How Often Does Cardiotoxicity Lead to Discontinuation of Trastuzumab? ..... corded in the right (RV, n 5 62) and/or left (LV, n 5 9) ventricle during RV pacing.
The 12th Annual Scientific Meeting
HFSA
S7
Oral Presentations: Leading Clinical Research 016 How Often Does Cardiotoxicity Lead to Discontinuation of Trastuzumab? Gregory R. Hartlage1, Ren Chen2, Maya E. Guglin1; 1University of South Florida, Tampa, FL; 2H Lee Moffitt Cancer Center, Tampa, FL Background: Trastuzumab (Herceptin) reduces the recurrence of HER2 positive breast cancer. Trastuzumab causes cardiotoxicity which is usually reversible. Nevertheless, once left ventricular ejection fraction (EF) decreases, trastuzumab is often discontinued, with the therapeutic advantage being lost or truncated. Objective: To determine how often cardiotoxicity leads to discontinuation of trastuzumab. Methods: We retrospectively reviewed the charts of 118 subsequent patients with advanced breast cancer (2003 to 2007) who received trastuzumab as an adjuvant treatment. EF was evaluated before treatment, then every 3 months by MUGA or Echo. Cardiotoxicity was defined as decrease of EF to ! 50%, or by $10% from the baseline, or symptoms of heart failure regardless of EF. Statistical analysis was done with Chi-square test and Fisher exact test. Results: All 118 women had EF O 50% before treatment. The difference from the baseline was significant at all follow-ups (p ! 0.001), with no significant further decline after 3 months. Table 1. Baseline
0e3 months
3e6 months
6e9 months
9e12 months
O12 months
EF,% 60.2 6 5.4 56.7 6 7.2 57.1 6 7.4 56.9 6 6.6 57.9 6 5.8 56.0 6 8.0 Cardiotoxicity, 16 (13.6) 10 (8.5) 6 (5.1) 6 (5.1) 1 (0.9) total (%) Cardiotoxicity, 7 (5.9) 7 (5.9) 1 (0.9) 1 (0.9) 1 (0.9) EF ! 50% (%) 7 (5.9) 2 (1.7) 5 (4.2) 5 (4.2) Cardiotoxicity, EF decrease $10% (%) 2 (1.7) 1 (0.9) HF symptoms, preserved EF (%) 14 (11.9) 8 (6.8) 1 (0.9) 1 (0.9) Discontinued Trastuzumab, total (%)
Total 39 (33.0) 17 (14.4) 19 (21.2)
3 (2.5)
24 (20.3)
Cardiotoxicity developed in 39 women (33%). Trastuzumab was discontinued, permanently or temporarily, in 24 (20.3%). Lower EF at baseline had a strong association with a $10% drop of EF from baseline (p ! 0.001). Age and radiation did not influence cardiotoxicity.
Comorbidities, hypertension in particular, were associated with cardiotoxicity (p ! 0.05). In patients with comorbidities (n 5 40), those treated with ACE inhibitors, beta-blockers, and/or statins appeared to have less overall cardiotoxicity (36% vs. 60%), decrease of EF to ! 50% (12% vs. 33.3%), and trastuzumab discontinuation (20% vs. 40%) than those treated with other drugs. Conclusions: Highly prevalent cardiotoxicity (33%) led to discontinuation of trastuzumab in 20% of women with advanced breast cancer. Lower baseline EF and comorbidities, especially hypertension were the most significant predictors of cardiotoxicity. Further studies on possible prevention in high risk women are warranted.
017 Can the Seattle Heart Failure Model Be Used to Risk Stratify Patients for an LVAD: Application to REMATCH Patients Wayne C. Levy1, Dariush Mozaffarian2, David T. Linker1, David Farrar3, Leslie W. Miller4; 1Cardiology, University of Washington, Seattle, WA; 2Harvard School of Public Health, Boston, MA; 3Thoratec, Pleaston, CA; 4Cardiology, Georgetown, Washington, DC Purpose: In the REMATCH trial left ventricular assist device (LVAD) therapy in patients with severe heart failure resulted in a 48% reduction in mortality compared to medical management. The ACC/AHA guidelines recommend a !50% 1 year survival for candidacy for LVAD implantation and CMS requires a survival of #2 years. The purpose of this analysis was to determine if the Seattle Heart Failure Model (SHFM-SeattleHeartFailureModel.org), a previously validated multivariate risk model, can be used to estimate the expected survival if the patient remained on medical therapy. This knowledge may be useful in selecting appropriate patients for LVADs. Methods and Materials: The SHFM was applied prospectively to data from the REMATCH trial. Variables missing in REMATCH were imputed from the primary database used to derive the SHFM. The use of inotropic agents and intra aortic balloon pump/ventilator were prospectively added to the previously published model. A hazard ratio of 1.17 was used for each inotrope used (COCHRANE meta analysis) and 2.92 for IABP/Ventilator use (COCPIT Model). Results: The SHFM was highly predictive of outcomes (P 5 0.0004). The use of dobutamine and/or milrinone had a similar hazard ratio as the COCHRANE meta analysis (1.09 95% CI 0.78e1.53, p 5 0.60 vs anticipated hazard ratio 1.17), although not significant. The use of IABP/Ventilator was also associated with risk (hazard ratio 2.1, 95% CI 1.1e3.9, p 5 0.02), similar to the anticipated hazard ratio of 2.92 from the COCPIT model. The addition of these variables to the SHFM
improved the accuracy (1 year ROC 0.69 to 0.71). The 1 year predicted vs actual survival for the medical group (30% vs 28%) and LVAD group (49% vs 52%) were similar. 81% of patients had SHFM # 50% 1 year survival. There was no evidence that the benefit of the LVAD varied in the lower vs. higher risk patients. The lowest risk tertile had a hazard ratio of 0.55 (95% CI 0.28e1.09, p 5 0.09). Conclusions: The Seattle Heart Failure Model can be used to risk stratify end-stage heart failure patients, provided known markers of increased risk such as inotrope use and IABP/Ventilator support are included. This model may facilitate identification of high risk patients to evaluate for potential LVAD implantation prior to inotrope or IABP dependency.
018 Features and Hospital Outcomes for Nonadherent Patients with Heart Failure: Findings from GWTG-HF Amrut V. Ambardekar1, Wenqin Pan2, Steven L. Peterson1, Gregg C. Fonarow3, Laura E. Webb2, Adrian F. Hernandez2, Christopher P. Cannon4, Eric D. Peterson2, Mori J. Krantz1; 1U. of Colorado; 2Duke; 3UCLA; 4Harvard Introduction: Medication and dietary nonadherence are often precipitating factors for heart failure (HF) hospitalization. Recognizing predictors of nonadherence may provide a means to reduce rehospitalization for this vulnerable population. Hypothesis: Nonadherence is a common HF precipitant and is associated with different clinical characteristics and short term outcomes. Methods: Get With The Guidelines (GWTG) HF data were collected from 236 hospitals and 54,322 patients from 01/01/ 05e12/30/07. Demographics, clinical characteristics, quality of care, and in-hospital outcomes were stratified by precipitating factor for HF admission. Results: Clinicians listed dietary and/or medication nonadherence as the reason for admission in 5576 (10.3%) of all HF hospitalizations. Patients with nonadherence were more likely to be young, male, minority, uninsured, and have nonischemic HF (Table). These patients had a history of more frequent HF hospitalizations, but a shorter length of stay and lower in-hospital mortality (OR 0.71, 95% CI 0.56e0.90) in multivariate regression analysis. Nonadherent patients were equally or more likely to receive guideline-based therapy as adherent patients. Conclusions: Among GWTG-HF participating hospitals, patients with nonadherence as a factor for hospitalization tend to be younger and more sociodemographically disadvantaged, yet have better in-hospital outcomes. Given the high resource utilization in this group, targeted efforts to assess predictors of HF readmission for this vulnerable population have the potential to improve care and lower hospital costs.
Nonadherence (N 5 5576, 10.3%) Baseline Characteristics Male (%) 60.4 Age (yrs) 64.2 Non-Caucasian (%) 47.0 Uninsured (%) 11.7 LVEF (%) 34.9 Nonischemic HF (%) 57.4 18.2 $2 HF admits in preceding 6 months (%) In-hospital Outcomes Mortality (%) 1.55 Length of Stay 4.99 (days) GWTG Performance Measures (%) Appropriate 82.6 Discharge Instructions Documentation of 94.5 LVEF ACEI/ARB for 89.9 LVSD Smoking Cessation 91.5 Counseling 91.6 Beta-blocker for LVSD
Other Precipitants (N 5 24,436 45.0%)
No Known Precipitant (N 5 24,310 44.7%)
48.1 73.8 28.2 3.5 40.0 52.3 13.5
48.6 73.4 22.6 3.0 39.3 48.8 8.9
3.98 5.91
3.00 5.35
Univariate P-value * * * * * * *
* *
81.5
81.9
0.2285
93.6
94.2
0.0084
84.3
85.7
*
88.3
91.6
*
89.5
89.0
0.0007
*!0.0001
019 Weekend Hospital Admission for Heart Failure: Influence on Quality of Care, Length of Stay, and In-Hospital Mortality Tamara B. Horwich Gregg C. Fonarow1, Kenneth A. LaBresh2, Clyde Yancy3, Nancy M. Albert4, Adrian F. Hernandez5, Li Liang5, GWTG Steering Committee and
S8 Journal of Cardiac Failure Vol. 14 No. 6S Suppl. 2008 Hospitals; 1UCLA, LA, CA; 2MassPro, Waltham, MA; 3Baylor, Dallas, TX; 4CCF, Cleveland, OH; 5Duke, Durham, NC
1 Division of Cardiology, UCSF, San Francisco, CA; 2CVRI, UCSF, San Francisco, CA
Background: Hospital admissions during weekends have been associated with worse outcomes in some but not all medical conditions. The impact of weekend vs. weekday admission for heart failure (HF) has not been well studied. The objectives of this study are to compare weekend vs. weekday HF admission for 1) quality of care (QOC), 2) length of stay (LOS), and 3) in-hospital mortality. Hypothesis: Weekend admission for HF is associated with lower QOC, longer LOS, and higher in-hospital mortality. Methods: Get with the Guidelines-HF (GWTG) employs a collaborative model of care and a web-based Management ToolÔ (Outcome, Cambridge, MA). Baseline data was recorded for 59,876 HF admissions at 264 sites from 1/05 e 4/ 07. The cohort was stratified by weekend vs. weekday admission. Generalized Estimating Equations adjusted for patient and hospital characteristics and clustering. Results: Mean age was 73 6 14 yrs, LVEF 40% 6 17. In-hospital mortality was 3.3% and median LOS 5d. Patients admitted on weekends had similar comorbidities to those admitted on weekdays, but were slightly older with higher BNP levels. Weekend admission was associated with decreased odds of LVEF documentation and ICD implantation; other QOC measures were similar. There was no difference in LOS for weekend vs. weekday admission. There was a non-significant trend toward increased in-hospital mortality for weekend HF admissions.
Background: Although idiopathic pulmonary arterial hypertension (IPAH) has been associated with mutations in BMPR2 in few affected families, the genetic factors predisposing to IPAH in the majority of patients are poorly understood. We hypothesized that gene variants in caveoline1 (CAV-1) and caveoline2 (CAV-2) could contribute to the development of IPAH. These two genes, expressed in endothelium and pneumocytes, encode structural proteins in caveolae, membrane invaginations that play a critical role in many signaling pathways. Phenotypes of CAV-1 ( / ) and CAV2 ( / ) mice closely resemble IPAH with CAV-2 ( / ) strictly limited to a pulmonary phenotype. Methods: We screened coding, promoter and splice-sites of CAV-1 and CAVe2 to identify informative mutations and single nucleotide polymorphisms (SNPs) using DGGE and direct sequencing. Caucasian patients were diagnosed with IPAH after left and right heart catheterization, chest CT, echocardiography, and serologic testing to exclude other etiologies of pulmonary hypertension. Controls consisted of healthy Caucasian subjects. Differences in gene allele frequency were analyzed using the chi-square test. Results: For CAV-1, 62 patients with IPAH and 600 unrelated controls were screened using DGGE and sequencing. Four intronic SNPs and three coding region synonymous SNPs were identified. Non-synonymous coding region or frameshift mutations were absent. Statistical analysis of CAV-1 showed no significant difference in SNP frequency between cases and controls. For CAV-2, 35 cases with IPAH and 92 controls were sequenced to identify CAV-2 SNPs. A total of 14 SNPs were identified, 12 previously identified in dbSNP and two novel SNPs. Analysis of SNP allele frequencies in cases versus controls showed that one SNP located in the 5’ UTR of exon 1 was enriched for the homozygous TT genotype (p 5 0.05). Conclusions: We did not find any coding mutations in CAV-1 or CAV-2 that correlated with the IPAH phenotype. However, we identified a SNP in the 5’ UTR of CAV-2 that was nominally associated with IPAH (p 5 0.05). Because this polymorphism could affect transcriptional regulation, the significance of this SNP will be tested using correlation of this SNP with clinical data to identify mechanisms by which this gene variant may contribute to the PAH phenotype.
Comparison of Weekend vs. Weekday Admissions GWTG QOC Measures
Weekend Weekday Univariate n 5 13,194 n 5 46,682 P value
Adjusted OR (95% CI)
Discharge Instructions, % 78.1 76.9 0.03 1.06 (1.0 e1.12) LVEF Documentation, % 91.6 92.9 !0.0001 0.85 (0.79 e0.92) LVSD on ACEI / ARB 85.1 84.5 0.43 1.05 (0.96 e1.15) LVSD on evidence-based 67.5 69.2 0.02 0.95 (0.88 e 1.02) beta-blocker ICD in LVEF # 30, % 24.3 31.5 !0.0001 0.76 (0.67 e 0.87) LENGTH OF STAY, days, 5 (4 e 7) 5 (3 e 8) 0.40 1.00 (0.99e1.01) median DEATH IN HOSPITAL, % 3.6 3.2 0.06 1.12 (0.99e1.26)
Conclusions: Among GWTG hospitals, weekend admission for HF was associated with similar QOC in most but not all measures. LOS was similar but risk adjusted mortality was marginally higher for weekend HF admission.
020 Human Myocardial b1 389 Arg/Arg Adrenergic Receptors Exhibit a Propensity for Constitutively Active, High Affinity Agonist Binding and Are Selectively Inactivated by Bucindolol Ryan Walsh1, Ryan Farmer1, Mara Kelly1, Penny Blain-Nelson1, Jennifer Morrison1, J. David Port1,2, Michael R. Bristow1,2; 1Division of Cardiology, University of Colorado Health Sciences Center, Denver, CO; 2ARCA biopharma, Inc., Denver, CO b1-adrenergic (b1 AR) and many other receptors exist in two activation states: active (‘‘R*’’) and inactive (‘‘Ri’’). R* are detected by high affinity binding to agonists, plus conversion of R* to Ri by GTP or its nonhydrolyzable analogues. R* receptors may also be inactivated to the Ri state by certain receptor ligands with ‘‘inverse agonist’’ properties, whereas agonists function to convert Ri to R*. In human left ventricular membranes that were O75% b1 (n 5 12) we determined the degree of R* and Ri in the codon 389 Arg/Arg or Gly/Gly genotype, by performing computer modeling of [125]ICYP-(S) norepinephrine competition curves. The R* state was confirmed by conversion of two-site fits to one site by 30 uM Gpp(NH)p. In addition, in preparations of isolated human failing right ventricle (n 5 41) b1 AR 389 Arg/Arg receptors were compared to Gly carriers by determining the inverse agonist properties of the b1-AR antagonists bucindolol, carvedilol, metoprolol and the partial b1-agonist xamoterol, using the readout of systolic function in the presence of forskolin to augment signal transduction. Results: In b1 AR 389 Arg/Arg receptors 42.0 6 21.8% were in the R* state, compared to 11.6 6 16.4% for Gly/Gly (p 5 0.025). In isolated human heart preparations genotyped as b1 AR 389 Arg/Arg bucindolol was an inverse agonist (p 5 0.0008), whereas metoprolol and carvedilol were neutral antagonists and xamoterol was an agonist. In b1 AR 389 Gly receptors bucindolol, metoprolol, carvedilol and xamoterol were all neutral antagonists. Conclusions: These data provide a molecular mechanism for bucindolol’s novel enhancement of efficacy in patients who have the b1 AR 389 Arg/Arg genotype, which is selective activation of the large number of R* in this high functioning receptor variant.
021 Gene Variants in Caveolin-1 and Caveolin-2 in Patients with Idiopathic Pulmonary Arterial Hypertension Christian Zellner1, Wilson Liao2, Clive R. Pullinger2, Annie Poon2, Pui Kwok2, Mary J. Malloy2, John P. Kane2, Dana McGlothlin1, Kanu Chatterjee1, Teresa DeMarco1;
022 Action Potential Dynamics Explain Arrhythmic Susceptibility in Systolic Heart Failure Gautam G. Lalani1, Jason Bayer2, Natalia A. Trayanova2, Sanjiv M. Narayan1; 1 Department of Cardiology/Electrophysiology, University of California, San Diego, La Jolla, CA; 2Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD Background: It is unclear why systolic dysfunction causes malignant ventricular arrhythmias (VT/VF). We hypothesized that, in patients with systolic heart failure, calcium overload causes oscillations of cytosolic calcium at modest heart rate acceleration, causing fluctuations in action potential (AP) shape and providing a mechanism for VT/VF. We tested this hypothesis clinically and using computer modeling to test if action potential fluctuations are best explained by abnormal calcium handling, sodium inactivation or transient outward current (Ito). Methods and Results: We studied 53 patients with LVEF 28 6 8% (47 with coronary disease, BNP 640 6 825 pg/ml) and 18 controls with LVEF 58 6 12%. Monophasic AP were recorded in the right (RV, n 5 62) and/or left (LV, n 5 9) ventricle during RV pacing at 109 beats/min. AP variations were measured spectrally as the k-score, and greater in heart failure than control patients, particularly in AP phase II (p 5 0.04) but not phase III (p 5 0.08). Figure (left) shows APs during RV pacing, and (right): phase II alternans with separation of even beats (red) from odd beats (blue). Computer simulations of human LV wedge at 109 beats/min showed that reduced sarcoplasmic reticulum calcium uptake, but neither delayed sodium channel inactivation nor Ito variations explained AP phase II alternans. On 949 6 553 days’ follow-up, 17 patients experienced VT/VF. Receiver operating characteristics analysis on the training sample (n 5 26) showed that spectral AP Alternans k-score $ 1.7 optimally predicted VT/VF with 86 % sensitivity and 73 % specificity. Applied prospectively to the test sample, this cutpoint predicted VT/VF on Kaplan-Meier analysis (p 5 0.02). Conclusions: Patients with systolic dysfunction show alternans in ventricular AP phase II at modest heart rate elevations #109 beats/min, but not AP phase III, that predict VT/ VF prospectively. In computer models, AP phase II alternans was best explained by reduced sarcolemmal calcium reuptake. These data provide a cellular mechanism linking failing human ventricles with AP alternans and VT/VF.
