The Critical Role of MCS Registries

Origins of Intermacs/Pedimacs

In The Artificial Heart: Prototypes, Policies, and Patients: Institute of Medicine Report from 1991, the committee opined that “maintaining a registry of mechanical circulatory support (MCS) recipients should be considered a routine aspect of this care.” With the approval of the HeartMate XVE (Thoratec, Pleasanton, CA) for reimbursement as long-term “destination therapy” (DT) by the Center for Medicare and Medicaid Services (CMS) in 2003, the stage was set for lifelong mechanical circulatory support uncoupled from cardiac transplantation. Subsequently, under the vision of Dr. John Watson and others at the National Heart, Lung, and Blood Institute (NHLBI), a Request for Proposals was assembled to create a national database for patients receiving this longer-term therapy. In June 2005, the Contract was awarded to the University of Alabama at Birmingham, with Dr. James Kirklin as principal investigator (PI) and Drs. David Naftel, Robert Kormos, and Lynne W. Stevenson as co-PIs. In 2011, under the contract renewal, Dr. Frank Pagani was added as a co-PI.

The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) was conceived as a unique joint effort between the NHLBI, CMS, the Food and Drug Administration, clinicians, scientists, and industry, thereby including the major stakeholders in this expensive, life-sustaining therapy. Over the next decade, INTERMACS investigators chronicled, analyzed, and facilitated the transition from bulky, flawed pulsatile technology to more durable revolutionary continuous-flow (CF) pumps ( Table 20.1 ). INTERMACS became a platform for progress—their investigators generating more than 80 publications, four NHLBI grants, and several grants from the American Heart Association. By the end of 2017, over 20,000 patients from more than 150 participating institutions had been entered into the database. As part of a long-term sustainability plan, with the conclusion of the NHLBI contract, ownership of INTERMACS transitioned to the Society of Thoracic Surgeons on January 1, 2018.

As part of the first NHLBI contract, INTERMACS was charged with creating a separate database within the INTERMACS platform that would focus on pediatric MCS. A separate database was created with variables and fields specific to the practice and clinical science of devices (both temporary and durable) for the infant, child, and teenager. Data collection commenced on September 19, 2012. By the end of 2017, over 500 patients on support from 46 pediatric centers had been entered into the Pediatric Interagency Registry for Mechanical Circulatory Support (PediMACS) database.

Intermacs Patient profiles

To track the national experience with ventricular assist devices, it became increasingly important to characterize clinical profiles at the time of implantation. The modern evolution of classifications for severity of disease is strongly impelled by the therapeutic options. When transplantation was the only approved therapy, the persistence of New York Heart Association (NYHA) Class IV symptoms at rest or minimal exertion was adequate to define Stage D, refractory heart failure (HF). For those patients deteriorating while awaiting transplantation, invasive hemodynamic parameters were used to guide therapy with short-term circulatory support such as intraaortic balloon counterpulsation, although benefit was difficult to establish in the absence of true control groups. As the benefits of durable devices extended into prolonged support outside of the hospital, they began to be considered for prevention as well as treatment of terminal hemodynamic decompensation leading to secondary organ dysfunction. When they were being used only as bridges to transplantation, the duration of support and device complications was relatively short for most patients.

Once the left ventricular assist device (LVAD) was approved for DT after the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, it became increasingly important to track the longer-term outcomes. As major purposes of the registry included the refinement of patient and device selection and identification of best practices, it was considered essential to distinguish patients with various levels of compromise to standardize comparison of outcomes for different devices, different patients, and different implanting centers. Definition of NYHA Class IV was no longer adequate to distinguish these indications, and other states were informally proposed, such as “Class IV-B” and “Class V.”

Relationship of Intermacs Profiles to Outcomes

The first year’s report of INTERMACS demonstrated the surprising finding that a substantial proportion of devices were being implanted in patients with Profile 1. In view of the obvious high risk from preoperative hypoperfusion and organ system compromise, it had been assumed that not many patients would have gone through a major surgical procedure from the “crash and burn” status, which instead represented 44% of all patients included in the first INTERMACS report ( Table 20.3 ). Outcomes were significantly worse, with over 50% mortality at 1 year, compared with 35% for patients in Profile 2. The best outcomes were in those patients who were stable on intravenous inotropic therapy at the time of device implantation ( Fig. 20.1 ). One of the other notable features of the INTERMACS Profile 1 patients was the relatively higher rate of need for right ventricular support. This has particular relevance when considering whether Profile 1 patients are candidates for lifelong DT, for which the devices are approved for left ventricular support.

Table 20.3

Evolving INTERMACS Patient Profiles Across Implant Eras

	CFLVAD Implants: April 2008–December 2017 Follow-up Through June 2018
	Implant Date Era						Total
Patient Profile at Time of Implantation	2008–2010		2011–2014		2015–2017
	n	Col %	n	Col %	n	Col %	n	Col %
1. Critical cardiogenic shock	394	15%	1154	14%	1104	15%	2652	14%
2. Progressive decline	1134	43%	3102	36%	2525	35%	6761	37%
3. Stable but inotrope dependent	627	23%	2706	32%	2742	38%	6075	33%
4. Resting symptoms	357	13%	1241	14%	800	11%	2398	13%
5. Exertion intolerant	77	3%	245	3%	94	1%	416	2%
6. Exertion limited	44	2%	86	< 1%	29	< 1%	159	< 1%
7. Advanced NYHA Class 3	27	1%	37	< 1%	9	< 1%	73	< 1%
Totals	2660	100%	8571	100%	7303	100%	18,534	100%

CFLVAD , Continuous-flow left ventricular assist device; NYHA , New York Heart Association.

Over the following 10 years, the proportion of INTERMACS Profile 1 patients declined, with a corresponding increase in the proportion of Profile 3 patients. Although the indication for durable devices includes Class IV symptoms with peak oxygen consumption < 12–14 mL/kg/min, this remains a small proportion of patients undergoing device therapy as of 2018. Although designed to track the outcomes for patients undergoing implantation of durable mechanical support, the INTERMACS profiles have provided useful calibration for other decisions. This was particularly important for patients undergoing urgent heart transplantation in Spain. Patients transplanted from Profile 1 had over 40% in-hospital mortality, which was more than 2-fold higher than from Profile 2 and over 4-fold higher for Profile 1 compared to Profile 3 or 4. The excess mortality was attributed most often to primary graft failure and renal failure after transplantation. Comparison to contemporary outcomes with CF devices suggests that MCS offers better early outcomes than transplantation from a Profile 1 status. The INTERMACS profiles have provided further discrimination for outcomes in patients with ambulatory advanced HF followed in programs at centers that also have active MCS programs ( Fig. 20.2 ).

Evolving intent of durable mcs placement

First- and second-generation MCS devices were first approved as a bridge to transplantation (BTT) in part because transplant listed patients had a “bail-out option” in the event of device malfunction. Strategic designation for implant defined the Food and Drug Administration (FDA) indication for device therapy as well as CMS reimbursement. Additional device strategies used for FDA approval include lifelong DT and bridge to recovery. However, even in the early days of MCS, there was widespread recognition that many patients who were not actively listed for transplant at the time of implantation could potentially become transplant candidates following MCS due to improved end-organ function, reversal of pulmonary hypertension, and resolution of noncardiac comorbidities. Such patients have been referred to as bridge to decision (BTD), a designation that reflects the dynamic trajectory of real-world patients who require MCS and one that currently comprises a quarter of current registered implants in INTERMACS.

As the field has evolved from pulsatile to CF-LVADs, there has been a shift in implant strategy from BTT to BTD and, more recently, to DT or lifelong MCS. The use of LVADs as permanent replacement therapy in patients not listed for transplant increased over 10-fold since the approval of a CF device in early 2010 DT, a trend documented by INTERMACS. Since 2011, DT has been the most common intent or strategy at the time of ventricular assist device (VAD) implantation. DT recipients represented 51% of all registered device implants by 2016, including over 70% of axial flow LVADs ( Fig. 20.3 ). Given ongoing donor organ scarcity and improving LVAD outcomes, recipients of LVAD therapy who are not transplant candidates at implantation are often being prepared for lifetime mechanical support.

Patients receiving LVAD for DT are older and have an accumulated burden of comorbid medication conditions such as chronic lung or kidney disease that would otherwise render them ineligible for transplant ( Table 20.4 ). Patients receiving an implant strategy of DT have worse survival than BTT patients do, with 2-year survival of 69% for DT and 80% for BTT in CF MCS recipients ( Fig. 20.4 ). The Kaplan-Meier 5-year survival estimated for DT recipients of secondary generation MCS devices is 41%. In adjusted analyses of mortality after LVAD, DT recipients consistently demonstrate a 20% increased late hazard of death comparing to recipients of a bridging device. The differences in outcomes between the sicker DT recipients and BTT patients are anticipated, but perhaps less than might be expected, due to the older age and higher burden of comorbidities. DT LVAD therapy has become a widely used, effective alternative to inotropic or palliative HF therapies and has uncoupled MCS use from donor organ supply.

Table 20.4

Device Recipient Comorbidities According to Implant Strategy

	CFLVAD Implants: April 2008–December 2017 Follow-up Through June 2018
Overall CFLVAD, n = 18,539
Comorbidities Contraindications to Transplant	Bridge to Decision ( n = 5508)	Destination Therapy ( n = 8033)	Bridge to Transplant Listed–Concerns ( n = 4881)
Advanced age	161 (2.9%)	2415 (30.1%)	39 (< 1%)
Chronic renal disease	376 (6.8%)	1153 (14.4%)	621 (12.7%)
Currently smoking	386 (7.0%)	504 (6.3%)	28 (<1%)
Frailty	261 (4.7%)	490 (6.1%)	89 (1.8%)
Frequent ICD shocks	20 (< 1%)	49 (< 1%)	187 (3.8%)
History of alcohol abuse	198 (3.6%)	289 (3.6%)	184 (3.8%)
History of atrial arrhythmia	34 (< 1%)	128 (1.6%)	762 (15.6%)
History of bone marrow TX	0 (0%)	3 (< 1%)	3 (< 1%)
History of drug use	260 (4.7%)	320 (4.0%)	174 (3.6%)
History of smoking	320 (5.8%)	610 (7.6%)	874 (17.9%)
History of solid organ cancer	107 (1.9%)	443 (5.5%)	89 (1.8%)
High BMI	774 (14.1%)	1223 (15.2%)	228 (4.7%)
Limited social support	255 (4.6%)	355 (4.4%)	59 (1.2%)
Other comorbidity	376 (6.8%)	669 (8.3%)	231 (4.7%)
Peripheral vascular disease	69 (1.3%)	330 (4.1%)	82 (1.7%)
Pulmonary disease	136 (2.5%)	468 (5.8%)	230 (4.7%)
Pulmonary hypertension	576 (10.5%)	1157 (14.4%)	593 (12.2%)
Repeated noncompliance	191 (3.5%)	282 (3.5%)	27 (< 1%)
Severe diabetes	171 (3.1%)	513 (6.4%)	206 (4.2%)

Comorbidities that are contraindications to transplantation for bridge-to-decision patients and destination therapy patients are shown.

Comorbidities are collected on the preimplantation form. Comorbidity data collection has evolved over the life of INTERMACS. This specific list of questions became available on the web-based data entry as of May 2, 2012 (version 3.0). So for this table, only primary continuous-flow implants from May 2, 2012, through December 31, 2017, have been included. Also, multiple comorbidities may be selected for a patient. The last column entitled “Bridge to Transplant Listed” will reflect the “concern” that was entered by the site.

BMI , Body mass index; CFLVAD , continuous-flow left ventricular assist device; ICD , implantable cardioverter defibrillator; TX , transplant.

Even as the transition of short-term support (BTT) to longer-term support (DT) was documented by INTERMACS, there was ongoing debate about whether the field of MCS should move beyond the artificial preimplant strategic distinctions contingent on transplant listing that were used to define reimbursement toward an MCS indication. From a regulatory and reimbursement standpoint, patients have been required to have their intended MCS strategy declared as either BTT or DT, yet INTERMACS has shown that nearly a quarter of current implants are instead the BTD when decision could not yet be made regarding transplant. Although many BTD patients may eventually be listed for transplant, some never become eligible or develop complications on MCS that subsequently make them permanently ineligible for transplantation, effectively changing their strategy to long-term support. Analysis of INTERMACS data documented that comorbidities and social risks were more common as the perceived likelihood of transplant decreased. Patients who received an LVAD and were listed at implant (BTT) had superior survival compared to those designated as BTC or DT. Even among those who were formally listed as BTT for transplant at the time of implantation, nearly 30% were still on LVAD support at 2 years. Furthermore, the strategic intent for a given patient continues to evolve over time. At 1 year, 15% of DT recipients had become potentially eligible for transplant. At 2 years, among BTT recipients still on support, 44% were no longer listed for transplant. Regardless of initial implant strategy, patients often have a long duration of support and strategies change over time, challenging the regulatory categorization of LVAD recipient as either BTT or DT. There is significant regional variation in the duration of support and resultant change in eligibility, with the most consistent progression from LVAD to transplant being seen in regions with shortest waiting time for donor hearts. The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial of the third-generation magnetically levitated HeartMate 3 device removed this artificial strategic designation, an important constraint on previous trial designs. Even after the device was proven to be safe and effective, when the manufacturer sought approval for short- and long-term support from a single trial with unified entry criteria without regard to transplant eligibility, the BTT/DT distinction has thus far remained necessary for regulatory and reimbursement structures.

Overall outcomes