CDU Contributing Editor

The most recent statistics from the American Heart Association (AHA; Dallas, Texas) indicate that 950,000 Americans die annually as a result of a panoply of cardiovascular-related diseases. Cardiac failure is by far the most significant contributor to cardiovascular-related deaths and falls into two broad categories: 1) Acute heart failure, such as myocardial infarction or ventricular tachycardia; 2) Congestive heart failure (CHF). Whereas the former may result in sudden cardiac death (SCD), the latter is a chronic, highly debilitating and degenerative disorder.

The AHA estimates that the domestic patient pool or prevalence of CHF patients is 4.7 million, with the number of new cases diagnosed annually (incidence) growing about 10% per year or 500,000 new patients per year. Other organizations, such as the National Heart, Lung and Blood Institute (Bethesda, Maryland) and the Heart Failure Society of America (HFSA; Minneapolis, Minnesota) estimate an incidence and prevalence of similar magnitude. The incidence of CHF is clearly age-related, as it begins to dramatically increase after the age of 55 years old and affects about 10% of all patients more than 75 years old. From a health care economic standpoint, it is estimated that CHF accounts for a staggering 5% of the total health care dollars spent annually in the U.S., likely because it is the leading cause of hospital admissions for patients older than 65 years. It is the direct, primary cause of 30,000 to 40,000 deaths per year and an indirect contributor to another 250,000 deaths. The HFSA estimates that the number of deaths from heart failure has more than doubled since 1979. According to the AHA, CHF is the only cardiovascular disease that is increasing in frequency and incidence, primarily due to the aging of the population.

Congestive heart failure is a very complex disease, caused by a variety of pathophysiological factors, including coronary artery disease, hypertension, valvular heart disease, myocarditis, diabetes and alcohol abuse. These changes weaken the heart muscle, reducing the heart's pumping power and causing a decreased supply of oxygen to vital organs such as the lungs, brain and kidneys. This deficiency of adequate oxygenation results in a complex of symptoms such as fatigue, extreme weakness, dyspnea (shortness of breath), fluid retention and pain in swollen limbs. In its early stages, CHF typically has a moderate impact on the patient's quality of life. However, 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 AHA estimates that the six-year mortality rate approaches 80% in men and 65% in women.

In order to characterize the patient's condition, the medical community categorizes CHF into a functional classification system, which was developed by the New York Heart Association. This system classifies the patient into one of four groups (Table 1), relying on patients' subjective assessment of their ability to perform normal levels of physical activity.

Congestive heart failure historically has been managed mainly with pharmaceutical agents. Until about five years ago, the key pharmacologic agents used for symptomatic relief included the diuretics, vasodilators and digoxin, which essentially provide palliation, aimed at the reduction of symptoms and an improvement in the patient's quality of life. Significant, positive results from the Randomized Aldactone Evaluation Study trial, reported in the Sept. 2, 1999, issue of The New England Journal of Medicine, established that medical management could provide a substantial reduction in the risk of both morbidity and death among patients with severe heart failure. In addition, several studies of beta blockers have demonstrated a substantial benefit and reduced mortality levels after their use. Indeed, three large, randomized, placebo-controlled trials, the Carvedilol Heart Failure Trials Program, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure Study (MERIT-HF), and the Cardiac Insufficiency Bisoprolol Study II, were stopped early because of large reductions in mortality in the active-treatment arms. In a meta-analysis of 22 trials involving 10,135 patients with heart failure, 3.8 lives were saved and four hospitalizations were avoided for every 100 patients treated for one year with a beta blocker.

Another important drug trial is COPERNICUS (CarvedilOl ProspEctive RaNdomiIzed CUmulative Survival), the largest study ever conducted in patients with advanced chronic heart failure. Carvedilol is the generic name for Coreg, sold worldwide by GlaxoSmithKline (London). COPERNICUS results were published in an article in the May 31, 2001, issue of The New England Journal of Medicine. The article, titled "Effect of Carvedilol on Survival in Severe Chronic Heart Failure," and authored by the principal investigator, Milton Packer, MD, professor of medicine at Columbia University College of Physicians & Surgeons (New York), showed that the addition of carvedilol to conventional medical treatment dramatically reduced the risk of death in patients with advanced heart failure. Patients treated with carvedilol had a 35% lower risk of dying than patients treated with placebo, with a reduction in the combined risk of death and hospitalization of 24%.

Despite these impressive and important therapeutic advances with medical management, the prognosis of patients with chronic, congestive heart failure remains poor, as the benefits of drug therapy are short-lived and become refractory over time. The complexity, severity and degenerative nature of CHF explain why no one therapy is successful over the long term in arresting or reversing its progression. As the CHF progresses, the well-being and exercise tolerance of patients deteriorates dramatically and the rates of hospitalization increase. Various non-pharmacologic therapies, such as heart transplantation and the use of implantable assist devices, are considered only in the later stages of the disease, are extremely costly and have limited potential due to the dearth of natural donor hearts.

The progress in the medical management arena is heartening and clearly provides hope for improved management of CHF patients. At the same time, tremendous progress has been made on the device side of the ledger, with cardiac resynchronization therapy (CRT) emerging as the most significant new technology. The main premise of CRT is that an estimated 30% to 50% of heart failure patients suffer from intra-ventricular conduction delay and that this lack of synchrony results in inefficient pumping of blood and contributes to their CHF. CRT involves the use of pacemaker-like devices that aim to create left and right ventricular synchrony in patients who suffer from intra-ventricular conduction delay. Pacemaker management of these patients is attractive because an estimated 35% of pacemaker patients have co-morbidities of bradycardia (too slow heartbeat) and CHF, which means that many patients can gain a double benefit, improved intra-ventricular conduction and elimination of their bradycardia as well. Another important fact is that CHF patients are vulnerable to a sudden cardiac death episode. Specifically, the MERIT-HF study showed that the percentages of sudden cardiac death ranged from 33% to 64% in Class II to Class IV heart failure patients. Other studies have shown that 40% to 50% of Class I and II succumb to a SCD. Thus, most CHF patients can benefit from a device which includes an implantable cardioverter-defibrillator (ICD) that can not only resynchronize ventricular contractions but also quickly terminate an episode of ventricular tachycardia, which may be a precursor to a lethal SCD episode. It is important, however, to appreciate that neither pacers or ICDs appear to address the underlying progression of the disease.

Cardiac resynchronization was one of the hot topics at this year's annual scientific sessions of the North American Society of Pacing and Electrophysiology (NASPE; Natick, Massachusetts), held in Boston, Massachusetts, in May. Numerous abstracts, poster sessions and physician symposia were offered to participants, who were eager to glean the latest data on this rapidly emerging CRM technology. Wall Street analysts and industry competitors were equally excited about CRT, which is not surprising, given that CRT represents a potentially large market for the cardiac rhythm management industry. The size of the market has been hotly debated by industry pundits, but one thing is clear, the potential market is huge, dwarfing nearly every medical device market today. Table 2 (click here) provides details of the potential opportunity as described by one well-regarded investment banking firm. This model assumes that between 15% and 20% of all congestive heart failure patients could qualify as candidates for CHF devices based on an NYHA functional class of either III or IV, that these patients have a QRS duration of more than 130 milliseconds and an ejection fraction below 35%. What is most important to realize is that the incremental growth derived from CHF market opportunity will buoy the growth rate for the relatively mature $3.0 billion global pacemaker market and the slowing momentum of the $1.8 billion global ICD market.

It is certainly not surprising that cardiac rhythm management industry leaders Medtronic (Minneapolis, Minneapolis) and Guidant (Indianapolis, Indiana), who together dominate the industry with a market share of nearly 75%, have been leading the charge. According to a talk given at NASPE by Dr. Leslie Saxon, MD, associate professor of medicine and director of implanted device services at the University of California, San Francisco (San Francisco, California), more than 2,500 patients have been enrolled in CRT clinical trials in the U.S. alone, with the lion's share of these trials being conducted under the auspices of these two leaders. Saxon also noted that about 15 clinical trials worldwide have addressed the use of pacing to treat CHF. Both companies are pursuing a variety of clinical studies both here and abroad. Details of the regulatory and clinical status of these two market leaders, as well as other key competitors, is provided in Table 3(click here).

The key cardiac resynchronization clinical trials, which include PATH-CHF, MIRACLE and MUSTIC, have firmly established that this therapy is both safe and effective. In fact, in some cases the benefits have been dramatic, with several patients who were scheduled to receive a heart transplant removed from the waiting list because they experienced such significant improvement in their medical condition. In early July, the FDA's Circulatory Systems Device Panel gave Medtronic's InSync cardiac resynchronization system unanimous recommendation for approval, based on the Multi-center InSync Randomized Clinical Evaluation (MIRACLE) trial results. Final FDA approval is likely before year-end.

Results from the MIRACLE trial showed that exercise capacity (measured by an increase in six-minute hall walk distance and an increase in exercise time), New York Heart Association functional class, quality of life (measured by the Minnesota Living With Heart Failure Questionnaire) and the number of days hospitalized were all substantially improved. In addition, other key measures of improved cardiac performance, such as increased peak oxygen consumption, increased left ventricular ejection fraction, reduction in severity of mitral regurgitation and reduction in QRS duration were observed. The MIRACLE study also measured changes in a composite response that takes into account the key factors such as patient survival, hospitalizations for heart failure, the patient's own assessment of their heart failure status, changes in NYHA class and other characteristics. Fully 63% of the patients receiving cardiac resynchronization therapy showed improvement as measured by this composite response, compared to 38% in the control group.

In addition to the MIRACLE trial, Medtronic has been involved in the Multi-center InSync Randomized Clinical Evaluation Implantable Cardioverter Defibrillator (MIRACLE ICD) trial to evaluate the safety and effectiveness of the InSync cardiac resynchronization system for heart failure patients who are also indicated for a ventricular defibrillator. Enrollment for the MIRACLE ICD trial, in which patients are implanted with the InSync ICD system, was completed in late 2000, and a premarket approval application was recently submitted. The timing of a final FDA approval will depend on whether a Circulatory Systems Device Panel meeting will be required by the FDA. That issue is unclear at the time of this writing.

Whereas Medtronic fared very well at last month's Circulatory Systems Device Panel meeting, Guidant suffered a bitter setback, as the panel recommended against approval for its Contak CD, a combination biventricular pacer and ICD device. Although this device clearly provided significant patient benefits (improvements in six-minute walk distance, an increase in peak oxygen consumption and a reduction of the NYHA class in a majority of the patients), the study failed to attain its primary endpoint, showing a lower-than-expected reduction of 21% in the composite CHF and ventricular arrhythmia symptom score, and not reaching the pre-trial statistical significance of a 25% reduction.

Guidant is obviously eager to overcome these issues and after a post-panel meeting with the FDA, it indicated that the data and analysis can be quickly provided to address the needs of the FDA and the advisory panel. In a mid-July conference call discussing its second-quarter results, Guidant CEO Ron Dollens indicated that additional analysis of the Contak CD trial data appears to support the efficacy of the product in CHF. The company was scheduled to meet with the FDA and discuss that data in greater detail.

Guidant also is involved in the Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure (COMPANION) trial, which is the first controlled study to evaluate the effects of cardiac resynchronization on both mortality and hospitalization rates. This three-armed trial will enroll on up to 2,200 patients at up to 120 U.S. centers and is designed to compare drug therapy alone or drug therapy along with either the Contak CD system or Contak TR system. The latter system provides cardiac resynchronization therapy without backup defibrillation therapy. As of mid-July, nearly 1000 patients have been enrolled in the COMPANION trial. A PMA could be submitted in the second half of 2001. Interestingly, the COMPANION study includes a 400-patient sub-study which looks at functional capacity in a similar fashion to the Contak CD. These data could be used to show appropriate efficacy and enable the company to gain far more rapid approval than by initiating a new CRT trial.