Cardiovascular Device Industry Keeps Beating

Recession doesn’t stop pacemaker, defibrillator and stent breakthroughs, and triggers increased outsourcing by OEMs.

Tim Sohn

While cardiovascular device companies are pulling back on initiating new projects a bit due to the global recession, progress continues to be made on research and development projects already in the pipeline.

At the 30th annual Heart Rhythm Society Scientific Sessions conference May 13-16 in Boston, Mass., 12 clinical trials were presented on various cardiovascular-related subjects, according to Dr. Richard Page, head of cardiology at the University of Washington, in Seattle, Wash., and president of the Washington, D.C.-based Heart Rhythm Society, an advocacy organization for cardiac arrhythmia professionals and patients, and the primary information resource on heart rhythm disorders.

“At the [Heart Rhythm] Society meetings, we had 12 late-breaking clinical trials that have been in the pipeline for a while. A robust amount of clinical research is being done,” said Page.

Clinical Trials: Defibrillator, Pacemaker Results

Here is a look at three of those trials:

• The results of one clinical trial called “ALTITUDE” show survival rates exceeding all previous data from other studies for patients with either an implantable cardioverter defibrillator (ICD) or a cardiac resynchronization therapy device (CRT-D). According to trial results, ICD survival rates of 91.8 percent were reported among 47,032 patients and CRT-D survival rates of 75.6 percent were reported among 38,967 patients. In addition, shock was associated with lower survival rates for both ICD and CRT-D patients. The five-year incidence of shock was 35.5 percent for ICD patients and 34.5 percent for CRT-D patients. The trial utilized data from 100,000 patients of a remote monitoring system. “We recognized the critical need for more current data on the effectiveness of device therapies,” said Dr. Leslie Saxton, of the University of Southern California Keck School of Medicine in Los Angeles, Calif. “Results reflect contemporary practice in terms of device technology, patient selection and the ability to monitor device function and symptom status over a network.”

• Another clinical trial evaluated the risk of people implanted with the investigational EnRhythm MRI SureScan pacing system, manufactured by Minneapolis, Minn.-based Medtronic, while being tested with magnetic resonance imaging (MRI). Dr. Bruce Wilkoff, director of cardiac pacing and tachyarrhythmia devices at Cleveland, Ohio-based Cleveland Clinic hospital and a Medtronic consultant who presented the study, said patients, especially older than the age of 65, often need an MRI. In the study, once the pacemaker and leads were successfully implanted, patients were either given an MRI or not given one. Wilkoff said 464 patients at 41 centers in the United States, Europe, Canada and Middle East were implanted with the pacing system; 244 MRI scan visits occurred and 44 patients were followed one month after an MRI scan/ control visit. No MRI-related complications or MRI-attributed sustained ventricular arrhythmias, asystole episodes or pacemaker malfunctions occurred. The system-related, complication-free rate was 91.7 percent.

“Currently, the decision to scan a patient with a pacemaker requires a considerable risk-benefit analysis due to the complication rates associated with the FDA-approved pacemaker system and requires intensive monitoring of the patients,” Wilkoff said. “This investigational study showed positive results, indicating that many more patients may have access to MRI, a vital and often irreplaceable tool in detecting and managing conditions such as cancer and neurological disorders,” he said.

The EnRhythm MRI SureScan system from Medtronic is currently an investigational system in the United States, but it obtained the European Union CE Mark in November 2008.

• The Multicenter Automatic Defibrillator Implantation Trial 2 (MADIT-2), presented by Dr. Illan Goldenberg of the University of Rochester Medical Center in Rochester, N.Y., found that ICD therapy continued to chip away at mortality four to eight years after implantation, compared with already significant survival gains in earlier years. The long-term benefits were best among patients who didn’t develop clinical heart failure or whose heart failure didn’t worsen during the first few years when the trial was active. Survival gains also were significantly greater among patients with dual-chamber ICDs programmed for backup right ventricular pacing. The clinical trial randomized 1,232 patients with left ventricular ejection fraction less than 30 percent and acute myocardial infarction more than 30 days before they either received or did not receive ICDs in addition to medical therapy. Trial subjects experienced a 41 percent decline in adjusted all-cause mortality over the next four years. Mortality in the ICD group fell another 29 percent during the subsequent four years, for a total eight-year benefit of 37 percent. In the trial’s previously defined primary analysis, published in 2002, the adjusted mortality reduction was 31 percent over 20 months. The MADIT-2 outcomes were instrumental in the acceptance and growth of primary-prevention ICD therapy, according to Goldenberg.

“Until now, patients could be told that the clinical trials indicated a survival benefit that was limited to a very short time period,” he said. “In the current eight-year analysis, he said, the LYS (life years saved) figure increased to 1.2. “So it has life-saving and cost-saving implications,” he said.

Another market where progress is being made in both research and technology is stents.

Bare-Metal Vs. Drug-Coated Stents

A study released in May by Swedish researchers dispels previous research that found drug-coated heart stents are less safe than its bare-metal counterparts.

Research unveiled in December 2006 by the same group concluded that patients who received drug-eluting stents were 18 percent more likely to die within three years. That conclusion caused the sales of stents manufactured by Natick, Mass.-based Boston Scientific and New Brunswick, N.J.-based Johnson & Johnson to plummet.

“The immediate impact was a decrease in the use of drug-eluting stents and a lot of scrutiny on safety,” Professor Franz Eberli of University Hospital Zurich in Switzerland said in a statement. Eberli added that the latest research on the same group of patients “provides a lot of reassurance.”

The results from the recent study, spearheaded by Dr. Stefan James of Uppsala University Hospital in Sweden and published in the New England Journal of Medicine, confirmed that the risk of death or heart attack is no greater among those who received drug-eluting stents or bare-metal stents.

Results from the Swedish study of about 48,000 patients show the devices work as promised, especially in high-risk patients, who had a 74 percent lower risk of having a clogged stent compared with similar patients who got a bare metal stent.

Another stent study, “Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction” (HORIZONS-AMI), released by New York-Presbyterian Hospital and Columbia University Medical Center in New York, N.Y., and the New York, N.Y.-based Cardiovascular Research Foundation, reinforced the benefits of using drug-eluting stents. In heart attack patients undergoing angioplasty, the use of paclitaxel-eluting stents reduces rates of target lesion revascularization and binary angiographic restenois when compared to the use of bare-metal stents after one year, the study concluded.

The use of paclitaxel-eluting stents also resulted in a significant reduction in binary restenosis after 13 months, the study found. Binary restenosis is the rate at which the artery re-narrows at least 50 percent following implantation of the stent, and was the secondary efficacy endpoint of the trial. The paclitaxel-eluting stent had a rate of 10 percent and the bare-metal stent had a rate of 22.9 percent.

The HORIZONS-AMI trial enrolled 3,602 heart attack patients at 123 centers in 11 countries, 3,006 of whom were randomized to paclitaxel-eluting stents versus otherwise identical bare-metal stents.

“Outcomes from prior registry and randomized trials of drug-eluting stents compared with bare-metal stents in heart attack patients have been conflicting. These results now provide definitive evidence that paclitaxel-eluting stents are superior in efficacy to bare-metal stents and have a comparable safety profile at one year,” said Dr. Gregg Stone, director of cardiovascular research and education in the Center for Interventional Vascular Therapy at New York-Presbyterian Hospital/Columbia University Medical Center. “The findings from the HORIZONS-AMI trial will have a major impact on how decisions are made regarding drug-eluting and bare-metal stents in the highest-risk patients, those in the early hours of a heart attack.”

The two studies are good news for Boston Scientific and Johnson & Johnson, which are rivaling each other for new drug-coated stents.

Boston Scientific has received approval from the U.S. Food and Drug Administration (FDA) for the Taxus Liberte Atom a drug-coated stent designed to hold open small blood vessels in the heart, and plans to begin selling the device this month. Officials at the firm said Taxus Liberte Atom was approved for use in vessels as small as 2.25 millimeter in diameter.

But Johnson & Johnson officials said a six-month study showed its new experimental stent was better than the Taxus device at preventing re-growth of tissue within the stent.

Data from the study will be used to support an application for European regulatory approval of Nevo, and the firm aims to seek U.S. approval by the end of 2011, according to J&J.

The safety and effectiveness of heart-defibrillator wires also have been questioned.

Making Heart “Leads”

Two years after Medtronic disclosed that its Spring Fidelis heart-defibrillator wires were fracturing at a rate higher than some other leads, causing several deaths, the firm received FDA approval of the Attain Ability left-heart lead for use with cardiac resynchronization therapy (CRT) devices in May.

Attain Ability incorporates insulation material that was evaluated for space applications, engines and harsh environments at Hampton, Va.-based NASA Langley Research Center. This application marks the first time a NASA-developed material has been used in this kind of implantable medical device.

“Attain Ability is the latest innovation in our long-term strategy to provide physicians with a broad portfolio of leads and delivery systems to meet the unique needs of their patients,” said Pat Mackin, senior vice president at Medtronic.

Officials at St. Jude Medical Inc., based in St. Paul, Minn., said the FDA has approved two of the company’s cardiac defibrillator product lines.

The Promote Plus and Current Plus defibrillators include features that allow doctors to customize therapy for patients with heart arrhythmias and heart failure. The new products also have a smoother header configuration to make the defibrillators more comfortable for patients, as well as provide more visibility at the connector site, where the thin wire that delivers electricity to the heart is connected, according to the firm.

The Heart Rhythm Society has recommended closer oversight of heart leads, including the release of more company data about the performance of the products.

Drug-coated stents have been found to have equal risk to bare-metal stents, and in some procedures, better results. In this series of images, a stent is used during a cardiothoracic technique.

“The measurement and reporting of lead performance are important for clinical decision making, for setting realistic expectations for patients and physicians, for transparency, and for monitoring and improving performance,” said Dr. William Maisel, a cardiologist at Beth Israel Deaconess Medical Center in Boston, Mass., and co-chair of the group’s task force on lead performance.

The group’s recommendations, released at the scientific sessions, would apply to both pre-market evaluation and post-market monitoring of the devices.

The statement made recommendations for four specific indications—infection, chronic pain, thrombosis or venous stenosis and “leads that are no longer clinically useful.”

According to the statement, both the device and the lead should be removed “in all patients with definite [cardiovascular implantable electronic device] system infection as evidenced by valvular endocarditis, lead endocarditis, or sepsis.”

Likewise, both the device and the leads should be removed in patients with occult gram positive bacteremia (not contaminant) device pocket infection and in patients with valvular endorcarditis without definite involvement of the leads and/or device.

Device and lead removal are not, however, recommended for a superficial or incisional infection without involvement of the device and/or leads, nor is removal suggested to treat chronic bacteremia when the source is not the device or leads.

For patients with chronic pain, the device should be removed when pain at the device or lead insertion site is not manageable by medical or surgical techniques, according to the HRS. The device and lead should be removed when thrombosis or venous stenosis occurs, but the level of evidence is weaker than the evidence in support of removing devices when there is an infection.

In most cases, the panel recommended removing nonfunctioning leads, but advised leaving them be in patients with a life expectancy of less than a year.

Recession Triggers More Outsourcing, Less Funding

The economic downturn has had multiple effects on cardiovascular firms, including an increased level of outsourcing, a decrease in venture capital funding and scaling back on some projects.

Maura Leahy, product manager at Galway, Ireland and Massachusetts-based Creganna, a supplier for manufacturers that build minimally invasive devices, said the global recession has forced companies to look for a competitive edge.

“In line with the trend of recent years, medical device companies are continuing to outsource increased levels of product design and manufacturing. It is well documented that this strategy increased levels of product design and manufacturing. It is well documented that this strategy enables these companies to gain competitive advantage by focusing on core competencies such as IP generation, clinical relationships and sales/marketing. Demand for outsourced services continues to increase, but there is a marked difference in the requirements profile. The outsourcing mindset has moved beyond seeking a contract manufacturing provider who can offer the lowest unit cost, to finding a design and manufacturing partner who can deliver the lowest total cost of ownership over the lifetime of a product combined with the lowest risk to the medical device company,” said Leahy.

The stagnant economy also has shrunk the availability of venture capital funding, which in turn, is affecting development, especially in start-up companies, said Daniel Kasprzyk, president and CEO of Flagstaff, Ariz.-based Machine Solutions Inc., a supplier of process and testing solutions for catheter and stent manufacturers.

“Significantly reduced capital spending in the first quarter of 2009 by large cap manufacturers and a decrease in venture capital infusion into the early stage start-up community has put a significant strain on companies servicing the capital equipment sector of the cardiovascular device business community, requiring a retrenching of product offerings and constant review of product mix. Market impact has been felt globally and without any specific region being immune to the economic forces,” said Kasprzyk.

The third annual “Predictions Survey” by the National Venture Capital Association found that 92 percent of venture capital firms predicted that investing will decline this year from 2008. More than 96 percent believed new companies will have a hard time getting investment in 2009, and more than 60 percent said overall funding will drop below $27 billion.

Future Looks Bright for Industry

Despite this bad news, a report by Global Markets Direct, “The Future of the Cardiovascular Devices Market to 2012,” concludes that the global drug-eluting stents market, valued at $5.75 billion in 2007, is expected to grow 7.2 percent by 2012, reaching $8.15 billion.

The cardiac rhythm management market was valued at $3.9 billion in 2007 and is forecast to grow by 17.6 percent annually to reach $8.76 billion by 2012, accounting for 54.7 percent of the cardiac rhythm management market value. And the global heart valves market, valued at $1.22 billion in 2007, is expected to grow 5.4 percent annually from 2007 to 2012 to reach $1.59 billion by 2012.

According to Kasprzyk, “there are many emerging therapies in cardiovascular DES (drug-eluting stent) products including bioabsorbable drug-eluting stent structures, drug-eluting balloons, plaque incision devices, genetic theraries, combinational drug/device advancements, as well as emerging solutions in the area of percutaneous heart valve replacement and repair.”

Page said an area under development is remote telemetry, which allows the monitoring of patients with implanted cardiac devices without requiring a face-to-face office visit.

Leahy sees valve repair and replacement as one of the next challenges for the cardiovascular industry. “Minimally invasive therapies to treat structural heart disease is the next a challenge for the industry—new treatment and delivery devices for valve repair or replacement is the focus of innovation for many cardiovascular com-panies,” she said.

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Overall, cardiovascular device manufacturers and suppliers are fairing quite well compared to other industries, such as automakers. But venture capital funding is taking a big hit, and the recession has more OEMs outsourcing. Clinical trials at the HRS scientific sessions showed breakthroughs especially with pacemakers and defibrillators. Both drug-coated stents and heart leads that previously took a bad rap are seeing a turnaround thanks to new products and studies.