August 31, 2003

Takeda Chemical Industries, Ltd.

CHARM* Programme demonstrates clear benefits
of candesartan in the treatment of
symptomatic heart failure

Candesartan is the first and only
Angiotensin Receptor Blocker (ARB)
proven to reduce cardiovascular death and hospitalisation
in chronic heart failure
when given together with conventional therapy

(Vienna, 31st August 2003) - Data presented today at the European Society of Cardiology (ESC) annual meeting demonstrated candesartan cilexetil to reduce both cardiovascular deaths as well as hospital admissions for heart failure, across a broad spectrum of patients with chronic heart failure.

Importantly, candesartan is the first Angiotensin Receptor Blocker (ARB) to increase survival in chronic heart failure patients with left ventricular dysfunction, whether or not they are taking an ACE-inhibitor.

CHARM co-chairman, Professor Karl Swedberg, Goteborg University and Sahlgrenska University Hospital/Ostra, Goteborg, Sweden introduced the rationale behind the CHARM Programme: "While the incidence of most cardiovascular disease is stabilising, chronic heart failure remains a serious and costly condition with patients being symptomatic and at risk of early death. Although major advances in the treatment of heart failure have occurred in the last decade or so, there is still a real need for additional, effective therapies and this requirement led us to devise the CHARM-Programme in order to evaluate the clinical benefits of candesartan in the treatment of this debilitating and distressing condition".

The CHARM Programme, which recruited 7,601 patients, is the largest ever trial programme conducted in heart failure with an AT1-receptor blocker. Patients with classic symptomatic chronic heart failure - depressed left ventricular (LV) systolic function (Left Ventricular Ejection Fraction (LVEF) < 40%), were randomised into one of two studies - either an ACE-inhibitor intolerant population (CHARM-Alternative), or the population treated with ACE-inhibitors (CHARM-Added). In addition, patients with preserved LV systolic function (LVEF> 40%) were also randomised into a third study (CHARM-Preserved). All patients received either candesartan cilexetil or placebo.

CHARM-Alternative
In patients who were not taking ACE-inhibitors due to previous intolerance, candesartan significantly reduced the risk of ardiovascular death or hospitalisation for chronic heart failure, with an overall risk reduction of 23% (p<0.0004). This is comparable to the benefit seen in heart failure studies using ACE-inhibitors alone.

Dr Christopher Granger, lead investigator in the CHARM-Alternative study, Duke University Medical Center, Durham, North Carolina, USA, commented: "This trial shows that for the heart failure patients who cannot take ACE inhibitors, candesartan reduces death and hospital admission for heart failure by 23%, which is highly significant".

CHARM-Added
In patients that were prescribed conventional therapy for chronic heart failure including an ACE inhibitor, candesartan demonstrated additional mortality and morbidity benefits. Candesartan produced an additional reduction in the risk of cardiovascular death or hospitalisation for chronic heart failure of 15% (p=0.011) when compared to conventional treatment alone. Importantly, candesartan demonstrated this efficacy,
along with a high level of tolerability, when taken as part of triple combination therapy that included an ACE-inhibitor and beta-blocker - standard treatments in patients with chronic heart failure.

Commenting on the study, Professor John McMurray, principal investigator in the CHARM-Added study, Glasgow University and Western Infirmary, Glasgow, Scotland, said "That candesartan improved outcome, even when added to full conventional therapy, is a very important treatment advance for these very sick patients".

CHARM-Preserved
The CHARM Programme also included the largest completed trial in chronic heart failure patients with preserved LV function, patients for whom little evidence based treatment guidance presently exist. In CHARM-Preserved the primary endpoint of cardiovascular death or hospitalisations for chronic heart failure showed a trend, 11% risk reduction in favour of candesartan (p=0.118), consistent with the significant findings seen in the other two studies - CHARM-Alternative and CHARM-Added. The total number of hospitalisations for CHF was significantly lower in the candesartan group (402 v 566). There was also a significant 40% reduction in the number of patients diagnosed with new onset diabetes (47 v 77; p=0.005).

Principal investigator of the CHARM-Preserved study, Professor Salim Yusuf, McMaster University, Ontario, Canada stated: "This is the largest trial evaluating the role of any therapy in heart failure patients with preserved left ventricular function. The reduction in hospitalisations for heart failure in this trial provides evidence of clinical benefit".

Pooled analysis of the three studies showed that candesartan provided a significant reduction in cardiovascular death and also demonstrated a positive trend in the overall reduction in all cause mortality approaching statistical significance (p=0.055). Interestingly, it also demonstrated a significant 22% reduction in onset of new diabetes, with 163 new cases of diabetes on candesartan compared with 202 on placebo.

CHARM co-chairman, Professor Karl Swedberg summarised the data: "CHARM will influence the way that clinicians treat heart failure. We cannot ignore the fact that this treatment will save lives in heart failure regardless of whether the person is taking an ACE-inhibitor or beta blocker. The benefits are also irrespective of left ventricular ejection fraction."

Professor Marc Pfeffer, CHARM co-chairman, Professor of Medicine, Harvard Medical School and Senior Physician, Brigham and Womenfs Hospital, Boston, Massachusetts, USA commented: "We conducted a unique programme of research across a broad range of heart failure patients and found that candesartan reduced both cardiovascular death and hospital admissions for heart failure. The clinical effectiveness of candesartan offers the opportunity to further reduce these important outcomes in this expanding segment of our aging population".

CHARM study was sponsored and conducted by AstraZeneca.
Candesartan was discovered and originally synthesized by Takeda Chemical Industries, Ltd, and it was jointly developed with AstraZeneca.
Candesartan is marketed worldwide under the brand name of Blopress by Takeda and Atacand by AstraZeneca in around 70 countries.

* Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity

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