CD&D National Editors

The anti-clotting action of the medication clopidogrel (Plavix) can be compromised by common drugs for the treatment of heartburn and ulcers resulting in a roughly 50% increase in the combined risk of hospitalization for heart attack, stroke and other serious cardiovascular illnesses, according to a study presented at the annual scientific sessions of the Society for Cardiovascular Angiography and Interventions.

The study focused on the effects of proton pump inhibitors (PPI) omeprazole (Prilosec), esomeprazole (Nexium), pantoprazole (Protonix), and lansoprazole (Prevacid), which accounted for about 96% of PPI use in the study.

Patients who receive a drug eluting stent (DES) benefit from taking anti-clotting medications, including thienopyradines and aspirin, for at least one year following the procedure. Doctors often also prescribe PPIs to patients taking clopidogrel because of pre-existing stomach disease or to reduce the risk of common side effects such as nausea and gastroesophageal reflux.

Before clopidogrel can exert its anti-clotting effects, it must be converted from its inactive, pro-drug form to an active drug by enzymes in the liver. PPIs can interfere with those liver enzymes, according to the study.

"Given the large number of patients who undergo coronary stent procedures each year, and the recommended and wide use of clopidogrel following this procedure, our findings have implications for many thousands of patients across the U.S.," said Eric Stanek, PharmD, senior director of research, personalized medicine research and development, Medco Health Solutions (Franklin Lakes, New Jersey) and the study's principal investigator. "Clopidogrel should continue to be taken as prescribed, and the need for PPI therapy should be carefully evaluated to ensure that it is prescribed only when clearly indicated."

For the study, researchers analyzed integrated data on pharmacy and medical claims from more than 10 million patients, including 16,690 patients taking clopidogrel for a full year following coronary stenting. Of these, 41% also took a PPI, on average, for more than nine months of the year. Over that 12-month period when patients took clopidogrel, investigators evaluated the risk of hospitalization for major adverse cardiovascular events (MACE), which they defined as a combination of heart attack, unstable angina, stroke or temporary stroke-like symptoms, repeat coronary procedures, or cardiovascular death.

The overall MACE risk was 51% higher among patients taking any PPI. The findings were equally concerning when the effects of individual PPIs were analyzed. Omeprazole correlated with a 39% increased risk of MACE, esomeprazole to a 57% increased risk, pantoprazole to a 61% increased risk and lansoprazole to a 39% increased risk. All of the associations were highly statistically significant. Overall, the incidence of hospitalization for upper gastrointestinal bleeding was only 1.1% among patients taking a PPI and 0.07% among those not taking a PPI.

The study was supported independently by Medco Health Solutions and conducted in collaboration with investigators from the Indiana University School of Medicine (Indianapolis).

Aspirin/plavix linked to infection post-CABG

Preoperative use of both aspirin and clopidogrel (Plavix) is associated with an increased risk of postoperative infection in patients undergoing coronary artery bypass grafting (CABG), according to a study reported in the April 27 issue of the Archives of Internal Medicine.

Among patients receiving dual antiplatelet therapy, the cumulative incidence of infection at 30 days was 23%, compared with 16% among those receiving aspirin alone, for an unadjusted hazard ratio of 1.5 (95% CI, 1.09 to 2.08), Elena Blasco-Colmenares, MD, PhD, of Johns Hopkins University (Baltimore) and colleagues reported. Transfusion rates were also higher in the dual therapy group, at 68%, compared with 60% in the monotherapy group (P=0.04).

Current guidelines recommend that clopidogrel be stopped at least five days before CABG surgery for patients with ST elevation myocardial infarction, but studies have also shown an increased risk of MI and death if the drug is withdrawn in patients with acute coronary syndrome or who have undergone recent stent placement.

To assess the effects of dual antiplatelet therapy on the risk of infection in CABG patients, Blasco-Colmenares and colleagues performed a retrospective cohort study of adult patients who underwent the procedure at Johns Hopkins between January 2000 and June 2003.

The study included 1,677 patients, all taking aspirin, and 194 (12%) also received clopidogrel within five days of surgery. A total of 278 patients developed a surgical-site infection or bacteremia during the month after surgery, for a 30-day cumulative incidence of 17%, the researchers reported.

The infection was at the sternal surgical site in 116 patients (42% of those with infection), at the saphenous vein harvest site in 93 (33%), and at both sites in 15 (5%). Bacteremia occurred in 54 patients (19%). The mean time to infection after surgery was 12 days.

Patients who developed infections were more likely to be older and female, to have a higher body-mass index, and to have a history of diabetes, congestive heart failure, or cerebrovascular disease. They also had longer preoperative hospital stays.

"The difference between groups in the rates of postoperative infection occurred early and persisted throughout the 30-day study interval," the investigators said.

Moreover, the association between clopidogrel use and infection persisted after adjustment for demographic and socioeconomic characteristics, as well as for preoperative and operative risk factors.

"This is the first study (to our knowledge) to demonstrate that preoperative use of dual antiplatelet therapy with aspirin and clopidogrel is associated with an increased risk of infection after CABG surgery," the researchers said.

Dual antiplatelet therapy also was associated with increased mortality, although this did not reach statistical significance (P=0.32).

Low BP/lowered LDL increases cardio risk

Data from the Treating to New Targets (TNT) trial presented at the American Society for Hypertension (ASH) meeting show that low BP levels may lead to increased risk of cardiovascular events, including heart attack and stroke. These data supplement previous findings from the TNT trial of atorvastatin showing aggressive LDL cholesterol-lowering reduced cardiovascular events.

Previous statistical analyses charting cardiovascular events have found a J-curve relationship exists between blood pressure and future cardiovascular events, where higher events were seen at the very low and very high blood pressure levels. However, there is some debate about the extent of this relationship in patients with intensive management of other cardiovascular risk factors, such as LDL-cholesterol.

In this study, researchers analyzed a total of 10,001 patients with coronary artery disease (CAD) who received either 10 mg of atorvastatin (n=5,006) or 80 mg of atorvastatin daily (n=4,995) for a primary composite endpoint of death from coronary disease, nonfatal myocardial infarction (MI), resuscitation after cardiac arrest, fatal or nonfatal stroke.

The relationship between systolic blood pressure (SBP) or diastolic blood pressure (DBP) and major cardiovascular events followed a J-curve with increased event rates above and below reference BP ranges (SBP 130-140 mm Hg and DBP 70-80 mm Hg). A non-linear Cox model identified a blood pressure of 140.6 mm Hg for SBP and 79.8 mm Hg for DBP where the event rate was lowest. The risk of major cardiovascular event increased 3.1-fold in the group with SBP ?110 mm Hg and 3.3-fold in the group with DBP ? 60 mm Hg. A similar J-curve relationship was found for the secondary endpoints of all-cause mortality, cardiovascular mortality, non-fatal MI and non-fatal stroke.

Study authors concluded that among a high-risk population with CAD enrolled in the TNT trial, despite substantial lowering of LDL-cholesterol, a J-curve relationship existed between both systolic and diastolic BP and the risk of future cardiovascular events, suggesting that low BP levels may be harmful.

"Our findings negate the dictum that with blood pressure, lower is always better," said study co-author Franz Messerli, MD, director, Hypertension Program at St. Luke's-Roosevelt Hospital (New York).

In brief ...

• Data presented at the ASH meetingshowed that the Azor Trial Evaluating Blood Pressure Reductions and Control (AZTEC) trial demonstrated that a stepwise amlodipine and olmesartan medoxomil-based titration regimen provided mean 24-hour ambulatory reductions in systolic blood pressure (SBP) of 21.4 mm Hg and diastolic blood pressure (DBP) of 12.7 mm Hg. In addition, 71% of patients in the study were able to safely and effectively achieve a 24-hour ambulatory target BP of <130/80 mm Hg. The study also showed large mean 24-hour ambulatory BP reductions in patients with hypertension from two groups with elevated risk for developing hypertension, Blacks (20.7/11 mm Hg) and patients with type 2 diabetes (21.5/12.6 mm Hg). Azor is manufactured by Daiichi Sankyo.

• Anthera Pharmaceuticals reported data from the Fewer Recurrent Acute coronary events with Near-term Cardiovascular Inflammation Suppression (FRANCIS) trial designed to examine the impact of 500mg of varespladib when administered to patients within 96 hours of an Acute Coronary Syndrome (ACS) event. It said the trail met its primary endpoint of a reduction in Low Density Lipoprotein Cholesterol (LDL-C). All patients in the FRANCIS trial received once daily doses of 80 mg of Lipitor (atorvastatin calcium), plus 500 mg of varespladib or matching placebo. Varespladib is a highly selective oral inhibitor of secretory phospholipase A2 (sPLA2), an inflammatory enzyme implicated in ACS, vascular inflammation, atherosclerosis and adverse lipid profiles.

• Teva Pharma has notified the European Medicines Agency that it decided to withdraw its application for a centralized marketing authorization for Clopidogrel Teva Pharma (clopidogrel hydrobromide) 75 mg film-coated tablets, developed as a generic medicine to be used for the prevention of atherothrombotic in patients who have myocardial infarction, ischaemic stroke or established peripheral arterial disease.

The reference medicine for Clopidogrel Teva Pharma is Plavix (clopidogrel hydrogensuphate), authorized in the European Union since July 1998. The application for Clopidogrel Teva Pharma was submitted to the Agency last July. At the time of withdrawal it was under review by the Agency's Committee for Medicinal Products for Human Use (CHMP). The company said it decided not to continue this application based on marketing considerations.

• Aastrom Biosciences (Ann Arbor, Michigan) said initial data from its Phase II IMPACT-DCM trial of its Cardiac Repair Cells showed that patients treated for both ischemic and non-ischemic dilated cardiomyopathy had improved from New York Heart Association Class III to Class II at the three-month follow-up visit. In contrast, NYHA class did not improve in two of three control patients. Those and other data were presented at the meeting of the International Society for Cellular Therapy in San Diego. To date, 13 of the planned 40 patients have been enrolled in the trial, which is on target to be completed by the end of this year.

• Amarin reported that it has reached agreement with the FDA under a Special Protocol Assessment (SPA) for its planned Phase III registration clinical trial of AMR101 (ethyl-EPA) in patients with hypertriglyceridemia, or very high triglyceride levels. The Phase III trial will be a multi-center, placebo-controlled, randomized, double-blind, 12-week study to evaluate the efficacy and safety of two doses of AMR101, a prescription grade Omega-3 fatty acid, in patients with fasting triglyceride levels of ?500 mg/dL (the AMR101 MARINE Study). The primary endpoint in the trial is the percentage change in triglyceride level from baseline to week 12. Following completion of the 12-week double-blind treatment period, patients will be eligible to enter a 40-week, open-label, extension period.

• Gilead Sciences (San Francisco) said data from a Phase III trial of darusentan, a once-daily, oral endothelin receptor agonist, as an add-on treatment for resistant hypertension demonstrated mean reductions in trough sitting systolic blood pressure from baseline of 16.5 mmHg, 18.1 mmHg, 18.1 mmHg and 8.6 mmHg for study arms testing of 50 mg, 100 mg, 300 mg and placebo, respectively, after 14 weeks of treatment. Mean reduction in trough sitting diastolic blood pressure from baseline of 10.1 mmHg, 9.9 mmHg, 10.7 mmHg and 5.3 mmHg were observed for the darusentan 50 mg, 100 mg, 300 mg and placebo groups, respectively. Data were presented at the ASH annual meeting.

• Cytokinetics (South San Francisco, California) presented data showing compound CK-2018509 demonstrates potent, selective inhibition of smooth muscle myosin, to evaluate its biochemical mechanism of action and its pharmacology in rodent hypertension models. Authors of the study concluded that CK-2018509 selectively inhibits the ATPase activity of smooth muscle myosin compared to other myosin II isoforms, including non-muscle myosin as well as cardiac and skeletal muscle myosins. Also, CK-2018509 relaxes phenylephrine pre-constricted aortic rings in a concentration-dependent manner, suggesting its potential use as a vasodilator. A poster was presented at the ASH meeting.

• D-Pharm (Rehovot, Israel) submitted an investigational new drug application and special protocol assessment request to the FDA for a pivotal Phase III clinical trial of DP-b99 in acute ischemic stroke. The company said it hopes to begin a randomized, double blind, placebo-controlled stroke study later this year comparing DP-b99 to placebo in 770 patients. DP-b99 is a neuroprotective agent based on D-Pharm's Membrane Activated Chelator (MAC) platform technology.

• Isis Pharmaceuticals (Carlsbad, Califirbua) and collaborators presented data on various advanced programs from Isis' cardiovascular franchise. The data were presented during the annual conference of the Arteriosclerosis, Thrombosis and Vascular Biology in Washington. The presentations included data from a post-hoc analysis of a recently completed study of mipomersen in which treatment with mipomersen resulted in a decrease in apolipoprotein C-III.

In addition, Isis presented pre-clinical data from two late-stage research programs, one on a direct antisense inhibitor of apoC-III which may provide a promising new drug to lower triglycerides, and a second on an antisense inhibitor to Factor XI, which has the potential to create a drug to decrease clotting without increasing bleeding. Isis and its collaborators also presented data on antisense inhibitors against 11 beta-HSD1 and apoF, potential new cardiovascular targets.

• ReNeuron (Cambridge, UK) said it has demonstrated successful automation of the manufacturing of its ReN001 neural stem cell line for stroke in TAP's CompacT SelecT automated cell culture system, and that the growth rate and the quality characteristics of the cells were identical to those manufactured manually. The data were published in Biotechnology Letters.

• Arteriocyte (Cleveland) said it received a $4.99 million award from the Ohio Third Frontier Commission's Research Commercialization Program to expand clinical applications of its commercially available Magellan Platelet Rich Plasma and bone marrow-derived stem cell product, Stem-Prep. Those funds also will be used to further develop its Nanex stem cell expansion technology for blood pharming.