Key words
ventricular assist devices, adverse events, stroke, risk factors, vad outcomes, device malfunction
Introduction
The evolution of ventricular assist devices (VAD) since the year 2000 has allowed patients with end-stage heart failure to survive with increased functional capacity and quality of life (QOL). Since the beginning of randomized clinical trials in the field, survival, QOL, and resource requirements have been limited by adverse events. In the case of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, pump malfunction due to nondurable components requiring a surgical exchange and stroke caused significant morbidity and mortality. As engineering in the field of mechanical circulatory support (MCS) has applied novel solutions to increase durability and to miniaturize the pumps for more facile implantation, the incidence and manifestations of certain adverse events have been altered or amplified, such as gastrointestinal (GI) bleeding and neurologic dysfunction, with a more complex pathogenesis in association with continuous-flow (CF) device support. As pump technology evolves over time, we should expect that newer devices designed to improve upon previous platforms will be associated with adverse events that require rigorous investigation and novel proposals to eliminate or mitigate their occurrence.
MCS with current-generation CF devices has provided a major improvement in duration of survival on device compared to prior pulsatile pumps. With current documented survival exceeding 80% at 1 year and 70% at 2 years, extension of this therapy into the ambulatory advanced heart failure population (Interagency Registry for Mechanically Assisted Circulatory Support [INTERMACS] levels 4–6) has been extensively discussed and implemented to a limited degree. However, the success of this therapy is a function not only of survival but also of QOL among survivors. A major determinant of QOL with CF pumps is the frequency, severity, and sequelae of major adverse events. Grady and colleagues demonstrated the major deleterious effect on QOL of certain adverse events at 6 months postimplantation. The Randomized Evaluation of VAD Intervention Before Inotropic Therapy (REVIVE-IT) trial was designed to test the hypothesis that device therapy was superior to optimal medical therapy for such patients. However, the presence of a higher-than-expected incidence of pump thrombosis in the HeartMate II (HMII) device during the era of the planned study caused the investigators to terminate the study prior to performing the first implantation. With increased awareness of the frequency and impact of major adverse events during CF MCS support, the application of these devices in patients with ambulatory class IV advanced heart failure has declined during recent years. The proportion of patients in INTERMACS levels 4–7 at implantation represented 18% from 2012 to 2014 and decreased to 13% in 2015–2016. With the exception of right heart failure, other adverse events are equally as likely in ambulatory heart failure patients as in patients more critically ill ( Figs. 13.1–13.3 ). Thus, understanding the frequency, severity, and impact of major adverse events is of critical importance; both for truly informed decision making by patient, family, and caregiver and to inform decisions about future pump design and patient management. Moreover, increased device durability and dramatically lower adverse events (AE) rates must be achieved before a substantial increase in mechanical circulatory support device (MCSD) usage occurs in less ill populations (e.g., INTERMACS levels 4–7).
Definitions
Accurate identification of adverse events and reliable calculation of incidence requires clear definitions. Throughout the history of MCS trials, differing applications and definitions have been applied. When INTERMACS was created in 2006 as the national database for US durable MCS devices approved by the Food and Drug Administration, extensive deliberations among expert clinicians, industry, governmental personnel, and engineers focused on adverse event definitions. These were incorporated into the national INTERMACS database. More recently, the Academic Research Consortium has participated in attempts to harmonize definitions of adverse events among countries. The definitions used by INTERMACS in the collection of postimplantation data on more than 20,000 patients are included in the Appendix .
| Event Type | Definition |
|---|---|
| Cardiac/Vascular | |
| Arrhythmia (ventricular or atrial) | Any documented ventricular or atrial arrhythmia that results in a clinical compromise (e.g., diminished VAD outflow, oliguria, presyncope, or syncope) that requires hospitalization or occurs during the hospital stay. |
| Ventricular arrhythmia: Sustained ventricular arrhythmia requiring defibrillation or cardioversion. | |
| Atrial arrhythmia: Sustained supraventricular arrhythmia requiring drug treatment or cardioversion. | |
| Right heart failure | Symptoms and signs of persistent right ventricular dysfunction (central venous pressure > 18 mm Hg with cardiac index < 2.0 L/min/m 2 in the absence of elevated left atrial or pulmonary capillary wedge pressure [> 18 mm Hg], tamponade, ventricular arrhythmias, or pneumothorax) requiring RVAD implantation or inotropic therapy, ≥ 14 days after LVAD implantation. |
| Hypertension | New-onset blood pressure elevation ≥ 140 mm Hg systolic or 90 mm Hg diastolic (pulsatile pump) or 110 mm Hg mean pressure (rotary pump). |
| Thromboembolism (arterial or venous) | Arterial thromboembolism: Acute systemic arterial perfusion deficit in any noncerebrovascular organ system confirmed by clinical and laboratory findings, operative, or autopsy. |
| Venous thromboembolism: Evidence of deep vein thrombosis or other venous thrombotic event. | |
| Hemolysis | Plasma free hemoglobin > 40 mg/dL in association with clinical signs of hemolysis (e.g., anemia, low hematocrit, and hyperbilirubinemia) occurring within the first 72 hours after implantation. Hemolysis related to documented non–device-related causes (e.g., transfusion or drug) is excluded from this definition. |
| MI | Two categories of MI: |
| Perioperative MI: Clinical suspicion of MI together with CK-MB or troponin > 10 times the local hospital upper limits of normal, found within 7 days after VAD implantation together with ECG findings consistent with acute MI. This definition uses the higher suggested limit for serum markers because of apical coring at the time of VAD placement and does not use wall motion changes because the apical sewing ring inherently creates new wall motion abnormalities. | |
Nonperioperative MI: The presence of two of the following three criteria at > 7 days after implantation:
| |
| Other Organ Systems | |
| Respiratory (tracheostomy or reintubation) | Impairment of respiratory function requiring reintubation, tracheostomy, or (for patients > 5 years old) the inability to discontinue ventilator support within 6 days (144 hours) after VAD implantation. This excludes intubation for reoperation or temporary intubation for diagnostic or therapeutic procedures. |
| Neurologic (infarct or hemorrhagic CVA or TIA) | Any new, temporary or permanent, focal or global neurologic deficit ascertained by standard neurologic examination (administered by a neurologist or other qualified physician and documented with appropriate diagnostic tests and consultation note). The examining physician distinguishes between TIA, which is fully reversible within 24 hours (and without evidence of infarction), and stroke, which lasts > 24 hours (or < 24 hours if there is evidence of infarction). The NIH Stroke Scale (for patients > 5 years old) must be readministered at 30 days and 60 days after the event to document the presence and severity of neurologic deficits. Each neurologic event must be subcategorized as follows:
|
| Renal | Acute renal dysfunction (abnormal kidney function requiring dialysis in patients who did not require this procedure before implantation or increase in serum creatinine > 3 times normal baseline or > 5 mg/dL) and chronic renal dysfunction (increase in serum creatinine of ≥ 2 mg/dL above baseline or requirement of hemodialysis for at least 90 days). |
| Hepatic | Increase in any two hepatic laboratory values (total bilirubin, AST, or ALT) to a level > 3 times the upper limit of normal 14 days after implantation (or if hepatic dysfunction is the primary cause of death). |
| Gastrointestinal | Cholecystitis, Crohn disease, diverticulitis, esophagitis, gastroesophageal reflux disease, hiatal hernia, ischemic bowel requiring surgical exploration, pancreatitis with abnormal amylase or lipase requiring nasogastric suction therapy, polyps, or ulcer. |
| Bleeding (coagulopathy, mediastinum or pocket, thorax, gastrointestinal) | Episode of internal or external bleeding in the mediastinum, pocket, thorax, or gastrointestinal system that results in death or the need for reoperation or hospitalization, or necessitates transfusions of red blood cells (≥ 4 U packed red blood cells within any 24-hour period in the first 7 days after implantation or ≥ 2 U packed red blood cells within any 24-hour period after 7 days after implantation). |
| Infection (driveline, bloodstream, pulmonary, mediastinum, or pocket) | Driveline, bloodstream, or pulmonary infection accompanied by pain, fever, drainage, or leukocytosis that is treated by antimicrobial agents (nonprophylactic). |
| Driveline infection: Positive culture from the skin, tissue, or both surrounding the driveline or from the tissue surrounding the external housing of a pump, with the need for treatment, when there is clinical evidence of infection (pain, fever, drainage, leukocytosis). A positive culture from the infected site or organ should be present unless strong clinical evidence indicates the need for treatment despite negative cultures. The general categories of infection are: | |
| Localized nondevice infection: Infection localized to any organ system or region (e.g., mediastinitis) without evidence of systemic involvement (see sepsis definition), ascertained by standard clinical methods and either associated with evidence of bacterial, viral, fungal, or protozoal infection or requiring empirical treatment. | |
| Percutaneous site or pocket infection: Positive culture from the skin or tissue surrounding the driveline or from the tissue surrounding the external housing of a pump implanted within the body, coupled with the need to treat with antimicrobial therapy, when there is clinical evidence of infection, such as pain, fever, drainage, or leukocytosis. | |
| Internal pump component, inflow or outflow tract infection: Infection of blood-contacting surfaces of LVAD documented by positive site culture. There should be a separate data field for paracorporeal pump that describes infection at the percutaneous cannula site (e.g., Thoratec PVAD). | |
| Sepsis: Evidence of systemic involvement by infection, manifested by positive blood cultures or hypotension, or both. | |
| Reoperation (bleeding, infection, wound dehiscence, wound debridement) | Return operation secondary to bleeding, infection, or disruption of the apposed surfaces of a surgical incision requiring surgical repair. |
| Pericardial fluid collection | Accumulation of fluid or clot in the pericardial space that requires surgical intervention or percutaneous catheter drainage. |
| This event is subdivided into events with clinical signs of tamponade (e.g., increased central venous pressure and decreased cardiac or VAD output) and events without signs of tamponade. | |
| Device malfunction | Device malfunction denotes a failure of one or more of the components of the MCS device system, which either directly causes or could potentially induce a state of inadequate circulatory support (low cardiac output state) or death. The manufacturer must confirm device failure. A failure that was iatrogenic or recipient induced would be classified as an iatrogenic/recipient-induced failure. |
Device failure should be classified according to which components fail:
| |
| Psychiatric episode | Disturbance in thinking, emotion, or behavior that causes substantial impairment in functioning or marked subjective distress requiring intervention. Intervention is the addition of new psychiatric medication, hospitalization, or referral to a mental health professional for treatment. Suicide is included in this definition. |
Time-related occurrence, contributing factors, and causation
Adverse events occurring early after implantation are often ascribed to the preoperative condition of the patient and often reflect the risks associated with preoperative morbidity—major cardiac surgery is being performed in patients with advanced heart failure, often decompensated and with altered metabolic status and end-organ injury. In contrast, the more chronically occurring events generally result from device design issues or management strategies.
From an analytic perspective, both the time to occurrence of a given adverse event and its repetitive nature (incidence) help characterize its impact. Although the exact “cutoff” is rather arbitrary, multiple analyses have identified different adverse events and frequencies that are more prominent early or later after implantation ( Table 13.1 ). Additional challenges are highlighted by the following examples. A single stroke can have relatively minor or devastating effects on the patient’s QOL. Strokes are discrete events in many cases, although extension of a stroke by hemorrhagic conversion may occur. By contrast, infections and especially device-related infections have slow onset so that the date of an infection AE often describes the date of diagnosis rather than the date of onset. Moreover, the date for resolution for an infection may reflect the cessation of antimicrobial therapy rather than a bona-fide eradication of infection. For example, driveline percutaneous exit site infections are typically treated for weeks with antibiotics and then the antibiotics are stopped. If erythema and purulent drainage at the site worsen, the patient will presumably be placed back on antibiotic therapy. Should this be counted as a de novo infection or persistence of a prior infection? If a driveline percutaneous exit site infection occurs, should all other episodes of driveline infection be considered recurrences of the initial event or only if the infecting organism changes? If the patient is placed on chronic suppressive antibiotic therapy, should the initial episode of driveline infection be considered as resolved or ongoing? Thus, considerable analytic challenges exist as we seek “truths” about the potential life-threatening complications of this therapy.
| Variable | Early | Constant | ||
|---|---|---|---|---|
| Hazard Ratio | P Value | Hazard Ratio | P Value | |
| Demographics | ||||
| 1.5 | < 0.0001 | 1.23 | < 0.0001 |
| 1.37 | 0.0001 | ||
| 1.11 | 0.0008 | 1.05 | 0.0053 |
| 1.15 | 0.0007 | ||
| 2.3 | < 0.0001 | ||
| 1.71 | < 0.0001 | ||
| 1.21 | 0.017 | ||
| 1.28 | 0.002 | ||
| 1.15 | 0.0011 | ||
| 1.39 | < 0.0001 | ||
| Clinical Status | ||||
| 1.42 | 0.0003 | ||
| 1.83 | < 0.0001 | ||
| 1.18 | 0.0002 | ||
| 2.27 | < 0.0001 | ||
| 1.17 | 0.0026 | ||
| 1.29 | 0.0009 | 1.14 | 0.0032 |
| Laboratory Values | ||||
| 3.67 | 0.0034 | 1.13 | 0.0009 |
| 1.16 | < 0.0001 | ||
| 1.08 | < 0.0001 | ||
| 0.77 | 0.0002 | ||
| 1.32 | < 0.0001 | ||
| 3.27 | < 0.0001 | ||
| Hemodynamics | ||||
| 1.59 | < 0.0001 | ||
| 0.82 | < 0.0001 | ||
| Echocardiographic Parameters | ||||
| 1.41 | < 0.0001 | ||
Risk Factors
The need for biventricular support because of severe left and right heart failure increases the risk of many adverse events, including respiratory failure, neurologic events, renal dysfunction, and cardiac arrhythmias. Obesity is a risk factor for adverse events in general, with greatest impact on infection incidence.
Adverse event burden and era effect
The overall impact of adverse events can be discussed under the descriptive category of “adverse event burden.” While nonquantitative, depictions such as freedom from any of a group of adverse events are a first step in such a description ( Fig. 13.4 ). As experience has accumulated in the care of patients with CF devices, the incidence of many adverse events has gradually decreased ( Table 13.2 ). This era effect is also in part accounted for by cumulative experience with these devices over time. For example, evaluation of multiple adverse events, along with survival (event-free survival), was an integral part of clinical trials with the HeartMate 3 (HM3) magnetically levitated centrifugal flow pump with wide pathways engineered to minimize friction during propulsion and avoid stasis with an intrinsic pulse design. The primary endpoint of the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial was survival free of disabling stroke and pump exchange. This combined endpoint showed superiority in the HM3 versus the HMII at 6 months and 2 years, largely related to a major reduction in pump exchange for thrombosis. The primary endpoint of comparing the CE Mark trial for the HM3 device to a recent report of “real-world” experience in Germany demonstrated improvement in the incidence of multiple adverse events during the first year in the postclinical trial experience: GI bleeding (12%–7%), right heart failure (10%–7.4%), stroke (18%–0%), and all bleeding (44%–30%).
| Adverse Event | Era 1 ( n = 4744) | Era 2 ( n = 7286): | Era 1 vs. Era 2 | |||
|---|---|---|---|---|---|---|
| Continuous 2008–2011 | Continuous 2012–2014 | 2008–2011/2012–2014 | ||||
| Events | Rate | Events | Rate | Ratio | P Value | |
| 3,932 | 9.41 | 4,420 | 7.79 | 1.21 | < 0.0001 |
| ||||||
| 238 | 0.57 | 276 | 0.49 | 1.17 | 0.07 |
| 29 | 0.07 | 34 | 0.06 | 1.16 | 0.55 |
| 2,007 | 4.80 | 2,303 | 4.06 | 1.18 | < 0.0001 |
| 271 | 0.65 | 305 | 0.54 | 1.21 | 0.02 |
| 182 | 0.44 | 115 | 0.20 | 2.15 | < 0.0001 |
| 70 | 0.17 | 94 | 0.17 | 1.01 | 0.93 |
| 304 | 0.73 | 286 | 0.50 | 1.44 | < 0.0001 |
| 200 | 0.48 | 314 | 0.55 | 0.87 | 0.11 |
| 3,435 | 8.22 | 4,132 | 7.28 | 1.13 | < 0.0001 |
| 487 | 1.17 | 916 | 1.61 | 0.72 | < 0.0001 |
| 601 | 1.44 | 876 | 1.54 | 0.93 | 0.19 |
| 246 | 0.59 | 326 | 0.57 | 1.02 | 0.76 |
| 1,104 | 2.64 | 1,551 | 2.73 | 0.97 | 0.39 |
| 81 | 0.19 | 96 | 0.17 | 1.15 | 0.36 |
| 486 | 1.16 | 525 | 0.93 | 1.26 | 0.0003 |
| 13,673 | 32.72 | 16,569 | 29.20 | 1.12 | < 0.0001 |
Adverse events contributing to death
The risk of death caused by various adverse events changes over time ( Fig. 13.5 ). The risk of death from right heart failure is greatest early postimplantation, whereas infection death has an early peak and then gradually increases again after about 2 years. The risk of neurologic death decreases rapidly during the first 6 months and then remains relatively constant. When viewed over a 6-year period, neurologic events account for the greatest cumulative risk of death, followed by infection adverse events ( Fig. 13.6 ). The dramatic impact of adverse events on subsequent mortality is underscored in an analysis from INTERMACS, which demonstrates the strong predictive value of multiple adverse events during the first 3 months on subsequent survival ( Table 13.3 , Fig. 13.7 ).
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