Thursday, March 30, 2006
hypertension highlights
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."
