PARIS, June 14, 2004 — Novartis announced today at the European Society of Hypertension meeting and simultaneously published online in The Lancet the results of VALUE (Valsartan Antihypertensive Long-term Use Evaluation Trial) a prospective, double-blind, randomised, active-controlled study conducted at 934 clinical sites in 31 countries, including 56 sites across Canada. VALUE was a study of a Diovan® (valsartan)-based regimen vs. an amlodipine-based regimen in 15,245 high blood pressure patients at risk for cardiovascular complications because of co-existing diseases or risk factors such as diabetes, history of stroke, and coronary artery disease. The trial was designed to test, for the same level of blood pressure control, whether a Diovan®-based treatment regimen would be more effective than an amlodipine-based treatment regimen in reducing cardiac mortality and morbidity in these high risk patients.
The results of VALUE highlight the need for both aggressive blood pressure lowering as well as cardiac and metabolic protective regimens in this patient population. There was no difference with respect to the incidence of the primary endpoint of cardiac mortality and morbidity between the two treatment groups (10.6% [n=810] for the Diovan® regimen vs. 10.4% [n=789] for the amlodipine regimen, p=0.49), no statistically significant difference between the Diovan® and amlodipine treatment groups in death from heart attack (0.86% vs. 0.84% respectively, p=0.81) and no statistically significant difference between the Diovan® [n=841] and amlodipine treatment groups [n=818] in all-cause death (p=0.45).
The two treatment regimes effectively lowered blood pressure. Despite unintended blood pressure differences especially early in the trial in favour of amlodipine-based regimen, there was no statistically significant difference in the primary composite cardiac morbidity and mortality endpoint. However, these unintended differences make interpretation of the secondary endpoints difficult.
Diabetes benefit shown with Diovan® regimen
The Diovan®-based regimen was associated with a reduction in new onset of diabetes by 23% vs. the amlodipine-based regimen (13.1% [n=690] vs. 16.4% [n=845], p<0.001). "Since hypertension regimens studied in previous trials may increase the risk of diabetes and as amlodipine is known to be neutral on glucose metabolism, this finding in VALUE is especially significant at a time when the prevalence of the condition continues to increase in Canada," said Dr. Pierre Larochelle, lead investigator for Canada and Professor of Pharmacology; and Chief, Internal Medicine Service, Centre Hospitalier University of Montreal.
While the VALUE trial demonstrated better blood pressure control compared to certain other large-scale studies, 40 per cent of patients in this high risk population did not achieve the predefined blood pressure goal (less than 140/90 mm Hg). "This highlights the need for earlier and more aggressive dosing as well as add-on therapies with proven combination treatments that can get high risk cardiovascular patients to target and protect them from adverse outcomes" said Dr. Larochelle.
In VALUE, the rate of hospitalization for congestive heart failure was 4.6% [n=354] with the Diovan®-based regimen vs. 5.3% [n=400] with the amlodipine-based regimen (p=0.12). The rate of stroke 4.2% [n=322] vs. 3.7% [n=281] with the Diovan® and amlodipine-based regimen respectively (p=0.08). The rate of heart attack was 4.8% [n=369] with the Diovan®-based regimen vs. 4.1% [n=313] for the amlodipine-based regimen (p=0.02).
Both treatment regimens were well tolerated though more patients discontinued the amlodipine-based regimen due to side effects (14.5%) than they did in the Diovan® group (13.4%; p=0.045).
"VALUE together with Val-HeFT and VALIANT reinforce the clinical benefit of Diovan® in treating high cardiovascular risk patients. The additional finding that Diovan® may be associated with the reduction in the onset of diabetes in a population at high risk is very exciting. The long-term benefits and clinical implications of this finding are being investigated in the ongoing NAVIGATOR trial which is fully enrolled and expected to report in 2008," said Joerg Reinhardt, Head of Development, Novartis Pharma AG.
About VALUE
Patients in VALUE were men and women aged 50 or older with high blood pressure and additional cardiovascular risk factors or cardiovascular disease. The mean age of patients was 67.2 years. Co-existing risk factors and diseases for patients at the start of the study included coronary heart disease (45.8% of patients), type 2 diabetes (31.7%), and history of stroke or transient ischemic attack (19.8%).
The vast majority of VALUE patients (92.3% of the study population) had already been treated with antihypertensive medications prior to the start of the trial. Patients were randomised to once-daily treatment with either Diovan® 80 mg or amlodipine 5 mg, with no wash-out period. The blood pressure goal was <140/90 mmHg. In both groups, if additional control was needed, patients were titrated up to Diovan® 160 mg (the maximum recommended dose at the time of the study start) or the maximum dose of amlodipine (10 mg), depending on their blood pressure. If still not at goal, hydrochlorothiazide was added first at 12.5 mg, then 25 mg. If still more blood pressure reduction was needed, physicians were free to add other types of antihypertensive drugs, with the exception of CCBs (calcium channel blockers), ARBs, or angiotensin-converting-enzyme (ACE) inhibitors. Patients with heart failure or certain types of renal disease were allowed to take ACE inhibitors during the course of the study. Provisions were made for faster up-titration of study drugs at the physician's discretion.
Patients in the Diovan®-based group were half as likely (15% vs. 33%) to experience the most frequently reported side effect, peripheral oedema. Adverse events reported more frequently in the Diovan®-based group vs. the amlodipine-based group respectively included dizziness and headache.
About high blood pressure
In Canada, approximately one in five adults have high blood pressure,1 and of those, only 13 per cent are treated and controlled.2 Uncontrolled high blood pressure leads to life-threatening health problems such as heart attack, heart failure and other potentially fatal events. Among the Canadians who meet the criteria for hypertension, approximately 42 per cent are unaware of their condition.2 Hypertension is more prevalent in men than in women and becomes more common with age. The majority of affected Canadians (73 per cent) are under 65.3
Novartis is focused on improving the care of patients with high blood pressure and heart disease through world-class research and unprecedented public health initiatives. The Diovan® clinical trial programme is one of the world's largest in cardiovascular research, involving approximately 50,000 patients including more than 9,500 patients with diabetes. Besides VALUE, recently completed Diovan® trials include VALIANT in post-heart attack patients and Val-HeFT in heart failure patient. Ongoing studies include NAVIGATOR in pre-diabetes patients at high risk for cardiovascular disease and Val-MARC, a study of the effects of Diovan® on C-reactive protein, an inflammatory marker for heart disease.
Diovan® is approved for the treatment of hypertension in more than 80 countries. In addition to powerful double-digit blood pressure reductions and superior tolerability, patient persistency and patient compliance, Diovan® has proven cardioprotective benefits beyond lowering blood pressure.
FORWARD LOOKING STATEMENT
The foregoing release contains forward-looking statements that can be identified by terminology such as "new," "intended," "designed to," "may explain" or similar expressions, or by discussions regarding potential new indications or labelling for Diovan®/Diovan-HCT®, or regarding the long-term impact of a patient's use of Diovan®/Diovan-HCT®. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results with Diovan®/Diovan-HCT® to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Diovan®/Diovan-HCT® will be approved for any additional indications or labelling in any market. In particular, management's ability to ensure satisfaction of the health authorities' further requirements is not guaranteed and management's expectations regarding commercialisation of Diovan®/Diovan-HCT® could be affected by, among other things, additional analysis of Diovan®/Diovan-HCT® clinical data; new clinical data; unexpected clinical trial results; unexpected regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; competition in general; and other risks and factors referred to in the Company's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialise, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.
