A completed paradigm shift for VADS in advanced HF: The INTERMACS registry at 5 years

A paradigm is an example or pattern, and as Thomas Kuhn noted in his 1962 text, The Structure of Scientific Revolutions, “… once a paradigm shift is complete, a scientist cannot, for example, posit the possibility that a miasma causes disease or that ether carries light.”

A paradigm shift, then, is an “extraordinary” or “revolutionary” new science. It is rare to witness a significant paradigm shift in medicine, particularly one that occurs so rapidly and carries with it substantial long-term implications, but the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) has done just that.

James B. Young

INTERMACS has just completed its first 5-year funding cycle from the NIH and is the largest multicenter scientific compendium of FDA-approved long-term circulatory assist devices implanted in patients with advanced HF. It has been under the capable leadership at the University of Alabama, Birmingham, with its extraordinary team in the INTERMACS Data Coordinating Center. Lynne Warner Stevenson, MD, of Brigham and Women’s Hospital, Harvard Medical School, and Robert Kormos, MD, of the University of Pittsburgh, are co-principal investigators.

INTERMACS was created to gain insight into what has recently been a rapidly advancing field. Indeed, it was just more than a half century ago that Kolf, for the first time, successfully kept a dog alive with an implanted total artificial heart. In 1966, DeBakey successfully “bridged” a patient to “recovery” with a pulsatile, pneumatic, paracorporeal left ventricular assist device manufactured in his surgical laboratory. Cooley, a few years later, became the first to use these types of devices as a “bridge to heart transplantation.” Progress in this remarkable field was stuttering at best, however, until more widespread reports of successes using these pumps came available in the 1990s.

Today, use of mechanical circulatory support devices has become common. Indeed, it is a daily event in CV surgery centers when one counts rudimentary cardiopulmonary bypass machines necessary for stopped or arrested open-heart operations. Longer-term and more “complete” implantation of these devices has achieved dramatic recent milestones.

As exciting as these innovative machines are, they can at times cause significant morbidity and even mortality, particularly in the severely ill, the cachectic and elderly patients who have non-cardiac comorbidities, besides terminal HF. In the now close-eyed accounting of health care resources, the justification for this new technology must include proof of extension not only of survival, but also of improved quality of that survival.

Because of the challenges of studying mechanical circulatory support device (MCSD) implantation in large-scale randomized clinical trials, a practical option for obtaining representative results is the large-scale clinical registry. Most registries, however, have been sponsored by industries interested in the application of and outcomes for a single product line (with incentives that can influence how the data are collected, defined and managed). Thus, registries have often been deservedly criticized for not being sufficiently rigorous to adequately collect and evaluate clinical data.

INTERMACS was carefully designed and implemented to obviate many of these problems and present data in an impartial and appropriately analyzed fashion. Another unique aspect of INTERMACS is the tri-partite nature of the program, with the FDA and CMS partnering with the NIH to offer different perspectives about the data.

INTERMACS patient profiles

Besides determining what endpoints were important to study, designing the Web-based data collection templates, and defining (as well as standardizing) adverse events, an early task was to develop a patient descriptor that had not been previously utilized but that would also better characterize the patient population being studied. A descriptive categorization (or “profile”) of patients was developed, rather than a progressive staging system such as the NYHA functional classification. The INTERMACS patient profiles include seven categorizations, with five of them characterizing patients who are clearly NYHA Class IV. These profiles create a far better description of patients than simply referring to one as “American College of Cardiology (ACC)/American Heart Association (AHA) Stage D, NYHA Class IV despite optimal medical therapy.”

The INTERMACS profiles incorporate both the severity of symptoms and the trajectory of decline over time. They also include commonly used jargon. Profile 1 describes a “critical cardiogenic shock” patient who is “crashing and burning,” in which a patient has life-threatening hypotension and rapid escalating IV inotropic support. Profile 2 describes “progressive decline” or “sliding fast on inotropes,” and is a patient who has been documented “dependent” on IV inotropic agents but who nonetheless shows signs of continuous deterioration. Profile 3, “stable but inotrope-dependent,” describes a patient who is clinically stable on mild-moderate doses of an IV inotrope (or has temporary MCSD) and has had repeated attempts at weaning with documented failures. Profile 4 is a patient with “resting symptoms” who can remain at home on oral therapy, but who has symptoms of congestion at rest or with minimal activities of daily living. Profile 5, which describes a patient as “exertion-intolerant” and “housebound,” is someone comfortable at rest but unable to engage in any meaningful activity (who is consequently largely confined to their home). Profile 6, known as “exertion-limited” or “walking wounded,” describes a patient comfortable at rest without evidence of fluid overload who is able to do some activity. Profile 7 characterizes “advanced NYHA III” patients who are clinically stable with a reasonable level of comfortable activity, despite a history of previous congestion that is not recent.

Slow but steady patient accrual

Currently, there are 109 centers actively participating INTERMACS and almost 3,500 patients logged into the registry. It should be noted that for centers to comply with CMS and to be reimbursed when a device is placed as a “destination home-permanent” therapy, they must be a participant in good standing with INTERMACS and report their data responsibly. An early analysis of INTERMACS revealed a slow but steady patient accrual that significantly increased when the HeartMate II (Thoratec) continuous flow device was approved by the FDA mid-year 2008 as a bridge to cardiac transplantation. This rather dramatic change in the number of patients undergoing MCSD implantation appeared constant and was likely driven by the fact that the newer device was a dramatic improvement over previous pulsatile MCSD choices. This was the beginning of the paradigm shift. Whereas most funding, development efforts and patient experience had previously focused on pulsatile devices, the science (and then clinical approach) to the patient changed.

Outcomes after MCSD implantation

INTERMACS demonstrates that survival after MCSD insertion using contemporary pumps is reasonable and steadily improving with incremental advances in the devices. As one may expect, improved outcomes were noted with intracorporeal continuous flow systems that were used as an LVAD. One competing outcomes analysis demonstrated that at 6-months follow-up, the likelihood of survival or heart transplant was higher with continuous flow devices than with pulsatile machines (88% vs. 80%). Still unknown is whether this difference will hold up with longer-term follow-up.

Another important observation that can be made is that removal of these devices due to “adequate recovery of myocardial function” that is believed adequate enough to handle the entire burden of circulatory demand (also called “bridge-to-recovery”) is rare, occurring in about 1% of patients. This observation emphasizes that the concept still needs tremendous work to clarify, if there is any reality to the concept to begin with.

Not surprising is the fact that there appears to be a significant difference in the outcomes of patients based on entrance profile when overall survival is analyzed. Profile 1 patients (the “crash and burning” group with critical cardiogenic shock) have higher mortality than the stable patient defined simply as “inotrope-dependent,” or Profile 3. This is an important observation and suggests that, if possible, it is likely best to move earlier on some patients rather than waiting until they are in dire straits.

Summary

INTERMACS is an example of a successful NIH-funded, interagency-supported registry that has chronicled, analyzed and contributed to the clinical, scientific and academic medical niche of mechanical circulatory assistance for deathly ill patients with advanced HF. Particularly important is the fact that INTERMACS has documented a shift in the approach to these patients with overwhelming use of continuous flow mechanical circulatory support systems occurring today. With the recent NIH request for proposals for a 5-year extension of the registry contract, even more data and knowledge will accrue that may drive more paradigm shifts in the future. The public can explore the nuances of this registry further by reviewing the INTERMACS website here.

For more information:

• Holman W. J Am Coll Surg. 2009;28:755-761.
• Kirklin J. Circ Heart Fail. 2008;1:200-5.
• Kirklin J. ISHLT Monograph Series Volume 4: History of International Heart and Lung Transplantation. Philadelphia: Elsevier; 2010.
• Kirklin J. J Heart Lung Transplant. 2008;27:1065-1072.
• Kirklin J. J Heart Lung Transplant. 2010;29:1-10.
• Warner-Stevenson L. J Heart Lung Transplant. 2009;28:535-541.