Author + information
- Stavros G. Drakos, MD, PhD∗ ()
- Division of Cardiovascular Medicine & Cardiac Mechanical Support Program, University of Utah and the Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program, Salt Lake City, Utah
- ↵∗Reprints and correspondence:
Dr. Stavros G. Drakos, Division of Cardiovascular Medicine, University of Utah, 30 North 1900 East, Room 4A100 SOM, Salt Lake City, Utah, 84132.
The field of mechanical circulatory support (MCS) has made significant progress that has been achieved over a long period of time and required tremendous efforts from various groups around the globe: from the early 1960s, when Moulopoulos and Kolff pioneered intra-aortic balloon counterpulsation (1) and Andrian Kantrowitz struggled to apply it clinically, to the early 1980s, when again Kolff’s group pioneered the first total artificial heart at the University of Utah (2). Since then, further intensive experimental and clinical research has led to the relatively recent establishment of long-term MCS as a bridge to heart transplantation. The field is now attempting to further expand MCS as lifetime therapy (so-called “destination therapy” [DT]) in patients with advanced chronic heart failure (HF).
HF is a growing epidemic around the globe, and it often progresses to its advanced stages despite current optimal medical therapies. Patients with advanced HF are considered for heart transplantation, MCS, intravenous inotropic support, or hospice. MCS has already proven effective as a bridge to heart transplantation. Furthermore, landmark randomized controlled trials have led to Food and Drug Administration (FDA) approval of the first pulsatile, and then later, continuous-flow MCS devices as lifetime DT therapy for carefully selected transplant-ineligible patients. The question arising now, a few years after the approval by the FDA of the continuous-flow HeartMate II device (Thoratec, Pleasanton, California) for DT, is whether the application of this therapy has been working as well in the real world as in the initial pivotal clinical trial (3), and consequently, whether this therapy could now be appropriately expanded further in the United States and the rest of the world, where resources might be even more limited.
In this issue of the Journal, Jorde et al. (4) used the national INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) to prospectively examine outcomes of the first 247 U.S. patients who received the HM II left ventricular assist device as lifetime therapy (DT) after the FDA approval. The investigators compared their findings to the outcomes achieved in the multicenter clinical trial cohort (n = 133) to see whether the clinical trial outcomes (3) were successfully translated into every day clinical practice. This study was one of the requirements that the FDA set when it approved the HM II left ventricular assist device for DT. Patients were enrolled from January to September 2010 at 61 U.S. centers and were followed for 2 years. Kaplan-Meier survival at 12 and 24 months for the post-approval group was 74 ± 3% and 61 ± 3%, respectively, compared with the trial’s group of 68 ± 4% and 58 ± 4% (p = NS). These survival outcomes were accompanied by early and sustained improvements in quality of life and functional status that were similar to the previously published improvements derived from the pre-approval trial data. Adverse events such as infections, strokes, bleeding, and pump replacements were either reduced or trended toward a decrease, although the adverse event burden remained highly significant. Specifically, at the 2-year follow-up, only 43% of the patients were alive and free of a serious adverse event (e.g., stroke, infection, or pump replacement). If we also add the bleeding complications (both perioperative and long-term), we can understand the current unattractive adverse event profile of this therapy in DT patients. In this context, it is particularly notable that the study was limited by the fact that the adverse events and complications data for the post-approval cohort might be underestimated, given that they were collected by treating physicians through INTERMACS and not adjudicated by a clinical events committee, as was the case in the multicenter clinical trial. Along the same lines, the investigators acknowledged the discrepancies between the reported increased hemolysis (from 3.8% in the clinical trial to 6.5% in the post-approval cohort), and that this was not accompanied by increased reporting of pump thrombosis as would be expected (the pump thrombosis rate remained the same at approximately 3.7%). This might also reflect variability between centers in clinical diagnosis and management of hemolysis and pump thrombosis. Given the recent reports that indicated increased prevalence of pump thrombosis that began approximately in 2010 to 2011 (i.e., close to the time patients were enrolled in this study), this issue warrants further investigation.
Overall, the results reported in this issue of the Journal are consistent with the outcomes summarized in the latest fifth annual INTERMACS report (5). Taking into consideration that the mean survival of advanced HF patients who receive intravenous inotropic support is only 6 months, it is easy to appreciate that the real-world use of continuous-flow left ventricular assist devices has dramatically increased the life expectancy of these patients over the last few years. This is clearly shown in Figure 8 included by Jorde et al. (4) in the discussion section of their study, which compared survival outcomes from trials and registry reports among first generation pulsatile devices, second generation continuous-flow devices, and optimal medical therapy performed over the last 15 years. However, as physicians, we should always remind ourselves that the life-saving nature of a therapy is not the only criterion that a patient considers when making this kind of decision. The majority of patients consider expected quality of life and functional capacity to be equally important as expected survival (6). In this context, 3 of the main issues that are currently being debated within the advanced HF field include the following. 1) In patients who are eligible for heart transplantation, is long-term MCS therapy ready for a head-to-head trial as an alternative to transplantation? 2) In patients with refractory HF who are ineligible for heart transplantation due to age and/or comorbidities, is MCS a safe and viable first-line, standard-of-care therapy (7)? 3) Do patients with moderately advanced HF, who are not yet ill enough to be candidates for heart transplantation, do better with long-term MCS therapy or standard medical therapy (8)? How do the results of the study reported in this issue of the Journal affect these 3 issues and how are they further integrated into clinical practice?
In regard to the first issue of a head-to-head comparison between long-term MCS and heart transplantation, the data reported by Jorde et al. (4), in combination with other available evidence, would probably support that there is not yet sufficient equipoise to perform such a trial. Although survival outcomes with long-term MCS have steadily improved over the last 15 years, these outcomes are still clearly inferior to the 1- and 2-year survival results derived from heart transplantation (Fig. 1). Longer term survival results derived from large patient populations on MCS are still pending. Some may object that the comparison depicted in Figure 1 is not completely fair, given that the patients receiving heart transplantation are usually at lower risk compared with the patients enrolled in the DT trials and DT registry reports. However, as shown in the latest INTERMACS report, the survival rates with MCS in these 2 study groups (listed for and bridged to transplant vs. DT) are not so different. Specifically, the unadjusted 1-year survival difference between MCS patients listed for and bridged to transplantation versus DT was relatively small, and after adjusting for risk factor prevalence, the difference in predicted 1-year survival was approximately 5% (5). These long-term MCS survival results, along with the MCS-related adverse event burden (which seems far more severe than the one associated with transplantation), suggest that long-term MCS using currently available devices is not ready for a direct bras de fer with heart transplantation.
The second issue of using lifetime MCS as a first-line, standard-of-care therapy in patients with refractory HF who are too ill and/or too old to be considered for heart transplantation is an issue that sparks intense debate (7). One of the main arguments criticizing such a strategy is that there is a significant overlap between risk factors for poor outcome after heart transplantation and MCS as DT. These risk factors, which are associated with significant morbidity and mortality after heart transplantation, preclude us from offering this therapy to our patients because of the high likelihood for a poor outcome, loss of the donor organ (which is a scarce resource), and at the same time, a large expenditure of money (7). For the same reasons, some argue, most of these patients should also not be offered MCS as DT because of a high likelihood of poor outcome and even larger money expenditure, which is also an increasingly scarce resource (7). In addition, important long-term MCS survival data are missing, and patient selection criteria are not well defined (7). In this context, the results of the study published in this issue of the Journal do provide further evidence derived from the post-FDA approval actual patient-care setting that further strengthens the pre-approval clinical trial data. In many transplant-ineligible patients, despite the serious adverse event burden, the mortality and quality of life with MCS as DT has significantly improved. This study did not provide much information on how to better select and manage these patients to optimize long-term outcomes and minimize serious adverse events, but the field is making slow and steady progress in these areas as well. Putting everything together, it seems that we currently have evidence supporting the notion that, for carefully selected transplant-ineligible patients, lifetime MCS is a reasonable therapeutic approach. However, these decisions are usually not straight forward and should be made with prudence by experienced clinicians within the context of multidisciplinary committees in specialized HF centers.
Regarding the third issue of optimal therapeutic strategies for moderately advanced, less ill HF patients, Jorde et al. (4) stratified survival outcomes by severity of HF, as reflected by the INTERMACS profile levels. Specifically, in the post-approval cohort, the survival at 1 and 2 years was 82% and 69% for profiles 4 to 7 (healthier) versus 72% and 60% for profiles 1 to 3 (sicker patients). The survival benefit observed in the healthier subgroup is encouraging for the ongoing National Institutes of Health sponsored trial REVIVE-IT (Randomized Evaluation of VAD Intervention Before Inotropic Therapy). This trial is testing the hypothesis that long-term MCS may improve both survival and quality of life in patients with moderately advanced HF who are neither inotrope-dependent nor exercise-intolerant, and have not yet developed serious consequences (e.g., malnourishment, end-organ damage, and immobility) (8). However, the adverse events results are not as promising. The serious adverse events following MCS in the study by Jorde et al. (4) were not stratified by severity of disease. However, this kind of analysis was done in the latest INTERMACS report, in which the rate of serious adverse events following MCS was not improved in either the less sick or younger HF patients (5).
Half a century after the first description of what proved to be the first widely applied form of MCS (1), the field is slowly making its way forward. The medical and scientific community within academia, medical centers, industry, and all of us who genuinely care for the field to make progress and fulfill its noble missions should concentrate on the major targets mentioned in Table 1 to address many of the previously described issues in the near future. HF is a global epidemic. The need is huge and immediate, and the work that remains to be done is enormous (Table 1). Given the more than 50-year-long struggles that the field has gone through and the magnitude of the clinical problem, a sense of urgency is justified. Long-term MCS, ‘destination’ therapy, and in general, ‘cardiac replacement’, as an invigorating concept that inspired early workers in the field indeed proved to be during the last half century an Odyssey. The journey will probably continue to be long, and, as in every Odyssey, we need to remember that our real ‘destination’ is nothing more than what we learn during the journey.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Drakos has received funding from the Doris Duke Foundation (Clinical Scientist Development Grant 7/2013) and the Deseret Foundation/IRMF (#00571); and is a consultant for Abiomed.
- American College of Cardiology Foundation
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