Shelley Wood

February 04, 2013

BARCELONA, Spain — There's an air of impatience clouding the 2013 International Conference on Prehypertension and Cardiometabolic Syndrome. Most patients diagnosed with higher-than-optimal blood pressure will go on to develop hypertension, but there are no good data to suggest if or how this can be averted.

That frustrates experts gathered here, some of whom say they can't wait for results from ongoing clinical trials--they are proceeding with low-dose pharmacological treatment in select high-risk patients.

"If we wait for the evidence, we'll all be buried before the evidence is in," Dr Flavio Fuchs (Hospital de Clinicas de Port Alegre, Brazil) pronounced. "Four out of five prehypertensives will be hypertensive by age 60. . . . For my [prehypertensive] patients, I am offering the option of using low-dose drugs if they are close to becoming hypertensive."

Dr Stevo Julius (University of Michigan, Ann Arbor) put it more bluntly: "If your brother had prehypertension, you would treat him."

But Dr Yuqing Zhang (Fu Wai Hospital, Beijing, China) pointed out that it is not just the question of drug efficacy in high-normal BP, "we also need to answer the question of cost-effectiveness, because the incidence of hard outcomes is very low in these subjects, maybe 7% per 100-person years. So much lower than in those with established hypertension--this is an area where we really need to get some answers."

CHINOM to Provide Some Answers

Zhang is one of the investigators in the largest ongoing trial in this area, the Chinese High Normal Blood Pressure (CHINOM) trial. The study has finished enrollment of 10 689 patients with blood pressure in the range of 130–139/85–89 mm Hg and at least one other cardiovascular disease risk factor (but no established diabetes, renal or hepatic dysfunction, or history of stroke or CVD).

Presenting an overview of the study here, Zhang explained that patients are being randomized to one of three parallel treatment groups: telmisartan 40 mg, indapamide 1.5 mg, or, in the third group, placebo or a combination pill of hydrochlorothiazide 12.5 mg, triamterene 12.5 mg, dihydralazine 12.5 mg, and reserpine 0.1 mg. The primary end point of the study is combined CV events (nonfatal stroke, nonfatal MI, and CVD death), while a secondary end point addresses new-onset hypertension and new-onset diabetes.

While the first results are still several years away, baseline characteristics of study subjects are already revealing. For example, he noted, 70% of subjects enrolled actually have more than one CV risk factor, with metabolic syndrome being the most common. More than three-quarters of participants are overweight or obese, 42% have high triglycerides, and over one-third have a family history of hypertension.

"This is not a benign population," he said.

Importantly, Zhang said, a family history of stroke is more than twice as common in the CHINOM cohort as a family history of MI (12% vs 5%).

Investigators plan to do an interim analysis when they've accumulated 100 events; they are just shy of 90 now, Zhang said.

PREVER-Prevention in Brazil

Fuchs, meanwhile, is the co-principal investigator in the Prevention of Hypertension in Patients with Prehypertension (PREVER) study of subjects with blood pressures in the range of 120–139/80–89. In a presentation on PREVER, Fuchs admitted he previously had little faith in the long-term effectiveness of nondrug interventions. He's since revised that stance following a number of recent studies--including one by his own group [1]--showing drops in systolic BP after adhering to advice to follow a low-salt/low-calorie diet.

But he also argued that "prehypertension" is just a "pit stop on the road to hypertension," offering a "window of opportunity" to treat patients before arterial and organ damage develop. And lifestyle changes don't always cut it.

According to Fuchs, PREVER has finished enrollment of 1053 patients. According to the study design, patients who are still prehypertensive after three months of recommended lifestyle changes are randomized to a low-dose combination of chlorthalidone plus amiloride or to placebo. Preliminary results from the study indicate that a full 659 (77%) of subjects remained "prehypertensive" and were randomized according to the study protocol; another 7.5% had abnormal lab values. Of note, 6.2% had progressed to developing hypertension, while 9% had seen their blood pressures drop to within normal values.

That movement may be partly explained by worsening disease, or, for those whose BP dropped, due to the lifestyle changes, Fuchs told heartwire . More likely it reflects patients who were hovering on the borderline between prehypertension and hypertension at the study outset. Final results from the trial, looking at progression to hypertension as well as adverse events, are still several years away.

Seeking Enrichment

Julius, moderating Saturday's discussion, asked panelists how future study-enrollment criteria could be refined to best capture prehypertension patients who would truly benefit from drug treatment. Even ongoing trials may not have enough power to demonstrate an effect, Julius predicted.

"When you take the prehypertension definition according to JNC 7 and include all other forms of hypertension, you are left with only 10% of the male population as 'healthy,' and that's absolutely crazy," he said. "We need to not only narrow this, we need to also talk about tests that may tell us who is going to eventually have an event. Otherwise we may never know the truth."

Researchers have proposed using only patients who develop high BP after exercise, or patients with sustained prehypertension on ambulatory BP, or certain genetic markers, but no one can agree on what would sufficiently "enrich" the study population.

"This is urgent," Dr Sverre Kjeldsen (University Hospital Ullevål, Oslo, Norway) warned the audience. The upcoming 2013 ESC/ESH guidelines explicitly state that no drug treatment is warranted in prehypertensive patients, even in the setting of left ventricular hypertrophy or other organ damage. "No drugs," he said, "because there is no evidence. So we have to provide the evidence."

Fuchs, for his part, points out that the majority of strokes actually occur in people whose systolic blood pressure is in the range of 120 to 140 mm Hg. That's enough for him.

"I myself have a strong family history of coronary heart disease and hypertension in both branches," he told heartwire . "I practice a healthy lifestyle, I take care, I'm not obese, I exercise, I watch my salt, and I eat the DASH diet, yet my blood pressure on 24-hour monitoring showed that I had prehypertension, 135/80 mm Hg. I started using very low doses [of the same drug combination being studied in PREVER], and my BP is now 120/80 every time that I read it."