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Warfarin, Rifampin, and LVADs- OH MY: Effect of Rifampin on INR and Time in the Therapeutic Range in Patients with a Left Ventricular Assist Device
S418
The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016
One or more ADRs was recorded in 23 patients (62%), these required drug discontinuation in 13 patients. The median level at which treatment was stopped due to ADRs was 5.03 mg/L, (IQ range 3.77-6.66 mg/L) Conclusion: On site analysis of sVRZ has shortened LTR and increased TTR. This allows optimisation of patients with invasive infections. In the preemptive treatment group TDM was used to assign causality for ADRs with many patients having TDM at the time of stopping therapy. Most patients who had to stop due to ADRs were within the quoted therapeutic range. We will re-evaluate the existing TR for both groups in light of the findings that patients appear to respond well to treatment at levels currently considered sub-therapeutic, but suffer more ADRs in the upper range of the TR. 1( 172) Warfarin, Rifampin, and LVADs- OH MY: Effect of Rifampin on INR and Time in the Therapeutic Range in Patients with a Left Ventricular Assist Device J.E. Mangum , M.L. Hurtik, A. Pekarek, S.R. Laskar. Emory University Hospital, Atlanta, GA. Purpose: Driveline infection is a serious complication reported in 21% of patients with a Left Ventricular Assist Device (LVAD) according to registry data. Rifampin, a potent cytochrome P450 (CYP) enzyme inducer, is often used in conjunction with other antibiotics to penetrate biofilm-producing species such as Staphylococcus aureus. Maintaining appropriate INR values in LVAD patients during rifampin initiation is particularly challenging due to increased warfarin metabolism as a result of CYP induction. As the time in the therapeutic range (TTR) decreases, the potential for adverse events including device thrombosis, gastrointestinal bleed, and stroke increases in this patient population. This study was designed to compare the TTR in LVAD patients prior to and during therapy with rifampin. Methods: Between January 2009 and August 2015, 14 patients with an LVAD (4 HeartWare, 10 HeartMate II) implanted at our institution and followed by the anticoagulation clinic received rifampin. Indications for rifampin included driveline infection (9), LVAD endocarditis (3), sternal pustule (1), and osteomyelitis (1). TTR was calculated using the Rosendaal method and analyzed using a paired t-test. Results: Twelve patients had complete data available for analysis. Two patients were excluded for insufficient data. Mean TTR for all patients was 38% (± 12%) prior to initiation of rifampin and 28% (± 18%) during rifampin treatment (p= 0.0411). The mean therapeutic weekly dose of warfarin during rifampin treatment was nearly double that of pre-rifampin requirements (84mg [± 62 mg] vs 49 mg [± 19 mg], respectively; p= 0.0275). It took an average of 25 days (± 20 days) to achieve the first therapeutic INR after initiating rifampin. Two patients experienced serious adverse events during rifampin treatment: one patient died and another experienced a transient ischemic attack. Both patients had a subtherapeutic INR prior to hospital admission. Conclusion: Warfarin management is a complex practice in LVAD recipients. This study demonstrates that the addition of rifampin has significant effects on TTR, warfarin dose requirements, and it often takes several weeks to achieve a therapeutic INR. Increasing the weekly warfarin dose more aggressively after initiating rifampin therapy may lead to improved TTR and possibly a decrease in serious adverse events. 1( 173) Intra-Patient Variability of Tacrolimus Levels and Cardiac Allograft Outcomes H. Lyster , A. Suarez Barrientos, A. Khokar, J. Smith, N. Leaver, A. Simon, N.R. Banner. Royal Brompton & Harefield NHS Foundation Trust, Middlesex, United Kingdom. Purpose: Intra-patient variability (IPV) of tacrolimus (TAC) levels is a risk factor for poor long-term outcomes after renal transplantation. Immunosuppression was induction with rabbit anti-thymocyte globulin, TAC, mycophenolate mofetil and corticosteroids. Steroids were weaned over 6-12 months and TAC dose reduced. The aim of this study was to investigate whether high IPV of TAC levels within the first year after heart transplantation was associated with poor outcomes. Methods: Retrospective analysis of transplants from July 2007-August 2014 identified heart transplant recipients who received TAC, with a target level of 10-15 ng/ml for the first 3 months, gradually reduced to 5-7 ng/ml. Coefficient
of variance (COV) was defined as SD/mean of TAC levels taken at monthly intervals. We excluded patient who died or had TAC discontinued within 1-year. High variability (HV) was defined as a COV greater than the median. The proportion of time in therapeutic range was analysed. Outcomes were eGFR< 60 ml/min/1.73 m2, cardiac allograft vasculopathy (CAV) detected by angiography or CT, donor specific antibodies (DSA) and death. Results: 87 patients were included (66 male) with a median follow up of 1192 (range 384-2987) days. The median COV of tacrolimus levels was 0.255, 43 patients were in the HV group. There was no significant difference between the HV and non-HV groups in the incidence of poor outcomes (Table) but there was a strong trend (p= 0.06) towards a worse composite outcome. The cohort spent mean of 36±19% within the target range, with a mean of 57±25% time above the target range and only 7.7±13% of the time below the target range. Conclusion: We found no evidence that intra-patient variability of TAC levels was associated with a poor outcome; however, patients were more likely to be above rather than below the target range which, coupled with the use of induction therapy, may have masked an effect.
HV (n= 43) LV (n= 44) P value
CAV
DSA
death
Renal (eGFR< 60)
Composite end-point (incidence of RI, CAV, DSA or death).
11 6 ns
8 5 ns
4 2 ns
25 24 ns
28 (65%) 21 (48%) 0.06
1( 174) Concomitant Warfarin and Aspirin Versus Warfarin Alone for the Prevention of Embolic Events in Patients with a Left Ventricular Assist Device [Thoratec HeartMate II®] J.S. Van Tuyl ,1 I.B. Hollis,2 K.A. Alburikan,3 R. Tran,4 B.P. Murray,2 J.E. Rodgers,4 J.N. Katz,5 B. Sheridan.5 1St. Louis College of Pharmacy, St. Louis, MO; 2University of North Carolina Hospitals, Chapel Hill, NC; 3King Saud University, Riyadh, Saudi Arabia; 4University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC; 5University of North Carolina School of Medicine, Chapel Hill, NC. Purpose: Bleeding is significantly more common than embolic events after left ventricular assist device (LVAD) placement. For this reason, from 2010 to 2011 our institution did not prescribe aspirin (ASA) to new LVAD recipients. This study compares outcomes between antithrombotic regimens with and without ASA in patients implanted with a Thoratec HeartMate II® (HM II) LVAD at our institution. Methods: Seventy-six adult patients with a HM II placed from 2008 to 2013 and initiated on warfarin (goal INR 2.0) and aspirin (ASA) 81 mg oral daily (n= 44) or warfarin (goal INR 2.0) alone (n= 32) at time of LVAD placement were compared. Patients with ASA initiated after initial LVAD discharge and prior to a study outcome were excluded from analysis. The primary outcome was a composite of bleeding events, thrombotic events, or death from date of implant to 18 months. Fischer’s exact test and Wilcoxon Rank-Sum test were utilized for analysis. Results: Baseline characteristics, including age, heart failure etiology, INTERMACS score, and baseline organ function were similar between groups except male gender (66% in warfarin and ASA vs 91% in warfarin alone, p= 0.015) and use of aldosterone antagonists (23% vs 47%, respectively, p= 0.047). The median INR in the warfarin and ASA group and warfarin alone group was 2.0 and 2.1, respectively (p= 0.886). No difference in the primary outcome was observed between warfarin and ASA and warfarin alone (p= 0.645). Both regimens demonstrated similar bleeding and thrombotic rates. Conclusion: In patients with a HM II, warfarin alone compared to warfarin and ASA was associated with no significant difference in a composite outcome of bleeding events, thrombotic events, or death, nor the individual components of this outcome.
The Journal of Heart and Lung Transplantation, Vol 35, No 4S, April 2016
One or more ADRs was recorded in 23 patients (62%), these required drug discontinuation in 13 patients. The median level at which treatment was stopped due to ADRs was 5.03 mg/L, (IQ range 3.77-6.66 mg/L) Conclusion: On site analysis of sVRZ has shortened LTR and increased TTR. This allows optimisation of patients with invasive infections. In the preemptive treatment group TDM was used to assign causality for ADRs with many patients having TDM at the time of stopping therapy. Most patients who had to stop due to ADRs were within the quoted therapeutic range. We will re-evaluate the existing TR for both groups in light of the findings that patients appear to respond well to treatment at levels currently considered sub-therapeutic, but suffer more ADRs in the upper range of the TR. 1( 172) Warfarin, Rifampin, and LVADs- OH MY: Effect of Rifampin on INR and Time in the Therapeutic Range in Patients with a Left Ventricular Assist Device J.E. Mangum , M.L. Hurtik, A. Pekarek, S.R. Laskar. Emory University Hospital, Atlanta, GA. Purpose: Driveline infection is a serious complication reported in 21% of patients with a Left Ventricular Assist Device (LVAD) according to registry data. Rifampin, a potent cytochrome P450 (CYP) enzyme inducer, is often used in conjunction with other antibiotics to penetrate biofilm-producing species such as Staphylococcus aureus. Maintaining appropriate INR values in LVAD patients during rifampin initiation is particularly challenging due to increased warfarin metabolism as a result of CYP induction. As the time in the therapeutic range (TTR) decreases, the potential for adverse events including device thrombosis, gastrointestinal bleed, and stroke increases in this patient population. This study was designed to compare the TTR in LVAD patients prior to and during therapy with rifampin. Methods: Between January 2009 and August 2015, 14 patients with an LVAD (4 HeartWare, 10 HeartMate II) implanted at our institution and followed by the anticoagulation clinic received rifampin. Indications for rifampin included driveline infection (9), LVAD endocarditis (3), sternal pustule (1), and osteomyelitis (1). TTR was calculated using the Rosendaal method and analyzed using a paired t-test. Results: Twelve patients had complete data available for analysis. Two patients were excluded for insufficient data. Mean TTR for all patients was 38% (± 12%) prior to initiation of rifampin and 28% (± 18%) during rifampin treatment (p= 0.0411). The mean therapeutic weekly dose of warfarin during rifampin treatment was nearly double that of pre-rifampin requirements (84mg [± 62 mg] vs 49 mg [± 19 mg], respectively; p= 0.0275). It took an average of 25 days (± 20 days) to achieve the first therapeutic INR after initiating rifampin. Two patients experienced serious adverse events during rifampin treatment: one patient died and another experienced a transient ischemic attack. Both patients had a subtherapeutic INR prior to hospital admission. Conclusion: Warfarin management is a complex practice in LVAD recipients. This study demonstrates that the addition of rifampin has significant effects on TTR, warfarin dose requirements, and it often takes several weeks to achieve a therapeutic INR. Increasing the weekly warfarin dose more aggressively after initiating rifampin therapy may lead to improved TTR and possibly a decrease in serious adverse events. 1( 173) Intra-Patient Variability of Tacrolimus Levels and Cardiac Allograft Outcomes H. Lyster , A. Suarez Barrientos, A. Khokar, J. Smith, N. Leaver, A. Simon, N.R. Banner. Royal Brompton & Harefield NHS Foundation Trust, Middlesex, United Kingdom. Purpose: Intra-patient variability (IPV) of tacrolimus (TAC) levels is a risk factor for poor long-term outcomes after renal transplantation. Immunosuppression was induction with rabbit anti-thymocyte globulin, TAC, mycophenolate mofetil and corticosteroids. Steroids were weaned over 6-12 months and TAC dose reduced. The aim of this study was to investigate whether high IPV of TAC levels within the first year after heart transplantation was associated with poor outcomes. Methods: Retrospective analysis of transplants from July 2007-August 2014 identified heart transplant recipients who received TAC, with a target level of 10-15 ng/ml for the first 3 months, gradually reduced to 5-7 ng/ml. Coefficient
of variance (COV) was defined as SD/mean of TAC levels taken at monthly intervals. We excluded patient who died or had TAC discontinued within 1-year. High variability (HV) was defined as a COV greater than the median. The proportion of time in therapeutic range was analysed. Outcomes were eGFR< 60 ml/min/1.73 m2, cardiac allograft vasculopathy (CAV) detected by angiography or CT, donor specific antibodies (DSA) and death. Results: 87 patients were included (66 male) with a median follow up of 1192 (range 384-2987) days. The median COV of tacrolimus levels was 0.255, 43 patients were in the HV group. There was no significant difference between the HV and non-HV groups in the incidence of poor outcomes (Table) but there was a strong trend (p= 0.06) towards a worse composite outcome. The cohort spent mean of 36±19% within the target range, with a mean of 57±25% time above the target range and only 7.7±13% of the time below the target range. Conclusion: We found no evidence that intra-patient variability of TAC levels was associated with a poor outcome; however, patients were more likely to be above rather than below the target range which, coupled with the use of induction therapy, may have masked an effect.
HV (n= 43) LV (n= 44) P value
CAV
DSA
death
Renal (eGFR< 60)
Composite end-point (incidence of RI, CAV, DSA or death).
11 6 ns
8 5 ns
4 2 ns
25 24 ns
28 (65%) 21 (48%) 0.06
1( 174) Concomitant Warfarin and Aspirin Versus Warfarin Alone for the Prevention of Embolic Events in Patients with a Left Ventricular Assist Device [Thoratec HeartMate II®] J.S. Van Tuyl ,1 I.B. Hollis,2 K.A. Alburikan,3 R. Tran,4 B.P. Murray,2 J.E. Rodgers,4 J.N. Katz,5 B. Sheridan.5 1St. Louis College of Pharmacy, St. Louis, MO; 2University of North Carolina Hospitals, Chapel Hill, NC; 3King Saud University, Riyadh, Saudi Arabia; 4University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC; 5University of North Carolina School of Medicine, Chapel Hill, NC. Purpose: Bleeding is significantly more common than embolic events after left ventricular assist device (LVAD) placement. For this reason, from 2010 to 2011 our institution did not prescribe aspirin (ASA) to new LVAD recipients. This study compares outcomes between antithrombotic regimens with and without ASA in patients implanted with a Thoratec HeartMate II® (HM II) LVAD at our institution. Methods: Seventy-six adult patients with a HM II placed from 2008 to 2013 and initiated on warfarin (goal INR 2.0) and aspirin (ASA) 81 mg oral daily (n= 44) or warfarin (goal INR 2.0) alone (n= 32) at time of LVAD placement were compared. Patients with ASA initiated after initial LVAD discharge and prior to a study outcome were excluded from analysis. The primary outcome was a composite of bleeding events, thrombotic events, or death from date of implant to 18 months. Fischer’s exact test and Wilcoxon Rank-Sum test were utilized for analysis. Results: Baseline characteristics, including age, heart failure etiology, INTERMACS score, and baseline organ function were similar between groups except male gender (66% in warfarin and ASA vs 91% in warfarin alone, p= 0.015) and use of aldosterone antagonists (23% vs 47%, respectively, p= 0.047). The median INR in the warfarin and ASA group and warfarin alone group was 2.0 and 2.1, respectively (p= 0.886). No difference in the primary outcome was observed between warfarin and ASA and warfarin alone (p= 0.645). Both regimens demonstrated similar bleeding and thrombotic rates. Conclusion: In patients with a HM II, warfarin alone compared to warfarin and ASA was associated with no significant difference in a composite outcome of bleeding events, thrombotic events, or death, nor the individual components of this outcome.