysis as significantly associated with blood pressure. Three other regions, significantly but less strongly implicated, were identified on chromosomes 2q, 5q, and 9q. The UK researchers acknowledge that the chromosomal regions identified in their study are unlikely to reflect all genetic effects on hypertension.

In an accompanying commentary,[12] Professor Stephen B. Harrap, MB BS, PhD (University of Melbourne, Australia), cautions that the end of a chromosome, where the principal locus in the BRIGHT study was identified, is a region where computer linkage programs can occasionally generate misleading evidence. He points out that this study, a recent US analysis,[13] and other blood pressure genome scans have shown no consistency in the loci reported and suggests that this is probably due to the numerous blood pressure alleles and their small individual impact and uneven distribution between populations. Professor Harrap believes that genetics might never contribute to the diagnosis of common diseases such as hypertension, simply because of their complexities.

Racial Disparities Highlighted in US Cardiovascular Health

A new analysis of data from NHANES III (1999-2000), National Health Interview Surveys (1997 and 2001), and National Hospital Discharge Surveys (1992 and 2000) highlights the differences and disparities in cardiovascular health, particularly hypertension, between black and white adults in the United States.[14] The collaborative study by the National Medical Association (NMA) and Pfizer Inc notes that although the prevalence of hypertension has increased in blacks and whites since 1992, it is it currently higher among blacks (36% vs 30%, respectively), with the greatest racial difference in those aged 40-59 years (50% vs 30%, respectively). This group also showed the greatest increase in prevalence over time (24% vs 19% among whites). The prevalence of undiagnosed hypertension is the same (9%) in black and white populations, but awareness (percentage of prevalent cases diagnosed) is higher among blacks (74% vs 69%). Awareness is particularly high among black women (82% vs 64% in black men), but among blacks in the age group 20-39 years, awareness has decreased by 26% to 48%.

Treatment rates have increased by over 9% in each racial group and are currently slightly higher among blacks than whites (62% vs 58%). Black women are more likely to be treated than black men (70% vs 52%). Treatment rates remain highest among blacks aged ≥ 60 years (76% vs 61% in same-aged whites). Among blacks with hypertension, only 25% have their blood pressure controlled at goal, almost unchanged from NHANES III, whereas the control rate among whites with hypertension rose over the same time from 22% to 31%. Fewer blacks than whites with prescription medications achieve blood pressure control (40% vs 54%, a decrease of 2% for blacks, but an increase of 13% for whites, since NHANES III).

These findings in hypertension, which contrast with decreases shown in heart disease and stroke death rates in both racial groups, point to concern, the study's authors say. "This study shows that simply prescribing treatments and telling a patient what to do is not enough," says Elijah Saunders, MD (University of Maryland School of Medicine, Baltimore), chair of the cardiology section of the NMA. "Health providers have a responsibility to follow up with their patients and encourage them to adhere to treatments," he urges.

References

  1. US Preventive Services Task Force, Screening for high blood pressure. Recommendations and rationale. Am J Prev Med. 2003;25:159-164. Available at
    http://www.ahrq.gov/clinic/ 3rduspstf/highbloodsc/hibloodrr.htm. Accessed August 14, 2003.

  2. Screening for hypertension. In: US Preventive Services Task Force. Guide to Clinical Preventive Services. 2nd ed. Washington, DC: Office of Disease Prevention and Health Promotion: 1996;39-51.

  3. US Department of Health and Human Services. Healthy People 2010: Understanding and Improving Health. 2nd ed. Washington, DC: US Government Printing Office: November 2000. Healthy People 2010: Focus Area 12. Heart Disease and Stroke available online at
    http://www.cdc.gov/cvh/hp2010 /objectives.htm#blood_pressure. Accessed August 14, 2003.

  4. Vos LE, Oren A, Uiterwaal C, et al. Adolescent blood pressure and blood pressure tracking into young adulthood are related to subclinical atherosclerosis: the Atherosclerosis Risk in Young Adults (ARYA) study. Am J Hypertens. 2003;16:549-555.

  5. Naismith DJ, Braschi A. The effect of low-dose potassium supplementation on blood pressure in apparently healthy volunteers. Br J Nutr. 2003;90:53-60.

  6. Chiasson J-L, Josse RG, Gomis R, et al. Acarbose for prevention of type 2 diabetes mellitus, treatment: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077.

  7. Chiasson J-L, Josse RG, Gomis R, et al, for The STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance. The STOP-NIDDM trial. JAMA. 2003;290:486-494.

  8. Alteon's ALT-711 shows efficacy against uncontrolled systolic hypertension: Prespecified endpoints not met in phase 2b SAPPHIRE and SILVER trials. Available at
    http://www.corporate-ir.net/ireye /ir_site.zhtml?ticker=ALT& script=416&layout=7 &item_id=432201. Accessed August 14, 2003.

  9. Kass DA, Shapiro EP, Kawaguchi M, et al. Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation. 2001;104:1464-1470.

  10. Full data from Alteon's ALT-711 DIAMOND trial in diastolic heart failure strengthens and extends positive preliminary findings. Available at
    http://www.corporate-ir.net/ ireye/ir_site.zhtml?ticker=ALT&script= 416&layout=7&item_id=395649. Accessed August 14, 2003.

  11. Caulfield M, Munroe P, Pembroke J, et al, for the MRC British Generic of Hypertension Study. Genome-wide mapping of human loci for essential hypertension. Lancet. 2003;361:2118-2123.

  12. Harrap SB. Where are all the blood pressure genes? Lancet. 2003;361:2149-2151.

  13. Province MA, Kardia SL, Ranade K, et al. A meta-analysis of genome-wide linkage scans for hypertension: The National Heart, Lung and Blood Institute Family Blood Pressure Program. Am J Hypertens. 2003;16:144-147.

  14. Saunders E, Herz RP, Kim K, McDonald M. Pfizer Facts: Racial Differences in Cardiovascular Health. Findings from the National Health and Nutrition Examination Surveys (NHANES) III and 1999-2000. Available at:
    http://www.pfizer.com/download/ health/pubs_facts_racialdiff_CV.pdf. Accessed August 14, 2003.