Левожелудочковые вспомогательные устройства: клиническое применение и результаты

Резюме

Хроническая сердечная недостаточность - одна из главных причин заболеваемости и смертности, а также основная причина затрат на медицинское обслуживание. Несмотря на внедрение высокоэффективных фармакологических методов лечения и устройств, в том числе сердечной ресинхронизирующей терапии, способствующих снижению смертности и улучшению сердечной функции и качества жизни, многие пациенты не отвечают на лечение либо, несмотря на применение оптимальных медикаментозных и/или интервенционных методов лечения, заболевание у них прогрессирует.

Таким пациентам показана трансплантация сердца, но ее проведение зависит от доступности донорского органа, а также от наличия сопутствующих заболеваний, негативно влияющих на выживаемость после трансплантации. В качестве альтернативы у этих пациентов возможно применение левожелудочковых вспомогательных устройств (LVADs), которые способствуют улучшению выживаемости, переносимости физической нагрузки и качества жизни.

С развитием технологий LVADs удалось усовершенствовать, что, в свою очередь, способствовало увеличению срока службы этих устройств и уменьшению постимплантационных осложнений. После установки LVADs последнего поколения реже развиваются тромбозы помпы, инсульты и желудочно-кишечные кровотечения, что делает такого рода таргетную терапию, при которой желудочковые вспомогательные устройства имплантируют пациентам с тяжелой сердечной недостаточностью на постоянной основе, реальностью и подходящим вариантом. У многих пациентов этот подход позволяет увеличить отдаленную выживаемость. Однако постимплантационная правожелудочковая недостаточность остается серьезным осложнением, требующим более эффективных способов выявления пациентов группы риска и подходов к ведению пациентов с этим осложнением.

Ключевые слова:трансплантация, нежелательные явления, правожелудочковая недостаточность, качество таргетной терапии

Финансирование. Исследование не имело спонсорской поддержки.
Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.
Для цитирования: Лави Дж., Бопре Р.А., Морган А.Дж. Левожелудочковые вспомогательные устройства: клиническое применение и результаты // Клиническая и экспериментальная хирургия. Журнал имени академика Б.В. Петровского. 2020. Т. 8, № 3. С. 123-128. DOI: https://doi.org/10.33029/2308-1198-2020-8-3-123-128 (англ.)

Continuous flow LVADs: second and third generation LVADs

LVAD design evolved radically after the REMATCH trial with the development of continuous flow (CF) LVADs. These were no longer pulsatile. Instead, blood was propelled through a rotor. Flow was continuous and not pulsatile as in native hearts. These devices as opposed to the earlier HeartMate I required systemic anticoagulation. An initial study of 133 patients awaiting cardiac transplantation underwent implantation of the HeartMate II LVAD, a second generation VAD with an axial flow design. Mean time of support was 126 days and the survival rate was 75% at 6 months and 68% at 1 year [1]. The latter represented and improvement from the 52% 1 year survival seen at 1 year in the REMATCH trial with the HeartMate. The functional status and Quality of Life improved 3 months after implantation of the CF LVADs [2]. Major adverse events included right ventricular (RV) failure, postoperative bleeding, stroke, percutaneous lead infection and pump thrombosis.

A subsequent study in patients not eligible for cardiac transplantation compared the Heartmate II to the HeartMate I in a 2:1 randomization ratio. The 134 patients received the HeartMate II and 66 received the HeartMate I [3]. At 2 years, patients receiving the HeartMate II had a 58% survival compared to 24% for the HeartMate I recipients. HeartMate II recipients had greater freedom from stroke or VAD replacement indicating that the HeartMate II was a more durable VAD than its predecessor [3]. These results led to FDA approval of the HeartMate II for MCS for DT and the obsolescence of the HeartMate I which subsequently was no longer produced.

Third generation LVADs were CF devices which had centrifugal flow which meant that flow in the VAD was perpendicular to flow coming in from the left ventricle. These devices were smaller than the HeartMate II and had a moving impeller suspended by magnetic and hydrodynamic forces to reduce shear and prolong LVAD durability. The archetype LVAD in this group is the HeartWare ventricular assist device (HVAD) which was studied in the HeartWare™ Ventricular Assist System as Destination Therapy of Advanced Heart Failure (ENDURANCE) study which was a comparison to of the HVAD centrifugal flow VAD to the HeartMate II axial flow device. The 446 patients were randomized in a 2:1 manner to the HVAD (n=297) vs the HeartMate II (n=148) [4]. The primary end point was survival at 2 years free from disabling stroke or device removal for malfunction or failure. The primary endpoint was achieved in 554.1% of HVAD and 59.1% of HeartMate II patients (p=NS) [3]. More patients in the HeartMate II group had VAD malfunction or failure requiring replacement (16.2 vs 8.8%) while the stroke rate was higher in the HVAD group compared to the HeartMate II group (29.7 vs 12.1%). Strokes were associated with higher blood pressures [3]. Thus, while the HVAD appeared to be more durable than the HeartMate II, it was associated with a higher stroke rate [3].

Complications of LVADs

Right ventricular failure

RV failure is a feared post-LVAD implantation complication which heralds a 20% decrement in perioperative survival [5-7]. A recent metanalysis of 36 studies reported an incidence of RV failure of 35% in 4,428 patients. The causes of post-LVAD implantation include the unloading of the left ventricular (LV) after LVAD implantation which results in septal shifts, increased RV preload and ultimately decreased RV contractility and function. Prediction of post-operative RV failure before LVAD implantation has been a challenge. Predictive scoring systems have been developed but have not been very successful and are not used often.

Often, RV failure will be manifested in the operating room during LVAD implantation. This may necessitate implantation of a right ventricular assist device (RVAD). Sometimes RV failure is diagnosed clinically in the intensive care unit after LVAD implantation. This is manifested clinically by decreased blood pressures, cardiac outputs and urine outputs. Management would include implantation of an RVAD. Often, RVADs can serve as bridges to RV recovery and after several days to weeks, can be explanted as RV function improves.

Gastrointestinal bleeding

The most common source of bleeding in patients with CF LVADs is from the GI tract. GI bleeding rates in LVAD patients ranges from 10-61% [8-11]. A metanalysis of 1,697 patients showed a GI bleeding rate of 23% [12]. The most common etiology of GI bleeding in LVAD patients is arteriovenous malformations or angiodysplasia which occur in 29% of LVAD patients. It is thought that the CF in the second and third generation LVADs may contribute to the development of angiodysplasias. The most common location of GI bleeding in these patients is the upper GI tract (48%) of patients [12]. The pathophysiology of GI angiodysplasia in CF LVAD patients is incompletely understood but there is evidence that the hypoxia-inducible factor (HIF)-1α/angiopeptin pathway may be involved [13, 14].

Although the incidence of GI bleeding is higher in recipients of second and third generation LVADs compare to the first generation pulsatile LVADs, mortality from GI bleeds is actually lower in recipients of the newer, CF LVADs compared to the pulsatile LVADs (20.9 vs 43.7%, respectively) [12]. From the DT clinical trial comparing HeartMate II to HeartMate I, there was no difference in GI bleeding episodes that required transfusions or surgery. Increasing experience with managing the newer CF LVADs has resulted in a reduction in GI bleeding incidence. Mortality from GI bleeding has also declined.

Pump thrombosis and strokes

Patients with second and third generation CF LVADs are at risk of the sequelae of thromboembolic events despite receiving systemic anticoagulation and having acquired Von Willebrand Syndrome. The incidence of strokes ranges from 2-42 to 2-5% for transient ischemic attacks [15-18]. A more ominous complication is pump thrombosis. The incidence of pump thrombosis increased from 2% in 2011 to 5% in 2015 at 6 months post implant in HeartMate II LVADs (p<0.0001) in date from 6,251 patients from INTER-MACS [19]. In a review from 3 institutions of 837 patients in whom 895 HeartMate II devices were implanted between 2004 and 2011. The 72 pump thromboses were observed in 66 patients [20]. From March 2011, the incidence of pump thrombosis increased from 2.2% at 3 months post-implant to 8.4% in March 2013. The median time post-implant to thrombosis declined from 18.6 months before March 1, 2011 to 2.7 months afterward. Pump thrombosis in these patients was managed by cardiac transplantation in 11 patients and LVAD replacement in 21. Of the remaining 40 patients with pump thromboses but who did not get a cardiac transplant or pump exchange, mortality was high at 48.2% at 6 months after pump exchange was diagnosed [20]. The PREVENTION of HeartMate II Pump Thrombosis through Clinical Management (PREVENT) study of 300 patients who underwent HeartMate II implantation at 24 medical centers showed a pump thrombosis rate of 2.9% at 3 months and 4.8% at 6 months 21]. Heparin bridging within 48 hours post-operatively, initiation of warfarin at 48 hours with a target INR of 2.0-2.5, and addition of aspirin (81-325 mg daily) 2-5 days post implantation if there was no bleeding and maintaining pump speeds >9,000 RPMs reduced the incidence of pump thrombosis from 8.9 to 1.9% (p<0.01) and the incidence of ischemic stroke from 17.7 to 5.7% (p<0.01) at 6 months post implant.

Recent data from INTERMACS indicates that the incidence of HeartMate II pump thrombosis at 6 months peaked at 8% in 2013 but declined to 5% in 2014 [22]. Results from the HVAD Evaluation of the HeartWare Left Ventricular Assist Device for the Treatment of Advanced Heart Failure (ADVANCE) study showed that this device had a 4% pump thrombosis incidence at 6 months.

For those patients who cannot get heart transplants rapidly or who are receiving LVADs as DT, a pump exchange with explantation of the old LVAD and replaced with a new LVAD are definitive treatments of this problem. Thrombolytic therapy should be avoided given the risk of intra-cranial hemorrhage with this therapy.

Infection

Infections can occur anywhere throughout the LVAD circuit including the LVAD pocket where the LVAD is implanted, the LVAD itself or the cannulae that go from the left ventricle to the VAD and from the LVAD to the aorta and the driveline which goes from the LVAD through the skin to the LVAD power source. The latter is the most common site of LVAD infections because it represents a pathway from the external environment to the LVAD interior. The most common organisms causing LVAD infections are skin flora such as Staphylococcus aureus and coagulase-negative staphylococci. These are particularly common in driveline infections. Infections of the LVAD and other internal components can be caused by other organisms as well such as Serratia, Klebsiella, and Enteroccocus species, Pseudomonas aeruginosa. Candida can cause up to ten percent of infections [23]. Bacteremia from another infection can seed the LVAD and infect it. Infections have declined from 38% of patients reported in the first year of INTER-MACS to 17.6% reported in 2014 by INTERMACS. Mortality from sepsis has declined from 41% reported in the REMATCH study to 8.8% in recent INTERMACS reports [19].

The management of LVAD related infections includes debridement of infected tissue and administration of intravenous antibiotics. Often, the driveline site where the driveline traverses the skin can provide insight into the presence of infection as there may be erythema and purulent discharge. When the VAD or the cannulae are infected, the only cure is explantation. If the patient is on the transplant list, an LVAD related infection will raise the patient on the priority list allowing for earlier transplantation and removal of the infected LVAD. Antibiotics can be used to suppress the infection. For DT patients, the infected LVAD may need to be explanted. Temporary nondurable support with an Impella can be used to support the patient hemodynamically until the infection is eradicated at which point a new LVAD can be implanted.

The HeartMate 3: further advances in LVAD technology

the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) study was a pivotal LVAD clinical trial involving the randomization of 294 patients to receive the HeartMate 3, a fully magnetically levitated centrifugal CF LVAD to the axial flow HeartMate II (see fugire). The 152 patients received the HeartMate 3 while 142 received the axial flow HeartMate II [25]. The primary end point was a composite of survival free of disabling stroke or survival free of reoperation to replace or remove the device at 6 months after implantation. The 131 (86.2%) patients in the HeartMate 3 group reached the primary endpoint vs 109 (76.8%) patients in the HeartMate II study. There was no significant difference in rate of deaths or disabling strokes in the two groups. However, reoperation for pump malfunction was less common in the HeartMate 3 group vs. the HeartMate II group [1 (0.7%) vs 11 (7.7%), p=0.002]. No suspected or confirmed pump thromboses were seen in the HeartMate 3 group vs 14 (10.1%) patients in the HeartMate II group.

In a follow up study, 366 patients were enrolled, 190 of whom received the HeartMate 3 and 176 of whom received the HeartMate II [25]. The primary end point was a composite of survival free of disabling stroke or survival free of reoperation to replace or remove the device at 2 years after implantation [24]. The 151 (79.5%) of HeartMate 3 patients reached the primary endpoint compared to 106 (60.2%) in the HeartMate II group. Reoperation for pump malfunction was less common in the HeartMate 3 group compared to the HeartMate II group [3 (1.6%) s 30 (7.0%), p=0.01]. Death rates were similar between the two groups but rate of disabling strokes was less in the HeartMate 3 group compared to the HeartMate II group (10.1% vs 19.2%, p=0.02) [25].

A final phase of the MOMENTUM 3 trial enrolled 1,028 patients, of which 516 received the HeartMate 3 and 512 received the HeartMate II [25]. The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years. The 397 (76.9%) patients in the HeartMate 3 group reached the primary endpoint compared to 332 (64.8%) in the HeartMate II group [25]. Pump replacement for malfunction was less common in the HeartMate 3 group compared to the HeartMate II group [12 (2.3%) vs 57 (11.3%), p<0.001] [26]. Patients in the HeartMate 3 group had fewer strokes, major bleeding, GI bleeding or ventricular arrhythmias than in the HeartMate II group. Thus, this newest LVAD has fewer pump thromboses and LVAD replacements for LVAD malfunction. There are unique aspects of this device which may account for its superior outcomes: It has wide blood flow conduits which reduces shear of the blood, it is frictionless without mechanical bearings and it has an intrinsic pulse which is designed to reduce stasis and prevent pump thrombosis. The intrinsic pulse may help to prevent GI angiodysplasia.

The ELEVATE registry, which is a voluntary, multicenter, multi-national, observational registry in which HeartMate 3 consecutive patients in 26 centers were enrolled, evaluated patients who received the HM3 as their primary implant (n=463) as well as the survival of the 540 patients in the full cohort [27]. The full cohort survival at 6 months was 82±2%. In the enrolled primary implant patients, there was no incidence of pump thrombosis, major bleeding was 25%, major infection 35%, and any stroke type 5% [27]. Functional capacity improved significantly (Δ6MWD 230±191 m) as did QOL (ΔVAS 31±23). Freedom from unplanned rehospitalizations at 6 months was 68±2%. These 6-month outcomes of the HM3 LVAD demonstrate a highly reliable, thrombosis-free device with low incidence of stroke and improved functional capacity, and QOL.

The HeartMate 3 LVAD can also be used for biventricular support as described in the multi-center report by Lavee and colleagues, in which 14 patients at 6 medical centers underwent implantation of a HeartMate 3 BIVAD. Eight of the 9 were maintained on BiVAD support for 95 to 636 (mean 266) days: 7 at home, and 1 successfully transplanted after 98 days of support. Nine of the patients (64%) were alive at the time of the publication of the manuscript [28].

LVADs compared to cardiac transplantation

lVAD outcomes have improved consistently over the past 20 years since the results of the REMATCH trial. Outcomes for cardiac transplantation have also improved mainly due to improvements in the survival in the first 6 months to 1 year post-transplant as a result of a lower incidence of rejection and infection in this time period and better outcomes when these events occur. This is from the Registry on the International Society of Heart and Lung Transplantation (ISHLT). Notably, the incidence of cardiac allograft vasculopathy (CAV) and malignancy post-transplant have declined modestly in recent years with better outcomes. Despite this, survival beyond the first year post-transplant has not changed substantially with CAV and malignancy being the major causes of death in these patients [29].

The ISHLT Registry reports survival at 1 year in excess of 90% [29]. In contrast, the best 1 year survival reported for LVADs is in the high 80s, inferior to transplants although there has been no randomized comparison (fig.). Advantages of LVADs over transplant include the fact that they are readily available, essentially "off-the-shelf". The post-transplant complications, CAV, malignancy, rejection, infection and nephrotoxicity (from immunosuppression) do not occur in LVAD patients. There is no limits in LVADs as there is in donor hearts and this explains why more LVADs are being performed than cardiac transplants. As the heart failure population continues to age, this will further shift the numbers toward LVADs.

Improvement in Survial Rates through Time

Who should get transplants instead of LVADs? Generally younger patients with few comorbidities should get transplants as transplants have kept many patients alive for decades and longer than has been seen with LVADs. This will likely improve over time. LVAD survival will likely improve with improvements in technology. More durable, reliable VADs with lower stroke rates, GI bleeding and pump thrombosis rates that are totally implantable may give transplants competition in terms of outcomes. At presents, VADs should be used in older patients with co-morbidities including recent malignancies, and smoking should be considered for VADs.

Conclusions

Management of advanced heart failure with LVADs and transplant has improved dramatically over the past few decades. LVADs represent a significant advance in that they allow patients who were critically ill to survive to transplant and to function including becoming physically active. As the technology has improved and outcomes have improved, LVADs have become viable and realistic alternatives for patients who might not be optimal transplant candidates. As the technology continues to improve and disseminate worldwide, the number of patients who receive LVADs will continue to grow. Eventually with improved technology, LVADs may provide realistic competition to cardiac transplantation in most patients.

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