INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support): A New Paradigm for Translating Registry Data Into Clinical Practice

• Centers for Medicare and Medicaid Services
• Food and Drug Administration
• National Heart, Lung, and Blood Institute
• heart failure
• mechanical circulatory support
• randomized clinical trial
• registry
• transplant
• ventricular assist device

The National Institutes of Health supports research that informs clinical practice. To do this effectively, it employs a variety of approaches to gather and disseminate information on the safety and efficacy of medical interventions. The accepted gold standard for generation of rigorous clinical evidence is the randomized clinical trial. Randomized clinical trials (RCTs), however, have drawbacks; they are generally expensive, have a long duration, are focused on a selected patient population, and their findings may be obsolete by the time the results are published. For some clinical research, a more practical option is the large clinical registry. Consequently, the National Heart, Lung, and Blood Institute (NHLBI) supports both approaches in its clinical research programs directed at the prevention and treatment of cardiovascular, lung, blood, and sleep disorders. However, although a clinical registry is not a randomized clinical trial, it shares the same goal: to translate efficiently and effectively rigorous clinical knowledge into improved care and clinical outcomes for patients and public health. The capability of registries to reach this goal is evident in the products and outcomes of an NHLBI-supported registry for patients with mechanical circulatory support devices. This registry, which is described below, demonstrates its value and effectiveness by how it speeds the practical adoption of evidence into clinical practice, provides a means for post-market surveillance of devices, and supports research on comparative effectiveness, clinical care, and patient management involving mechanical circulatory support therapy.

Since the National Institutes of Health's artificial heart program was established in 1964, the NHLBI has funded a series of grants and contracts to develop mechanical circulatory support (MCS) devices, to improve related technology, and to conduct clinical trials involving the devices. A growing number of Food and Drug Administration (FDA)-approved MCS devices have emerged that provide useful clinical therapies for late and end-stage heart failure patients (1). During this period, NHLBI has also funded other basic, translational, and clinical research on heart failure and MCS, including circulatory support strategies for children (2).

The purpose of MCS devices is to augment or supplant failing myocardial performance (3,4). These devices can be used to provide necessary circulatory support until a donor heart is available for transplantation or until a patient's heart sufficiently recovers. In these cases, the device is referred to as a bridge-to-transplant or a bridge-to-recovery, respectively. For chronic, severe heart failure patients who are not eligible for heart transplantation and have little chance of recovery, MCS devices are used as permanent implants, otherwise known as destination therapy. The benefit of destination therapy was first demonstrated in the NHLBI-sponsored REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) trial, conducted from 1998 through 2001. The trial results clearly demonstrated a clinically meaningful survival benefit and an improved quality of life with ventricular assist device therapy in end-stage heart failure patients as compared with those receiving optimal medical management (5). Despite the benefits, the mortality and adverse events associated with device use in the REMATCH trial highlighted the need to understand the implications of the therapy for the intended patient population and to monitor device performance and clinical outcomes closely over time. As device technology evolves, improvements are expected to reduce the risk of adverse events and to improve quality of life in these patients and enhance the potential for recovery in others (6,7).

Because of the nature of MCS devices and the desire to improve outcomes, a registry for patients who receive MCS devices is well justified. The need for such a registry was envisioned almost 2 decades ago when the Institute of Medicine (IOM) recommended that NHLBI maintain a registry of MCS device recipients as a “routine aspect of this care” (8). The IOM recognized this need based on patients' dependence on the devices and the uncertainty of the long-term benefits and drawbacks. The immediate need for such a registry was realized in 2003 by the Centers for Medicare and Medicaid Services (CMS). At that time, in their decision to cover destination therapy, the CMS required that any patient who received a ventricular assist device as destination therapy should be entered into a nationally audited registry.

With the clear and publically disclosed need for a MCS device registry, NHLBI issued a Request for Proposals in 2004 for an Interagency Registry of Mechanical Circulatory Support for End-Stage Heart Failure. The overall expectation of the registry was that it would help to advance the understanding and application of MCS to improve the mortality, morbidity, and health status in patients with advanced heart failure. The result of the solicitation was a competitive contract awarded in May 2005 to the University of Alabama at Birmingham (9) to establish and manage what has become known as the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). Since the registry's launch in June 2006, INTERMACS has become the national registry of patients receiving FDA-approved durable MCS devices to treat advanced heart failure. Specific objectives of INTERMACS include: 1) collecting and disseminating quality data that help to improve patient selection and clinical management of patients receiving MCS devices; 2) advancing the development and regulation of existing and next-generation devices; and 3) enabling research into heart failure and recovery (9,10). As of January 1, 2010, INTERMACS had more than 100 participating hospitals, more than 2,000 patients entered into the registry, and more than 90% data reporting and completeness of forms (11).

INTERMACS resulted from the cooperative efforts of MCS clinicians, scientists, manufacturers, and federal partners. The 3 federal partners involved are: 1) the NHLBI, which funds and oversees the registry; 2) the FDA, which regulates MCS devices; and 3) the CMS, which reimburses for MCS device use. The stake holders worked cooperatively to develop standard definitions, data elements, and data collection time points through an iterative process over the first year of the contract. These processes and standards were necessary to assure accurate, timely, and comprehensive data collection, which began in June 2006. As a result, INTERMACS has become a rigorous tool that is well positioned to help develop guidelines and improve clinical practice, because it incorporates many elements of RCTs. Examples include: 1) well-defined inclusion and exclusion criteria; 2) precise adverse event definitions; 3) complete data collection and follow-up; 4) adjudication of outcomes and events; 5) planned statistical analyses; 6) training for investigators and coordinators; and 7) committee oversight, such as that by the Observational Study Monitoring Board established by the NHLBI.

Because INTERMACS is a registry, it can facilitate the translation of evidence into clinical practice more quickly than RCTs can (12). Although RCTs have the benefit of an experimental design, they are restricted by the initial inclusion and exclusion criteria, definitions, and available therapies. They are also often difficult to begin and manage, long in duration, and focused on a highly selected patient population that may not reflect clinicians' daily practice. Dissemination of data and findings from an RCT also are usually constrained until well after the trial is completed. Registries like INTERMACS are much more flexible and allow for more timely data dissemination. Reports generated from the analyzed audited INTERMACS data are provided to the collaborating clinical sites, federal partners, industry collaborators, and principal investigators on a quarterly basis. Site-specific data are used by participating hospitals to meet joint commission hospital compliance quality reporting requirements and to drive improvements in hospital performance. Device-related serious adverse events now also are reported directly to the FDA by INTERMACS. This, in turn, has obviated the need for participating hospitals to report device-related events, has expedited receipt by the FDA, and has helped to fulfill the FDA requirements for reporting of these data.

The rapid dissemination of data from INTERMACS has facilitated the recognition of real-time trends in medical practice that involve MCS. For example, during the first 3 years of data collection, INTERMACS documented important trends in device characteristics and use and in patient outcomes (13,14). When the registry was launched, the vast majority of devices being implanted were large, positive-displacement, pulsatile devices developed in the 1970s and 1980s, such as the Heartmate XVE (Thoratec Corp., Pleasanton, California) and NovaCor PC (World Heart Corp., Oakland, California). INTERMACS captured the trend toward implantation of smaller continuous flow pumps developed in the 1990s and early 2000s and recently approved by the FDA (Table 1).In addition, INTERMACS has shown that the therapeutic goals articulated at the time of implantation of durable pumps can evolve (15). Instead of a strict differentiation between device implantation as either a bridge-to-transplant or destination therapy, the data suggest that some destination therapy patients, who initially were determined to be unsuitable for transplantation, may resolve physiologic or psychosocial barriers while receiving MCS and may become suitable for transplantation. Similarly, in patients treated with a bridge-to-transplant strategy, conditions or complications may develop that make transplantation an unsuitable option (16).

INTERMACS also has been designed to stratify patients that MCS therapy targets by defining subsets within the New York Heart Association functional class III and IV categories. These have been termed INTERMACS patient profilesand include: profile 1, Critical Cardiogenic Shock; profile 2, Progressive Decline on Inotropic Support; profile 3, Stable but Inotrope Dependent; profile 4, Resting Symptoms Home on Oral Therapy; and profiles 5, 6, and 7, Continuum of Class IV Patients with Restricted Activity and with Little Fluid Overload (17). After the first year of collection, INTERMACS data have revealed that almost 42% of patients receiving devices are in the highest severity profile. Over the last 2 years, the registry has documented a decrease in the proportion of profile 1 patients to 28%, with a shift toward profiles 2 through 7. INTERMACS also has documented that profiles 1 and 2 account for a high proportion of the early mortality. Thus, INTERMACS has been able to document a significant change in practice during a short period, as clinicians now seek to improve the clinical status to better profiles before implantation (18).

INTERMACS demonstrates how a well-designed registry can facilitate the adoption of evidence into clinical practice. The vision beyond INTERMACS is for the registry to become a definitive resource to inform patient selection, to advance scientific investigation and device development, to guide clinical practice, to contribute to the advancement of a technology, and ultimately to improve the treatment of advanced heart failure. On a larger scale, INTERMACS may serve as a model for developing and using registries more commonly to facilitate, improve, and accelerate the adoption of other therapies.

• Received March 5, 2010.
• Revision received May 14, 2010.
• Accepted May 17, 2010.

• American College of Cardiology Foundation