In a properly automated and educated world, then, machines may prove to be the true humanizing influence. It may be that machines will do the work that makes life possible and that human beings will do all the other things that make life pleasant and worthwhile. -ISAAC ASIMOV
The term Cyborg, short for cybernetic organism, was first coined by Manfred Clynes and Nathan Kline in a 1960 article entitled Cyborgs and Space(1). In this article Clynes and Kline suggest that for prolonged space travel to be possible it is more logical to alter man to meet the requirements of an extraterrestrial environment than to attempt to provide an earthly environment in space. Slowly gaining fame and recognition, the Cyborg Foundation was finally founded in 2010 by Cyborg activists Neil Harbisson and Moon Ribas with the simple mission to help humans become cyborgs, to promote the use of cybernetics as part of the human body and (of course) to defend cyborg rights(2). In modern medicine the Man-Machine interface is now a reality in the form of Mechanical Circulatory Support (MCS) devices, more commonly known as ventricular assist devices (VADs). Though the average LVAD patient is in no way similar to the marching hoards of Cybermen, as depicted in Dr. Who, or the unstoppable chiseled T800 from the Terminator series, they are in their own right miracles of modern medicine. Constructed using a small centrifugal pump and inlet and outlet flow grafts, these devices in their various iterations have proven they are capable of extending and improving the lives of patients in severe heart failure. Since their initial approval in 2001, the use of LVADs has steadily grown. Originally intended for patients who were not candidates for transplants, they soon provided a bridge to transplant in patients waiting for a donor. Safer, smaller, more durable devices were built with more compact battery packs to encourage a more “active lifestyle”. This public success hit its first obstacle in November 2013 with the publication of the NEJM article warning us of the alarming increase in pump thrombosis in the current model of ventricular assist devices.
In what is essentially a phase IV post-marketing trial, Starling et al published the findings from three major LVAD centers(3). Using data extracted from each institute's respective registries, the authors examined the results of every device inserted at these three centers from January 2004 to May 2013. Patients' baseline characteristics, LDH levels and outcome measures were all recorded. Confirmed pump thrombosis was defined as a thrombus found on the blood-contacting surfaces of the HeartMate II, its inflow cannula, or its outflow conduit at pump replacement, urgent transplantation, or autopsy. The authors found an alarming increase in the rate of pump thrombosis beginning in 2011. The increase was seen across all three sites and could not be isolated to individual treatment protocols or a specific surgical technique. In a postscript of the article. the authors describe an additional 150 VADs implanted at the University of Pennsylvania from 2004 to 2013. Though these devices were not included in the official data set, they too observed an alarming rise in the rate of pump thrombosis after 2011, further demonstrating this is not a site specific phenomenon. Even the national registry, the INTERMACS database, confirmed a similar trend in the rate of thrombosis since 2011 with a 6 month incidence of 5%(4). According to Starling's data what once was a rate of 2% thrombosis in a 12-month period, ballooned to close to 8% after 2011. The majority of this increased risk is seen within the first 30 days (1.4%) with a gradual decrease over the initial 6 months and finally plateauing at a much smaller but still elevated risk of 0.4% per month.
It is important to remember that the evidence for the use of MCS devices is based primarily on a single open label trial entitled the REMATCH trial, which compared a pulsatile LVAD to optimized medical management in 129 severely sick heart failure patients (5). To date this is the only RCT comparing MCS devices with optimal medical management. Published in the NEJM in 2001, this trial found the LVAD to be superior to medical management in both mortality and quality of life measures. It wasn't that the VAD patients did well, on the contrary they did horribly. Over the first year, 48% of the patients in the VAD group had died. By two years the mortality rate had reached 77%. The majority of these deaths were due to complications of the VAD itself, 41% due to sepsis and 17% due to device failure. This of course would be an utter failure if it was not for the fact that the control group fared far worse. At one year, only 25% of the control patients were still alive. By two years the mortality reached a staggering 92%, almost all these deaths due to terminal heart failure.
These devices showed promise, but were not without their own complications. It is very important to understand that the device’s success was due in part to the high acuity of the patients selected. The great majority of these patients were categorized as NYHA class IV, the average ejection fraction was 17%, and close to 75% of them were on inotropic support. In addition, an open trial of 129 patients leaves a lot to be desired methodologically speaking, especially considering the extra attention almost certainly given to the VAD group. For those of you who work in a center that installs and maintains these devices and have witnessed the quantity of attention they garner upon arrival in the Emergency Department, it is not hard to imagine the disparity of care that may have occurred between the VAD patients and their controls. The FDA clearly had similar concerns when they approved the use of these devices and stipulated that post-marketing research must be performed demonstrating similar outcomes could be obtained outside the arena of clinical trials. Thus The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) was born (6). INTERMACS is a prospective registry that collects clinical data, including follow up, essentially as it happens. Post-implant follow up data is collected at 1 week, 1 month, 3 months, 6 months and every 6 months thereafter. Major outcomes after implant, e.g. death, explant, rehospitalization and adverse events, are entered as they occur and also as part of the defined follow-up scheduled intervals.
Since the REMATCH trial, LVAD technology has vastly improved. In 2007, the NEJM published the initial findings of a continuous LVAD, the HEARTMATE II, in patients awaiting transplant (7). This was followed in 2009 by a RCT comparing the original pulsatile devices to their new continuous flow counterparts as destination therapy in heart failure patients not appropriate for transplant (8). These trials not only established that continuous VAD devices could provide a bridge to transplant, but also that they performed far better than their pulsatile counterparts. In the 2009 NEJM article, Slaughter et al found continuous flow devices had better outcomes with 46% of patients surviving complication free at 2-years compared to only 11% of the pulsatile group. Interestingly the pulsatile group in 2009 performed far better than their historical counterpart from the original REMATCH trial.
It is important to remember that the INTERMACS data is an observational registry, and suffers from all the relevant biases of such data sets. Though survival rates have increased, without randomized controls we are unable to determine if this is due to enhancements in VAD technology or simply due to improvements in heart failure management. Even with the improved outcomes and decreased adverse event rates reported in the INTERMACS database, VAD implantation and management is not a benign procedure and risk of mortality and complications are still high. The 30 day, 1 year and 2 year mortality are 5%, 20% and 30% respectively (9). 41% of patients will have some form of a pump related event in the first 30 days after implantation. In 2001, when VADS were first approved for use in patients with severe heart failure, they were implanted in the sickest of the sick. Before 2011, 64% were implanted into patients in cardiovascular shock or severe decompensated heart failure. In 2012, this number dropped to just under 54% (10). Though these patients are still well within the entry criteria first proposed by the REMATCH trial, certainly there is a trend to installation of VAD devices in a healthier population.
The exact cause of the increased rate of pump thrombosis is still unclear. Some have hypothesized various explanations including; the change from pulsatile to continuous flow devices, which in direct comparison had slightly higher rates of pump thrombosis (8), the recent change in anticoagulant recommendations from an INR of 2-3 to 1.5-2.5 secondary to increased bleeding risk found with continuous devices when compared to their pulsatile counterparts (10), the increase in VAD use for destination therapy(9), overall a slightly sicker population, or a yet to-be-identified mechanical defect in the Heartmate II itself. What is clear is that this increased risk of thrombosis should be considered before installing one of these devices.
For better or worse this increased risk of pump thrombosis does very little to change our management in the Emergency Department. If a patient presents with the clinical and pump characteristics of thrombosis then they should be managed in the appropriate fashion whether their risk is 0.4% or 1.4%. What this article does provide is some guidance in the diagnosis and management of pump thrombosis, for example the authors demonstrate a clear association between increased levels of lactate dehydrogenase (LDH) and clinically obvious pump thrombosis (3). Whether this association is strong enough to differentiate thrombosis from the baseline hemolysis that occurs with LVADs is not explored in this paper. Two small case-control trials demonstrate excellent test characteristics for LDH in the diagnosis of pump thrombosis, but this data was retrospectively fitted to the levels of optimal performance and requires prospective validation before their clinical utility can be assessed (11,12).
Very little high quality data exists to guide us in the management of pump thrombosis but what Starling's paper demonstrates is we have little to offer these patients in the Emergency Department. In this cohort, 19 of the 38 patients with confirmed pump thrombosis who were managed medically died (48%). In contrast, those with confirmed pump thrombosis who were managed surgically with either transplant or pump replacement had survival rates similar to those without thrombosis (16%). Ideally these patients are already optimized on Warfarin therapy so other than starting those who have sub-therapeutic INRs on heparin, there is little more to offer. Some recommendations suggest giving these patients tPA but there is no evidence of its benefit in these situations and given their already elevated bleeding risks it seems the downside is too high to justify its use. Once we have stabilized the patients and ruled out other more imminent causes of their distress (sepsis, hemorrhage, etc. ), we must provide them with the resources they need to correct the problem, specifically someone with the capabilities to either replace the pump or if appropriate progress the patient to a heart transplant.
Although the cyborgs of today are far less virile than what our beloved science fiction stories promised, they are a population that we will inevitably encounter. The third generation of ventricular assist devices are currently undergoing clinical testing and are in the early stages of use. Some reports are boasting 1-year survival rates as high as 90% (13). Becoming comfortable with the diagnostic and resuscitative intricacies of these devices will become ever more important as they become the standard treatment of end stage heart failure. It is a brave new world indeed…
1. Manfred E. Clynes and Nathan S. Kline.Cyborgs and Space ,” in Astronautics (September 1960)
2.Cyborg Foundation: http://eyeborg.wix.com/cyborg
3. Starling et al. Unexpected Abrupt Increase in Left Ventricular Assist Device Thrombosis. NEJM, November 27, 2013
4. Initial analyses of suspected pump thrombosis. 2013 (http://www.uab.edu/ medicine/intermacs/images/INTERMACS _PI_and_Website_Notice_9-6-2013_2.pdf).
5 Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. NEJM 2001;345:1435-43.
6. Kirklin et al.INTERMACS database for durable devices for circulatory support: first annual report. J Heart Lung Transplant. 2008;27:1065–1072
7. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. NEJM 2007;357:885-96
8. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist de-vice. NEJM 2009;361:2241-51.
9. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: risk fac-tor analysis from more than 6,000 mechan-ical circulatory support patients. J Heart Lung Transplant
10. Crowe et al. Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg 2009;137:208-15
11. Palak et al. Diagnosis of hemolysis and device thrombosis with lactate dehydrogenase during left ventricular assist device support. The Journal of Heart and Lung Transplantation, article in press
12. Uriel et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous flow left ventricular assist devices: The Columbia Ramp Study. J Am Coll Cardiol. 2012 October 30; 60(18): 1764–1775.
13. Yamazaki et al. Japanese clinical trial results of an implantable centrifugal blood pump “EVAHEART”. J. Heart Lung Transplant. 27, S246 (2008).