SphygmoCor in Clinical Outcome Trials

SphygmoCor is currently being used in several large outcome trials, as well as many other smaller studies in many fields of medicine, that have an interest in cardiovascular disease, including areas such as hypertension, heart failure, renal disease, diabetes, rheumatology, preventative and alternative medicine, pregnancy and pre-eclampsia.

As a quick, reproducible and non-invasive test, the SphygmoCor Px Aortic BP Waveform Analysis system provides a tool that can easily be incorporated into clinical trials. The versatile nature of the product has lead to its inclusion in many clinical trials - in outcome studies for ascertaining independent predictors of morbidity and mortality, pipeline drug development, discovering early markers for CAD and interventional studies. The addition of SphygmoCor Vx Pulse Wave Velocity system to the SphygmoCor Px system provides a complete system to assess arterial stiffness, wave reflection and the effects of these important physiological events on key central heart function parameters. In addition, the SphygmoCor Pulse Wave Analysis system has been shown to be an reproducible tool for assessment of endothelial function.

The following summary provides a list of some of the large clinical trials that SphygmoCor has been included in.

1. A key outcome study in End Stage Renal Disease in Patients on Dialysis, showed that aortic pulse wave velocity (PWV) and more significantly Augmentation Index (AIx), assessed by SphygmoCor Pulse Wave Analysis, to be independent predictors of morbidity and mortality in ESRD patients on haemodialysis. The study showed that for each 10% increase in AIx the risk ratio is 1.51 for all cause mortality and 1.48 for cardiovascular mortality and for each 1 m/s increase in PWV the all cause mortality-adjusted odds ration is 1.39 and more significantly, the risk ratio for each. Importantly these associations were independent of other known risk factors, including brachial blood pressure. [Blacher J, Guerin AP, Pannier B, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99:2434-2439. London GM, Blacher J, Pannier B, et al. Arterial Wave Reflections and Survival in End-Stage Renal Failure. Hypertension 2001;38:434-38.]

2. The Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) commenced in 1997 to assess antihypertensives and the use of statins. The Antihypertensive arm compared the ability of two different treatment regimens to reduce a composite endpoint of nonfatal myocardial infarction and fatal coronary heart disease in more than 19,000 hypertensive patients in the UK, Ireland and Nordic regions. The treatment regimes tested were the calcium channel blocker amlodipine with the ACE inhibitor perindopril or the beta-blocker atenolol and the diuretic bendroflumethiazide. The study’s steering committee stopped the study early, in December 2004, after observing significant benefit in the amlodipine plus perindopril arm of the study. PWA was added as a Substudy in 2002 in 5 centres in the UK. The Ascot Study

3. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study has been designed to establish whether there are substantial effects of fenofibrate treatment on clinical cardiovascular events in patients with type 2 diabetes. Patients were recruited during the period of 1997-2000, with 6 monthly follow-up until median 5 years follow-up has occurred. The study is being conducted in 63 clinical centres across Australia, New Zealand and Finland, with SphygmoCor being incorporated into a Substudy based in Finland. Findings from the main study are expected to be available in late 2005.
The FIELD Study

4. The Study of the Effectiveness of Additional Reductions in Cholesterol and Homcysteine (SEARCH) is testing whether more aggressive lipid lowering is beneficial. The study being run nationally in the UK over a 4 year period, will evaluate whether the additional reduction in cholesterol with simvastatin and homocysteine with folic acid/Vitamin B12 will reduce coronary events. SphygmoCor is in a Substudy in two centres. The studied finished during 2004 and findings have not been released yet.

5. The Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind Study (REASON) is a multi-centre trial being conducted over 13 countries. The study has recently shown that an ACE inhibitor/diuretic combination could reduce central pressure augmentation and LV mass in comparison to a beta blocker despite similar effects on measured diastolic pressure. Data has been published over a number of publications:

1. “Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose Perindopril/Indapamide combination in hypertensive patient. A comparison with Atenolol. Asmar RG, London GM, O’Rourke MF, Safar ME. Hypertension 2001;38:922-926.” This paper evaluated whether a fixed ACE inhibitor + diuretic combination was a suitable therapy for selectively reducing SBP and PP by improving arterial stiffness (aortic stiffness and wave reflections) and showed that Per/Ind was able to do this.
2. “Amelioration of arterial properties with a perindopril-indapamide very-low-dose combination. Asmar RG, London GM, O’Rourke MF, etal. J Hypertens Suppl 2001;19:S15-20.” This study was aimed to address whether the reduction in SBP through the reduction of arterial stiffness (aorta and wave reflections) from Per/Ind was attributed to a reduction in aortic stiffness (PWV), reduction in the intensity or delay of wave reflections (Augmentation Index), or a combination of both. Per/Ind provided a significantly greater reduction in SBP and PP than atenolol. While the two therapies produced a reduction in pwv, only the Per/Ind combination significantly attenuated wave reflections (AIx).

6. The Strong Heart Study (SHS) is a study of cardiovascular disease and its risk factors among American Indian men and women, supported by the National Heart, Lung and Blood Institute since October 1998 and is the largest epidemiological study of American Indians ever undertaken. The study includes 13 American Indian tribes and communities in three geographic areas in Arizona, Oklahoma and Nth and Sth Dakota. Phase IV of the study is currently underway which includes SphygmoCor Pulse Wave Analysis, along with carotid arterial ultrasonography to provide a non-invasive assessment of arterial stiffness and haemodynamics of arterial hypertrophy and detection and quantification of atherosclerosis, as well as left ventricular structure and function from echocardiography. There are a large number of publications on earlier stages of the study, with the first from this phase appearing in 2002, which showed that significant heritabilities were detected for Augmentation Index, even after accounting for the effects of covariants such as sex, age, diabetes, impaired glucose tolerance, smoking, cholesterol, body surface area and hypertension. [“Heritability of carotid artery structure and function. The Strong Heart Family Study. North KE, MacCluer JW, Devereux RB, etal. Aterioscler Thromb Vasc Biol. 2002;22:1698-1703.”] Strong Heart Study

7. The Calcification Outcome in Renal Disease (CORD) is a prospective observational non interventional study being run by Genzyme. The study, which commenced in 2003, includes approximately 50 dialysis centres across the Benelux and Scandinavian regions. SphygmoCor Pulse Wave Analysis and Pulse Wave Velocity allow for cross-sectional documentation of arterials stiffness, while other measures include analysis of calcification. While the study has another 12 months to run, it is anticipated that baseline data will be available the end of 2005.

8. Predictive medicine company IMI International Medical Innovations Inc. will initiate a new clinical trial to evaluate the relationship between skin sterol values and a variety of new and established coronary artery disease (CAD) markers, in high-risk patients. The study, being performed at Providence Hospital, British Columbia, will involve 100 patients at high-risk for cardiovascular disease not currently taking cholesterol-lowering medication, includes SphygmoCor Pulse Wave Analysis. Vascular Disease Management

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