Archief Roodbont

JNC 7 introduced the concept of "prehypertension" -- and now the results of TROPHY show that "treating" it has some benefit; but for how long, and at what cost? Two UK communications deal with hypertension guidelines: The first finds that clinical trial-based recommendations for BP lowering in patients post stroke or post TIA are probably not applicable in general clinical practice. The second reports consensus among British hypertension guidelines that treatment should be based on a dihydropyridine CCB plus ACE inhibitor strategy -- in other words, except for certain conditions, beta-blockers have scant place. Finally, for diagnosis, CRP is not predictive of hypertension in young adults (but obesity is confounding), and SBP is (still) the best predictor of CVD risk in men. And for treatment, a new endothelin antagonist shows benefit in resistant hypertension, and yes -- more evidence that chocolate lowers BP and the risk for death.

TROPHY Results Lead to Debate About Treatment of Prehypertension

The hypothesis that early pharmacologic treatment can prevent or at least postpone the development of hypertension in people with prehypertension appears to have been proven by the recently announced results of the TRial Of Preventing HYpertension (TROPHY). However, the results of this study are raising concerns because many of the investigators stress that they do not recommend medical treatment for all prehypertensive people, and others are concerned that this is how the study could (and will?) be misinterpreted. This could lead to a change in medical practice by altering the threshold for blood pressure (BP) treatment from the traditional 140/90 mm Hg to one within the prehypertension range, ie, 130-139/85-89 mm Hg. The potential cost of medicating everyone with BP in this range is what is causing alarm. To date, BP management guidelines have emphasized lifestyle changes for the treatment of prehypertension.

The results of TROPHY were presented at the American College of Cardiology 55th Annual Scientific Session, held March 11-14 in Atlanta, Georgia,^[1] by lead investigator Stevo Julius, MD, DSc (University of Michigan, Ann Arbor) and published simultaneously online in The New England Journal of Medicine.^[2] The study, supported by AstraZeneca, was a US multicenter, double-blind, placebo-controlled trial. The trial was begun in 1999,^[3] and so was based on the sixth report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC VI)^[4] rather than JNC 7, which introduced the "prehypertension" BP class in 2003.^[5]

TROPHY recruited 809 previously untreated subjects aged 30-65 years with BPs within the "high-normal" (per JNC VI) range, defined as systolic BP (SBP) 130-139 mm Hg and diastolic BP (DBP) ≤ 89 mm Hg, or SBP ≤ 139 mm Hg and DBP 85-89 mm Hg. Subjects were randomized in double-blind fashion to receive placebo or the angiotensin receptor blocker (ARB) candesartan 16 mg daily. After 2 years, all of the subjects on candesartan were switched to placebo and all subjects continued on placebo for an additional 2 years. All participants were instructed to make lifestyle changes to reduce BP throughout the trial.

The main study endpoint was the development of clinical hypertension, defined as:

After an endpoint had been reached, no-cost treatment with extended-release metoprolol succinate 50 mg or hydrochlorothiazide 12.5 mg was offered, or other antihypertensive medications except ARBs could be prescribed.

During the first 2 years, hypertension developed in 40.4% of subjects in the placebo group compared with only 13.6% of those in the candesartan group, a relative risk reduction of 66.3% (P < .0001). After 4 years, hypertension had developed in 63.0% of subjects on placebo vs only 53.2% on candesartan (relative risk reduction, 15.6%; P < .0069). Median time to development of hypertension was greater in the candesartan group (3.3 years vs 2.2 years for placebo). In addition, BP decreased more rapidly in the candesartan group during the first 2 years of the study, but increased more rapidly after candesartan was discontinued. However, it remained lower in the candesartan group, and by the end of the study at 4 years was still 2.0/1.1 mm Hg lower than in the placebo group. Treatment with candesartan appeared to be well tolerated in this study.

The TROPHY investigators pointed out that their study was carried out in relatively young people (average age, 49 years) compared with other recent studies, and that it is not possible to conclude whether the same treatment would be effective in other age groups, or how long treatment should be given to be effective. The study did not investigate whether the delay in onset of hypertension was due to BP-lowering actions of candesartan or to other effects of angiotensin blockade.

In an editorial accompanying publication of TROPHY in The New England Journal of Medicine, Prof. Heribert Schunkert, MD^[6] (Medizinische Klinik, University of Lübeck, Lübeck, Germany) urged caution about interpreting the TROPHY results because he believes that the difference between the 2 treatment groups with respect to true prevention of hypertension may have been overestimated. He also raised safety concerns as well as the potentially "prohibitive financial cost of what would approach population-wide drug treatment." He added, "If there is a future for drug treatment for prehypertension, we need to learn who should be treated, for how many years, and with which drug and at what dose," stressing that "for now, a healthy lifestyle is the foundation for all therapies in people with prehypertension."

New UK Consultation Document Unites National Hypertension Treatment Guidelines

A provisional hypertension guidelines update has been issued by the National Institute for Clinical Excellence (NICE), an independent organization within the UK National Health Service (NHS) that provides guidance on treatments in England and Wales. The update, called a "draft for consultation," was made available online in February for comment through March and contained substantial changes to the treatment recommendations made in the previous NICE guidelines, published in 2004.^[12] Calcium channel blockers (CCBs) and ACE inhibitors are now the drugs of first choice over thiazide-type diuretics and beta-blockers in older and younger patients, respectively.

NICE has updated its guidelines after reviewing new data from 20 clinical trials published since 2004, including the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA).^[13] The update represents a major change not only to NICE treatment guidelines but also to those of the BHS, also issued in 2004.^[9] The BHS, which last year recommended that there should be a review of the existing NICE guideline recommendations dealing with pharmacologic treatment of hypertension, is working in collaboration with NICE to review this section of the guidelines; the final joint document is scheduled to be published by June 2006. UK physicians will then have a unified set of guidelines instead of 2, which many had regarded as too much to read.

The new update's first choice for drug therapy in people aged 55 years and older, or in black patients of any age, is a dihydropyridine CCB, with a thiazide-type diuretic as an alternative. In patients younger than 55 years, the guidelines recommend an ACE inhibitor or an ARB if an ACE inhibitor is not tolerated. After a dihydropyridine CCB or a thiazide-type diuretic, an ACE inhibitor is the second choice, and after an ACE inhibitor a dihydropyridine CCB or a thiazide-type diuretic.

The 2004 BHS treatment recommendations were based on classification of hypertensionas "high renin" or "low renin" and followed the "ABCD" algorithm, combining 2 categoriesof antihypertensive drug: those that inhibit the renin-angiotensinsystem, ie, ACE inhibitors or ARBs (A) or beta-blockers (B), and those that do not, ie, CCBs (C) or diuretics (D). According to Prof. Morris J. Brown, MD (University of Cambridge, Cambridge, United Kingdom), President of BHS and a member of the NICE/BHS guidance group, the new treatment algorithm will look more like "AbCd."

In the new NICE guidelines, beta-blockers are no longer preferred as routine initial therapy, but may be considered in younger women and patients with hypertension and evidence of increased sympathetic drive or intolerance to ACE inhibitors or ARBs. Beta-blockers should not be replaced in patients whose BP is already controlled with these drugs or who have compelling indications for beta-blockade, such as asymptomatic angina or myocardial infarction.

Systolic Blood Pressure Still the Best Predictor of Cardiovascular Risk in Men

An evaluation of over 50,000 men who participated in the Physicians' Health Study (PHS) has shown that SBP alone is a consistent predictor of cardiovascular death in men of all ages. This finding is consistent with the "continuing emphasis on the clinical use of SBP to predict the risk of incident cardiovascular disease," say Thomas S. Bowman, MD, MPH (Massachusetts Veterans Affairs Epidemiology, Research, and Information Center, Boston) and colleagues^[15] in the American Journal of Hypertension.

In a study funded by the US National Institutes of Health, Dr. Bowman's team studied 53,528 male physicians, mean age 53 years, who provided information about BP to the PHS in 1983. In this population, mean SBP was 124.8 mm Hg and mean DBP was 78.0 mm Hg. Subjects had no previous or current treatment for hypertension or history of any serious disease, including myocardial infarction, stroke/TIA, cancer, or gastrointestinal or liver disease. Other information was obtained through questionnaires. The men were followed for a median of 5.7 years. Information about deaths was obtained from the National Death Index and the cause of death derived from international classifications of diseases.

During follow-up, 459 men died from cardiovascular causes. For each 10-mm Hg increase in SBP, the relative risks, adjusted for age, tobacco use, BMI, diabetes, alcohol intake, exercise, and aspirin or multivitamin use, were 1.46, 1.43, 1.24, and 1.13 in the age groups 39-49, 50-59, 60-69, and 70-84 years, respectively. Similarly, adjusted relative risks for each 10-mm Hg increase in DBP were 1.25, 1.20, 1.28, and 1.07, respectively. Compared with SBP, pulse pressure and mean arterial pressure were not consistent predictors across age ranges, and combining SBP with any other parameter did not improve the model compared with using SBP alone in any age group (all P > .05).

Dr. Bowman and colleagues stress that "although DBP, pulse pressure and mean arterial pressure were also associated with elevated risk, none of these other blood pressure parameters was superior in determining risk or enhanced multivariable models that already contained SBP." They believe that although men already having hypertension were excluded at baseline, because some participants may have started taking antihypertensive medications during the study, the association between BP and cardiovascular disease death may have been underestimated. They also note that the PHS participants were healthy male physicians, which may affect application of the study findings to other populations, although "we have no reason to believe that the biological mechanism by which blood pressure may be associated with cardiovascular disease death is unique to our study population," they contend.