Continuous-flow left ventricular assist devices (CF-LVADs) are associated with complications such as thromboembolic (TE) events,1 renal dysfunction,2 bleeding,3 and infection,4 which can all result in high morbidity and mortality. Studies have shown varying rates of bleeding events, ranging from 15% to 50% and TE events occur in approximately 1% to 6% of patients implanted with CF-LVAD. Although in the past decade we have seen great progress in mechanical circulatory support devices, resulting in improved quality of life, survival, and functional capacity, it is not possible to pronounce the same for complications, and today, we are still trying to find new ways of overcoming complications. Hemorrhage and thrombosis after device implantation are multifactorial phenomenons, which are affected by anticoagulant management, presence of infection, and high blood pressure. There have been a great number of studies describing the rate of bleeding and TE events in CF-LVAD patients, also evaluating the possible risk factors before and after implantation.5 But, no scoring system is defined for patients with CF-LVADs to determine the risk of bleeding and TE events.
CHA2DS2-VASc6,7 is a scoring system recommended to predict the annual stroke risk in nonrheumatic atrial fibrillation (AF) patients, which allows the physician to decide on anticoagulant treatment. HAS-BLED8,9 is a scoring system developed to assess 1 year risk of bleeding in patients with AF and guides physicians to detect and protect high-risk patients. There are limited number of studies using scoring systems to predict possible complications after LVAD implantation. Koene et al.10 have studied the predictability of these two scoring tools in a single group of LVADs, HeartMate II (HMII; Thoratec Corporation, Pleasanton, CA), although further studies are needed to warrant the utility of these scoring systems. Moreover, different types of LVADs are being used worldwide, and for this reason, it is necessary to evaluate the effectiveness of scoring tools not only in a single group of LVADs but also in different device groups.
Our aim was to evaluate the utility of basal CHA2DS2-VASc and HAS-BLED scores of patients as a predictor of TE and bleeding events risk after CF-LVAD implantation. Our hypothesis was that basal CHA2DS2-VASc and HAS-BLED scores would expose high-risk patients for bleeding and TE events after CF-LVAD implantation.
We retrospectively reviewed charts of all patients who underwent CF-LVAD implantation from December 2010 through December 2014 at a single center. A total of 145 patients received CF-LVAD with a mean age of 50.7 ± 11.2 years and 85.5% being male. The majority of the patients, 113, were implanted with HVAD (HeartWare, Framingham, MA), 31 patients received HMII (HeartMate II, Thoratec Corporation, Pleasanton, CA), and 1 patient received Heart Assist 5 (Reliant Heart Inc., Houston, TX), of which all were continuous-flow devices. Demographic data, presence, and etiology of bleeding and presence and etiology of TE events were recorded for all.
After device implantation, all patients were on warfarin (goal international normalized ratio [INR] 2–3) as well as 300 mg of aspirin daily at discharge. All patients received conventional heart failure therapy and were on routine follow-up for the assessment of their general status and device review. Follow-up began at the time of CF-LVAD implantation, and patients were censored at death, heart transplantation, or end of data collection, whichever came first. Blood pressure was measured with Doppler USG (Hadeco Echo Sounder ES-101EX 2MHz) and the target mean pressure was 85 mmHg. Bleeding event was described as any occurrence of systemic bleeding that required hospital admission or blood transfusion at any time during admission outside the 48 hour immediate postoperative period. Hemorrhagic conversion from ischemic stroke and iatrogenic bleeding, such as that caused by tissue plasminogen activator or unfractioned intravenous heparin use, were excluded. TE events were described as ischemic stroke, transient ischemic attack (TIA), systemic embolus, or pump thrombosis. Pump thrombosis was defined as echocardiographic appearance of a thrombus or diagnosis of pump thrombosis based on criteria including symptoms, intravascular hemolysis, and altered pump parameters (Figure 1). Surgery-related complications and events that occurred at postoperative first 48 hours were excluded. Baseline CHA2DS2-VASc and HAS-BLED scores were retrospectively determined for all 145 patients from the medical history at the time of implantation.
CHA2DS2-VASc scores were calculated using the original scoring system6,7 from patient data before CF-LVAD implantation: congestive heart failure/left ventricular dysfunction (1 point); known hypertension (1 point); age ≥ 75 (2 points); diabetes (1 point); history of stroke, TIA, or TE event (2 points); vascular disease, coronary heart disease, peripheral artery disease, or complex aortic plaque (1 point); female sex (1 point) and age more than 65 to less than 75 years (1 point).
HAS-BLED scores were calculated using the original scoring system8,9 from patient data before CF-LVAD implantation: uncontrolled hypertension, more than 160 mmHg systolic (1 point); abnormal renal/liver function (1 point for each); previous history of stroke (1 point); bleeding history or predisposition (anemia; 1 point); labile INR (1 point); elderly, older than 65 years (1 point); drug use—antiplatelet agents or nonsteroidal antiinflammatory drugs—and alcohol consumption (1 point each).
All statistical analyses were performed using SPSS for Windows (version 18.0; SPSS, Chicago, IL). Data are presented as percentages for discrete variables and as mean ± standard deviation for continuous variables. A p value of less than 0.05 (two-sided) was regarded as statistically significant. Comparisons between groups were made by t-test or by Mann–Whitney U test based on the distribution pattern of the variables. Discrete variables were compared by Fisher exact test or by χ2 analysis, as appropriate.
The etiology of heart failure was ischemic in 77 (53.1%) and nonischemic in 68 (46.9%). Median follow-up was 316 days (range 31–1,060), and baseline characteristics of the patients are presented in Table 1. All patients received anticoagulation, the target INR was 2–3, and all were on 300 mg daily aspirin after CF-LVAD implantation.
Of the 145 patients, 22 (15.2%) experienced at least one TE event and 4 patients (2.7%) experienced both ≥1 bleeding event and ≥1 TE event. Among the 22 patients who had a TE event, 10 had pump thrombosis, 8 had ischemic stroke, and 4 had both during follow-up. Patients who experienced both TE and bleeding event had a TE event followed by a bleeding event. The mean CHA2DS2-VASc score at the time of implantation was 2.3 ± 1.4 and 2.5 ± 1.2 (p = 0.2) in patients with and without TE event, respectively.
Of the 145 patients, 32 (22.1%) experienced at least one bleeding event and 4 patients (2.7%) experienced both ≥1 bleeding event and ≥1 TE event. Of the 32 patients, 15 had gastrointestinal bleeding (GIB), 14 had intracranial bleeding, and 3 had both during follow-up. The mean HAS-BLED score at the time of implantation was 1.8 ± 0.8 and 1.4 ± 0.6 (p = 0.004) in patients with and without bleeding, respectively. Distribution of TE and bleeding events according to HAS-BLED and CHA2DS2-VASc scores are listed in Table 2.
During follow-up, 23 (33.3%) patients had orthotropic heart transplantation and 33 (47.8%) had died. Reason of death was device-related sepsis in 10 patients and pneumonia in 4 patients. Eleven patients had died because of intracranial bleeding and multiorgan failure (MOF), and the HAS-BLED score was ≥ 2 in six of the patients. Two patients had died because of ischemic stroke and sepsis, and the CHA2DS2-VASc scores were 6 and 3, respectively. Four patients had died after pump thrombosis, one of them because of sepsis (CHA2DS2-VASc score 3), two because of MOF and intracranial bleeding caused by thrombolytic therapy (CHA2DS2-VASc score was 4 and 1, respectively; HAS-BLED score was 1 in both), and one after pump exchange (CHA2DS2-VASc score was 4). One patient was found dead at home because of device malfunctioning, and reason of death is not known in one patient.
Difference Between Devices
The only patient with Heart Assist 5 had CHA2DS2-VASc and HAS-BLED score of 2 points. During follow-up of this patient, pump thrombosis occurred and was treated with unfractioned heparin infusion. Statistical analysis repeated with a total of 144 patients after exclusion of single-type LVAD showed no significant change in results. Yet again, with the study population divided into two groups as HMII (n = 31) and HVAD (n = 113), there was no difference regarding TE events (p = 0.5) between the two devices, although patients with HVAD had higher bleeding events. A total of 32 patients had a bleeding event and 30 of these patients had HVAD implanted. Mean HAS-BLED score of patients with HVAD with bleeding was 1.8 ± 0.8 and 1.4 ± 0.6 without bleeding event (p = 0.01).
Today, with LVAD implantation, survival at 1 and 2 years has reached 80% and 70%, respectively, and regarding Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry, survival is highest for CF-LVADs.11 Long-term survival was mostly affected by hemorrhagic and TE complications. There are many studies addressing the possible causes and pathophysiology of complications after CF-LVAD implantation,1,12,13 but there are still lots of concerns addressing the use of anticoagulants and target INR levels in balancing TE and bleeding events. No matter how high the risks of bleeding and thrombotic complications are, antiplatelet and anticoagulant treatments are mandatory after LVAD implantation. Bleeding and thrombotic complications are multifactorial; anticoagulation regime, functioning of organs, blood pressure measurements, and patient adherence to treatment are just some components after device implantation. There is still no standard anticoagulant protocol approved worldwide. Despite current guidelines recommended to balance thrombotic and hemorrhagic risk with an INR target of 1.5–2.5 and with low-dose aspirin,14 we do still experience adverse events after device implantation. Any scientific development in terms of prediction and prevention of those complications will improve survival after LVAD implantation.
Thrombosis in CF-LVAD patients is said to be multifactorial, and besides pump thrombosis, ischemic stroke and TIA are relatively common and often severe complications that impair quality of life. A study from INTERMACS registry found estimated 1 month, 3 month, and 1 year ischemic stroke rates of 3%, 5%, and 11%, respectively, in patients with CF-LVAD.15 The rate of TE event in our study was 15.2% and pump thrombosis was slightly more than ischemic stroke. One of the largest retrospective study evaluating preoperative risk factors for hemorrhagic and TE events by Boyle et al.12 has shown that for pump thrombosis, female sex and higher body mass index and for ischemic stroke, female sex and a history of diabetes were significant factors. Yet again, females below 65 years of age were at a higher risk of hemorrhagic stroke, whereas older women were at a higher risk of ischemic stroke. Besides, baseline INR and etiology of heart failure (ischemic and nonischemic) were shown to have an impact on postdischarge ischemic stroke and pump thrombosis. CHA2DS2-VASc is a scoring system recommended to predict the annual stroke risk in nonrheumatic AF patients,6 although it has been evaluated as a stroke risk predictor after device implantation such as transcatheter aortic valve implantation (TAVI) and LVAD. The Italian Transcatheter Balloon-Expandable Valve Implantation Registry, a multicenter study, has shown that CHA2DS2-VASc score provided a strong correlation for in-hospital stroke after TAVI.16
CHA2DS2-VASc score includes a plurality of specified factors; therefore, although in our study the scoring system was not a predictor of TE events, we suggest that it may give an idea of the risk of a TE event after CF-LVAD implantation, pointing out especially patients who had died because of pump thrombosis and ischemic stroke and their remarkably high CHA2DS2-VASc scores. One reason for CHA2DS2-VASc score not being able to predict TE event could be the relatively small number of events (15.2% of the cohort had TE event) in our study. Yet again, there was no difference regarding TE events between the two different types of devices, HMII and HVAD (p = 0.5), making it unable to permit definitive comparison of how the scores perform in the different device populations.
Koene et al.10 did a single and large study evaluating these scoring systems in LVAD patients. They have evaluated these scoring systems in patients with HMII and shown that a baseline CHA2DS2-VASc score of ≥ 3 conferred significantly higher risks of TE events.10 In our study, CHA2DS2-VASc score was not predictive of TE events and the majority of our patient population consisted of HVAD CF-LVADs, distinguishing it from the prior study. Regarding the differences between devices, studies have shown an abrupt increase in the rate of pump thrombosis at 3 months postimplant of HMII.17 The type of implanted device might have contributed to the results of the study conducted by Koene et al.10 Taking into consideration the lately increasing rate of ischemic stroke and pump thrombosis, we routinely give 300 mg daily aspirin to all patients. This treatment is standard.
Increased bleeding (commonly gastrointestinal, epistaxis, or rarely intracranial) complications have been associated with CF-LVAD implantation, and there are reported rates that differ from 19%,18 22.8%19 to as high as 44.3%.3 A rate of 22.1% bleeding event in our study correlates well with the literature. Risk factors for increased risk of bleeding in patients with CF-LVADs include a prior history of GIB, lower body mass index, old age, smoking, elevated INR, and a low platelet count.19 Meyer et al.20 studied whether centrifugal (HVAD) versus axial (HMII) devices may lead to differences in the von Willebrand profile. The degree of decrease in large-molecular-weight multimers of von Willebrand factors (vWFs) was similar across both devices. However, device speed appeared to affect the vWF profile in HVAD patients but not in patients with the HMII.20 Crow et al.13 demonstrated in a multicenter study that all CF-LVAD recipients developed acquired von Willebrand syndrome after device implantation, although with their results they concluded that the loss of high-molecular-weight vWF multimers alone cannot predict bleeding risk in this patient group. Prior studies comparing HMII and HVAD have shown higher GIB rates in HVAD population.21 Besides device type, there are more factors contributing to bleeding. Boyle et al.12 demonstrated more than 65 years of age, sex, ischemic etiology, and lowest quartile hematocrit as independent risk factors for bleeding. Men older than 65 years had a lower incidence of bleeding event than a woman at same age.12 In our study, HAS-BLED score was a predictor of bleeding events after CF-LVAD implantation. Similarly, Koene et al.10 had shown that a HAS-BLED score of greater than 3 was predictive of bleeding events in patients with HMII. Subgroup analysis depending on device type showed that bleeding event rates were higher in patients with HVAD and basal HAS-BLED score was again predictive of bleeding event in our cohort.
Koene et al.10 have analyzed in detail the risk factor components of HAS-BLED and CHA2DS2-VASc scores in their patients and has determined event risks by the scores, concluding that both scoring systems could give an idea for possible complications. In our study, we have questioned independent from these factors whether the scoring systems as a whole may be useful for predicting complications. We performed a retrospective review characterizing the rates and etiologies of bleeding and TE events in patients after CF-LVAD implantation and evaluated the utility of basal CHA2DS2-VASc and HAS-BLED scoring systems as predictors of these events.
Four (2.7%) patients experienced both TE and bleeding events, and all had a TE event followed by a bleeding. Therefore, it is certainly possible that a patient with a TE event could be at a higher risk of a bleeding event. As some variables of CHA2DS2-VASc and HAS-BLED score overlap, it does actually reflect that a patient can be prone to both bleeding and TE event. According to our results, basal HAS-BLED score predicts bleeding after CF-LVAD implantation and CHA2DS2-VASc score may give an idea of TE event risk.
There are several limitations of our investigation; first of all, it was a retrospective analysis. Second, bias and confounding effects can be introduced because there was no randomization or blinding. Third, both axial and centrifugal LVADs were included. Also, by calculating CHA2DS2-VASc and HAS-BLED scores before device implantation, we have neglected postimplantation possible factors.
Preoperative CHA2DS2-VASc and HAS-BLED scores were evaluated in advanced heart failure patients receiving different types of CF-LVADs. HAS-BLED score was predictive of bleeding events after implantation, whereas in contrast to prior studies, baseline CHA2DS2-VASc score was not predictive of TE events.
Subgroup analysis comparing devices HMII and HVAD have shown higher bleeding event rates and significant higher basal HAS-BLED score predictive of bleeding in patients with HVAD.
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