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PUBLIC RELEASE DATE:
26-Mar-2007

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Contact: Leslie Humbel
lhumbel@spectrumscience.com
504-613-2418
American College of Cardiology
@ACCinTouch

Drug/intervention combinations offer benefit in severe CVD

Studies test options for cardiogenic shock, severe cardiac dysfunction

While millions of Americans suffer from severe cardiac dysfunction, only about 3,000 heart transplants are possible each year. In the meantime, doctors are trying to identify new combinations of medicines and interventions that will increase survival rates among this high-risk population. Research presented today at the American College of Cardiology's 56th Annual Scientific Session offers new insight into the most effective therapies for patients with severe left ventricular dysfunction, cardiogenic shock and perioperative hypertension. ACC.07 is the premier cardiovascular medical meeting, bringing together specialists from around the world to further breakthroughs in cardiovascular medicine.

F-18-Fluorodeoxyglucose Positron Emission Tomography Imaging-Guided Management of Patients with Coronary Artery Disease and Severe Left Ventricular Dysfunction: A Randomized Controlled Trial (PARR-2) (Presentation Number: 412-7)

Positron emission tomography (PET) is a widely used research tool to map normal brain and heart function. Recently, it has proven beneficial in assisting physicians in selecting therapies by visualizing a patient's heart metabolism. The PET and Recovery Following Revascularization (PARR-2) study looked at patients with poor left ventricular (LV) function and used PET imaging to guide therapy choices, seeking to determine if using the imaging technique would result in a better outcome than standard therapy.

Study investigators from the University of Ottawa Heart Institute, University of Washington and eight other sites enrolled 430 patients who were referred for revascularization, cardiac transplantation or heart failure, or were likely to benefit from fluorodeoxyglucose (FDG, a commonly used injection agent that is visualized on tomography) PET-guided therapy. A total of 218 patients received PET-guided therapy and 212 patients received the standard therapy. Researchers tracked the composite rates of cardiac death, heart attack, transplantation or re-hospitalization for cardiac reasons.

The study found that patients with poor LV function who received FDG PET imaging yielded fewer cardiac events over the course of a year compared with patients who received standard care (HR=0.81) but this did not reach statistical significance. However, among those patients who had not recently had an angiography X-ray exam, the PET-guided therapy significantly reduced cardiac death rates compared to those who received standard care (HR=0.4).

"Overall the study was too small to detect a significant benefit with PET imaging. With subsequent analysis, our results suggest that physician decisions about therapies for left ventricular dysfunction could be more accurate and effective with the use of imaging technologies like PET-guided therapy, particularly to manage disease in patients without a recent angiography," said Robert Beanlands, M.D., of the University of Ottawa Heart Institute, and lead author of the study. "Long-term follow up will determine whether or not these benefits are sustained and cost effective."

Dr. Beanlands will present his study on Monday, March 26, at 4:45 p.m. in Hall A.


A Phase III International Study to Assess the Safety and Efficacy of Nitric Oxide Synthase Inhibition with Tilarginine Acetate Injection in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction (Presentation Number: 412-8)

Cardiogenic shock (CS) is one of the most common causes of death among hospitalized patients with acute myocardial infarction (AMI). The TRIUMPH Study tested whether nitric oxide synthase (NOS) inhibition with Tilarginine Acetate (TAI) would reduce mortality with refractory CS, despite an open infarct-related artery. The TRIUMPH study will be simultaneously published in the Journal of the American Medical Association (JAMA) and will appear in the March 28 print issue.

Cardiogenic shock is diagnosed when the heart's ability to pump is markedly reduced, causing a "shock-like" state; the condition often occurs as a result of AMI. Studies have shown that overproduction of nitric oxide after a heart attack may play a significant role in the development and persistence of CS, and researchers predicted that Tilarginine Acetate (TAI) may play a role in inhibiting nitric oxide to prevent further damage to the heart muscle, improve blood pressure and improve survival after cardiogenic shock.

Patients with cardiogenic shock due to LV failure (ejection fraction <40 %) and systolic blood pressure (SBP) less than 100mmHg despite vasopressor support for at least one hour post-open artery (coronary angioplasty in the vast majority) were randomized to placebo or TAI 1mg/kg bolus and 1mg/kg/hr for five hours. Researchers compared rates of SBP and 30-day and six-month mortality rates, stratifying patients by age (less than 75 vs. greater than or equal to 75 years). A total of 383 patients received TAI after persistent shock was reconfirmed, prior to drug administration. The Data and Safety Monitoring Board recommended termination of enrollment due to futility based on prespecified stopping rules after review of 317 subjects.

There was a significant rise in blood pressure at two hours in response to Tilarginine compared to placebo (12 vs. 7 mmHg average rise in SBP). However, the primary endpoint at 30 days showed no difference in mortality rates among those treated with TAI versus placebo (48% vs. 42%, risk ratio=1.14).

At six months there were similar outcomes in those in the TAI and placebo groups (58% vs. 59%, hazard ratio=1.04). Rates of adverse events, CS resolution and causes of death were similar. Investigators concluded that while the use of TAI resulted in a significant rise in blood pressure the therapy offered no significant benefit in overall mortality rates in high-risk CS patients. Although the early mortality rate remains high in this condition, an important finding of this study is that functional capacity was quite good in survivors, even though these patients were very high risk based on persistence of cardiogenic shock after angioplasty and requirement for multiple vasopressor drugs.

"Preliminary findings in prior small studies looked positive, but the use of TAI in this largest trial of cardiogenic shock patients ever conducted showed no impact on mortality in these patients," said Judith S. Hochman, of the New York University School of Medicine, and Chair of the study. "Further investigation is needed to provide more options in treating this high-risk population."

Dr. Hochman will present her study on Monday, March 26, at 5:00 p.m. in Hall A


Blood Pressure Control Is an Independent Predictor of Short-term Mortality in Cardiac Surgery Patients: Analysis From the Three Randomized ECLIPSE Trials (Presentation Number: 412-5)

It is common but undesirable for a patient to experience excessively high or low blood pressure control during this time would improve clinical outcomes. The ECLIPSE trial (Evaluation of CLevidipine In the Postoperative Treatment of Hypertension Assessing Safety Events), was designed to compare the safety of clevidipine to two standard blood pressure therapies, nitroglycerin and sodium nitroprusside and a less-often used therapy, nicardipine. In three separate open-label trials conducted by researchers from Duke University Medical Center in Durham, N.C., patients undergoing cardiac surgery were equally randomized to receive clevidipine versus nitroglycerin, nitroprusside or nicardipine. Systolic blood pressure was monitored for 24 hours and the magnitude and duration of excursions outside of pre-defined acceptable ranges (85-145 mmHg pre- and post-operatively, and 75-135 mmHg intra-operatively) were determined by the area under the curve (AUC). Median AUC values were calculated for each treatment and multiple logistic regressions were used to estimate the risk of death within 30 days predicted by AUC values, adjusting for other risk variables.

The investigators found that an average blood pressure excursion of one mmHg per minute for 60 minutes resulted in a 20 percent increased 30-day mortality risk, and the risk rose rapidly for each additional 1 mmHg/min -- an excursion of 5 mmHg/min for 60 minutes was associated with a 146 percent increased risk of death.

A second, separate analysis showed that median perioperative blood pressure excursions were significantly lower for clevidipine than nitroglycerin and nitroprusside (p<0.05). Blood pressure excursions were the same for clevidipine and nicardipine, though that comparison was restricted to the post-operative period, since nicardipine is not generally used during surgery due to its slower onset of action and prolonged offset of action. In all three trials, the different treatment groups had similar clinical outcomes in the rate of death, stroke, heart attack and kidney dysfunction.

"The results of this study show that blood pressure control is a significant predictor of increased 30- day mortality, so managing perioperative hypertension is extremely important," said Solomon Aronson, M.D., of Duke University Medical Center and lead author on this study. "In addition, we found that risk rises rapidly for each additional level of digression in blood pressure levels, and clevidipine provides better overall control than current blood pressure therapies."

Dr. Aronson will present his study on Monday, March 26, at 4:15 p.m. in Hall A. He will present additional data from the ECLIPSE Trial on Tuesday, March 27 at noon, in the same location.

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The American College of Cardiology (www.acc.org) represents the majority of board certified cardiovascular physicians in the United States. Its mission is to advocate for quality cardiovascular care through education, research, promotion, development and application of standards and guidelines- and to influence health care policy. ACC.07 and the i2 Summit is the largest cardiovascular meeting, bringing together cardiologists and cardiovascular specialists to share the newest discoveries in treatment and prevention, while helping the ACC achieve its mission to address and improve issues in cardiovascular medicine.



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