Published online before print August 11, 2008, doi: 10.1161/HYPERTENSIONAHA.108.113068
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(Hypertension. 2008;52:522.)
© 2008 American Heart Association, Inc.
Original Articles |
Efficacy and Safety of Atrasentan in Patients With Cardiovascular Risk and Early Atherosclerosis
From the Division of Cardiovascular Diseases (E.R., A.P., V.M., B.K., D.R.H., G.M.P., R.E.N., L.O.L., A.L.), Center for Coronary Physiology and Imaging (E.R., G.M.P., R.E.N., A.L.), and Division of Nephrology and Hypertension (L.O.L.), Mayo Clinic, Rochester, Minn.
Correspondence to Amir Lerman, Division of Cardiovascular Disease, Mayo Clinic, Mary Bright 4-523, First St SW, Rochester, MN 55905. E-mail Lerman.Amir{at}mayo.edu
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Abstract |
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Endothelin plays an important role in the pathogenesis of atherosclerosis. The aim of the study was to evaluate the safety and hemodynamic and metabolic responses to 6 months treatment with atrasentan, the selective endothelin-A receptor antagonist. Seventy-two patients with multiple cardiovascular risk factors and nonobstructive coronary artery disease on coronary angiogram were randomly assigned in a double-blind manner to atrasentan or placebo. Mean aortic blood pressure decreased from 92±10 to 80±10 mm Hg (P<0.001) in the atrasentan group and did not change in the placebo group (93±10 and 92±11 mm Hg; P=0.84). The difference between the groups was significant (P<0.001). No effect on heart rate was observed. In a subgroup of patients not treated with angiotensin-converting enzyme inhibitor, creatinine level decreased in the atrasentan versus the placebo group (P=0.011). Fasting glucose (P=0.026), glycosylated hemoglobin level (P=0.041), triglyceride l (P=0.013), lipoprotein-A (P=0.046), and uric acid levels (P=0.048) decreased significantly in the atrasentan group compared with the placebo group. No progression of angiographic coronary disease was observed. The most common adverse effects with atrasentan were nasal stuffiness, headache, and edema. In conclusion, 6 months of treatment with atrasentan results in a reduction of blood pressure and improvement in glucose and lipid metabolism. These findings suggest the beneficial role of atrasentan in the treatment of hypertension and metabolic syndrome.
Key Words: blood pressure • hypertension • metabolic syndrome • endothelin • endothelin-A receptor • edema
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Introduction |
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Endothelin-1 (ET-1) is a potent vasoconstrictor contributing to the complex regulation of vascular tone.1 Beyond the effect in promoting vasoconstriction, it has become evident that ET-1 plays a seminal role in the atherogenic process.2 Moreover, cardiac risk factors cause an increase in endothelin level and impairment of endothelial vasodilator function,3–7 which is considered an important phase in atherogenesis.8
The actions of ET-1 are mediated via two distinct receptor subtypes, endothelin A (ETA) and endothelin B (ETB). Most of the ET-1-mediated pressor effect results from stimulation of the ETA receptor. The ETB receptor mediates pulmonary clearance9 and reuptake of ET-1 by endothelial cells,10 promotes production of NO, and prevent apoptosis.11 Thus, the influence of the ETB receptor on arterial pressure regulation is more controversial.
In animal studies, an ET-1 receptor antagonist treatment resulted in reduced arterial pressure,12,13 prevention or even regression of structural renal lesions,14,15 and improvement of insulin action with significant reduction of hyperglycemia.16,17 To date, only acute effects of ET receptor blockade on renal function18 and insulin resistance19 have been investigated in humans. Clinical experience on the impact of medium- to long-term ETA receptor blockade on blood pressure, renal function, and metabolic markers in patients with early atherosclerosis and cardiovascular risk factors is limited.
Atrasentan (Abbott Laboratory, ABT-627, A-147627; trade name, Xinlay), an orally available, potent, and highly selective antagonist of the ETA receptor,20 has been used previously in patients with various forms of cancer. There is a growing body of evidence to suggest that atrasentan is safe and effective in humans.21,22 The aim of this study was to assess the hemodynamic and metabolic responses to chronic ETA receptor antagonism with atrasentan in patients with mild coronary atherosclerosis and multiple cardiovascular risk factors.
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Methods |
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The current study was a part of a National Institutes of Health study addressing the role of atrasentan in early coronary atherosclerosis in humans. The study protocol was approved by the Mayo Clinic Institutional Review Board. Between July 2001 and December 2006, 139 patients with hypertension (blood pressure
140/9023 and/or the need for pharmacological therapy) and other multiple cardiovascular risk factors were referred to coronary angiography for the evaluation of coronary artery disease. Patients were brought to the cardiac catheterization laboratory in the fasting state. Diagnostic coronary angiography was performed using the standard femoral percutaneous approach and administrating 2000 IU of heparin IV at the beginning of the procedure. Systolic, diastolic, and mean aortic blood pressures were measured in ascending aorta during the procedure before diagnostic coronary angiography.
Exclusion criteria were age <18 or >85 years, >40% diameter stenosis of any coronary artery, previous myocardial infarction or angioplasty, unstable angina pectoris, uncontrolled hypertension, peripheral vascular disease, ejection fraction <55%, pregnancy, lactation, or severe endocrine, hepatic, renal, or inflammatory disease (Figure S1, available at http://hyper.ahajournals.org).
Seventy-two patients were randomly assigned and treated in a double-blind fashion according to a computer-generated code with either the ETA receptor antagonist atrasentan (ABT 627, Abbott Laboratory) at the dose of 10 mg PO once a day or placebo, in addition to standard medical therapy. Treatment assignments were concealed from participants and study staff except for the pharmacist technician. Study and placebo tablets (provided by Abbott Laboratory) were distributed in bottles and were identical in appearance. Written informed consent was obtained from all of the patients.
The patients were contacted once a week for the first month and once a month for the remaining 5 months. The occurrence of adverse effects was recorded based on patient self-report at these time points. Liver function tests and total blood count were assessed every week for the first month and once a month for the remaining study period by the local physician. Plasma lipid profile, glucose, and insulin were measured by standard methods. The homeostasis model assessment index [fasting serum insulin (µU/mL)xfasting plasma glucose (mmol/L)/22.5] was used as indicator of insulin sensitivity. Because of the high prevalence of overweight patients in the study cohort, we estimated creatinine clearance from the Salazar -Corcoran formula
, as follows:
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This has been validated and shown to better correlate with renal function in overweight patients.24
Office measurement of systolic blood pressure, diastolic blood pressure, and heart rate was performed before random assignment and once a month for the remaining study period using a semiautomatic device (Omron HEM-907 XL) with built-in clock and printer. The mean of 3 readings taken in sitting position in 1-minute intervals after 5 minutes of rest was made (before intake of the study medication). Heart rate was measured manually at the same time as blood pressure.
After the 6-month period, the patients returned for a follow up. Blood tests, hemodynamics, and coronary artery angiogram were reassessed.
Statistical Analysis
Data are displayed as means±SDs or count and percentage where appropriate. Analysis to compare different demographic and baseline clinical data between the randomized groups was performed using the t test for continuous data and the 
2 test for categorical data. Differences from baseline to a 6-month follow-up within the groups were compared using a paired t test. Differences between the groups in the primary and secondary end points, as well as other hemodynamic and laboratory characteristics, were compared using ANCOVA with 6-month follow-up value as the dependent variable and the baseline value as the adjusting covariable. A P<0.05 was considered to be statistically significant. No adjustment was made for hypothesis tests of multiple end points.
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Results |
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Characteristics of the Patients
The groups were well matched with regard to age, gender, race, coronary risk factors, and medical treatment (Table 1). Of the 72 patients studied, 58% were women, 14% were diabetic, 61% were hyperlipidemic, and 49% of them were treated with statins at study entry. Fifty-three percent of patients had smoked, and 39% were obese (body mass index: 34.8±4.6; range: 30.1 to 46.7).
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Baseline blood pressure and heart rate did not differ between the groups (Table 2A and 2B). There were no differences in baseline laboratory values and body mass index (Table 3 and Table S2).
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The number of stenotic coronary segments (1.5±1.2 versus 1.3±1.2; P=0.65) and degree of the coronary stenosis (23±13% versus 20±14%; P=0.96) did not differ between the groups. Over the course of the study, no progression of angiographic coronary disease was observed. Left ventricular ejection fraction assessed by echocardiogram did not differ between the groups (65±8 and 62±8; P=0.42) and remained normal in all of the patients.
Blood Pressure
Chronic administration of atrasentan resulted in a significant reduction of invasively assessed systolic (P<0.001), diastolic (P<0.001), and mean aortic blood pressure (P<0.001). The effect of atrasentan as compared with placebo was significant in the reduction of systolic aortic blood pressure (P=0.009), diastolic aortic blood pressure (P<0.0001), and mean aortic blood pressure (P<0.0001; Table 2A). Systolic, diastolic, and mean aortic blood pressures did not change in the placebo group. Treatment with angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB) did not affect aortic blood pressure in the atrasentan (–13.2±14.0 versus –9.9±12.4; P=0.53) or the placebo (–1.01±12.0 versus 1.8±8.3; P=0.48) groups.
Significant reduction in systolic blood pressure and diastolic blood pressure was demonstrated during the office measurements, and the effect was apparent as early as 1 month of treatment (Table 2B). Indeed, antihypertensive medications were discontinued in 4 patients in the atrasentan group. In contrast, 3 patients needed an increase in antihypertensive treatment in the placebo group. No effect on heart rate was observed.
Renal Function
No significant difference in changes of the creatinine level between the groups was demonstrated (P=0.25; Table 3). However, in the subgroup of patients not treated with ACE inhibitors/ARB, atrasentan significantly decreased the creatinine level (from 0.98±0.15 to 0.90±0.12; paired P=0.0076; n=18), whereas no change in the creatinine level was observed in the placebo group (1.01±0.13 and 1.01±0.12; paired P=0.56; n=19). The reduction in the creatinine level during atrasentan treatment was significant as compared with placebo (P=0.011) in this subgroup of patients and remained significant after adjustment to changes in hemoglobin concentration (P=0.03).
No significant difference between the groups was demonstrated in changes of the estimated creatinine clearance (P=0.09; Table 3). In patients not treated with ACE inhibitors/ARB, creatinine clearance increased significantly in the atrasentan group as compared with placebo (P=0.02). The difference remained significant after adjustment to changes in hemoglobin concentration (P=0.042). Uric acid level significantly decreased in the atrasentan group (P=0.006), and at 6 months the changes between the groups differed significantly (P=0.048).
Blood Glucose
There were no changes in antihyperglycemic medications during the study period. Changes in fasting blood glucose (P=0.026) and glycosylated hemoglobin (P=0.041) differed significantly between the 2 groups. No significant changes in insulin level were observed. Homeostasis model assessment of insulin resistance in the atrasentan group was nonsignificantly decreased compared with the placebo group (P=0.08; Table 3).
Lipids
Fifty-six percent of the atrasentan group patients and 52% of the placebo group patients were maintained on routine lipid-lowering therapy with pravastatin, simvastatin, or atorvastatin at the start of the study, and changes in lipid values were serially monitored. There were no changes in the lipid-lowering medications and in the diet during the study period. Triglyceride levels decreased significantly in the atrasentan-treated patients as compared with the placebo-treated patients (P=0.013). No changes were observed in high-density lipoprotein cholesterol level. Lipoprotein-A level decreased significantly in the atrasentan group as compared with the placebo-treated group (P=0.046; Table 3).
Adverse Effects
Atrasentan was generally well tolerated. The incidence of reported adverse effects was similar between the treatment groups (Table 4). The most common adverse effect with atrasentan was nasal stuffiness, which occurred in the first week after atrasentan initiation and persisted during the study period. Headache occurred with a higher incidence in the patients receiving atrasentan in the first month but was reported at the same rate in the both groups in further follow-up (Table S3). Edema (upper extremities and facial) occurred more frequently with the initiation of atrasentan, but after 2 months of follow-up there were no differences between the groups (Table S3).
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There were no changes in body weight in the patients treated with atrasentan (Table 3). Seven patients in the atrasentan group and 8 patients in the placebo group gained >1 kg (P=0.72). There were no changes in serum sodium (140.6±2.3 versus 140.6±2.2; P=0.42) in the atrasentan group (Appendix Table S2). Blood albumin level did not change (4.0±0.4 versus 3.8±0.3; P=0.27). No patient developed proteinuria or hematuria during the study period.
These adverse effects were mild to moderate in intensity, reversible, and, when necessary, readily controlled with symptomatic treatment. There were no serious adverse events in any of the patients.
Four patients from the atrasentan group discontinued the treatment because of noncompliance (n=1), respiratory infection (n=2), and conjunctivitis (n=1). Five patients from the placebo group discontinued the treatment because of noncompliance (n=2), respiratory infection (n=1), elevation in liver enzymes (n=1), and rash (n=1).
Over the course of the study period, a mild drop in hemoglobin concentration was observed within the first month of treatment. Hemoglobin level remains stable within the subsequent 5 months. In the atrasentan group, the reductions of mean hemoglobin at the end of the double-blind treatment were 1·18±1·17 g/dL as compared with 0.63±0.90 g/dL in the placebo group (P=0.04). However, no patient developed anemia or required blood transfusion during the study period. No significant changes were observed in white blood count or platelet count in the atrasentan-treated patients. There were no increases and no clinically significant changes in liver enzymes (Table S2).
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Discussion |
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The current study demonstrates that chronic administration of the selective ETA receptor antagonist atrasentan in patients with early atherosclerosis and multiple cardiovascular risk factors resulted in a reduction of blood pressure and improvement of glucose and lipid metabolism. Atrasentan was used previously in oncology patients21,22 in dosages that varied between 5 and 60 mg. Because higher incidence of adverse events and potential loss of ETA receptor selectivity was reported with increasing doses (>20 mg),25 the dosage of 10 mg daily was used in our study.
Rifampin may affect atrasentan pharmacokinetics.26 No interaction with cardiovascular drugs has been reported.
Atrasentan and Blood Pressure
Although bosentan (a nonselective ETA/ETB antagonist) reduced vascular tone in animal studies12 and significantly reduced BP in subjects with mild-to-moderate essential hypertension,27 it has been demonstrated recently that selective blockade of the ETA receptor in animals is superior to nonselective ETA/ETB in attenuating hypertension and hypertensive organ damage.13 Darusentan, an ETA receptor antagonist that still presents a relatively high affinity for the ETB subtype,28 reduced systolic and diastolic blood pressure in subjects with moderate hypertension during a 5-week follow-up.29
The current study demonstrated that atrasentan, a highly selective ETA receptor antagonist (relative ETA/ETB selectivity is x186028), significantly reduces systolic, diastolic, and mean blood pressure assessed invasively and in the office. Atrasentan-associated reduction in blood pressure in the present study was not accompanied by reflexive increases in the heart rate, which suggests the absence of reflexive neurohormonal activation with endothelin-receptor antagonism. In previous studies no changes in neurohormones level were demonstrated during 4 weeks of bosentan treatment.27
Atrasentan and Renal Function
The current study suggests that chronic treatment with atrasentan may protect renal function in patients not treated with ACE inhibitor/ARB. Although the benefit could be mediated by vasodilation and reduction in blood pressure alone, experimental data suggested that ET-1 antagonists abolish the profibrotic actions of angiotensin II, prevent structural lesions in the renal vasculature,30 produce renal vasodilation, and reduce proteinuria.18
Uric acid also significantly decreased in patients treated with atrasentan. This effect can be partially explained by atrasentan-induced hemodilution; however, experimental data suggested that endothelin blockade attenuates stimulation of the xanthine oxidase pathway by angiotensin II.31
Atrasentan and Blood Glucose
Many lines of evidence suggest that endothelin may interact and impair glucose metabolism,32,33 and the proposed mechanisms are a rapid and sustained stimulation of glycogenolysis,34 direct influence on insulin-stimulated glucose transport, and impaired ability of the vasculature to vasodilatate and actively redistribute blood flow in response to insulin.35
Animal studies showed that combined ETA+ETB receptor blockade results in favorable effects on glucose metabolism,17,36 and it is assumed that most of the pathophysiological effects are mediated via stimulation of the ETA receptor.16,37 To date, in humans, only an acute effect of the combined ETA+ETB receptor blockade on insulin resistance was investigated.19 The current study showed the reduction in glucose and glycosylated hemoglobin level and suggested that chronic ERA blockage with atrasentan may improve glucose metabolism.
Atrasentan and Lipids
Our study is the first to show that atrasentan treatment caused a significant decrease in triglyceride levels, which possibly resulted from improvement in insulin sensitivity. This study also demonstrated a significant reduction in the level of lipoprotein-A in patients treated with atrasentan, suggesting a link between lipoprotein-A and the endothelin system in humans. Of note, a high lipoprotein-A level is a risk factor for a variety of atherosclerotic disorders38 and relative resistance to pharmacological interventions, including statin therapy.39
Coronary Angiography
It has been shown previously that acute intravenous administration of bosentan to patients with angiographic stable coronary artery disease produced an increase in the coronary diameter in those vessels with minimal angiographic changes.40 The selective ETA receptor blocker given to patients with stable angina was shown to prevent distal coronary vasoconstriction after percutaneous transluminal coronary angioplasty.40 In our study, no angiographic changes in coronary artery disease were demonstrated in either treatment group during the 6-month follow-up.
Adverse Effects
Our study demonstrated that atrasentan is safe and well tolerated. No increase in hepatic enzymes was observed in the patients treated with atrasentan. Adverse events such as nasal stuffiness and headache were probably related to the transient nonspecific vasodilating effect of atrasentan.
The increased incidence of peripheral edema was apparent during the short-term administration of atrasentan, but after 2 months of follow-up there were no statistically significant differences between the groups. The mechanism of peripheral edema with ET receptor antagonism remains unclear and probably related to a vasodilating effect of atrasentan. The experimental data support that ETB receptor activation may result in diuresis by renal vasodilatation and reduction of water reabsorption in the distal tubules and collecting ducts, suggesting that peripheral edema associated with vasodilatation could be aggravated by mixed ETA/B blockade.41 Hence, selective ETA receptor antagonism may be more beneficial to diuresis than dual ETA+ETB receptor inhibition.42 However, in clinical trials, fluid retention seems to occur with both selective ETA and mixed ETA/B receptor antagonists. Dose-dependent peripheral edema was reported as the most important drug-related adverse event during a 
3-month follow-up with other selective ETA receptor antagonists.29,43,44 In patients with chronic heart failure, however, the "biphasic" pattern of response with short-term deterioration and late benefit was reported with ET-1 receptor antagonists treatment.45 In the present study the relatively high incidence of self-reported identification of edema in the placebo group made it challenging to interpret the comparative edema rates between the control and atrasentan groups during the long-term follow-up.
In line with previous studies, we observed an early and mild decrease in hemoglobin, which did not progress; could not be explained by hemolysis, bone marrow depression, or bleeding; and had no clinical significance. Although a decrease in red cell counts could be related to hemodilution, it has also been observed with the use of the ACE inhibitor enalapril46 and suggested to be secondary to a reduction in erythropoietin level.47
Study Limitations
Because of the placebo-controlled study design, only the patients with mild hypertension or controlled by standard medical treatment were enrolled. Similarly, there was no significant impairment in renal function in our study cohort. Although in the subgroup of patients not treated with ACE inhibitor/ARB a statistically significant improvement in renal function was reached during atrasentan treatment, clinically this improvement was nonsignificant. Our data justify further evaluation of the effect of selective ETA blockade in patients with more significant hypertension, diabetes, and target-organ damage.
In the present study we did not follow the endothelin levels and did not evaluate the mechanisms underlying the effects of atrasentan on renal function or metabolic markers. Although vasodilation takes place, based on previous experimental data we suggest that ETA blockade has a role in the favorable effect of atrasentan on renal function and metabolic markers.
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Conclusion |
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Six months of treatment of patients with early atherosclerosis and multiple cardiovascular risk factors with atrasentan resulted in a significant reduction in blood pressure. Moreover, our data suggested favorable effects of chronic atrasentan treatment on metabolic parameters, such as an improvement in glucose metabolism, a reduction of lipoprotein-A and triglycerides concentrations, and a decrease in uric acid levels.
Perspectives
Chronic treatment with atrasentan, an ETA receptor antagonist, may offer significant advantages in the treatment of hypertension and may result in modification of metabolic markers. These effects suggest a potential beneficial role of atrasentan in the treatment of metabolic syndrome and prevention of progression of early atherosclerosis. The effect of selective ETA blockade on metabolic markers and renal function in patients with more significant hypertension, diabetes, and target-organ damage needs further evaluation.
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Acknowledgments |
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We thank the Abbott Laboratory for providing atrasentan and the placebo.
Source of Funding
This work was supported by National Institutes of Health grant 5 R01 HL63911-02.
Disclosures
None.
Received March 6, 2008; first decision March 24, 2008; accepted June 27, 2008.
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