CD&D National Editors

While this month's lead story from the European Society of Cardiology (Sophia Antipolis, France) annual congress focuses on developments in device therapies and radiology, the conference also provided an overview of some of the latest research in pharmaceutical interventions for cardiovascular care.

Following is a summary of the key reports:

• A report on Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study concluded that intensive LDL-cholesterol lowering with the combination of simvastatin and ezetimibe in patients with mild to moderate aortic stenosis appears to reduce the risk of coronary artery disease events (as has been shown in previous trials), but not the rate of progression of aortic valve disease. The use of simvastatin and ezetimibe in such patients was generally well tolerated and safe.

SEAS investigated the effects of intensive cholesterol lowering with the combination of simvastatin (40 mg daily) and ezetimibe (10 mg daily) in patients with aortic stenosis, common among older people in Western populations. Left untreated, it can progress to death from heart failure or cardiac arrest.

Compared with placebo, the combination of simvastatin and ezetimibe reduced LDL-cholesterol (the primary endpoint) by an average of 61%, corresponding to a reduction of about 2 mmol/L (76 mg/dl). The combination of simvastatin and ezetimibe did, however, produce a statistically significant 22% proportional reduction in the secondary endpoint of atherosclerotic events alone: 148 (15.7%) in the simvastatin plus ezetimibe group versus 187 (20.1%) in the placebo group.

The study was initiated and designed by academic researchers in Scandinavia, and carried out at 173 clinical centers in Norway, Denmark, Sweden, Finland, Germany, UK and Ireland.

• A report was presented on the DECREASE III Study, conducted in the Netherlands between June 2004 and April 2008, concluding that patients treated with Fluvastatin, a product from Novartis (Basel, Switzerland), showed an improved cardiac outcome after surgery.

In the study, 497 statin-naive patients scheduled for vascular surgery were included in the trial at Erasmus MC (Rotterdam, the Netherlands). Patients were randomized to receive either placebo or fluvastatin extended release, 80 mg, once daily. Treatment was started at the outpatient clinic on the day of randomization, median 37 days prior to surgery and was continued during the first 30 days after surgery. Inflammatory markers at baseline, including hs-CRP and IL-6 were assessed in patients allocated to fluvastatin or placebo.

At hospital admission, levels of hs-CRP and IL-6 were significantly lower in patients on fluvastatin. The primary analysis was intention-to-treat and involved all patients who were randomly assigned to either fluvastatin or placebo.

Directly after surgery, study treatment was temporarily discontinued in about one-third of patients for a variety of reasons.

Myocardial ischemia (the primary endpoint) was detected in 74 (14.9%) patients within 30 days of the initial vascular surgical procedure. A total of 27/250 (10.9%) patients allocated to fluvastatin reached the primary endpoint compared to 47/247 (18.9%) patients allocated to placebo treatment (OR 0.53; 95% CI 0.32-0.88). Hence, the number needed to treat (NNT) to prevent one patient experiencing myocardial ischemia was 12.5 patients.

A total of 18 (3.6%) patients died within 30 days after surgery (the secondary endpoint) of which 12 (2.4%) were attributable to cardiovascular causes. Additionally, 25 (5.0%) patients experienced a nonfatal myocardial infarction within 30 days after surgery. The combined endpoint of cardiovascular death and nonfatal myocardial infarction was reached in 37/497 (7.4%) patients.

A total of 12/250 (4.8%) patients allocated to fluvastatin therapy reached the combined endpoint, compared to 25/247 (10.1%) allocated to placebo. Hence, fluvastatin therapy was associated with a 52% relative reduction in the incidence of MI (OR 0.48; 95% CI 0.24-0.95). The NNT for the composite endpoint of cardiovascular death or nonfatal MI is 18.9 patients.

• The management of acute coronary syndromes requires the use of anticoagulants, antiplatelet agents (aspirin, clopidogrel and/or glycoprotein [GP] IIb/IIIa inhibitors), beta-blockers, thrombolytics in some cases, and revascularization/reperfusion. In all, bleeding and possibly also blood transfusion have emerged as major contributors to worse outcome in patients with acute coronary syndrome.

A study presented at the conference underlined the need for the appropriate selection of drugs, drug doses and arterial approaches, combined with systematic evaluation of the bleeding risk prior to starting therapy to help prevent bleeding and improve patient outcome.

A past history of bleeding, the presence of renal failure, the use of an early invasive approach, excess dose of antithrombotic agents, and use of GP IIb/IIIa inhibitors have also been identified as strong predictors of the risk of bleeding. Conversely, careful selection of drugs, giving precedence to drugs with less potential for bleeding, use of a radial vs. femoral approach for invasive strategy, and systematic use of proton pump inhibitors to avoid gastro-intestinal bleeding during the initial phase, are all measures that have the potential to reduce the bleeding risk.

The study concluded that more consistent inhibition of platelet aggregation leads to better clinical outcome, albeit with an increased risk of bleeding.

• Since rofecoxib (Vioxx) was withdrawn from the worldwide market based on the safety findings of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study, the uncertainty around the cardiovascular safety of NSAIDs and COX-2 inhibitors remains and leaves practitioners with difficult decisions for the hundreds of millions of patients worldwide who continue to require pain-relieving therapy to maintain an acceptable quality of life.

A report summarized the goal of the Prospective Radomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen and Naproxen (PRECISION), now underway, addressing the cardiovascular risks of anti-inflammatory drugs used to treat arthritis, involving 2,000 patients. Questions concerning anti-inflammatory drugs, the PRECISION Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen and Naproxen trial in more than 20,000 patients with osteoarthritis is now under way.

Importantly, the FDA recently summarized a statement that in various controlled clinical trials the cardiovascular risks of COX-2 selective drugs have been indistinguishable from non-selective NSAIDs, thus also raising serious questions about the safety of the latter. As such, the FDA mandated a "boxed warning" for COX-2 selective inhibitors and traditional NSAIDs alike in view of the potential of these agents to increase adverse cardiovascular outcomes. Unfortunately, none of the reported randomized trials undertaken with NSAIDs and COX-2 selective inhibitors have thus far been specifically designed to examine cardiovascular outcomes. Thus, the current situation is one of classic "equipoise." Adequately powered, independently run randomized clinical trials prospectively designed to capture cardiovascular outcomes are urgently needed.

The report said that until trials such as PRECISION are completed, careful risk/benefit analysis needs to be undertaken for all anti-inflammatory agents regarding their potential cardiovascular risk, hypertension and its clinical sequels.

• GlaxoSmithKline (GSK; London) reported that the results of the Integrated Biomarkers and Imaging Study-2 (IBIS-2) showed that use of the selective Lp-PLA2 (lipoprotein-associated phospholipase A2) inhibitor, darapladib, in addition to standard of care treatment, prevented expansion of the necrotic core, a region within coronary plaque associated with a high risk of rupture.

Preventing expansion of the necrotic core may reduce the risk of recurrent heart attacks in patients with coronary heart disease (CHD), according to GSK. Although the differences between treatment groups in the primary endpoints of plaque deformability or reduction of the inflammatory biomarker hsCRP were not significant, darapladib significantly reduced activity of the enzyme Lp-PLA2. Numerous studies suggest that high levels of Lp-PLA2 are predictive of coronary heart disease.

The Phase II exploratory IBIS-2 trial showed: that the co-primary endpoints of plaque deformability and plasma levels of hsCRP, showed no significant differences between darapladib and placebo treatment groups, but trended positively; and key secondary endpoints showed significant effects of darapladib on plaque composition and plasma levels of Lp-PLA2 activity.

On average, after 12 months, patients treated with placebo experienced a significant increase in necrotic core volume while expansion of the necrotic core was halted in the darapladib-treated group. This resulted in a significant treatment difference in favor of darapladib. The effect of darapladib on necrotic core was consistent among several subgroups. The activity of circulating Lp-PLA2 was reduced by 59% over placebo. Patients received recommended standard of care, including antiplatelet agents (99%) and statins (90%).

Overall, darapladib was well tolerated with no major safety concerns observed. The incidence of adverse events leading to withdrawal was similar with 7% (n=11) in placebo and 4% (n=7) in the darapladib group. There were no differences in the composite of CV death, MI, stroke and coronary revascularization. Lp-PLA2 is an enzyme found in blood and atherosclerotic plaque. Enhanced Lp-PLA2 activity has been implicated in the development and progression of atherosclerosis and large amounts of Lp-PLA2 are present in the necrotic core of rupture-prone human coronary plaques.

• Medicure (Winnipeg, Manitoba) said at the meeting that data from a 263-patient trial of Aggrastate (tirofiban HCL) showed that the drug significantly lowered the incidence of heart attack after elective coronary angioplasty in coronary artery disease patients who have shown poor response to standard oral antiplatelet agents, aspirin and clopidogrel. Results of the study, designated 3T/2R (Tailoring Treatment with Tirofiban in patients showing Resistance to aspirin and/or Resistance to clopidogrel), demonstrated proof of concept, with 20.4% of patients in the Aggrastate group showing periprocedural myocardial infarction defined as the elevation of Troponin I or T at least three times the upper limit of normal within 48 hours after the procedure vs. 35.1% of patients in the placebo group.

CVT opens first FGF-1 site

CardioVascular BioTherapeutics (CVBT; Las Vegas) reported the opening of its first U.S. site for patient enrollment for its Phase II clinical trial for the treatment of severe coronary heart disease. In the coming weeks, CVBT said it will announce additional sites as they open for enrollment. In the Phase II trial, CVBT's drug candidate containing human fibroblast growth factor-1 (FGF-1) will be injected into patients' hearts, stimulating angiogenesis. The drug will be delivered using the NOGA XP Cardiac Navigation system and the MyoStar injection catheter.

Subjects will be between 25 and 75 years of age with at least a three month history of chronic stable angina triggered by physical exertion and must have a Canadian Cardiovascular Society anginal classification III or IV while receiving optimal medical therapy. Their treating cardiologist will have determined that they are generally not suitable for interventional therapy or bypass surgery.

"Developing a clinical trial protocol such as ours takes an extraordinary amount of time and effort, and I am pleased to finally open our Phase II heart trial for patient screening," said Daniel Montano, president/CEO of CVBT. "I expect additional investigators at other hospitals to begin screening patients in the coming weeks. Our target is 30 hospitals for this international Phase II heart trial."

CVBT is developing human FGF-1 for cardiovascular diseases characterized by inadequate blood flow to a tissue or organ. In addition to the Phase II trial it is conducting in patients with severe coronary heart disease, the company has two FDA-authorized clinical trials in the areas of impaired wound healing seen in diabetics and in patients suffering from peripheral artery disease of the legs. An additional study is being conducted in patients with chronic back pain who may have perfusion defects to their spine.

In brief ...

•Cytokinetics (South San Francisco, California) said it began its third Phase IIq trial of CK-1827452, a cardiac myosin activator in development for acutely decompensated or chronic heart failure. The study will test an intravenous formulation of the drug in patients with stable heart failure undergoing clinically indicated coronary angiography in the cardiac catheterization laboratory. The primary objet is to measure the potential effects of the drug on myocardial efficiency, defined as the ratio of ventricular performance to myocardial oxygen consumption. Secondary objectives include ventricular performance, myocardial oxygen consumption, hyemodynamics, pressure-volume relationships and systolic ejection time. CK-1827452 is partnered with Amgen (Thousand Oaks, California).

•Diffusion Pharmaceuticals (Charlottesville, Virginia) initiated a Phase I/II trial of lead product trans-sodium crocetinate (TSC) for intermittent claudication (severe leg pain) associated with peripheral artery disease. Data from the randomized, double-blind, placebo-controlled, doses-ranging study are expected in early 2010. Primary endpoints are peak walking time and claudication onset time. TSC is a small molecule intended to enhance diffusion of oxygen through blood plasma to treat hypoxia and related conditions.

•GTC Biotherapeutics (Framingham, Massachusetts) reported that the FDA assigned priority review to its biologics license application for ATryn 9recombinant human antithrombin) in the treatment of patients with hereditary antithrombin deficiency at risk of deep vein thrombosis and other thromboembollisms following surgery. The FDA's action date is Feb. 7, 2009. GTC signed a U.S. marketing deal for ATryn with Ovation Pharmaceuticals (Deerfield, Illinois) in June.