CDU Contributing Editor

WASHINGTON – The cardiac rhythm management (CRM) market, dominated by pacemakers which address bradycardia (too slow heartbeat) and implantable cardioverter defibrillators (ICDs), for the treatment of tachycardia (too fast heartbeat), is one of the largest medical device markets worldwide. It has enjoyed strong growth in recent years, fueled mainly by the dramatic clinical and market success for implantable cardioverter defibrillators (ICDs). As shown in Table 1 on page 2, Cardiovascular Device Update estimates that the global cardiac rhythm management market has grown steadily (at about an 11% compounded annual growth rate) from about $3 billion in 1995 to an estimated $5 billion in 2000, in spite of relatively modest gains in the largest EP market, pacemakers.

The annual meeting of the North American Society of Pacing and Electrophysiology (NASPE; Natick, Massachusetts) focuses exclusively on disorders caused by irregular cardiac rhythms and is regarded as the most important electrophysiology (EP) trade show of the year. It attracts companies and physicians from around the world. The NASPE gatherings of recent years have been highly supportive of an expanding role for ICDs, based on the very favorable results for three key clinical trials, the Multi-Center Automatic Implantation Defibrillator Trial (MADIT), the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial and the Multicenter Unsustained Tachycardia Trial (MUSTT). Table 2, also on page 2, provides the most current position statement from the American College of Cardiology (Bethesda, Maryland) on the indications for the implantation of an ICD.

The favorable outcomes of these large, randomized multicenter trials, which strongly supported the selection of ICDs over other options as the primary treatment for lethal ventricular arrhythmias, has provided the fuel to enable the global ICD market to grow at about 20% annually for the 1998-2000 period. Based on the powerful momentum generated by these highly-publicized studies, CDU believes that the worldwide ICD market is poised for an 18% to 20% average annual growth rate in the next three to five years. The ICD market, which debuted in the U.S. in the mid-1980s but only crossed the $100 million revenue level a decade ago, has been a pivotal contributor to the success of two of the medical device industry's juggernauts, Medtronic (Minneapolis, Minnesota) and Guidant (Indianapolis, Indiana). Together, these two companies, which are engaged in a spirited dogfight to maintain technological leadership, dominate the ICD market, with current shares of about 50% and 39% respectively. St Jude Medical (St. Paul, Minnesota) accounts for the lion's share of the rest of the market and is struggling to stem ICD market share losses until it can gain technological parity (that is, dual-chamber models) with the market leaders. Table 3 on page 3 provides details of estimated worldwide CRM revenue for the "Big Three" players in this market sector.

Small progress for ablation

Whereas the dynamic growth in the ICD market has met the expectations of the financial community in the past few years, progress in the smallest segment of CRM, catheter ablation, has been disappointing. Following torrid growth in the early and mid-1990s, when a large pool of patients suffering from certain types of atrial arrhythmias (primarily Wolff-Parkinson-White and AV nodal re-entry) were successfully treated with radiofrequency catheter ablation, annual gains have slowed considerably. Several factors have contributed, with perhaps the most important one being that new indications (notably atrial fibrillation and ventricular tachycardia) for catheter ablation technology have proven to be much larger clinical and technological hurdles than originally anticipated.

The growth of the catheter ablation sector also has been stymied by the nagging problem of catheter re-use, which is unique to EP relative to other important catheter-based, interventional technologies. Specifically, CDU believes that EP diagnostic catheters are re-used an average of five to six times, while therapeutic catheters are re-used an average of two to three times. The incidence of EP catheter re-use may begin declining in the future, as the FDA has recently issued a final guidance on the practice of reusing devices intended for single use. Titled "Enforcement Priorities for Single-Use Devices Reprocessed by Third Parties and Hospitals," it will regulate third-party processors and hospitals that reprocess such devices themselves in the same manner as it does those who originally made the devices. The regulations, which conceivably will discourage rampant re-use, will include premarket notification and approval requirements, registration and listing of firms involved, submission of adverse-event reports, manufacturing and labeling requirements, medical device tracking and correcting or removing from the market devices found to be unsafe.

These regulations are in response to the growing trend of reprocessing medical devices labeled, or intended, for only one use, as well as the complexity of the devices being reprocessed. This trend has intensified concern about patient safety, informed consent, the ethics of this practice and the equitable regulation of original equipment manufacturers and reprocessing firms.

New applications for pacing

The largest of the CRM markets, pacemakers, has been growing at a tepid 6% annual pace in the past few years, mainly reflecting a mature market for its primary applications, atrioventricular block and sinus node disease. However, several new niche applications for this technology are beginning to emerge, and CDU believes that growth in this very large device market may begin to accelerate in the next few years.

Potentially the largest market opportunity for pacemaker technology is for the treatment of congestive heart failure (CHF), a disease that occurs when the pumping power of the heart is reduced by a weakening of the heart muscle, which in turn impairs the heart's ability to fill or empty the left ventricle properly. Although CHF typically has a moderate impact on the patient's quality of life in its early stages, it has a devastating long term impact.

The patient's condition gradually but steadily deteriorates, with severe limitations on even moderate physical activity eventually leading to arrhythmic episodes, progressive pump failure and premature death; the American Heart Association (Dallas, Texas) estimates that the six-year mortality rate approaches 80% in men and 65% in women.

The Heart Failure Society of America (HFSA; Minneapolis, Minnesota) has said that heart failure currently affects nearly 5 million Americans, with an estimated 400,000 to 700,000 newly diagnosed cases per year. In addition, the HFSA estimates that the number of deaths from heart failure has more than doubled since 1979, reaching about 250,000 per year. The incidence of CHF significantly increases with age; it is the leading cause of hospital admissions for patients older than 65, and the rate of admission to treat this condition has doubled in the past decade. CHF is the primary diagnosis in about 850,000 hospital discharges per year, the primary or secondary diagnosis in roughly 2 million discharges annually and the primary cause of 30,000 to 40,000 deaths per year. According to the American Heart Association, CHF is the only cardiovascular disease that is increasing in frequency and incidence, primarily due to the aging of the population. Finally, it is estimated that CHF accounts for over 5% of the total health care dollars spent annually in the U.S.

In recent years, several pharmaceutical clinical trials have demonstrated that medical management can play a significant role in the management of CHF patients. In particular, the Randomized Aldosterone Evaluation Study (RALES) of the aldosterone-receptor blocker spironolactone (along with standard therapy), reported in the Sept. 2, 1999, issue of the New England Journal of Medicine, showed a substantial reduction in the risk of both morbidity and death among patients with severe heart failure. The metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) study, reported in the March 8, 2000, issue of the Journal of the American Medical Association, indicated that the beta-blocker metoprolol reduced hospitalizations, improved the functional class of CHF and had an overall beneficial effect on patient well-being. More recently, the August 8, 2000, issue of Circulation published an article that showed that the beta blocker carvedilol provided an even bigger benefit (in the form of greater increases in left ventricular ejection fraction) for heart failure patients than did metoprolol and could play an important role in helping early-stage CHF patients.

While this progress in the medical management arena is an important and encouraging development, tremendous progress has been made on the device side of the ledger. In particular, Guidant and Medtronic have been pressing forward with several initiatives to tackle CHF that may have a major impact on the treatment protocol for this devastating disease.

An estimated 35% of pacemaker patients have co-morbidities of bradycardia and CHF, which explains why many patients are treated with dual chamber pacers. Meanwhile, since various studies have shown that 40% to 50% of Class I or II (early stage) CHF patients succumb to a sudden cardiac death incident and thus these patients are increasingly likely to receive an ICD implant to prevent such an outcome. It is important. However, to appreciate that neither pacers nor ICDs address the underlying progression of the disease.

Cardiac re-synchronization therapy (CRT), also called biventricular pacing (BVP), is one of the most promising applications of CRM technology to CHF. CRT involves the use of pacer-like devices that aim to create left and right ventricular synchrony in patients whose heart contractions are not properly coordinated. Improved synchrony is believed likely to improve circulation and buoy the patient's quality of life. The enormity of the CHF market and financial opportunity was highlighted by the April 2000 agreement between Guidant and Cordis (Miami Lakes, Florida), a wholly owned subsidiary of Johnson & Johnson (New Brunswick, New Jersey), whereby Guidant obtained an exclusive option to evaluate emerging cardiovascular technology and patents for the treatment of heart failure from the Dutch company Impulse Dynamics NV. For this option, Guidant made an initial payment of $125 million, with the option to exclusive rights to this technology for a total payment of approximately $425 million, plus contingent payments based on future sales of covered products. The agreement between Guidant and Cordis also provided for the dismissal of the pending patent disputes between the two companies.

At last year's NASPE gathering, promising early results of the Pacing Therapy for Congestive Heart Failure (PATH-CHF) trial were reported. This trial is being conducted in Europe, with five centers in Germany and one in the Netherlands. Patients in this study demonstrated significant improvements in hemodynamic status, functional capacity and quality of life. In fact, several patients who were scheduled to receive a heart transplant were removed from the waiting list because they experienced such significant improvement in their medical condition. Further encouraging PATH-CHF results were reported at this year's meeting by Dr. Angelo Auricchio, associate professor, cardiology, and director of the cardiac catheterization lab at the University of Magdeburg (Magdeburg, Germany). Patients receiving CRT enjoyed an 18% increase in exercise capacity, as their heart rate pumping efficiency jumped 15%. Most importantly, the CRT patients enjoyed a vastly improved quality of life.

At this year's NASPE gathering, the prospects for CRT were further enhanced with the release of the Multisite Stimulation in Cardiomyopathy (MUSTIC) trial, the first randomized, controlled study investigating the benefit of multisite pacing in heart failure. This multicenter study was sponsored by the European Society of Cardiology and involves devices developed by both Medtronic and ELA Medical (Paris). In the MUSTIC trial, 58 patients with no conventional indications for pacemaker therapy were randomized into two study arms using a crossover, single-blinded design. The first arm started with BVP, the second with no BVP (biventricular pacing of 40 beats per minute). After three months, the pacing modes were switched. MUSTIC's primary endpoint was exercise tolerance as measured by six-minute walking distance. Secondary endpoints included quality of life, peak oxygen uptake and patient preference of pacing mode.

MUSTIC's results are encouraging. To wit, biventricular pacing improved exercise tolerance 23%, quality of life 30% and peak oxygen uptake 8% in chronic and severe heart failure patients with preserved sinus rhythm and major ventricular asynchrony. Investigators also found significantly fewer hospitalizations with the BVP and, although it was not designed as a mortality trial, a low six-month mortality rate of 5%.

Medtronic and Guidant, which are now marketing these devices in Europe, are engaged in a neck-and-neck race to gain the first domestic approval. The latter completed its Contak CD clinicals in late June and expects to submit its PMA filing in 1Q01. The company uses the patented EasyTrack transvenous over-the-wire lead placement system, which appears to be the most elegant manner of placing the leads that pace the ventricle. Guidant also recently commenced the Companion trial, which is a 2,000-patient, 80-center trial whose main endpoint will be the mortality rate. This three-arm trial will compare patients treated with BVP alone, BVP plus an ICD vs. standard drug therapy and is very similar to the MUSTT implantable cardioverter defibrillator trial in that it could potentially expand the patient pool suitable for implantable devices to treat CHF. Companion is expected to take at least two years to complete, followed by a one-ear follow-up period.

In the U.S., Medtronic is involved in both the North American Multi-center InSync Randomized Clinical Evaluation (MIRACLE) and Multi-center InSync Randomized Clinical Evaluation Implantable Cardioverter Defibrillator (MIRACLE ICD) trials to evaluate the safety and effectiveness of the InSync cardiac resynchronization system. The latter trial is evaluating resynchronization therapy for heart failure patients who are also indicated for a ventricular defibrillator, a study in which patients are implanted with the Medtronic InSync ICD system. Thirty-five U.S. and Canadian medical institutions have participated in this trial. The company has completed enrollment for the MIRACLE trial and will submit its PMA in 1H01. Enrollment for the MIRACLE ICD trial will be completed before year-end and a PMA also will be submitted in the first half of 2001.

St. Jude Medical recently began a European multicenter clinical trial (called the Left Ventricular Pacing in Pacemaker Patients with CHF or LV3P-CHF trial) to evaluate left ventricular-based stimulation vs. right ventricular pacing. This trial is the first study to assess whether left ventricular-based stimulation for the treatment of heart failure patients with a pacing indication has a positive impact on patients' exercise tolerance, as compared to conventional right ventricular pacing. It will involve 25 centers in eight European countries and will be a prospective, single-blind, randomized controlled study that will evaluate the typical endpoints, i.e., exercise tolerance and the quality of life. St. Jude's device for this study will be the Frontier 3x2 three-port, multi-chamber stimulation device, an innovative new approach for treating both congestive heart failure and suppressing atrial fibrillation. The Frontier device is a component of St. Jude's Genesis system, a device-based ventricular resynchronization system for the treatment of heart failure.

While the technological challenges in this evolving therapy appear to be resolved, the adoption rate remains a wild card. It is noteworthy that most CHF patients are initially managed by an internist, then later by either a general cardiologist or a CHF specialist. Neither the internist or CHF specialist is well-educated about pacemaker technology; indeed, the latter is primarily skilled in and possibly even biased toward medical management. Thus, for this market to reach significance, the CRM companies will be forced to expend substantial time and money to educate these physicians. Nevertheless, CDU estimates that the global market by 2005 could easily exceed $100 million, thus spurring growth of the overall cardiac rhythm management marketplace.