CD&D National Editor and Staff Reports
The cardio device sector took a small step back last month – minor, perhaps, but nevertheless an advance for the cardio drug arena – with the much anticipated results of the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D).
BARI 2D indicated that there is no significant advantage of prompt revascularization over intensive medical therapy – meaning the aggressive use of drugs — on mortality and major cardiovascular events in patients with Type 2 diabetes and stable coronary artery disease (CAD).
At five years, there was no difference in the primary outcome – rate of death – between patients randomly assigned to revascularization (88.3%) – percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery – compared with intensive medical therapy alone (87.8%). Rates of survival also were similar between patients assigned to insulin sensitization (88.2%) vs. insulin provision therapy (87.9%).
Prompt revascularization also had no benefit on freedom from major CV events (composite of death, myocardial infarction or death), another primary outcome, compared with intensive therapy (77.2% vs. 75.9%). And there was no significant difference in the insulin sensitization (77.7%) and insulin provision groups (75.4%).
"BARI 2D has shown that neither prompt revascularization vs. delayed revascularization or insulin sensitization vs. insulin provision was superior in terms of mortality," Trevor Orchard, MD, professor of epidemiology, University of Pittsburgh Graduate School of Public Health. Orchard and colleagues presented the data at last month's annual meeting of the American Diabetes Association (Alexandria, Virginia) in New Orleans.
PCI alone vs. medical therapy showed no differences in rate of death or CV events. But prompt CABG, compared with medical therapy alone, yielded significantly better outcomes when major CV events were considered in addition to death (22.4% vs. 30.5%;), according to Orchard. Much of this benefit with CABG was an observed reduction in nonfatal MI, which has never before been shown this intervention (7.4% vs. 14.6%).
The data build on that from the first BARI trial, published in 1996, comparing CABG and PCI using balloon angioplasty in patients with CAD. Results demonstrated no difference in long-term mortality rate and MI; however, results indicated slightly better survival after CABG among patients with diabetes.
A second component of the study compared whether controlling diabetes with insulin-sensitizing drugs (metformin and thiazolidinediones) had an advantage over insulin-providing drugs (insulin, sulfonylureas), and the same patient population was randomly assigned to one of the two treatment arms.
"From the diabetes viewpoint, we are assured that treatment with insulin-sensitizing drugs, which have been a concern in the past, are not harmful and this is a perfectly reasonable alternative to diabetes management, Orchard said.
Writing online, an expert representing the Gerson Lehrman Group (New York; London) said that the trial data "will benefit pharma companies and pharmacies, especially ones making insulin sensitizing drugs as they showed a small benefit over insulin based therapies."
He added that the study "has the potential to severely undermine the profitability of many cardiologists and many hospitals whose profitability is largely driven by diagnostic cardiac catheterization and then angioplasty with or without a stent. Some insurance companies on the basis of this will likely begin denying initial coverage for angioplasty until an 'adequate trial' of aggressive control of cholesterol, diabetes and blood pressure is undertaken."
"The intent was to determine if prompt revascularization would reduce event rates vs. simply treating them medically," Robert Frye, MD, of the Mayo Clinic (Rochester, Minnesota), said.
"From the cardiology perspective, the most striking finding was the identification of a high-risk group of patients who were selected for CABG and had the most extensive CAD who benefited from prompt CABG. It is the first demonstration in a properly conducted randomized trial that CABG reduces nonfatal MI," Frye said.
The finding "emphasizes the important of continuing what has been a long-time effort," he said.
Plus for Heparin prior to vein harvest
Maquet Cardiovascular (Rastatt, Germany) reported that data presented at the annual meeting of the International Society for Minimally Invasive Cardiothoracic Surgery (Beverly, Massachusetts) show that administration of a heparin bolus with doses as low as 2500U prior to endoscopic vein harvest (EVH) was associated with improved acute saphenous vein (SV) graft patency in patients undergoing off-pump coronary artery bypass (OPCAB). Pre-heparinization was also linked to a significant reduction in the incidence and volume of residual clot strands within the vein.
EVH reduces patient discomfort, scarring and wound complications and hastens recovery time compared to traditional techniques that involve a long incision to expose the entire length of the vein.
"In our experience, the impact of pre-heparinization on surgical bleeding is minimal, making it a promising strategy that may improve patient outcomes with minimally invasive vein harvesting," said lead investigator Robert Poston, MD, chief of the division of cardiac surgery at Boston University.
The prospective study examined acute patency rates in 460 patients that underwent OPCAB using veins acquired through EVH, comparing patients receiving no heparin prior to harvest to those who received one of three doses of heparin prior to the procedure. A subset of the most recent 110 patients underwent catheter-based infrared imaging (OCT) of the full tract of harvested SV in order to measure residual clot within the vein. Overall, vein graft patency was 98.9% in patients treated with heparin compared to 95.2% in the controls.
In the subset of the most recent patients, 42% of patients receiving pre-heparinization showed residual clot in the harvested vein compared with 85% of patients that didn't receive heparin. Clot volume and the percentage of the vein containing clot were also significantly reduced with the use of heparin prior to EVH.
"These data are evidence that with pre-heparinization, EVH can be performed with excellent patency results in patients who require coronary artery bypass grafting, reinforcing the efficacy of this procedure," said Poston.
Rolofylline fails in acute HF trial
Preliminary results for the pivotal Phase III study of rolofylline (MK-7418) – an investigational drug for acute heart failure from Merck & Co. (Whitehouse Station, New Jersey) – show that it failed to meet the primary and secondary efficacy endpoints. Merck said it would continue to analyze the data with outside experts, but that it would not seek regulatory approval this year.
Dan Bloomfield, MD, executive director, cardiovascular research at Merck Research Laboratories, said that the results were "disappointing because we had been hopeful that blocking the adenosine A1 receptor with rolofylline would prove to be a useful new approach for these patients."
The primary hypothesis of the 2,033-patient pivotal Phase III study, PROTECT, was that rolofylline 30 mg would improve symptoms of acute heart failure compared to placebo. The secondary endpoints were that rolofylline 30 mg would reduce the risk of death or cardiovascular or renal re-hospitalization 60 days after treatment, and that rolofylline 30 mg would reduce the incidence of persistent kidney impairment.
Rolofylline was acquired by Merck through the acquisition of NovaCardia (San Diego), which Merck purchased in 2007 for $350 million in stock. "We think this drug has tremendous potential," said Merck's CEO at the time in announcing the purchase. "We are absolutely delighted a company like Merck will be taking this drug forward."
Results from the PROTECT pilot study, presented at previous medical meetings and published in 2008, had showed an overall trend for the drug toward efficacy (more patients with improved shortness of breath, fewer patients with worsening renal function and/or worsening heart failure).
Merck's late-stage pipeline of investigational medicines for cardiovascular disease includes MK-524A (approved in some markets outside the U.S.), MK-524B, ezetimibe/atorvastatin, and anacetrapib (MK-0859) for atherosclerosis, and vernakalant for atrial fibrillation.
Mixed results for Rosiglitazone
Using rosiglitazone (Avandia) in combination with standard diabetes treatments (metformin or a sulfonylurea) to lower blood glucose in Type 2 diabetics does not increase the risk of cardiovascular disease or death, according to a study published in The Lancet and simultaneously presented at the annual meeting of the ADA in New Orleans.
However, researchers said the RECORD study confirms that using rosiglitazone more than doubles the risks of heart failure, and also increases the risk of fractures, mainly in women.
Rosiglitazone – marketed by GlaxoSmithKline (London) — belongs to a class of drugs called thiazolidinediones, and proven as an effective agent to control blood glucose. But studies have also suggested an increased risk of heart attacks caused by the rosiglitazone, and concern about adverse effects has reduced its use.
Professor Philip Home of the Medical School of Newcastle University (Newcastle, UK) and colleagues looked at 4,447 patients with Type 2 diabetes already on either metformin or a sulfonylurea. Patients were assigned received addition of either rosiglitazone or to a combination of metformin and sulfonylurea. The primary endpoint was cardiovascular hospitalisation or cardiovascular death.
The researchers found that 321 people in the rosiglitazone reached the primary endpoint compared with 323 in the control group — indicating no statistically significant difference. They also found that heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the control group-thus risk of heart failure was more than doubled for rosiglitazone patients.
The risk of arm and lower leg fractures also increased by 57% in patients given rosiglitazone-although the increased risk for women (82%) was much higher than that for men (23%).
In a comment on the study, Dr. Ravi Retnakaran and Dr. Bernard Zinman, of Mount Sinai Hospital (Toronto) and University of Toronto, said that half-maximum doses of rosiglitazone (or a related drug pioglitazone) in combination therapy could be considered as it is generally accepted that half-doses give better-than-half results, while limiting side-effects."
Roche to start final tests for aleglitazar
Roche Holding (Basel, Switzerland) said it will start final tests on its aleglitazar treatment after study results suggested it may help reduce cardiovascular and stroke risk in diabetics. The experimental medicine helped control blood sugar and cholesterol levels, according to a study of more than 300 patients that was funded by Roche. The data were published in The Lancet and presented at this year's ADA meeting.
Luke Miels, head of marketing for metabolic diseases for Roche, said the final study may be completed by 2013, clearing the way for regulatory filings the next year. Roche cited one analyst estimate that the drug may generate 1 billion Swiss francs ($918 million) a year.
The study excluded patients who had a heart attack within the previous six months, the group Roche is targeting in the final trial, as well as those with heart failure and liver or kidney problems. Because swelling and weight gain rose along with the dose of the drug, Roche chose a l50-microgram level once daily to develop further.
Aleglitazar is in a class of drugs called PPAR agonists, which target mechanisms in the cell that control the absorption of fat and sugar in the bloodstream. Diabetes develops when the body doesn't properly use or produce the hormone insulin to convert blood sugar, or glucose, into energy. Roche designed the final trial of aleglitazar to determine if it could reduce the risk of heart attack, stroke and death from cardiovascular disease by 15% to 20%. The drug will be given in addition to standard therapy such as statins, aspirin and Plavix.
In brief . . . .
• Allergan (Irvine, California) said it received a complete response letter from the FDA regarding Botox (botulinum toxin Type A) to treat upper limb spasticity in post-stroke adults. The FDA has identified items that must be completed before the supplemental biologic license application, submitted last year, can be considered, including a risk minimization plan and safety update, independent verification of underlying patient source documentation at study sites from 1999, and labeling revisions. Allergan plans to respond to the FDA's proposed label revisions and will develop a pediatric plan to further study Botox in children.
• BioLineRx (Jerusalem) said preliminary results from the ongoing Phase I/II clinical trial showed there were no complications in 15 patients treated with BL-1040, a resorbable liquid polymer that is administered via the coronary artery during standard catheterization and flows into the damaged heart muscle. In addition, six-month follow-up results from the first five patients showed BL-1040 was effective in preventing cardiac remodeling and preserving cardiac function.
• Cordex Pharma (La Jolla, California) said that the FDA approved the design of pivotal Phase IIb/III trials evaluating its lead product ATPace as an antiarrhytmic drug for the acute treatment of patients with paroxysmal supraventricular tachycardia under a special protocol assessment. Cordex said it plans to begin prospective, double-blind, placebo-controlled and randomized trials with ATPace in about 200 patients to demonstrate clinical safety and efficacy to support a new drug application filing of ATPace for the treatment of PSVT in emergency room patients.
• D-Pharm (Rehovot, Israel) reported approval of its investigational new drug application for a pivotal Phase III trial of neuroprotective drug DP-b99 in acute ischemic stroke patients. The 700-patient Membrane Activated Chelator Stroke Intervention (MACSI) study is designed to compare the effect on ischemic stroke outcome between DP-b99 and placebo. The trial is expected to start in the coming months.
• Talecris Biotherapeutics (Research Triangle Park, North Carolina) reported receiving FDA orphan drug designation for Plasmin (Human) to treat acute peripheral arterial occlusion. A Phase I/II trial is ongoing. Plasmin, derived from human plasma, is a stabilized formulation of an enzyme that dissolves blood clots. In early June, the Federal Trade Commission blocked Talecris' proposed $3.1 billion merger with CSL (Melbourne, Australia), the agency supporting its decision by saying the merger would reduce competition in the blood-products markets.
• United Therapeutics (Silver Spring, Maryland) and Eli Lilly and Co. (Indianapolis) presented results of a pivotal 16-week study showing that once-daily tadalafil was generally well tolerated, improved exercise capacity and improved time to clinical worsening in patients with pulmonary arterial hypertension. Results from the study were published in the June 9 issue of Circulation.
• VIA Pharmaceuticals (San Francisco) reported completing an end of Phase IIa meeting with the FDA for VIA-2291 (atreleuton), a selective and reversible inhibitor of 5 Lipoxygenase, a key enzyme in the biosynthesis of leukotrienes.
The firm said regulators provided guidance on the company's trial design for its Phase III study, which will assess the effect of VIA-2291 in preventing cardiovascular events such as heart attack, stroke and cardiovascular mortality in patients with recent heart attack or established atherosclerotic cardiovascular disease.
VIA said it intends to submit its proposed Phase III plan to the FDA, including a request for a special protocol assessment. The firm noted that it is exploring opportunities for launching the drug's final phase of development.