More Guidelines, CCBs, ACEs, and ARBs, and Novel Predictors, Positive or Negative

Linda Brookes, MSc

September 14, 2004

Introduction

This month's hypertension news begins with publication of yet another updated set of guidelines, this time the latest US government guidelines for hypertension in children (originally announced at the 2004 ASH conference). This is followed by 3 drug therapy items: (1) the combination of the CCB amlodipine or any ACE inhibitor with the ARB candesartan is more beneficial than candesartan monotherapy in nondiabetic renal disease; (2) not all dihydropyridine CCBs are the same; and (3) the European expert consensus document on ACE inhibitors has been released. Two novel predictors of hypertension have been reported, the first pertaining to erectile dysfunction in rats and the second based on retinal blood vessel changes in humans. And finally, yet another LIFE substudy has been published, this time reporting that baseline albuminuria is not a predictor of benefit with losartan.

Latest US Government Guidelines for Hypertension in Children Published

The revised US national guidelines for the diagnosis and treatment of hypertension in children, sponsored by the National Heart, Lung, and Blood Institute (NHLBI), have been published as a supplement to the August issue of the journal Pediatrics.[1] The publication of The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents was announced earlier this year at the annual meeting of the American Society of Hypertension in New York.

The new report updates the previous guidelines, published in 1996,[2] and is based on the latest data from the National Health and Nutrition Examination Survey (NHANES) conducted in 1999 and 2000.[3-5] The new report conforms to the latest US national hypertension guidelines for adults, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), issued last year.[6]

The definition of hypertension in children and adolescents is based on the normative distribution of blood pressure in healthy children. The revised blood pressure tables have added the 50th and 99th percentiles to the 90th and 95th percentiles. The 50th percentile defines the midpoint of the normal blood pressure range, and the 99th percentile allows for more precise staging of hypertension, which is defined as beginning at the 95th percentile.

In line with JNC 7, the new blood pressure classification in children and adolescents redefines the old "high normal" category as "prehypertension" (≥ 90th percentile or ≥ 120 mm Hg but ≤ 95th percentile). The definition of hypertension remains unchanged, at systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) ≥ 95th percentile for age, gender, and height measured on at least 3 separate occasions. "White coat hypertension" is said to exist in children if they have blood pressure levels > 95th percentile in the physician's office or clinic but < 90th percentile outside the clinical setting. Furthermore, the report recommends that regular blood pressure measurement in children should begin at age 3 years, and earlier in preterm infants. The preferred method of measurement is auscultation.

In children who are prehypertensive, weight and diet management, introduction of physical activity, and counseling for the overweight should be "instituted or strongly encouraged." Therapeutic lifestyle changes should also be encouraged in those who are hypertensive, but should be concomitant with initiation of drug therapy in stage 1 or stage 2 hypertension unless there is a dramatic response to lifestyle changes. Drug therapy may also be appropriate for the treatment of prehypertension if there are compelling indications such as renal disease, diabetes, or left ventricular hypertrophy (LVH).

Antihypertensive drug administration should begin with a single drug at the lowest recommended dose, increasing the dose until the target blood pressure is reached. A second drug may be added if blood pressure is not controlled at the highest recommended dose or if the child experiences side effects. The guidelines state that suitable drugs may include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs), or diuretics. Following JNC 7, specific classes of drugs may be used preferentially in children with specific underlying or concurrent medical conditions, the report notes.

Recommendations are given for identification of comorbidities, ie, associated risk factors for cardiovascular disease, particularly obesity, lipid disorders, glucose metabolism abnormalities including familial history of diabetes, and sleep disorders. The report also recommends that children should be evaluated for target organ damage. Children should have an echocardiogram to detect any LVH as part of their evaluation.

Amlodipine or ACE Inhibitor With Candesartan More Beneficial Than Candesartan Monotherapy in Treating Nondiabetic Renal Disease

Combining the ARB candesartan with the CCB amlodipine or an ACE inhibitor has a more beneficial effect on renal impairment than treatment with candesartan alone, despite similar blood pressure-lowering effects, Japanese researchers reported in the Journal of Human Hypertension (advance online publication).[7]

Koichiro Homma, MD, and colleagues, from Keio University (Tokyo, Japan), followed patients with hypertension (systolic blood pressure [SBP] > 140 mm Hg and/or diastolic blood pressure [DBP] > 90 mm Hg) and proteinuria (> 0.5 mg/day) or chronic renal parenchymal disease who received candesartan 4-12 mg/day for 12 months. Nineteen of the patients were not on any other antihypertensive medication, and 29 were taking amlodipine 2.5-10 mg/day and 10 were taking an ACE inhibitor (enalapril 5-10 mg/day, lisinopril 10-20 mg/day, or trandolapril 0.5-1.0 mg/day) in addition to candesartan. Target blood pressure was < 140/90 mm Hg. Urinary protein excretion was measured daily by obtaining 24-hour urine samples. Blood pressure was measured twice monthly.

After 1 month of treatment with candesartan, the mean reduction in SBP was similar in the patients who had been on candesartan monotherapy and those who had been taking candesartan plus amlodipine or an ACE inhibitor (8 mm Hg vs 9 mm Hg, respectively). This similarity persisted throughout the 12 months of treatment. Although proteinuria values were similar in the monotherapy and combination therapy groups at the start of the study, urinary protein excretion at 3 months was significantly decreased by 43% in the candesartan group (P < .01) compared with a 58% decrease in the candesartan plus amlodipine/ACE inhibitor group (P < .01). These values persisted throughout the study. There was no difference in proteinuria-sparing effect between the candesartan/amlodipine and candesartan/ACE inhibitor groups. Both of these combinations represent important strategies in the treatment of hypertension with renal impairment, Dr. Homma and colleagues report.

The mechanism for the additive effect of candesartan on proteinuria in this study may be different in the amlodipine and ACE inhibitor treatment groups. The researchers suggest that combining an ARB and CCB may produce a greater reduction in glomerular capillary therapy pressure than ARB therapy alone. Alternatively, the CCB may enhance the vascular protective effect of the ARB. Many studies have demonstrated the beneficial effects of combination therapy with an ARB and an ACE inhibitor in patients with chronic renal disease. These have been attributed to complete blockade of the renin-angiotensin system or to suppression of plasma aldosterone by the ARB, thereby suppressing aldosterone breakthrough, which can occur with long-term ACE inhibitor therapy.

Dihydropyridine Calcium Antagonists Not All the Same

According to researchers from the University of Glasgow (UK), there is sufficient evidence that CCBs of the dihydropyridine type differ from one another to the extent that they cannot be substituted. Peter A Meredith, PhD, and Henry L Elliott, MD,[8] write in the September issue of the Journal of Hypertension that "the outcome credentials of nifedipine GITS [gastrointestinal therapeutic system] and amlodipine set them apart from all other dihydropyridine CCBs, and so do their sustained pharmacokinetic profiles." Drs. Meredith and Elliott particularly challenge the assumption that the findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)[9] for amlodipine can be extrapolated to other dihydropyridine CCBs, describing the notion as "an oversimplification" that "should be viewed with considerable caution."

The differences between the dihydropyridine CCBs and the other commonly used CCBs, verapamil and diltiazem, are well known. Drs. Meredith and Elliott assert that there are also "significant differences" between the dihydropyridine CCBs. They point out that newer CCBs have longer elimination half-lives; they are either new derivatives with longer elimination half-lives, such as amlodipine, which has a plasma half-life of approximately 40 hours, or older compounds with modified-release characteristics of the drug formulation, such as nifedipine GITS and felodipine extended-release tablets (felodipine ER). Other, lipophilic dihydropyridine CCBs, such as lacidipine and lercanidipine, have relatively short plasma half-lives but longer duration of action due to their increased degree of membrane binding. These variations – which also apply to different formulations of the same parent molecule as well as different chemical entities within the dihydropyridine class -- account for the difference between the pharmacokinetic characteristics among these agents, and they should not be assumed to be equivalent in terms of their pharmacologic profiles, duration of action, or overall antihypertensive activity, the authors emphasize. In particular, evidence regarding the nonsubstitutability of extended-release formulations of nifedipine is well founded, the authors say.

Although concerns about the safety of CCBs "should have been finally laid to rest," the issue of whether the long-acting dihydropyridine CCBs increase sympathetic activation remains confusing, the authors say. However, it is clear that the magnitude of any sympathetic activation by the long-acting compounds is less than that seen with the short-acting dihydropyridine CCBs, they conclude. However, they dispute the claim that all dihydropyridine CCBs are equivalent to ACE inhibitors in their ability to regress left ventricular (LV) mass, noting that nifedipine GITS has been shown to be superior to felodipine ER in this respect.[10]

Drs. Meredith and Elliott emphasize that there are "important therapeutic consequences" of the "significant differences" among the dihydropyridine CCBs, while also contending that these differences are often ignored.

European Expert Consensus Document on ACE inhibitors

The European Society of Cardiology (ESC) has issued an expert consensus document on ACE inhibitors in cardiovascular disease.[11] Like the ESC consensus document on beta-blockers released last month,[12] the rationale and clinical evidence for the use of ACE inhibitors is based on original research reported in peer-reviewed journals. It also takes into account guidelines produced by the ESC, the American College of Cardiology, and the American Heart Association. Recommendations in the document are ranked from Class I (overall evidence/agreement that treatment is useful/effective) through Class III (overall evidence/agreement that treatment is not useful/effective or may even be harmful). Three levels of evidence are presented, from A (multiple randomized clinical trials or meta-analyses) through C (consensus of opinion and/or small studies).

The document classifies ACE inhibitors on the basis of their chemical structure, according to the group that binds the zinc atom of the ACE molecule: sulfhydryl (eg, captopril), carboxyl (the largest group, including enalapril, lisinopril, and ramipril) or phosphoryl (eg, fosinopril). Although the mechanisms of action of all ACE inhibitors are the same, important differences in binding affinity to ACE and individual pharmacokinetic properties may result in marked differences in tissue concentration and in different clinical effects, the document says, while noting that the clinical relevance of these differences has never been demonstrated. All currently available ACE inhibitors are equally effective in lowering blood pressure and are well tolerated in most patients, it confirms. The propensity for the well-known side effect of cough does not differ among the ACE inhibitors, which occurs in 8% to 10% of all patients taking ACE inhibitors and more frequently among women and in Asian populations. Angioedema is noted as a rare but potentially life-threatening side effect.

ACE inhibitors are indicated in the treatment of hypertension (Class I recommendation based on level of evidence A). The document notes that the blood pressure level or reduction is more important than the specific treatment and that blood pressure control may only be achieved with combination therapy. Evidence from trials studying other cardiovascular conditions, however, supports the use of ACE inhibitors as first-choice therapy in specific groups of hypertensive patients, ie, those with heart failure, reduced LV ejection fraction, previous myocardial infarction or stroke, or diabetes or who are at high risk of cardiovascular disease, the document says.

Erectile Dysfunction an Early Warning Sign for Hypertension?

A slightly remarkable bit of laboratory research has reported that spontaneously hypertensive rats (SHR) demonstrate detectable erectile dysfunction (ED) before the onset of hypertension This may be due to earlier manifestation of the effects of endothelial dysfunction and tissue remodeling in erectile tissue compared with vascular tissue, according to French researchers.[13] If confirmed in humans, ED could be regarded as an early sign of hypertension and common therapeutic strategies targeting both ED and hypertension should be investigated, the researchers say. Men with hypertension are known to have a higher prevalence of ED than the general population. About 8% to 10% of untreated male patients have ED at the time of their hypertension diagnosis.

Delphine Behr-Roussel, PhD (Pelvipharm, Gif sur Yvette, France), and colleagues compared erectile responses and their pathophysiology in 6-, 12-, and 24-week old SHR and normotensive (Wistar Kyoto) rats. Erectile responses were found to be dramatically (P < .001) reduced in SHR compared with the age-matched normotensive rats at all ages, including 6-week SHR, which are regarded as being "prehypertensive." Endothelium-dependent relaxation responses to acetylcholine challenge in erectile tissue (corpus cavernosum) and aortic tissue were reduced progressively with increasing age in SHR and normotensive rats, but were more marked and occurred at an earlier age in erectile tissue (12 weeks) than in aortic tissue (24 weeks), suggesting that the erectile tissue in SHR is not protected from the functional changes induced by chronic high blood pressure.

If confirmed by further research, evidence will point to the possibility that the erectile tissue is at the front line of development of endothelial dysfunction and thus represents an early target end organ, according to the researchers. They also showed striking and consistent changes in the distribution of collagen types I, III, and V in both erectile and aortic tissue of SHR, detectable earlier in penile tissue. These changes could lead to functional disturbances of the collagenous network within erectile and aortic tissue of SHR and may be involved in the pathogenesis of ED.

These researchers say that their results support the use of inhibitors of the renin-angiotensin system, such as ACE inhibitors or ARBs, to target both ED and hypertension, but suggest that innovative pharmacologic strategies that act on remodeling should be investigated to address the alterations that take place in the general vasculature as well as at the level of the target end organ, the penis.

Eye Vessel Changes May Predict Development of Severe Hypertension

Small changes in the retinal vessel wall may predict the development of severe (grade 2 or 3) hypertension within 5 years, according to the results of an Australian study published in the October issue of Hypertension.[14] Study coauthor, Professor Paul Mitchell, MD, PhD (University of Sydney, Australia) and coinvestigators report that people with narrowing of the retinal arterioles are twice as likely to develop severe hypertension than people who have these retinal microvascular signs. This risk appeared to be independent of other risk factors, such as age, gender, body mass index, smoking, blood glucose levels, and blood pressure status at baseline.

The Blue Mountains Eye Study initially examined 3654 individuals aged ≥ 49 years living in an urban area west of Sydney between 1982 and 1994. Five years later, 2335 (75.1%) of these participants were re-examined. Both examinations involved stereoscopic retinal photography, and blood pressure was measured and categorized according to the 2003 World Health Organization/International Society of Hypertension classification.[15]

At the first examination, 1982 participants were classified as being at risk of developing severe hypertension, ie, were normotensive or had mild (grade 1) hypertension (SBP 140-159 mm Hg or DBP 90-99 mm Hg). Of the 1319 participants in this group who returned for the 5-year examination, 390 (29.6%) had developed severe hypertension, ie, had hypertension diagnosed and were using antihypertensive medication or had SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg, over the preceding 5 years. After adjustment for age, gender, body mass index, smoking, blood glucose, and serum cholesterol levels, participants with generalized retinal arteriolar narrowing at the start of the study were found to be at higher risk for the development of severe hypertension (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-3.9). This association remained significant after adjustment for baseline mean arterial blood pressure or for baseline blood pressure status, and was found to be stronger in participants aged < 65 years than in those aged ≥ 65 years.

These results support those of the earlier Atherosclerosis Risk in Communities (ARIC) study,[16] which found that the risk of developing incident hypertension within 3 years was 60% higher in normotensive individuals with generalized or focal retinal arteriolar narrowing than in individuals who did not have these signs, regardless of other vascular risk factors.

The 2 studies suggest that retinal microvascular signs may be used to identify individuals at risk for the development of clinically severe hypertension, although new, automated methods to measure arteriolar caliber are needed before this may be applied in clinical practice, the researchers say. However they point out that these structural signs could be a more stable measure of risk than functional measures, such as blood pressure, which vary over time.

Baseline Albuminuria Not a Predictor of Benefit With Losartan in the LIFE Trial

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, baseline albuminuria was a powerful predictor of risk for subsequent cardiovascular morbidity and mortality, but it did not identify the patients who had the greatest benefit with losartan, the LIFE trial investigators reported in the September issue of the Journal of Hypertension.[17] As first announced at last year's meeting of the European Society of Hypertension, the benefit of losartan relative to atenolol was seen across the whole range of baseline albuminuria, and only one fifth of the benefit of losartan treatment over atenolol could be explained by a greater reduction in albuminuria over time.

The main LIFE study showed that in patients aged 55-80 years with previously untreated or treated hypertension and LVH, losartan was associated with a 13% lower rate of the primary composite cardiovascular endpoint (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared with atenolol.[18] This difference was mainly driven by a 25% reduction in stroke. Blood pressure reduction was similar in both treatment groups.

The latest LIFE substudy examined the relation between albuminuria and losartan treatment in the 8206 patients who had baseline urine albumin and creatinine measurements, as prespecified by the LIFE albuminuria protocol. Patient characteristics in this group did not differ from those of the 987 LIFE patients who did not deliver a urine sample. An approximate 4.5-fold increase was seen in event rate for the primary composite endpoint from the lowest to the highest decile of albuminuria (urine albumin/creatinine ratio), but there was no consistent pattern for superiority of losartan over atenolol per decile. The benefit of losartan over atenolol with regard to the primary composite endpoint and stroke tended to be greater among patients with baseline albuminuria above median value (1.28 mg/mol). The decrease in albuminuria was significantly greater with losartan vs atenolol throughout the study (33% vs 25%, respectively, at first and second year of follow-up). The superior benefit of losartan over atenolol was attributable to its effect on albuminuria in Approximately one fifth (17%) of the benefit of losartan relative to atenolol was explained by the greater reduction in albuminuria associated with losartan.

Hans Ibsen, MD, and coauthors speculate that the superior effect of losartan in reducing albuminuria may be related to its greater effect on regression of structural vascular changes, endothelial function, and/or insulin sensitivity and glucose metabolism. They note that the low levels of albuminuria in the study (only 4% of the study patients had urinary albumin excretion > 35 mg/mmol) might have prevented demonstration of a stronger relationship between baseline albuminuria and benefit from losartan, since the risk probably continued to rise beyond the level of albuminuria in this study.

References

  1. 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 (suppl):555-576. Available online at http://pediatrics.aappublications.org/current.shtml#SUPPLS2

  2. National High Blood Pressure Education Program. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A working group report from the National High Blood Pressure Education Program. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics. 1996;98:649-658.

  3. NHANES 1999-2000 public data release file documentation. Available at http://www.cdc.gov/nchs/data/nhanes/gendoc.pdf

  4. Blood pressure section of the physician examination, NHANES 1999-2000. Available at http://www.cdc.gov/nchs/about/major/nhanes/NHANES99_00.htm

  5. NHANES 1999-2000 addendum to the NHANES III analytical guidelines. Available at http://www.cdc.gov/nchs/data//nhanes/guidelines1.pdf

  6. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.

  7. Homma K, Hayashi K, Kanda T, et al. Beneficial action of candesartan cilexetil plus amlodipine or ACE inhibitors in chronic nondiabetic renal disease. J Hum Hypertens. 2004;Aug 5 epub ahead of print. Available online at http://www.nature.com

  8. Meredith PA, Elliott HL. Dihydropyridine calcium channel blockers: basic pharmacological similarities but fundamental therapeutic differences. J Hypertens. 2004;22:1641-1648.

  9. Appel LJ. The verdict from ALLHAT – thiazide diuretics are the preferred initial therapy for hypertension. JAMA. 2002;288:3039-3042.

  10. Leenen FH, Myers MG, Joyner CD, Toal CB. Differential effects of once daily antihypertensive drugs on blood pressure, left ventricular mass and sympathetic activity: nifedipine GITS versus felodipine ER versus enalapril. Can J Cardiol. 2002;18:1285-1293.

  11. The Task Force on ACE-inhibitors of the European Society of Cardiology. Expert consensus document on ACE-inhibitors of the European Society of Cardiology. Eur Heart J. 2004;25:1454-1470.

  12. The Task Force on Beta-Blockers of the European Society of Cardiology. Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J. 2004;25:1341-362.

  13. Behr-Roussel D, Gorny D, Mevel K, et al. Erectile dysfunction: An early marker for hypertension? A longitudinal study in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2004;epub ahead of print.

  14. Smith W, Wang JJ, Wong TY, et al. Retinal arteriolar narrowing is associated with 5-year incident severe hypertension. The Blue Mountains Eye Study. Hypertension. 2004;44:1-6.

  15. World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21:1983-1992.

  16. Wong TY, Klein R, Sharrett AR, et al. Retinal arteriolar diameter and risk for hypertension. Ann Intern Med. 2004;140:248-255.

  17. Ibsen H, Wachtell K, Olsen MH, et al. Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy. J Hypertens. 2004;22:1805-1811.

  18. Dahlof B, Devereux RB, Kjeldsen SE, et al, for the LIFE study group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.