If confirmed, the concept may offer a chance to keep many people from facing the high risk of heart disease and stroke that currently confronts the 65 million Americans with hypertension. But for now, the researchers call it a "proof of principle" result and note that this is the first study to address the issue thoroughly.
The results come from a rigorous four-year study of 772 people with a condition called pre-hypertension, in which blood pressure is elevated over normal levels but not high enough to meet the criteria for a formal diagnosis of hypertension.
University of Michigan Cardiovascular Center researcher Stevo Julius, M.D., Sc.D., and colleagues will present the data today at the American College of Cardiology annual meeting and in a simultaneous paper in the New England Journal of Medicine.
For the first two years of the study, half the patients received a placebo and half received a blood pressure drug called candesartan. For the next two years, all participants received a placebo, allowing the researchers to detect any lasting effects from drug treatment. All participants received guidance on diet and exercise to control blood pressure, and all had regular blood pressure measurements at home and in clinic visits. The participants were randomized to their study group and the researchers were blinded as to which group participants were in.
Throughout the study, there was a significant difference between the two groups in the development of hypertension. By study's end, the participants who received the blood pressure drug for two years and then stopped had a 15.6 percent lower risk of developing hypertension relative to those who received placebo for four years. The researchers suspect the drug treatment interrupted blood-vessel processes that raise blood pressure, a phenomenon that has been seen previously in animal studies.
"This study, which is the first of its kind, shows that postponement of hypertension onset through medical treatment is feasible, and without side effects," says Julius, an active emeritus professor of cardiovascular medicine at the U-M Medical School. "However, the effect is moderate, and further studies in younger people and over longer periods of time are needed in order to demonstrate clinical usefulness."
The study, called the Trial of Preventing Hypertension or TROPHY study, was funded by AstraZeneca, the pharmaceutical company that makes candesartan and sells it as ATACAND (candesartan cilexetil).
Julius and his colleagues proposed the study design to AstraZeneca, which agreed to fund and organize the study. The data were collected and compiled by the company, and then provided to Julius and his colleagues for analysis.
The study involved adults between the ages of 30 and 65 who were enrolled at 71 centers in the United States. The average age was 48, and 60 percent of participants were men.
At the beginning of the study, all had average blood pressure readings that included either a systolic (top number) reading between 130 and 139 mmHg, or a diastolic (bottom number) reading between 80 and 89 mmHg. This range is considered pre-hypertensive.
The study's main goal was to see how many participants from each group (drug vs. placebo) progressed to having full-blown hypertension, defined as a systolic reading over 140 mmHg or a diastolic reading over 90 mmHg, at three of their clinic visits during the study or at the four-year visit.
At the end of two years, 40 percent of the 381 participants who received only placebo had developed hypertension, compared with 13.6 percent of the 391 participants who had received candesartan for those two years. By the end of four years, 63 percent of the participants who received only placebo had developed hypertension, compared with 53 percent of the participants who received candesartan for two years followed by placebo for two years. There was no difference between the groups in adverse events, serious or otherwise, suggesting no side effects from the drug.
Julius and his colleagues emphasize that the study addresses one of hypertension's most insidious characteristics: the rapid pace at which it develops and worsens, setting individuals up for heart disease and stroke.
"Rising blood pressure is not a linear process. It goes exponentially, and as blood vessels start to respond to higher pressure, they develop hypertrophy, which causes further aggravation of hypertension," Julius explains. "The concept behind this study, based on a phenomenon observed in animal studies, is that by preventing the escalating effect on the blood vessels, one can interrupt the process of hypertension."
The need for better strategies for pre-hypertensive people is urgent, Julius adds. "What we have done so far is tell them to exercise and watch their diet, but these measures have not had any impact on public health. Rates of pre-hypertension are actually increasing," he says. "The time has come to look at this problem in a new way, and that is what this study set out to do. It's not the answer for everything, but it looks pretty promising, though one would like to see stronger results."
Now, the researchers say, more studies of pre-hypertension are needed, to complement the large amount of research on end-stage hypertension that has been carried out in recent years.
According to the American Heart Association, high blood pressure was listed as a primary or contributing cause of death in about 277,000 American deaths in the year 2003. About 69 percent of people who have a first heart attack, 77 percent of those who have a first stroke, and 74 percent of patients with heart failure have blood pressure higher than 140/90 mmHg.
In addition to Julius, the study's authors include Niko Kaciroti, Ph.D. and M. Anthony Schork, Ph.D. of the U-M; and researchers from the University of Texas Southwestern Medical Center at Dallas, the Medical University of South Carolina; AstraZeneca; Rush University Medical Center; St. Luke's-Roosevelt Hospital Center; Hennepin County Medical Center in Minneapolis; the University of Alabama at Birmingham; and the State University of New York Downstate College of Medicine.
Reference: New England Journal of Medicine, DOI OA060838, to be printed in the April 20 issue