Advanced heart failure: Transplantation, LVADs, and beyond

MECHANICAL CIRCULATORY SUPPORT: BRIDGE OR DESTINATION?

Mechanical circulatory support devices are increasingly being used to sustain patients with advanced heart failure. Currently at Cleveland Clinic, more LVADs are implanted than hearts are transplanted.

Mechanical circulatory support is indicated for patients who are listed for transplant to keep them functioning as well as possible while they are waiting (bridge to transplant). For others it is “destination therapy”: they are not candidates for a transplant, but a device may improve and prolong the rest of their life.

Case 2: A good outcome despite a poor prognosis

A 71-year-old man was rejected for transplantation by his local hospital because of his age and also because he had pulmonary artery hypertension (78/42 mm Hg; reference range 15–30/5–15 mm Hg) and creatinine elevation (3.0 mg/dL; reference range 0.6–1.5 mg/dL). Nevertheless, he did well on a mechanical device and was accepted for transplantation by Cleveland Clinic. He received a transplant and is still alive and active 14 years later.

Comment. Determining that a patient is not a good transplantation candidate is often impossible. Putting the patient on mechanical support for a period of time can often help clarify whether transplantation is advisable. Probably most patients who receive mechanical support do so as a bridge to decision: most are acutely ill and many have organ dysfunction, pulmonary hypertension, and renal insufficiency. After a period of support, they can be assessed for suitability for transplantation.

LVADs continue to improve

Many devices are available for mechanical circulatory support.¹⁴ In addition to LVADs, there are right-ventricular assist devices (RVADs), and devices that simultaneously support both ventricles (BiVADs). Total artificial hearts are also available, as are acute temporary percutaneous devices. These temporary devices—TandemHeart (CardiacAssist, Pittsburgh, PA) and Impella (Abiomed, Danvers, MD)—can be used before a long-term mechanical device can be surgically implanted.

LVADs are of three types:

• Pulsatile volume-displacement pumps, which mimic the pumping action of the natural heart. These early devices were large and placed in the abdomen.
• Continuous axial-flow pumps, which do not have a “heartbeat.” These are quieter and lighter than the early pumps, and use a turbine that spins at 8,000 to 10,000 rpm.
• Continuous centrifugal-flow pumps. These have a rotor spinning at 2,000 to 3,000 rpm, and most of them are magnetically powered and suspended.

The superiority of LVADs over medical therapy was clearly shown even in early studies that used pulsatile LVADs.¹⁵ The results of such studies and the increased durability of the devices have led to their rapidly expanded use.

The newer continuous-flow pumps offer significant improvements over the old pulsatile-flow pumps, being smaller, lighter, quieter, and more durable (Table 1). A 2007 study of 133 patients on a continuous axial-flow LVAD (HeartMate II) found that 76% were still alive after 6 months, and patients had significant improvement in functional status and quality of life.¹⁶ In a postapproval study based on registry data, HeartMate II was found superior to pulsatile pumps in terms of survival up to 12 months, percentage of patients reaching transplant, and cardiac recovery. Adverse event rates were similar or lower for HeartMate II.¹⁷

Another study compared a continuousflow with a pulsatile-flow LVAD for patients who were ineligible for transplantation. Survival at 2 years was 58% with the continuousflow device vs 24% with the pulsatile-flow device (P = .008).¹⁸ Since then, postmarket data of patients who received an LVAD showed that 85% are still alive at 1 year.¹⁹ This study can be viewed as supporting the use of LVADs as destination therapy.

Quality of life for patients receiving an LVAD has been excellent. When biventricular pacemakers for resynchronization therapy first became available, distances on the 6-minute walk test improved by 39 m, which was deemed a big improvement. LVAD devices have increased the 6-minute walk distance by 156 m.²⁰

Adverse events with LVADs have improved, but continue to be of concern

Infections can arise in the blood stream, in the device pocket, or especially where the driveline exits the skin. As devices have become smaller, driveline diameters have become smaller as well, allowing for a better seal at the skin and making this less of a problem. Some centers report the incidence of driveline infections as less than 20%, but they continue to be a focus of concern.¹⁸

Stroke rates continue to improve, although patients still require intensive lifelong anticoagulation. The target international normalized ratio varies by device manufacturer, ranging from 1.7 to 2.5.

Bleeding. Acquired von Willebrand syndrome can develop in patients who have an LVAD, with the gastrointestinal system being the most frequent site of bleeding.²¹

Device thrombosis occurs very rarely (2%–3%) but is very serious and may require pump exchange.

Mechanical malfunction. As duration of therapy lengthens, problems are arising with aging devices, such as broken wires or short circuits. New-generation pumps have markedly improved durability and reliability.

Good data are kept on device outcomes

The Interagency for Mechanically Assisted Circulatory Support (INTERMACS) maintains a national registry of patients with a mechanical circulatory support device to treat advanced heart failure. It was jointly established in 2006 by the National Heart, Lung, and Blood Institute, Centers for Medicare and Medicaid Services (CMS), the US Food and Drug Administration, and others. Reporting to INTERMACS is required for CMS reimbursement.

The INTERMACS database now has about 4,500 patients at 126 medical centers and is yielding useful information that is published in annual reports.²² The 2011 report focused on the experience with mechanical circulatory support as destination therapy and showed that patients who receive continuousflow pumps have significantly better survival rates than those with pulsatile-flow pumps.²³ An earlier report showed that the level of illness at the time of implantation predicts survival²⁴; this information now drives cardiologists to try to improve patient status with a temporary support device or intra-aortic balloon pump before implanting a durable device. The sickest patients (INTERMACS level 1) have the poorest outcomes, and centers now do fewer implantations in patients in this category. We have learned this important lesson from the INTERMACS registry.

The new devices have received a lot of media attention, and patient accrual has increased steadily as the devices have been approved.

On November 20, 2012, the US Food and Drug Administration approved the HeartWare Ventricular Assist System (HeartWare, Framingham, MA) for heart failure patients awaiting a transplant.

FUTURE DIRECTIONS

PROCEED II is an ongoing global clinical trial comparing the outcomes with donor hearts transported in standard cold storage to those transported in an experimental transport device that pumps the heart under physiologic conditions. If proven effective, this device could allow long-distance transport of donor hearts and expand the donor population.

A prospective, randomized study is now enrolling patients to evaluate induction therapy with rituximab (Rituxan) plus conventional immunosuppression (tacrolimus [Prograf], mycophenolate, steroid taper) vs placebo induction plus conventional immunosuppression. The study will enroll 400 patients (200 to each treatment arm) at 25 sites and will have a 36-month accrual period with 12-month follow-up (see https://clinicaltrials.gov/show/NCT01278745). The study is based on data in primates that found that eliminating B cells with an anti-CD20 drug before transplantation markedly reduced the incidence of coronary artery vasculopathy.