Linda Brookes, MSc

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

Presenter: Stevo Julius, MD, DSc (University of Michigan, Ann Arbor)

According to the results of the TRial Of Preventing HYpertension (TROPHY), it is possible to prevent or delay the onset of clinical hypertension in people with blood pressure that falls within the "prehypertension" category -- ie, systolic blood pressure (SBP) 120-139 mm Hg or diastolic blood pressure (DBP) 80-89 mm Hg -- with drug treatment.[1] To date, blood pressure management guidelines have emphasized lifestyle changes for the treatment of prehypertension.

In TROPHY, 2 years of treatment with candesartan 16 mg once daily in almost 800 prehypertensive subjects delayed the onset of stage 1 hypertension for up to 2 years after discontinuation of treatment. However, the TROPHY investigators are not recommending medical treatment of all people who are prehypertensive. Their study was carried out in relatively young people compared with populations enrolled in other recent studies, and it is not known 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 blood pressure-lowering actions of the study drug, the angiotensin receptor blocker (ARB) candesartan, or to other "extra-antihypertensive" effects of angiotensin blockade. However, the primary hypothesis of the study, that early pharmacologic treatment of prehypertension can delay or prevent development of clinical hypertension, was proven.

The results of TROPHY were published simultaneously online in TheNew England Journal of Medicine.[2]

Blood Pressure Criteria

Begun in 1999,[3] the TROPHY study was based on the blood pressure classification published in the Sixth Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC VI) in 1996.[4] The study recruited previously untreated subjects with blood pressure values within the "high-normal" range, defined in JNC VI as either SBP 130-139 mm Hg and DBP ≤ 89 mm Hg, or SBP ≤ 139 mm Hg and DBP 85-89 mm Hg. Subsequently, in 2003, the new JNC 7 guidelines[5] defined these same blood pressure ranges as "prehypertension" to emphasize that this stage may be a precursor to hypertension (Table 1).

Table 1. Blood Pressure Classification for Adults Aged ≥ 18 Years: JNC 7 vs JNC VI
JNC 7
Blood Pressure Category
JNC VI Blood Pressure Category SBP (mm Hg)   DBP (mm Hg)
Normal Optimal < 120 and < 80
Prehypertension   120-139 or 80-89
  Normal < 130 and < 85
  High-normal 130-139 or 85-89
Hypertension: Hypertension:      
Stage 1 Stage 1 140-159 or 90-99
Stage 2   ≥ 160 or ≥ 100
  Stage 2 160-179 or 100-109
  Stage 3 ≥180 or ≥110

Patients entered into TROPHY had to be between the ages of 30 and 65 years and previously untreated for hypertension; their blood pressure level could not exceed 155/99 mm Hg and ≤ 139/95-89 or 130-139/≤ 89 mm Hg as measured by an automated blood pressure measurement device at 3 clinic visits.

Study Design

TROPHY was an investigator-initiated 4-year study. At baseline, subjects were randomized in double-blind fashion to placebo or candesartan 16 mg daily. After 2 years, all the subjects on candesartan were switched to placebo and all subjects continued on placebo for an additional 2 years. Blood pressure was measured at entry and at 3-month intervals thereafter. Both the candesartan group and the placebo group were instructed to make changes in lifestyle to reduce blood pressure throughout the trial.

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

  • SBP ≥ 140 mm Hg and/or DBP 90 mm Hg at any 3 clinic visits during the study;

  • SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg at any single clinic visit;

  • SBP ≥ 140 mm Hg and/or DBP ≥ 90 mm Hg at the last study visit; and

  • Investigator-detected target organ damage or other condition requiring pharmacologic treatment.

After an endpoint was reached, treatment with extended-release metoprolol succinate 50 mg or hydrochlorothiazide 12.5 mg was offered at no cost. Any antihypertensive medications other than ARBs could be prescribed by study physicians. Further follow-up in the clinics was also offered.

Results

A total of 809 subjects (59% males; average age, 49.0 years) were enrolled at 71 study centers throughout the United States. For final analysis, data were available on 772 participants (391 in the candesartan group and 381 in the placebo group).

During the first 2 years, hypertension developed in 154 (40.4%) subjects in the placebo group compared with only 53 (13.6%) of those in the candesartan group, for a relative risk reduction of 66.3% (P <.0001; Table 2). After 4 years, hypertension had developed in 240 (63.0%) in the placebo group vs only 208 (53.2%) in the candesartan group (relative risk reduction, 15.6%; P <.0069).

Table 2. Patients Developing Hypertension
  Candesartan Placebo RR 95% CI P
No. of pts developing hypertension 208 240      
Hypertension at 2 yrs (%) 13.6 40.4 0.34 0.25-0.44 <.0001
Hypertension at 4 yrs (%) 53.2 63.0 0.84 0.75-0.95 .0069
Hypertension during study period     0.58 0.49-0.70 <.0001
CI = confidence interval; RR = relative risk

The beneficial effect of candesartan was seen regardless of baseline blood pressure, age, gender, body mass index, or weight.

Median time to development of hypertension was greater in the candesartan group, at 3.3 years compared with 2.2 years in the placebo group. Blood pressure decreased more rapidly in the candesartan group during the first 2 years of the study, but increased more rapidly in the same group after candesartan was discontinued. However, blood pressure remained lower in the candesartan group, and by the end of the study SBP was 2.0 mm Hg lower and DBP was 1.1 mm Hg lower than in the placebo group.

Safety

Treatment of prehypertension with candesartan appeared to be well tolerated. The incidence of adverse events over the 4-year study was similar in both groups (Table 3). Over the first 2 years of the study, serious adverse events occurred in 3.5% of subjects assigned to candesartan and 5.9% of those receiving placebo.

Table 3. Adverse Events
Incidence of Adverse Events Candesartan Placebo P
Serious adverse events (within 2 yrs) (%) 3.5 5.9 NS
Any cardiovascular events (%) 0.3 1.5 NS
Any adverse events (within 4 yrs) (%) 88.9 88.5 NS
NS = not significant
Implications

The results of the study support the investigators' primary hypothesis that pharmacologic treatment of prehypertension may prevent or postpone the development of hypertension. At 4 years (2 years after discontinuation of candesartan), there was a significant reduction in incident hypertension in subjects with prehypertension who had received candesartan compared with the subjects who had been taking placebo for 4 years. The relative proportion of participants who were hypertension-free was 26.5% greater in the candesartan group. The secondary hypothesis, that pharmacologic treatment of prehypertension may suppress the development of hypertension, was also proven.

"Prehypertension is currently treated by lifestyle modification, but this form of treatment has had little effect on public health," Dr. Julius pointed out. He compared TROPHY, in which the absolute reduction in the incidence of new-onset hypertension was 26.8%, with the Trials Of Hypertension Prevention (the only trial of lifestyle modification with a similar duration), in which the absolute reduction in the incidence of new-onset hypertension was 8%.[6] The TROPHY results also suggest that the effect of active treatment on delaying the onset of hypertension can extend to up to 2 years after the discontinuation of treatment, although the absolute reduction of 9.8% in incident hypertension at 4 years was modest.

Thus, the TROPHY data may be taken as encouraging; however, the TROPHY investigators do not recommend intermittent or continuous pharmacologic treatment for everyone with hypertension. They do recommend that people with prehypertension should be followed closely, preferably at 3-month intervals.

Commentary

In an editorial accompanying publication of TROPHY in TheNew England Journal of Medicine, Professor Heribert Schunkert, MD (Medizinische Klinik, University of Lübeck, Lübeck, Germany), urges caution about interpreting the TROPHY results.[7] "In epidemiologic studies, by definition, the need for medical treatment with antihypertensive agents such as candesartan would fulfill the criteria for arterial hypertension," he says. Had candesartan treatment not been omitted from the list of criteria defining the endpoint of hypertension in TROPHY, the average number of months in which participants took antihypertensive drugs would actually have been higher in the candesartan group, Prof. Schunkert points out. In addition, the profound decrease in blood pressure induced by active treatment with candesartan masked, rather than prevented, the main endpoint, stage 1 hypertension during the first phase of the study. Active treatment might also have affected the length of time until this endpoint was reached during the following placebo period.

In other words, Prof. Schunkert says, "the candesartan-related reduction in blood pressure may have slowed the buildup of an average blood pressure to above 140/90 mm Hg during the second phase (Years 3 and 4), when all study patients received placebo, and thus artifactually delayed the endpoint." Prof. Schunkert points out that the proportion of participants in the placebo group who were started on antihypertensive medication during Years 1 and 2 and the proportion of those in the candesartan group who were started on antihypertensive medication during Years 3 and 4 was almost identical (40.4% and 39.6%, respectively).

All these points, taken together, suggest that because of the study design, the difference between the 2 groups with respect to true prevention of hypertension may have been overestimated. He stresses that prehypertension should be explored in conjunction with other risk factors or manifestations of vascular disease.

Like Prof. Schunkert, ACC-designated commentator William Elliott, MD, PhD (Rush University Medical Center, Chicago), was concerned about the potential cost of medicating everyone with prehypertension. Dr. Elliott said that although the investigators did not recommend this, there was a "big concern" that the TROPHY results might change medical practice by altering the threshold for blood pressure treatment from the traditional 140/90 mm Hg to one that includes the middle of the prehypertension range, ie, 130-139/85-89 mm Hg. "It would be very expensive to give all these people medicines -- a rather large number of people -- and I quake in my boots to think that the American economy is strong enough to pay for that...," Dr. Elliott warned. About 25 million adults in the United States are currently believed to have prehypertension.

References
  1. Julius S, Nesbitt S, Egan B, Eric Michelson E. Trial Of Preventing Hypertension: Main results. ACC.06, the 55th Annual Scientific Session of the American College of Cardiology. Late Breaking Clinical Trials, Tuesday, March 14, 2006. Abstract 418-9.

  2. Julius S, Nesbitt SD, Egan BM, et al; the Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354. Published online before print on March 14, 2006, at www.nejm.org.

  3. Julius S, Nesbitt S, Egan B, et al; the TROPHY study group. Trial of Preventing Hypertension: Design and 2-year progress report. Hypertension. 2004;44:146-151. Abstract

  4. Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med. 1997;157:2413-2446. Abstract

  5. 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

  6. The Trials of Hypertension Prevention Collaborative Research Group. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure: the Trials of Hypertension Prevention, phase II. Arch Intern med. 1990;150:153-162. Abstract

  7. Schunkert H. Pharmacotherapy for prehypertension -- Mission accomplished? N Engl H Med. 2006;354. Published online before print on March 14, 2006, at www.nejm.org

 

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