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The World of Mechanical Circulatory Support after the FDA Approval of HeartWare: Is Competition the Answer to All Our Questions?


MATTHIAS LOEBE, MD, PhD, FACC, FCCP
ERIK E SUAREZ, MD
ARVIND BHIMARAJ, MD, MPH, FACC
Methodist DeBakey Heart & Vascular Center
The Methodist Hospital, Houston, Texas, USA
mloebe@tmhs.org


Humans compete usually for food and mates, though when these needs are met deep rivalries often arise over the pursuit of wealth, prestige, and fame. Competition is also a major tenet in market economy and business is often associated with competition as most companies are in competition with at least one other firm over the same group of customers.
—WIKIPEDIA, Definition of competition

There are two kinds of people, those who do the work and those who take the credit. Try to be in the first group; there is less competition there.
—Indira Gandhi

Competition has been shown to be useful up to a certain point and no further, but cooperation, which is the thing we must strive for today, begins where competition leaves off.
—Franklin D. Roosevelt


Mechanical circulatory support to help the failing heart has been around since the early 1960s. First used as post-cardiotomy support bridging patients to myocardial recovery (1), it was used as early as 1968 as a bridge to transplant (2). At the time, physicians were generally proponents of either transplantation or mechanical support devices. Few remember the bitter arguments between advocates of heart transplantation and advocates of mechanical circulatory support in those days (3). When heart transplantation re-entered the clinical arena in the late 1980s and early 1990s, the concept of mechanical support as a bridge to heart transplantation was revived. Some significant success was obtained with the use of pulsatile left ventricular assist devices (LVADs) and the REMATCH trial rekindled interest in the use of LVADs for destination therapy (4). However, device-related complications were significant and the long-term benefits with 1st generation LVADs were very limited. Thus, LVAD support remained a niche indication.

The implementation of 2nd generation, continuous flow pumps as long-term support in end-stage heart failure led to a dramatic change in the scope of mechanical circulatory support. When the first continuous flow pump for long-term support was implanted into a patient in Berlin in 1998, the doors were opened for an expansion of LVAD use (5). Since then, the numbers of patients supported by LVADs and the length of support duration have constantly increased. When the first continuous flow pump was tested in a randomized fashion against 1st generation LVADs, vast differences in performance and reliability were reported (6).

More recently, the first completed study of 3rd generation devices shows non-inferiority to 2nd generation devices (7). This clearly indicates that when 3rd generation devices become commercially available, one should not expect a game changing event similar to the explosion of LVAD use after implementation of 2nd generation devices. Still, as the devices we use today are far from perfect, one can hope and expect that having a new pump on the market will add some significant potential to our armamentarium. But realistically, what is the impact of such a new device becoming available?

Clinical Outcomes
If one looks at the performance parameters reported in the FDA trial, there is little if any difference between the 2nd and 3rd generation devices (7). However, the report does not indicate the incidence of adverse events in the control group, which is composed of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) data derived from concomitant LVAD implants. We know that the patient demographics are similar and that the control patients, having lower INTERMACS classes, seem to be sicker. It has also been pointed out that the risk of pump stoppage and pump thrombosis was somewhat higher with the 3rd generation HeartWare HVAD (HeartWare International, Framingham, MA) than in comparable reports for HeartMate II (Thoratec, Pleasanton, CA). Whether this is due to pump design-specific issues is unclear. It would, however, corroborate observations that pump thrombosis was not infrequent in the Ventracor trial, another 3rd generation device that did not progress to FDA approval due to financial collapse of the company. In the Ventracor experience, cable breakage, stroke, and pump thrombosis were not infrequent. It seems that the 3rd generation centrifugal pumps need higher levels of anticoagulation and are not as forgiving when anticoagulation is interrupted as the high RPM, axial flow, 2nd generation pumps (8-12); although an increased incidence of pump stoppage has been recently observed in the HeartMate II population as well. Some centers report up to 15-20% pump malfunction rates (personal communication), though the origin of this problem remains unclear. One might suspect subtle changes in pump production or in the management of patients on LVAD support. Unfortunately, a scientific, head-to-head comparison of 2nd and 3rd generation devices is still lacking.

Given the sensitivity of the device/patient system as a whole, this illustrates that one must be cautious in attributing differences between patient populations, such as in the HeartWare trial, to basic design principles. It remains unclear whether centrifugal pump design or magnetic levitation substantially improves the outcomes in clinical application of mechanical circulatory support.

Some have pointed out an increased incidence of right heart failure with the newer pumps (8,13). Again, it appears very questionable whether this phenomenon is rooted in the device design. One can only speculate that the smaller 3rd generation device does not provide as much support as the 2nd generation LVAD, leading to higher end diastolic filling pressure and less afterload reduction for the right ventricle. A smaller outflow graft may be responsible for a somewhat higher sensitivity to afterload increases for pump performance. However, both statements are, at this point, pure speculations that are not supported by clinical studies or bench testing. On the contrary, many feel, for the various reasons described below, that the technical advantages of the HeartWare device implant procedure will make it a preferred device.

Technical Considerations - Does size matter?
The 3rd generation device is smaller and can be implanted inside the pericardium. The smaller device may be more suitable for smaller patients, and preliminary experiences with pediatric and adolescent patients supported with the HeartWare LVAD are available (14-16). In addition, the snap connection at the left ventricular apical ring is a clear advantage. The device may lend itself more to a minimally invasive, off-pump approach for implantation (17). Not requiring a pump pocket also sounds like a significant advantage for 3rd generation devices; however, there seems to be no palpable disadvantage to having a pump pocket in 2nd generation devices. The feared pocket infections, a common reason for morbidity and mortality in first generation devices, are basically unheard of in the use of HeartMate II LVADs (18). Furthermore, the time it takes to create the pocket is of no significance. But can the pocket lead to issues in the geometry of the inflow cannula over time? Some have suggested that this is the case and we tend to agree: an intra-pericardial position could be of advantage. However, even with the pump sitting inside the pericardium, some believe that with an apical position, changes in chest geometry over time may affect pump function. As a result, implantation on the inferior surface of the left ventricle has been recommended (19).

Expanding the Realm beyond Approved Indications
A clear advantage of the newer pump design is their ability to be used for bi-ventricular support. Quite substantial experience has been published from Europe in this regard (13,20-22). However, due to regulatory constraints, this configuration has only been used in exceptional cases in the US (23,24). Obviously, a device that allows bi-ventricular support after simple, easy implantation would be a true extension of the surgical armamentarium. One could leave the native heart in the chest, start with left-sided support, and add a right-sided device when needed. The European experience shows the benefits of such an approach. One may also desire the more user-friendly external setup so that patients do not have to deal with multiple controllers and batteries (25).

Long-term Impacts
Everyone will agree that the future of LVAD therapy lays in the destination therapy application. At this point, however, FDA approval restricts the 3rd generation pump to use as bridge to heart transplantation. Not much is known about the long-term reliability of 3rd generation pumps. While more than 10,000 patients have received 2nd generation LVADs and some have lived for more than 7 years, the reported European experience with the 3rd generation pumps for long-term use is sketchy at best.

International Comparison
In Europe, 3rd generation pumps are widely used and seem to have close to a 50% market share in implants (26). Although reliable numbers are not available, with 2,500 implants worldwide and less than 150 in the US, HeartWare HVADs must have been used in more than 2,000 patients in Europe. Today, several single center retrospective observational reports from Europe offer some insight into the experience there. However, in contrast to the INTERMACS database, which reflects all implants in the US, no such in depth report exists from Europe making it impossible to value their isolated experiences with 3rd generation devices (27-31).

Game Changers in LVAD Therapy
In our opinion, the true game changing development today is the broad collection of data on LVAD patients in the INTERMACS database. The objective and detailed information available from INTERMACS and the conclusions derived from these observations have already started to transform the field of LVAD support (31). In a very short period of time, we will be able to answer many of the open questions that single-center experiences could not address.

Advantages of Free Market and Competition
In the end, a question remains as to whether competition will have a significant impact on our field. Of course competition is beneficial, even if the two products now FDA-approved for use as bridge to heart transplantation seem to have few discriminating features. Having options has helped to bring down the cost of mechanical heart valves and many other products in medicine. In addition, competition may prevent the field of mechanical support from being dominated by one company. One may expect that the end of a factual monopoly will be a good thing, but even this is hard to predict. As long as mechanical circulatory support remains a niche indication with fewer than 4,000 implants per year, none of the manufacturers will be able to produce large numbers of pumps - the only way to lower the sales price. It is likely that LVAD therapy will exit this niche position, although it will take quite some time before there are large numbers of device implants (32,33).

In addition to the above mentioned INTERMACS experience, a multitude of observations on LVAD support using 2nd generation devices have been and will be published. A search of PubMed yields 72 publications on HeartWare; not surprisingly, HeartMate exceeds this number with 261 publications. Again, in our opinion, these observations about LVADs will help us to advance the field as an evidence-based therapy. The implementation of a new and different device may add some interesting aspects to this.

We think everybody will agree that Thoratec, as virtually the sole player in the US market, has been quite responsible in understanding and supporting the needs of this therapy outside of the immediate sales function. Thoratec has supported education, outreach, and research in the application of mechanical support in the US more than any other manufacturer in the medical field. Increased competition may force them to reduce their role in paving the way for awareness and growth in the field of mechanical support for heart failure. Those obligations will then fall back under the responsibility of physicians and medical societies. Personally, we have no doubt that cooperative efforts like INTERMACS will have a much more profound impact on our field than the implementation of 3rd generation assist devices. Learning from our combined experience, improving patient selection, identification and management of complications of this therapy, and developing strategies to provide safe and effective continuing care for patients on devices will have enormous influence on the development of the field.

The next revolutionary step forward will be the advent of circulatory support devices that can be implanted and will continue to function long term without any procedure-related morbidity. Only then will family practitioners and general cardiologists embrace the concept of mechanical support and the hundreds of thousands of patients suffering from advanced heart failure will be deemed suitable candidates for device implantation.

Conclusion
Having a new kid on the block certainly expands the possibilities of mechanical circulatory support. Innovation is always good; stopping where we are can never be enough. However, as we have established LVAD therapy as a valuable option in end-stage heart disease supported by ample evidence and reproducible outcomes, technical innovation has to show positive advancements in solid clinical studies. The 3rd generation devices have some intriguing features that promise serious benefits. Having more choices as implanters is beneficial; being able to explore less invasive implant techniques is intriguing. Nevertheless, as LVADs are used more and more as long-term devices, additional solid data on the long-term reliability of 3rd generation LVADs is desired. The new kid on the block has to be measured by the rather high standards achieved in recent years in the field of mechanical support. The careful study of our combined experience in using LVADs with lessons derived in patient selection, management, surgery, and long-term care will continue to have a defining impact on how this type of care is delivered in the coming years. While competition amongst the industry may help, cooperation between the medical professionals using the technology will be crucial for the widespread acceptance of a very promising therapy.



Disclosure Statements: Dr. Matthias Loebe reports receiving consulting fees from Thoratec and HeartWare. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of this submitted article or other conflicts of interest to disclose.


Dr. Loebe is Chief of the Division of Transplant and Assist Devices in the Department of Cardiovascular Surgery at Methodist DeBakey Heart & Vascular Center, and Director of Thoracic Transplantation at the J. C. Walter Jr. Transplant Center, The Methodist Hospital, Houston, Texas, USA.

Dr. Suarez is a Cardiovascular Surgeon with the Methodist DeBakey Heart & Vascular Center, Houston, Texas, USA.

Dr. Bhimaraj is a Cardiologist with the Methodist DeBakey Heart & Vascular Center, Houston, Texas, USA.


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