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Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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Effects of Continuous Flow Left Ventricular Assist Device (LVAD) on
Pharmacokinetics of Routinely Administered Drugs
Jianzhu Luo, MD, PhD
Mark Slaughter, MD
Shesh Rai, PHD
Jaimin Trivedi, MD, MPH
Michael E. Brier PhD
School of Public Health and Informatics
Department of Renal Diseases
University of Louisville
Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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Abstract
BACKGROUND: The effects of continuous flow left ventricular assist devices (CF-LVAD)
on drug pharmacokinetics are not well studied.
HYPOTHESIS: Clearance of routinely administered drugs in heart failure patients
increases following the implantation of a continuous flow left ventricular assist device.
METHODS: Single center, retrospective study of patients who underwent HeartMate II
implantation between January 2014 and December 2015. Data of lab test (INR,
Hemoglobin, albumin, Creatinine, BUN, AST, ALT (Cr) and dosages of Warfarin and
Lisinopril were collected at pre-implantation and six weeks after LVAD implantation. Paired
t test were performed to compare both groups using SAS statistics software.
RESULTS: Data from 43 patients were analyzed. Compared to pre-LVAD, there was
significant increase of INR from 1.59 ± 0.65 to 2.77 ± 0.72 (p<0b.001). Although levels of
Hgb, AST and serum creatinine remained unchanged (p>0.05), there was significantly
decrease in levels of ALT (from 35.7 ± 39.21 to 22.02 ± 20.07, p <0.05), and significantly
increase in eGFR levels (from 66.26 ± 22.60 to 83.16 ± 39.95, p <0.01). In subgroup of
patients (n=17) had taken warfarin pre and six weeks of implantation, there was significant
increase of INR (from 1.76 ± 0.61 to 2.9 ± 0.76, p <0.001) while dosages of warfarin
remained unchanged (p>0.05). In subgroup of patients (n=20) had taken Lisinopril in pre
and six weeks of implantation, there was significant increase of INR (from 1.51 ± 0.55 to
2.4 ± 0.67, p< 0.001), decrease of Creatinine (1.32 ± 0.46 1.07 0.27) and improved eGFR
(from 67.95 ± 20.33 to 84.85 ± 26.79 p<0.05), while dosages of Lisinopril unchanged
before and after LVAD implantation (from 10.75± 9.97 to 10.13 ±8.68 mg/day).
CONCLUSION: CF-LVAD is associated with improved hepatic and renal function, and
may alter the pharmacokinetics of warfarin administered in patients implanted with LVAD.
Keywords: Continuous Flow Left Ventricle Assist Device (CF-LVAD), pharmacokinetics,
Warfarin, Lisinopril
Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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1. Introduction
According to the centers for disease control and prevention, Heart failure (HF) has a
prevalence of more than 5.1 million in the United States(1). Treatment of the disease is
estimated to cost $32 billion each year and increasing steadily (2). Heart transplant is the
ultimate cure for those patients with the end-stage heart failure, but the sources of heart
organ is very scarce; only 2000 patients have heart transplantation in US per year. Under
this circumstance, mechanical circulatory support became more and more popular in the
treatment of the end stage heart failure, and they have been used as a Bridge to
Transplantation or as a Destination Therapy. Continuous flow left ventricular assist
devices (LVADS) are now the standard of care for advanced heart failure patients
requiring long-term mechanical circulatory support. The development of left ventricular
assist devices (LVADs) has led to improved quality of life and long-term survival for
patients diagnosed with this devastating condition (3, 4). There are several generations of
the LVAD have been developed,
many technical issues have been addressed and
improved but one area that has not been sufficiently addressed is the impact of these
devices have on the pharmacokinetics of routinely administered drugs to this patient
population.
Pharmacokinetics is the study of the absorption, distribution, metabolism, and elimination
of a drug. In the presence of heart failure, it is predicted that the processes of metabolism
and elimination are impacted by decreased blood flow to the organs responsible for these
processes. Specifically, clearance of a drug from the systemic circulation is the product of
blood flow to the clearing organ and the fraction of drug eliminated as it passes through
the organ. Since the heart is responsible for supplying blood flow to the eliminating organs,
changes in heart function through the introduction of a continuous flow device is predicted
to alter drug clearance. Depending on the magnitude of the change in clearance and the
therapeutic concentrations associated with the drug, dose alterations may be needed as
cardiac function is improved post implantation of the continuous flow device.
This study is to determine the effect of LVAD implantation on the clearance of Lisinopril
which is primarily eliminated by the kidney, and the clearance of warfarin, a drug primarily
eliminated by metabolism, it is also the most frequently used drugs in patients have LVAD
implanted to prevent thromboembolism
Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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Methods
With institutional review board of the University of Louisville approval, we retrospectively
reviewed patient electronic medical record from patients who underwent LVAD
implantation in Jewish hospital from January 2014 to December 2015. Inclusion criteria
were age greater than 18 years and implantation with the HeartMate II between January 1,
2014 and December 31, 2015. Exclusion criteria were had LVAD before; for the
replacement of the LVAD or had LVAD implantation at other medical center (Figure1)
Demographics data such as age at LVAD insertion, sex, race, type of therapy (BTT or DT),
ideology of cardiomyopathy (ischemic or non-ischemic) will be recorded. The values of
International normalized ratio (INR) measurements, AST, ALT, Albumin, Hgb, BUN, and
Creatinine will be collected both pre and six weeks post LVAD surgery. For the subgroups
of warfarin and Lisinopril, only patients who took these drugs pre and six weeks post
LVAD will be included respectively. Warfarin and Lisinopril dosage were collected too.
eGFR was calculated using MDRD GFR equation.
The primary end point was the
difference in warfarin or Lisinopril dosage required.
Analysis. Data was analyzed using SAS statistical software.
Values are reported as
median ± SD. The lab data and drug dose were compared using a paired t-test between
before and after implantation.
Results with p-values less than 0.05 was considered
statistically significant.
Results
Total of 47 patients who had HeartMate II were selected, 4 were excluded from analysis
due the second LVAD placement. Of 43 Patients, 17 patients took warfarin both pre and
post LVAD implant were included in warfarin subgroup, 20 patients took Lisinopril both pre
and post LVAD implant were included in Lisinopril subgroup.
Baseline patient
demographics are provided in Table 1. The average age in Warfarin subgroup is 54.12
years, with 16 males (94.1%) and 1 female (5.9%), there were of 3 African American (17.6
%) and 14 white (82.4%); 10 of the patients had ischemic cardiomyopathy (58.5%), and 7
patients had non-ischemic cardiomyopathy (41.2%). 2 patients were implanted for bridge
to transplant, 15 was for destination therapy (88.2%). The average age in Lisinopril
Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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subgroup is 54.23 years, with 17 males (85.0%) and 3 female (15.0%), there are 3 African
American (17.6 %) and 14 white (82.4%). 13 of the patients had ischemic cardiomyopathy
(65%), and 7 patients had non-ischemic cardiomyopathy (35.0%). 2 patients (10.0 %)
were implanted for bridge to transplant, 18 (90.0%) was for destination therapy (88.2%).
The group data for all 43 patients was shown in Table 2 and Fig.2, Fig3.
The data
showed that compared to pre-LVAD, there was significant increase in INR (p<0.001); there
was reduced levels AST, and levels of ALT were significantly reduced (p<0.050).
Although levels of Creatinine stayed the same, there was reduced levels of BUN (p<0.04)
and increased levels of eGFR (p<0.05). These data indicated that implantation of LVAD
significantly improved the hepatic and renal function, these findings were also observed in
other studies(5) (6) (7).
Data from patients in Warfarin subgroup was shown in Table 3 and Fig.4. Compared to
pre-LVAD, there was significant increase in INR (p<0.001) while dosages of Warfarin
stayed the same as pre-LVAD. There was not significant change in AST, ALT, Albumin,
BUN, Creatinine and eGFR (p.0.05).
Data from patients in Lisinopril subgroup was shown in Table 4 and Fig.5, Fig.6.
Compared to pre-LVAD, there was significant increase in INR (p<0.001), also decreased
Creatinine levels and increased eGFR (p<0.05). However, the dosages of Lisinopril did
not change between pre- LVAD and six weeks post LVAD.
Discussion
According to The seventh annual report of the Interagency Registry for Mechanically
Assisted Circulatory Support (INTERMACS), between June23, 2006 and December31,
2014,15,745 patients who received a U.S. Food and Drug Administration (FDA)-approved
MCS device were entered in to the INTERMACS database. The rate of patient enrollment
has continued at a pace exceeding 2,000 patients per year (8). The development of LVAD
has been making great progresses in past decades, but only very few studies have
focused on the effects of LVAD have on drug pharmacokinetics. Pharmacokinetics of
vancomycin in patients with CF-LVADs was studied.
And reached conclusions that
general population methods may not accurately estimate the pharmacokinetic parameters
of vancomycin for compensated heart failure patients implanted with CF-LVADs(9).
Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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Our study was designed to investigate the dosage change in drugs before and after LVAD
implantation. We studied two most frequently administered drugs in patients implanted
with LVAD--- warfarin and Lisinopril.
The elimination of warfarin is almost entirely by metabolism. It is stereo selectively metabolized
by hepatic cytochrome P-450 (CYP450).
Lisinopril is the only ACE inhibitor that does not
require hepatic metabolism, it is almost cleared all by kidneys(10).
LVAD implantation causes consumption of coagulation proteins, activation of fibrinolysis,
and loss of high molecular weight von Willebrand protein multimers.(11) Anticoagulation
therapy is challenging to manage in LVAD patients. One study found that 54 % of patients
on long-term warfarin treatment required a change in warfarin dosing after VAD placement
without additional interacting medications (11).
CF-LVAD implantation, by improving organ perfusion and reducing congestion, may alter
the pharmacokinetics of drugs. There are impaired drug metabolism and drug clearance
have been shown previously in heart failure patients (12, 13). Reduction of blood flow to
the gastrointestinal tract may result in altered drug absorption; reduction to central organs
and peripheral tissue may result in altered drug distribution; and reduced flow to the liver
or kidney may result in altered elimination of drugs.
Drugs with clearance limited by
metabolism (eg, CYP enzymes) were generally thought to be minimally affected by heart
failure, however, study indicated that CYP-mediated drug metabolism is impaired in heart
failure patients. Furthermore, CYP2C19 activity is substantially reduced and is inversely
related to circulating concentrations of the pro-inflammatory cytokines tumour necrosis
factor-alpha (TNF-alpha) and interleukin 6 IL-6, which are expressed in myocardial in
many forms of cardiomyopathy and in circulation. (14, 15). In particular, alterations in
CYP-mediated drug metabolism could affect the metabolism of important cardiovascular
medications, including some β-blockers and angiotensin receptor antagonists (16).These
results may have important implications for pharmacologic treatment in patients with heart
failure.
CF-LVAD implantation significantly improved hemodynamic in patients. Patients showed
improved LV ejection fraction in both ischemic and non-ischemic patients. LV diastolic
Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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function parameters also improved. The improvement in myocardial structure and systolic
and diastolic function was largely completed within 6 months without subsequent
regression (17). The reverse remodeling was apparent in the early postoperative period
and was sustained at 6 months. (18). Peripheral vascular function is dependent upon
pulsatility and the associated shear stresses, and when these are disrupted, such as with
a continuous-flow LVAD, there are negative vascular consequences. Although central
hemodynamics are improved in patients with HFrEF by a continuous-flow LVAD,
peripheral vascular function is further compromised, which is likely due, at least in part, to
the reduction in pulsatility that is a characteristic of such a mechanical assist device(19).
Study showed that hepato-renal function demonstrates early improvement and then
remains stable in the majority of patients on CF-LVAD support for one year (20). PostMCS, early improvement in renal function is common but seems to be largely transient
and not necessarily indicative of an improved prognosis. This pattern was observed with
both pulsatile and continuous-flow devices(21). All the hemodynetic changes provided by
CF-LVAD would alter the pharmacokinetic and pharmacodynamics of the drugs.
Bleeding and thromboembolism are two of the most common complication in patients with
LVAD implantation (8). In addition to hemolysis, LVAD placement leads to significant
alterations in coagulation proteins, platelets [12] and von Willebrand protein[14, 15].
Decreased levels of coagulation proteins involved in the contact pathway (factor XI, factor
XII, and pre-kallikrein) are found in the first two weeks after LVAD implantation presumably
due to consumption [8]. Elevated levels of prothrombin fragment 1.2, D-dimer,
thrombinantithrombin and plasmin-antiplasmin complexes suggest thrombus formation
and activation of the fibrinolytic system in the presence of an LVAD [8–10]. Endothelial cell
activation persists as evidenced by increased levels of tissue factor, E-selectin, and
intercellular adhesion molecule on circulating endothelial cells of LVAD patients compared
to patients undergoing non-LVAD cardiac surgery [10]. Increased platelet aggregation and
thrombin production via a prothrombinase assay have also been reported [12, 13]. Nearly
all patients with implanted LVADs develop acquired von Willebrand syndrome with loss of
high molecular weight von Willebrand factor multimers. Almost all patients with LVAD
implanted have to take warfarin to prevent thromboembolism events.
Running Head: Effects of CF-LVAD on Pharmacokinetics of Warfarin and Lisinopril
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