Sandoz Statement: Calcium Channel Blocker StudyMedia Advisories are Inaccurate

September 10, 1996

/ADVANCE/ EAST HANOVER, N.J., 9/10/96 /PRNewswire/ -- SandozPharmaceuticals Corporation said today that media advisoriessummarizing findings from a multi-center clinical trialinaccurately link its calcium channel blocker, isradipine, withincreased risks for myocardial infarction, congestive heartfailure, stroke and sudden death.

The company said that data derived from the MulticenterIsradipine Diuretic Atherosclerosis Study (MIDAS) show thatwithin the category of major cardiovascular events, there was nostatistically significant difference between major vascularevents in patients treated with isradipine or a diuretic,hydrochlorothiazide (HCTZ). The data, which have been presentedpreviously at several medical meetings, are to be published inthe September 11 edition of the Journal of the American MedicalAssociation (JAMA).

Specifically, the company said there were no statisticallysignificant differences between the groups with regard tomyocardial infarction, stroke, congestive heart failure or suddendeath.

The company said the higher overall incidence for the combinedmajor cardiovascular events category was skewed by a higherincidence of hospitalized angina in the isradipine group, butthis difference may be related to a number of factors. Thosefactors include higher systolic blood pressure at baseline in theisradipine group that experienced major vascular events or ahigher prevalence of self-reported angina or a documented historyof angina in the isradipine group that experienced hospitalizedangina.

^"In looking at the MIDAS results it isimportant to remember that there were no differences between thetreatment groups for any morbid or fatal events. There were nodifferences for all-cause mortality, cardiovascular mortality ormyocardial infarction." said Helen Torley, M.D., head ofMedical Services for Sandoz.

Torley added that no increased risks for deaths, myocardialinfarctions, strokes, cancer and gastrointestinal bleeding weredetected in a recent meta-analysis commissioned by the company.The meta-analysis, performed by MetaWorks of Boston, collectedand analyzed data from more than 70 clinical trials involvingmore than 11,000 hypertensive patients.

Ballerup hotel rooms"Based on this entire body of evidence, isradipine whenused as recommended remains a safe and effective treatment forthe management of hypertension," said Torley.

In a statement, Franz Messerli, M.D., of the Ochsner Clinic ofNew Orleans said, "Since the study was not designed norpowered to detect differences in secondary end-points, one shouldresist the temptation to explicate and extrapolate thesefindings, particularly in view of the fact that an independentevaluation of the data base of isradipine did not reveal anyuntoward adverse effects. The numbers are small, and certainlyrequire a careful follow-up and further monitoring, but are, inmy opinion, not by themselves a reason for discontinuingantihypertensive therapy with isradipine in a patient whose bloodpressure is well controlled.'

Echoing Dr. Messerli’s comments, Dr. Torley noted thatthe study's authors did not call for switching patients from CCBtherapies to other antihypertensive therapies.

MIDAS was a randomized, double-blind trial of 883 patientsover three years comparing isradipine and the diuretichydrocholorothiazide. The study was sponsored by Sandoz to learnmore about the potential applications of isradipine for thetreatment of hypertension.

The primary objective of the study was to assess whether thetwo antihypertensive agents would have an effect on the progressof atherosclerosis in hypertensive patients. There was nodifference between the two treatment groups on the rate ofprogression of atherosclerosis.

Sandoz Pharmaceuticals Corporation is a leader in thediscovery, development, manufacturing and marketing of innovativepharmaceuticals and high-quality consumer health products.Particular emphasis and expertise are currently focused onfinding new breakthrough treatments or cures in the areas oftransplantation, oncology, dermatology and disorders of thecentral nervous system. Sandoz Pharmaceuticals Corporation,headquartered in East Hanover, NJ is an affiliate of Sandoz, Ltd.of Basel, Switzerland, a leading worldwide pharmaceuticals andnutrition company with additional activities in seed,agro-chemicals and construction chemicals.

The MIDAS trial was a landmark study which used an innovativetechnology, B-mode ultrasound, to assess the effectofantihypertensive therapy on the progression of atherosclerosis.The company wishes to thank the investigators who participated inthis important study. SOURCE Sandoz Pharmaceuticals Corporation

(CONTACT: William O'Donnell of Sandoz Pharmaceuticals.201-503-7070)

The following statement is by Franz H. Messerli, M.D., Ochsner Clinic:

Experimental data suggest calcium antagonists exert antiatheromatous effects (i.e., slow down arteriosclerosis) that are independent of the blood pressure lowering effect. The present data in MIDAS showing no difference in progression of carotid artery disease between isradipine and diuretic therapy are therefore disappointing. This unexpected outcome notwithstanding, one should be careful not to over-interpret the findings regarding the secondary end-points. Patients on isradipine had more (25 vs. 14) major vascular events than patients on diuretics. This was mainly due to the fact that patients on isradipine were hospitalized more often for angina (11 vs. 3). However, these differences may possibly be related to a higher baseline systolic pressure and to:

higher history of angina in the isradipine patients (5/Ilisradipine vs. 0/3 HCTZ) as well as to a higher syst(lic pressurethroughout the study in the isradipine arm. Of note, there was nosignificant difference in the occurrence of myocardialinfarction, congestive heart failure, stroke or sudden deathbetween the two groups. Interestingly enough, patients in theisradipine group had a somewhat lower risk of cancer (13 vs. 20)when compared to patients on diuretics. Since the study was notdesigned nor powered to detect differences in secondaryend-points one should resist the temptation to explicate andextrapolate these findings particularly in view of the fact thatan independent evaluation of the data base of isradipine did notreveal any untoward adverse effects. The numbers are small, andcertainly require a careful follow-up and further monitoring, butare in my opinion not by themselves a reason for discontinuingantihypertensive therapy with isradipine in a patient whose bloodpressure is well controlled. SOURCE Ochsner Clinic

(CONTACT: Franz H. Messerli, MD, FACC, FACP of Ochsner Clinic,504-842-3144/4077 or fax, 504-842-4220)

The following statement is by MetaWorks Inc.:

In March 1996 MetaWorks was engaged by Sandoz to perform a meta-analysis ofthe safety of isradipine, a calcium channel blocker (CCB), when used as monotherapy in patients with hypertension. Results are being submitted as a manuscript for publication in a peer-reviewed medical journal, and as a result, release of project-related details must await journal publication. However, in view of public safety concerns which continue to be raised about CCBs, as evidenced by the paper by Borhani et al (JAMA 1996; 276(10): 785-91), we believe it is appropriate to issue the following statement about the isradipine analysis.

MetaWorks' analysis encompassed both published and unpublishedrandomized control trials (RCTs) of all formulations ofisradipine in patients with hypertension, totaling 74 studies andmore than 11,000 patients. The analysis was performedsystematically, according to a prospectively determined protocol.Serious adverse events, including deaths, myocardial infarctions,strokes, cancer, and gastrointestinal bleeding were collected andanalyzed. No increased risk was noted for any of these adverseevents for any formulation of isradipine compared to other activecontrols or placebo. MetaWorks continues to analyze theliterature on additional CCBs. SOURCE MetaWorks Inc.

(CONTACT: James Ross, JHRoss@MetaWork.com, or Shubh Sethi,ShubhSethi@MetaWork.com, of MetaWorks, 800-767-2384)

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