Kim Brunisholz

A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II)

Background— Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. Methods and Results— A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ⩽1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance. Conclusions— These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.

Morbidity and mortality in heart transplant candidates supported with mechanical circulatory support: is reappraisal of the current United network for organ sharing thoracic organ allocation policy justified?

Background— Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list.nnMethods and Results— We analyzed mortality and morbidity in 33 073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P <0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P <0.0001) and similar to that in status 1B patients (HR, 1.04; P =0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P =0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P <0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P =0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P <0.0001) and temporary VADs (HR, 7.72; P <0.0001).nnConclusions— Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts.nn# Clinical Perspective {#article-title-31}Background— Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list. Methods and Results— We analyzed mortality and morbidity in 33 073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P<0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P<0.0001) and similar to that in status 1B patients (HR, 1.04; P=0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P=0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P<0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P=0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P<0.0001) and temporary VADs (HR, 7.72; P<0.0001). Conclusions— Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts.

Prior Human Leukocyte Antigen-Allosensitization and Left Ventricular Assist Device Type Affect Degree of Post-implantation Human Leukocyte Antigen-Allosensitization

Left ventricular assist device (LVAD) implantation before heart transplantation has been associated with formation of antibodies directed against human leukocyte antigens (HLA), often referred to as sensitization. This study investigated whether prior sensitization or LVAD type affected the degree of post-implantation sensitization. The records of consecutive HeartMate (HM) I and HM II LVAD patients were reviewed. Panel reactive antibody (PRA) was assessed before LVAD implantation and biweekly thereafter. Sensitization was defined as PRA > 10%, and high-degree sensitization was defined as PRA > 90%. An HM LVAD was implanted in 64 patients, and 11 received a HM II LVAD as a bridge to transplant. Ten HM I patients (16%) were sensitized before LVAD implantation (HM I-S), and 54 (84%) were not (HM I-Non-S). Nine HM I-S patients (90%) became highly sensitized (PRA > 90%) compared with 9 HM I-Non-S patients (16.7%; p < 0.001). The PRA remained elevated (> 90%) in 8 of the 9 (88.9%) highly sensitized HM I-S patients vs 5 of the 9 (55.6%) HM I-Non-S highly sensitized patients. The PRA levels in the rest of the HM I-S highly sensitized patients declined from 93% +/- 4% to 55% +/- 15% (p = 0.01). Among the 11 HM II patients, 1 (9%) was sensitized before LVAD implantation (PRA, 40%) and the PRA moderately increased to 80%. No other HM II patient became sensitized after implantation. Thus, 1 of 11 (9%) HM II patients became sensitized compared with 29 of 64 (45%) HM I patients (p = 0.04). Pre-sensitized patients are at higher risk for becoming and remaining highly HLA-allosensitized after LVAD implantation. The HeartMate II LVAD appears to cause less sensitization than HeartMate I.

Peripartum cardiomyopathy: post-transplant outcomes from the United Network for Organ Sharing Database.

BACKGROUNDnNearly 25% of patients with peripartum cardiomyopathy (PPCM) will require cardiac transplantation. Whether post-transplant outcomes differ among patients with PPCM compared with other recipients remains unsettled.nnnMETHODSnThe United Network for Organ Sharing database was queried for cardiac transplants, comparing characteristics and outcomes for PPCM, other women, and all others.nnnRESULTSnBetween 1987 and 2010, 42,406 patients (9,419 women and 32,987 men) received a heart transplant. Of these, 485 women who had PPCM as the indication were younger (p < 0.001), had higher sensitization (p < 0.001), required higher intensity of cardiovascular support pre-transplant (p = 0.026), and had higher listing status (p < 0.001). Those with PPCM had more post-transplant rejection during the index transplant hospitalization (p < 0.001) and during the first year (p = 0.003). Comparing PPCM with other women and all others, graft survival was inferior (p = 0.004 and p < 0.003, respectively) and age-adjusted survival was lower (p < 0.001 and p = 0.02, respectively).nnnCONCLUSIONSnThis large report shows outcomes of graft failure and death are inferior for recipients with PPCM, which may be partly explained by younger age, higher allosensitization, higher pre-transplant acuity, and increased rejection. More research is needed to determine management strategies to improve outcomes in PPCM heart transplant recipients.

Characterization of diffuse fibrosis in the failing human heart via diffusion tensor imaging and quantitative histological validation

Non‐invasive imaging techniques are highly desirable as an alternative to conventional biopsy for the characterization of the remodeling of tissues associated with disease progression, including end‐stage heart failure. Cardiac diffusion tensor imaging (DTI) has become an established method for the characterization of myocardial microstructure. However, the relationships between diffuse myocardial fibrosis, which is a key biomarker for staging and treatment planning of the failing heart, and measured DTI parameters have yet to be investigated systematically. In this study, DTI was performed on left ventricular specimens collected from patients with chronic end‐stage heart failure as a result of idiopathic dilated cardiomyopathy (nu2009=u200914) and from normal donors (nu2009=u20095). Scalar DTI parameters, including fractional anisotropy (FA) and mean (MD), primary (D1), secondary (D2) and tertiary (D3) diffusivities, were correlated with collagen content measured by digital microscopy. Compared with hearts from normal subjects, the FA in failing hearts decreased by 22%, whereas the MD, D2 and D3 increased by 12%, 14% and 24%, respectively (Pu2009<u20090.01). No significant change was detected for D1 between the two groups. Furthermore, significant correlation was observed between the DTI scalar indices and quantitative histological measurements of collagen (i.e. fibrosis). Pearsons correlation coefficients (r) between collagen content and FA, MD, D2 and D3 were –0.51, 0.59, 0.56 and 0.62 (Pu2009<u20090.05), respectively. The correlation between D1 and collagen content was not significant (ru2009=u20090.46, Pu2009=u20090.05). Computational modeling analysis indicated that the behaviors of the DTI parameters as a function of the degree of fibrosis were well explained by compartmental exchange between myocardial and collagenous tissues. Combined, these findings suggest that scalar DTI parameters can be used as metrics for the non‐invasive assessment of diffuse fibrosis in failing hearts. Copyright

Impact of high-dose inotropic donor support on early myocardial necrosis and outcomes in cardiac transplantation

Nixon JL, Kfoury AG, Brunisholz K, Horne BD, Myrick C, Miller DV, Budge D, Bader F, Everitt M, Saidi A, Stehlik J, Schmidt TC, Alharethi R. Impact of high‐dose inotropic donor support on early myocardial necrosis and outcomes in cardiac transplantation. u2028Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01504.x. u2028© 2011 John Wiley & Sons A/S.

Longitudinal evaluation of microvessel density in survivors vs. nonsurvivors of cardiac pathologic antibody-mediated rejection

BACKGROUNDnAntibody-mediated rejection (AMR) of cardiac allografts is associated with reduced long-term graft survival, but not every patient with AMR develops premature graft failure. The tissue level mechanisms leading to graft failure in some patients with antibody-mediated rejection are poorly characterized.nnnMETHODSnWe assessed changes in myocardial microvessel density (number of capillaries per unit area) in endomyocardial biopsies over time using whole-slide microscopic imaging of CD34-stained slides and computer-assisted image analysis. Changes were compared among eight heart transplant recipients with multiple episodes of pathologic AMR who died from cardiovascular causes, eight age- and gender-matched patients with pathologic AMR who were still alive at a similar follow-up interval, and six matched controls without AMR or cellular rejection.nnnRESULTSnMicrovessel density decreased in the last biopsies (mean 6.52 years post-transplant) from patients with pathologic AMR and cardiovascular mortality compared to their biopsies at 6 and 12 months post-transplant [respectively, -22% (P=.02) and -25% (P=.02)]. A similar decrease was not seen for the other groups.nnnCONCLUSIONSnSignificantly reduced myocardial microvessel density does occur in a subset of patients with pathologic AMR who have a worse outcome. These data provide insights into the interplay between AMR, microvascular injury, and clinical outcomes.

Clinical and Hemodynamic Effects of Renin–Angiotensin System Blockade in Cardiac Transplant Recipients

Chronic kidney disease continues to be a major limiting factor for long-term survival of heart transplant recipients. Little is known about the early use of renin-angiotensin system (RAS) blocking agents and their impact on renal function and hemodynamics in heart transplant recipients. In this cohort study all eligible recipients of orthotopic heart transplants at the UTAH cardiac transplantation program from 2001 through 2007 were divided into 2 groups-patients who were started on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers within the first 4 weeks of transplantation and continued on these for ≥4 weeks during the first 3 months (RAS blockade group, n = 75) and those who were not (non-RAS blockade group, n = 52). All patients were followed for 1 year after transplantation. There were no significant differences at baseline between the 2 groups. Estimated glomerular filtration rate at 12 months was significantly higher in the RAS blockade group compared to the non-RAS blockade group (mean ± SD, 56.3 ± 22.4 vs 47.3 ± 18.1 ml/min/1.73 m(2), p = 0.036). At 12 months pulmonary artery systolic pressure was significantly lower in the RAS blockade group compared to the non-RAS blockade group (30.2 ± 7.4 vs 32.9 ± 9.3 mm Hg, p = 0.023). Left ventricular ejection fraction and pulmonary capillary wedge pressure were similar between the 2 groups. In conclusion, early RAS blockade after heart transplantation is safe, well tolerated, and associated with better renal function and hemodynamic profile at 1 year after transplantation.

Lactic acidosis after cardiac transplantation: foe or common innocent bystander?

Background Lactic acidosis (LA) frequently occurs after heart transplantation (HTx). It is hypothesized to be related to inotropic support or metabolic derangements from chronic heart failure. As such, restoring hemodynamic stability with mechanical circulatory support before HTx should mitigate this problem. Our aim was to evaluate the incidence and outcomes of LA after HTx. Methods We evaluated HTx recipients January 2000 to May 2011. Post-HTx outcomes included graft dysfunction, length of intensive care unit stay, length of hospital stay, inotropic support, and survival. Results Of 143 eligible patients, 98.6% had LA, 67% severe, after HTx. Data were analyzed based on the severity of LA. Time to peak lactate, intensive care unit stay, length of hospital stay, peak glucose, inotropic dose, graft dysfunction, and survival after HTx were similar between groups. Statistically significant differences included pretransplant support (25.6% mechanical circulatory support in nonsevere vs. 44.9% severe LA), hospitalization at the time of HTx (37.2% vs. 21.4%), glucose at the time of peak lactate (182.88 ± 69.80 vs. 221.31 ± 56.91), ischemic time (187.4 ± 63.1 vs. 215.5 ± 68.1), and duration of inotrope. Conclusion Severe LA is common after HTx, though it appears to be transient and benign. Mechanical circulatory support after HTx does not prevent LA. High lactate levels are associated with longer ischemic times, longer duration of inotrope, and correspond with higher glucose levels. The underlying mechanism is yet to be satisfactorily elucidated.

Morbidity and Mortality in Heart Transplant Candidates Supported with Mechanical Circulatory Support. Is Reappraisal of the Current UNOS Thoracic Organ Allocation Policy Justified

Background— Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list.nnMethods and Results— We analyzed mortality and morbidity in 33 073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P <0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P <0.0001) and similar to that in status 1B patients (HR, 1.04; P =0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P =0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P <0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P =0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P <0.0001) and temporary VADs (HR, 7.72; P <0.0001).nnConclusions— Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts.nn# Clinical Perspective {#article-title-31}Background— Survival of patients on left ventricular assist devices (LVADs) has improved. We examined the differences in risk of adverse outcomes between LVAD-supported and medically managed candidates on the heart transplant waiting list. Methods and Results— We analyzed mortality and morbidity in 33 073 heart transplant candidates registered on the United Network for Organ Sharing (UNOS) waiting list between 1999 and 2011. Five groups were selected: patients without LVADs in urgency status 1A, 1B, and 2; patients with pulsatile-flow LVADs; and patients with continuous-flow LVADs. Outcomes in patients requiring biventricular assist devices, total artificial heart, and temporary VADs were also analyzed. Two eras were defined on the basis of the approval date of the first continuous-flow LVAD for bridge to transplantation in the United States (2008). Mortality was lower in the current compared with the first era (2.1%/mo versus 2.9%/mo; P<0.0001). In the first era, mortality of pulsatile-flow LVAD patients was higher than in status 2 (hazard ratio [HR], 2.15; P<0.0001) and similar to that in status 1B patients (HR, 1.04; P=0.61). In the current era, patients with continuous-flow LVADs had mortality similar to that of status 2 (HR, 0.80; P=0.12) and lower mortality compared with status 1A and 1B patients (HR, 0.24 and 0.47; P<0.0001 for both comparisons). However, status upgrade for LVAD-related complications occurred frequently (28%) and increased the mortality risk (HR, 1.75; P=0.001). Mortality was highest in patients with biventricular assist devices (HR, 5.00; P<0.0001) and temporary VADs (HR, 7.72; P<0.0001). Conclusions— Mortality and morbidity on the heart transplant waiting list have decreased. Candidates supported with contemporary continuous-flow LVADs have favorable waiting list outcomes; however, they worsen significantly once a serious LVAD-related complication occurs. Transplant candidates requiring temporary and biventricular support have the highest risk of adverse outcomes. These results may help to guide optimal allocation of donor hearts.