WILMINGTON, Del., April 20 /PRNewswire-FirstCall/ -- Results of TROPHY (Trial Of Preventing Hypertension) - the first study to evaluate the effects of pharmacological intervention in patients with prehypertension - were published today in the New England Journal of Medicine. For the primary study end point of development of hypertension in this four-year trial, there was a significant (15.6 percent) relative risk reduction in the group treated with ATACAND(R) (candesartan cilexetil), compared with the group treated with placebo (53.2% vs 63.0%, respectively, p<.007).
Principal investigator Stevo Julius, MD, ScD, Emeritus Professor of Internal Medicine and Physiology, University of Michigan, said, “TROPHY is novel because it is the first study to examine the potential to change the natural history of hypertension through early pharmacologic intervention in prehypertensive patients - and specifically those with a systolic blood pressure of 130 to 139 mm Hg and/or a diastolic pressure of 85 to 89 mm Hg.”
Extensive clinical experience supporting the efficacy, safety, and tolerability of ATACAND in hypertension made it an appropriate choice as the pharmacologic agent for investigation in TROPHY. ATACAND is indicated for the treatment of hypertension. ATACAND(R) (candesartan cilexetil) is not indicated to prevent the development of hypertension or for the treatment of prehypertension. In addition, ATACAND is indicated for the treatment of heart failure (NYHA class II-IV) in patients with left ventricular systolic dysfunction (ejection fraction less than or equal to 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations. ATACAND also has an added effect on these outcomes when used with an ACE inhibitor.
Hypertension is defined as a blood pressure of 140/90 mm Hg or higher(1) and is one of the most common cardiovascular diseases in the United States, affecting an estimated 65 million people, or approximately one in three adults.(2) Most of the mortality and morbidity from hypertension occur among subjects with stage 1 (mild) hypertension.(3) The rationale behind TROPHY is that if it were possible to prevent the transition from prehypertension to stage 1 hypertension, there could be a positive benefit on public health.(4)
The 7th report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) changed the classification of “high normal blood pressure” to “prehypertension” in 2003, for those in the range of 120-139 / 80-89 mm Hg, recognizing this condition as an increasing public health concern.(5) Fifty-nine million adults in the United States have prehypertension.(6)
“TROPHY was designed to provide proof-of-principle for the feasibility of using a pharmacologic intervention to affect the natural progression from prehypertension to hypertension,” said Dr Julius. “We look forward to additional studies that will help determine the long-term benefits of delaying the development of this disease.”
During the two-year active treatment phase of the trial, serious adverse events were reported in 3.5 percent of those in the group receiving ATACAND compared to 5.9 percent in the group receiving placebo.
About TROPHY
TROPHY was an investigator-initiated, four-year, multicenter (71 centers in the US), randomized, placebo-controlled study in 772 evaluable subjects (average age 48 years, 40% women) with prehypertension, defined as blood pressures (BP) of less than or equal to 139/85-89 mm Hg or 130-139/less than or equal to 89 mm Hg. The trial consisted of two years of double-blind treatment with candesartan cilexetil (16 mg once daily) or matching placebo followed by 2 years of single-blind treatment with matching placebo in both groups. All subjects received nonpharmacologic interventions throughout the study. Blood pressure was measured with an automated device at the beginning of the study and at 3-month intervals. The primary objective was to determine whether a 2-year period of active treatment with ATACAND(R) (candesartan cilexetil) would be sufficient to reduce the proportion of subjects developing hypertension over the 4-year duration of the trial. The primary study end point was the development of hypertension. Hypertension was defined as BP greater than or equal to 140/90 mm Hg at any 3 visits or at the 48-month visit, BP greater than or equal to 160/100 mm Hg at one visit, or clinical need for treatment. Patients reaching the hypertension end point were given active treatment and followed by clinics. A secondary objective in TROPHY was to evaluate the blood pressure lowering effects of ATACAND vs. placebo, during the two-year period of active treatment. In the ATACAND treated group, the reduction in blood pressure was approximately 10/6 mmHg greater than with placebo. The effect of reducing blood pressure in this population has not been established.(7)
About Hypertension
An estimated 65 million Americans (one in three adults) have hypertension or high blood pressure.(8) Thirty-one percent of patients with hypertension are unaware they have this condition, and among all hypertensive patients only 31% have their blood pressure under control.(9) Of patients receiving treatment for hypertension, 47% do not have their blood pressure properly controlled.(10) The prevalence of hypertension increases with age -- more than 50 percent of men and women ages 60-69 and approximately 75 percent of those age 70 and older have elevated blood pressure.(11)
Lifestyle changes, such as weight loss, exercise, stopping smoking, and dietary adjustments can help reduce elevated blood pressure, and there are a number of classes of antihypertensive medications for those individuals who require drug treatment.(12)
IMPORTANT SAFETY INFORMATION
The usual recommended starting dose of ATACAND(R) (candesartan cilexetil) is 16 mg once daily as monotherapy in patients who are not volume depleted. ATACAND can be administered once or twice daily with total doses ranging from 8 mg to 32 mg.
The recommended initial dose for treating heart failure is 4 mg once daily. The target dose is 32 mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient.
USE IN PREGNANCY: When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, ATACAND should be discontinued as soon as possible. For full Prescribing Information for ATACAND, including boxed WARNING, call 1-800-236-9933 or visit http://www.atacand-us.com.
In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of ATACAND, or the treatment should start under close medical supervision.
In heart failure patients receiving ATACAND, hypotension, increases in serum creatinine, and hyperkalemia have occurred. Caution should be observed for hypotension when initiating therapy. Evaluation of patients with heart failure should always include assessment of renal function and volume status. Monitoring of blood pressure, serum creatinine, and serum potassium is recommended during dose escalation and periodically thereafter.
During concomitant use of ATACAND(R) (candesartan cilexetil) and lithium, careful monitoring of serum lithium levels is recommended.
While overall incidence of adverse events of ATACAND in hypertension patients was similar to placebo in controlled clinical trials, some adverse events that occurred in at least 1% of patients treated with ATACAND were higher than with placebo, including upper respiratory infection (URI) (6% vs. 4%), dizziness (4% vs. 3%), back pain (3% vs. 2%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%).
The adverse-event profile of ATACAND in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing ATACAND in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued ATACAND for adverse events versus 16.1% of placebo patients.
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References (1) American Heart Association. The Heart Disease and Stroke Statistics - 2006 Update page. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1200026. Accessed February 9, 2006. (2) Ibid. (3) Neaton JD, Kuller L, Stamler J, Wentworth DN. Impact of systolic and diastolic blood pressure on cardiovascular mortality. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed, vol 1. New York, NY: Raven Press; 1995:127-144. (4) Julius S, Nesbitt S, Egan B, et al. Trial of Preventing Hypertension: Design and 2-Year Progress Report. Hypertension. 2004;44:146-151. (5) Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206-52. (6) American Heart Association. The Heart Disease and Stroke Statistics - 2006 Update page. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1200026. Accessed February 9, 2006. (7) Julius S, Nesbitt S, Egan B, et al. Feasibility of Treating Prehypertension with an Angiotensin-Receptor Blocker. The New England Journal of Medicine. 2006; 354. (8) American Heart Association. The Heart Disease and Stroke Statistics - 2006 Update page. Available at: http://www.americanheart.org/presenter.jhtml?identifier=1200026. Accessed February 9, 2006. (9) Haijar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA. 2003;290:199-206. (10) Ibid. (11) Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6):1206-52. (12) Ibid.
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