Michael E. Nassif

Systolic blood pressure on discharge after left ventricular assist device insertion is associated with subsequent stroke

BACKGROUND Stroke is a significant complication in patients supported with continuous-flow left ventricular assist devices (CF-LVAD) and hypertension is a significant risk factor for stroke, but the association between blood pressure and stroke in LVAD patients is not well characterized. METHODS We identified 275 consecutive patients who survived implant hospitalization between January 2005 and April 2013. Patients were grouped according to systolic blood pressure (SBP) as above a median and below a median of 100 mm Hg by their averaged systolic blood pressure during the 48 hours before discharge from implantation hospitalization. The groups were compared for the primary outcome of time to stroke. RESULTS The above-median SBP group had mean SBP of 110 mm Hg and the below-median SBP group had mean SBP of 95 mm Hg. There were no significant between-group differences in body mass index, smoking, vascular disease, hypertension, atrial fibrillation, or prior stroke. During a mean follow-up of 16 months, stroke occurred in 16% of the above-median SBP group vs in 7% of the below-median SBP group (hazard ratio, 2.38; 95% confidence interval, 1.11-5.11), with a similar proportion of hemorrhagic and ischemic strokes in each group. In Cox proportional hazard models adjusting for age, diabetes, or prior stroke, the hazard ratio remained statistically significant. SBP as a continuous variable predictor of stroke had an area under the curve of 0.64 in a receiver operating characteristic curve analysis. CONCLUSIONS In this large, CF-LVAD cohort, elevated SBP was independently associated with a greater risk of subsequent stroke. These results identify management of hypertension as a potential modifiable risk factor for reducing the incidence of stroke in patients supported by CF-LVAD.

Intra-Aortic Balloon Counterpulsation in Patients With Chronic Heart Failure and Cardiogenic Shock: Clinical Response and Predictors of Stabilization

OBJECTIVE The aim of this work was to characterize the clinical response and identify predictors of clinical stabilization after intra-aortic balloon counterpulsation (IABP) support in patients with chronic systolic heart failure in cardiogenic shock before implantation of a left ventricular assist device (LVAD). BACKGROUND Limited data exist regarding the clinical response to IABP in patients with chronic heart failure in cardiogenic shock. METHODS We identified 54 patients supported with IABP before LVAD implantation. Criteria for clinical decompensation after IABP insertion and before LVAD included the need for more advanced temporary support, initiation of mechanical ventilation or dialysis, increase in vasopressors/inotropes, refractory ventricular arrhythmias, or worsening acidosis. The absence of these indicated stabilization. RESULTS Clinical decompensation after IABP occurred in 23 patients (43%). Both patients who decompensated and those who stabilized had similar hemodynamic improvements after IABP support, but patients who decompensated required more vasopressors/inotropes. Clinical decompensation after IABP was associated with worse outcomes after LVAD implantation, including a 3-fold longer intensive care unit stay and 5-fold longer time on mechanical ventilation (P < .01 for both). Although baseline characteristics were similar between groups, right and left ventricular cardiac power indexes (cardiac power index = cardiac index × mean arterial pressure/451) identified patients who were likely to stabilize (area under the receiver operating characteristic curve = 0.82). CONCLUSIONS Among patients with chronic systolic heart failure who develop cardiogenic shock, more than one-half of patients stabilized with IABP support as a bridge to LVAD. Baseline measures of right and left ventricular cardiac power, reflecting work performed for a given flow and pressure, may allow clinicians to identify patients with sufficient contractile reserve who will be likely to stabilize with an IABP versus those who may need more aggressive ventricular support.

Relationship Between Anticoagulation Intensity and Thrombotic or Bleeding Outcomes Among Outpatients With Continuous-Flow Left Ventricular Assist Devices

Background—We evaluated thrombotic and bleeding outcomes in patients with continuous-flow left ventricular assist devices (CF-LVADs), stratified by anticoagulation intensity. Previous studies of outpatients with CF-LVADs have suggested that target international normalized ratio (INR) values <2.5 (range, 2–3) may be used. However, recent studies reported an increase in pump thrombosis among CF-LVADs, especially within the first 6 months of implant. Methods and Results—We retrospectively reviewed 249 outpatients at our center who received a CF-LVAD between January 2005 and August 2013. Using Poisson models, we analyzed their 10 927 INRs to determine INR-specific rates of thrombotic (ischemic stroke and suspected pump thrombosis) and hemorrhagic (gastrointestinal bleeding and hemorrhagic stroke) events occurring outside of the hospital. In multivariate analyses, we adjusted for age, sex, atrial fibrillation, coronary disease, and LVAD type as time-dependent Cox proportional hazard models. During a mean follow-up of 17.6±13.6 months, thrombotic events occurred in 46 outpatients. The highest event rate (0.40 thrombotic events per patient-year) was in the INR range of <1.5, but INR values of 1.5 to 1.99 also had high rates (0.16 thrombotic events per patient-year). INR was inversely associated with thrombotic events (hazard ratio, 0.40; 95% confidence interval, 0.22–0.72; P=0.002). The optimal INR based on weighted mortality of thrombotic and bleeding events was 2.6. Conclusions—INR is inversely related to thrombotic events occurring outside of the hospital among patients supported with CF-LVADs. INR values <2.0 increase the rate of thrombotic events occurring outside of the hospital among patients supported with CF-LVADs.

Incidence and Predictors of Cognitive Decline in Patients with Left Ventricular Assist Devices

Background—After left ventricular assist device (LVAD) placement for advanced heart failure, increased cerebral perfusion should result in improved cognitive function. However, stroke (a well-known LVAD complication) and subclinical cerebral ischemia may result in transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool. Methods and Results—Among 4419 patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent LVAD implantation between May 2012 and December 2013, cognitive function was assessed in 1173 patients with the Trail Making B Test before LVAD and at 3, 6, and 12 months. The test detects several forms of cognitive impairment, including subclinical stroke. Cognitive decline was defined as a clinically important increase during follow-up using a moderate Cohen d effect size of 0.5×baseline SD (32 s). The cumulative incidence of cognitive decline in the year after LVAD implantation, treating death and transplantation as competing risks, was 29.2%. In adjusted analysis, older age (≥70 versus <50 years; hazard ratio, 2.24; 95% confidence interval 1.46–3.44; Ptrend<0.001) and destination therapy (hazard ratio, 1.42; 95% confidence interval, 1.05–1.92) were significantly associated with greater risk of cognitive decline. Conclusions—Cognitive decline occurs commonly in patients in the year after LVAD and is associated with older age and destination therapy. These results could have important implications for patient selection and improved communication of risks before LVAD implantation. Additional studies are needed to explore the association between cognitive decline and subsequent stroke, health status, and mortality in patients after LVAD.

Systemic inflammatory response syndrome after transcatheter or surgical aortic valve replacement

Objective An inflammatory response after cardiac surgery is associated with worse clinical outcomes, but recent trials to attenuate it have been neutral. We evaluated the association between systemic inflammatory response syndrome (SIRS) and mortality after transcatheter (TAVR) and surgical aortic valve replacement (SAVR) for aortic stenosis (AS) and evaluated whether diabetes influenced this relationship. Methods Patients (n=747) with severe AS treated with TAVR (n=264) or SAVR (n=483) between January 2008 and December 2013 were included and 37% had diabetes mellitus. SIRS was defined by four criteria 12–48 h after aortic valve replacement (AVR): (1) white blood cell count <4 or >12; (2) heart rate >90; (3) temperature <36 or >38°C; or (4) respiratory rate >20. Severe SIRS was defined as meeting all four criteria. The primary endpoint was 6-month all-cause mortality (60 deaths occurred by 6 months). Inverse probability weighting (IPW) was performed on 44 baseline and procedural variables to minimise confounding. Results Severe SIRS developed in 6% of TAVR patients and 11% of SAVR patients (p=0.02). Six-month mortality tended to be higher in those with severe SIRS (15.5%) versus those without (7.4%) (p=0.07). After adjustment, severe SIRS was associated with higher 6-month mortality (IPW adjusted HR 2.77, 95% CI 2.04 to 3.76, p<0.001). Moreover, severe SIRS was more strongly associated with increased mortality in diabetic (IPW adjusted HR 4.12, 95% CI 2.69 to 6.31, p<0.001) than non-diabetic patients (IPW adjusted HR 1.74, 95% CI 1.10 to 2.73, p=0.02) (interaction p=0.007). The adverse effect of severe SIRS on mortality was similar after TAVR and SAVR. Conclusions Severe SIRS was associated with a higher mortality after SAVR or TAVR. It occurred more commonly after SAVR and had a greater effect on mortality in diabetic patients. These findings may have implications for treatment decisions in patients with AS, may help explain differences in outcomes between different AVR approaches and identify diabetic patients as a high-risk subgroup to target in clinical trials with therapies to attenuate SIRS.

Clinical outcomes associated with INTERMACS-defined right heart failure after left ventricular assist device implantation

Background: Left Ventricular Assist Device (LVAD) pump thrombosis (PT) is a devastating complication of mechanical circulatory support. The diagnosis of LVAD thrombus is difficult in vivo, often only suggested by markers of hemolysis and echocardiographic features, which lack sensitivity. We sought to test a probe with high avidity anti-fibrin 99mTc to localize and quantify thrombus within the high shear environment of titanium axial-flow pumps. Methods: Monomeric bifunctional ligands with a fibrin-specific peptide, a short spacer, and technetium chelating amino acid sequence (F1A) were covalently inter-coupled via a 4-arm-PEG2000 tetramer to form F4A. Each was radiolabeled with 99mTc using the IsoLink procedure. We collected 20 explanted HeartMate II LVADs, of which 9 were explanted for suspected pump thrombosis and 11 were explanted during heart transplant or exchange for other complications. Ex-vivo imaging of explanted pumps was conducted in plasma using a mock circulatory loop running at 9400 RPM for 30 minutes as has previously been described. After imaging the devices were sent to the manufacturer for disassembly and thorough inspection for thrombus. Results: The majority of patients were male (85%) with a mean age of 54.1 6 9.8 and a median INTERMACS profile of 2. The median time of LVAD support prior to explant was 7.6 6 7.2 months. Of the 9 patients exchanged for suspected pump thrombosis all had undetectable haptoglobin levels and mean LDH levels of 3520 6 2596. All 9 had CT scans prior to LVAD exchange without any visualized thrombus or kinking of the inflow or outflow cannulas. Two of the pumps have been disassembled and inspected by the manufacturer. Both pumps were in patients with suspected pump thrombosis and both the pumps had thrombus found on SPECT imaging and on visual inspection (Figure 1A and 1B). Conclusions: A novel, fibrin-specific 99mTc small tetrameric probe offers the potential to detect, localize, and quantify intra-LVAD thrombus noninvasively. Once verified in a large cohort this agent offers the opportunity to diagnose LVAD pump thrombosis at an earlier stage. Definite and early diagnosis may confer therapeutic options to avoid pump failure and/or costly and morbid LVAD exchange.

Video capsule endoscopy in left ventricular assist device recipients with obscure gastrointestinal bleeding.

AIM To assess whether video capsule endoscopy (VCE) affects the outcomes of left ventricular assist devices (LVADs) recipients with gastrointestinal bleeding. METHODS This is a retrospective study of LVAD recipients with obscure gastrointestinal bleeding (OGIB) who underwent VCE at a tertiary medical center between 2005 and 2013. All patients were admitted and monitored with telemetry and all VCE and subsequent endoscopic procedures were performed as inpatients. A VCE study was considered positive only when P2 lesions were found and was regarded as negative if P1 or P0 were identified. All patients were followed until heart transplant, death, or the end of the study. RESULTS Between 2005 and 2013, 30 patients with LVAD underwent VCE. Completion rate of VCE was 93.3% and there was no capsule retention. No interference of VCE recording or the function of LVAD was found. VCE was positive in 40% of patients (n = 12). The most common finding was active small intestinal bleeding (50%) and small intestinal angiodysplasia (33.3%). There was no difference in the rate of recurrent bleeding between patients with positive and negative VCE study (50.0% vs 55.6%, P = 1.00) during an average of 11.6 ± 9.6 mo follow up. Among patients with positive VCE, the recurrent bleeding rate did not differ whether subsequent endoscopy was performed (50% vs 50%, P = 1.00). CONCLUSION VCE can be safely performed in LVAD recipients with a diagnostic yield of 40%. VCE does not affect recurrent bleeding in LVAD patients regardless of findings.

Prospective Assessment of Frailty Using the Fried Criteria in Patients Undergoing Left Ventricular Assist Device Therapy

Frail patients are more prone to adverse events after cardiac surgery, particularly after implantation of left ventricular assist devices. Thus, frailty assessment may help identify patients unlikely to benefit from left ventricular assist device therapy. The purpose was to establish a suitable measure of frailty in adults with end-stage heart failure. In a prospective cohort of 75 patients (age 58 ± 12 years) with end-stage heart failure, we assessed the association between frailty (5-component Fried criteria) and the composite primary outcome of inpatient mortality or prolonged length of stay, as well as extubation status, time on ventilator, discharge status, and long-term mortality. Fried frailty criteria were met in 44 (59%) patients, but there was no association with the primary outcome (p = 0.10). However, an abridged set of 3 criteria (exhaustion, inactivity, and grip strength) was predictive of the primary outcome (odds ratio 2.9, 95% confidence interval 1.1 to 7.4), and of time to extubation and time to discharge. In patients with advanced heart failure, the 5-component Fried criteria may not be optimally sensitive to clinical differences. In conclusion, an abridged set of 3 frailty criteria was predictive of the primary outcome and several secondary outcomes, and may therefore be a clinically useful tool in this population.

Effect of glucose-lowering therapies on heart failure

Heart failure is one of the most common comorbidities of diabetes mellitus. Glucose-lowering therapies that can prevent heart failure or improve outcomes in patients with established heart failure are of critical importance among those with type 2 diabetes. Several types of glucose-lowering drugs have been assessed in this setting. Metformin has been shown to modestly improve the outcomes of patients with heart failure, whereas the effect of insulin in those with established heart failure is less clear. The effect of sulfonylureas on improving heart failure is controversial; observational reports have suggested that they are harmful in these patients, but these data have not been confirmed in randomized, controlled trials. Thiazolidinediones are contraindicated in patients with established heart failure and have also been known to cause heart failure. Furthermore, certain dipeptidyl peptidase 4 inhibitors seem to increase heart failure hospitalization. The effects of glucagon-like peptide 1 receptor agonists might differ in patients with or without established heart failure, particularly those with decompensated heart failure with a reduced ejection fraction. However, perhaps the most important finding has been that sodium/glucose cotransporter 2 (SGLT2; also known as SLC5A2) inhibitors reduce heart failure hospitalizations and, in the case of empagliflozin, markedly reduce the rate of cardiovascular death. Given the known neutral (or even harmful) effects of other glucose-lowering drugs on heart failure outcomes, SGLT2 inhibitors might well be considered the drug class of choice in patients with diabetes and heart failure, or in those at high risk of developing heart failure.

Prevalence of lactic acidaemia in patients with advanced heart failure and depressed cardiac output

Heart failure (HF) has been defined classically as a condition in which the heart is unable to deliver sufficient oxygen to match the needs of the metabolizing tissues. Surprisingly, this definition has never been validated. The goal of this study was to determine the prevalence of elevated lactate levels in a cohort of patients with advanced heart failure.