Acute and Chronic Hemodynamic Effects of Xamoterol in Mild to Moderate Congestive Heart Failure Surinder J.S. Virk, MRCP, FengxiaQiang, BMed, Nicholas H. Anfilogoff, MRCP, Robert G. Murray, FRCP, William A. Littler, MD and Michael K. Davies, MA, MD IMPORTANT: See ‘Addendum’,page 54C. Xamoterol, a new 81 partial agonist, has the potential to modulate cardiac response to variations in sympathetic tone in patients wlth heart failure. Its properties should result in &receptor stlmulatory effects at low levels of sympathetic tone and ~-IVceptor protective effects at higher levels of sympathetic tone. The acute effects of intravenous (i.v.) xamoterol on hemodynamics at rest and during exercise wet-0 studied in 36 patients with mikl to moderate heart faikue (13 patients in New York Heart Associatton class II; 17 in class III) due to ischemic (n = 24) or cardiomyopathic (n = 6) heart disease. Cardii index, stroke vohnne and stroke work index at rest were signitieantly improved after i.v. administration of xamoterol and consistent with net agonist effects. During exercise, heart rate and double product were signincantly reduced (net antagonist effects), but with preservation of the expected increases in cardiac index and systolic blood pressu4.e.Thess hemodynamic findings confum the ability of xamoterol to modulate cardiac response to variations in sympathetic tone. Tachyphylaxis and arrhythmogenicity limit the chronic use of drugs with full o-agonist properlies as positive inotropes in heart failure. The patients were therefore entered into a 6-month double-blind, placebo-controlled, crossover study of chronic oral xamoterol therapy, 266 mg twice daily, and the hemodynamic responses to i.v. xamoterol were repeated at the end of the trial. No impairment in either resting or exercise effects was observed, indiitive of a maintaimd response and absence of tachyphyktxis after chronk therapy. Furthermore, 24-hour ambulatory electrocardiographic moniteting showed no change in ventricular arrhythmias during oral treatment. In mild to moderate heart failure, xamoterol improves cardiac pedonnancs at rest and during exercise, the changes being consistent with its pharmaedogic profile. There was no evidence of tachyphylaxis or exacerbation of ventricular arrhythmias after chronic oral therapy. (Am J Cardiol 1661;67:46G64C) From the Department of Cardiovascular Medicine, University of Birmingham and Queen Elizabeth Hospital, Birmingham, United Kingdom. Addressfor reprints: Michael K. Davies, MD, Department of CardiovascularMedicine, QueenElizabeth Hospital, Edgbaston,Birmingham, B 15 2TH, United Kingdom.
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67
he sympathetic nervous systemis activated early in heart failure as a normal compensatorymechanism, with norepinephrine providing natural endogenousinotropic support to the failing heart.1-5The final common pathway regulating contraction (#kecep tor/adenylcyclase/cyclic adenosinemonophosphatesystem) needsto remain intact to enablethe heart to maintain the same level of responseto circulating catecholamines.However, it is now well recognizedthat chronic sympathetic nervous system overactivity seen in heart failure has deleteriouseffectson this pathway leading to p-receptor down-regulation.6-14This loss of p-receptor function or number subsequentlydeprivesthe heart of its ability to respondto inotropic support explaining the clinical findings that plasma norepinephrine concentration correlates with prognosis5J5and that progressiveheart failure occursdespitetherapy with therapeutic regimens that do not influence, or that increase,sympatheticdrive. Furthermore, enhanced &receptor down-regulation resulting from exogenousinotrope therapy would explain the frequent occurrence of tachyphylaxis to such agents,’2 and would also explain why no inotrope improves,and why someworsen,prognosis.16-18 Conversely, angiotensin-converting enzyme inhibitors have been shownto improve prognosis;I9this may be due, at least in part, to their ability to provide vasodilatation associated with reduced, rather than increased,sympathetic drive with a consequentrestoration of b-receptor function.20 Similarly, the apparent paradoxic useof P antagonistsin severeheart failure aimed at protecting P-receptorfunction has beenshownto have beneficial effectsin selected groupsof patients.21-23However,removal of sympathetic support when pure B antagonistsare being administered to patients with heart failure is potentially hazardous. Xamoterol is a cardioselective/31partial agonist with 43%of the intrinsic sympathomimeticactivity of the full agonist isoprenaline.24This novel profile providesthe potential to modulate the cardiac responsesto variations in sympathetic tone. At relatively low levels of sympathetic tone, such as at rest in mild to moderate heart failure, occupancyof the /3receptorby xamoterol should result in a net agonist effect. However, at higher levelsof sympathetic tone, occurring during exercise,a net antagonist effect should predominatebecauseof competitive inhibition of norepinephrine at the receptor level. This study reports the hemodynamiceffectsof xamoterol in patients with mild to moderate heart failure at rest and during exercise, and was designed to determine whether this profile of net agonism/antagonism, dependent on the
T
background level of sympathetic tone, occurs.The effects of xamoterol on ventricular arrhythmias and its potential to prevent the development of tachyphylaxis resultant on the stabilization of P-receptor stimulation is also examined. METHODS Patknts The study group consistedof 30 patients (27 men, 3 women, mean age 60 f 2 years, range 40 to 73 years) with mild to moderate heart failure (New York Heart Association class II [n = 131;class III [n = 171) due to ischemic (24 patients) or cardiomyopathic (6 patients) heart disease.During the study, concomitant therapy with xamoterol consisted of digoxin (12 patients), vasodilators (nitrates, calcium channel antagonists or ACE inhibitors, 16 patients) and diuretics (frusemide and/or amiloride, 28 patients). All patients underwent a symptom-limited exercise test on a bicycle ergometer 1 to 2 weeksbeforetheir initial hemodynamicstudy to determine their exercisecapacity. The initial work load of 25 watts was maintained for 3 minutes and then increasedby 25 watts every 3 minutes. The patients were selectedon their ability to completea minimum of 3 minutes of this exercise protocol with dyspnea as their limiting symptom.
STUDY PROTOCOL Initial invasive hemodynamic assessm enk A thermodilution Swan-Ganz catheter was inserted through the right subclavian vein and an intraarterial cannula was sited percutaneously into the right brachial artery. All hemcdynamic measurementswere obtained with the patient in a semirecumbentposition at 25” from the vertical. Hemodynamic variables at rest were recorded 1 hour after catheter insertion. ’ The patient then performed a symptom-limited bicycle exercisetest, with hemodynamic variables recorded during the last 30 secondsof each stage.Left ventricular ejection fraction wasmeasuredby radionuclide technetium-99m scanningat rest and during the last 2 minutes of each 3-minute exercisestage.Thermodilution cardiac output was determined in triplicate. The patients were then allowed to rest for 4 hours and at the endof this period hemodynamicmeasurementsat rest were recordedagain, before and 15 minutes after intravenous (i.v.) administration of xamoterol, 0.2 mg/kg. The exercisetest was then repeated as mentioned before. Chronic oral dosing: After theseinitial hemodynamic assessmentsthe patients .were entered into a (i-month, placebo-controlled,double-blind, crossoverstudy of oral xamoterol, 200 mg twice daily. Final hemodynamic assesAt the end of the chronic oral dosing phase, and after a 72-hour washout period, the hemodynamic assessments at rest and during exercise before and after i.v. administration of xamoterol, 0.2 mg/kg, were repeatedin the same manner as mentioned. Twenty-four-hour
ambulatory
electrocardiography:
Ambulatory electrocardiographic monitoring (Oxford Medilog 4000 II) wasperformedin all patients beforethe initial hemodynamic assessmentand repeatedin the last week of eachtreatment phaseduring oral therapy. Mean
hourly heart rates over the 24-hour period were obtained directly from computer analysis (Oxford Medilog 4500). The mean hourly ventricular ectopic frequency and arrhythmia classification were analyzed by direct visual analysis of each 24hour disclosure. Statistical analysis: The significance of differences was analyzed using Student’s I test for paired observations. Values are expressedas mean f standard error of the mean; p
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THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67
he sympathetic nervous systemis activated early in heart failure as a normal compensatorymechanism, with norepinephrine providing natural endogenousinotropic support to the failing heart.1-5The final common pathway regulating contraction (#kecep tor/adenylcyclase/cyclic adenosinemonophosphatesystem) needsto remain intact to enablethe heart to maintain the same level of responseto circulating catecholamines.However, it is now well recognizedthat chronic sympathetic nervous system overactivity seen in heart failure has deleteriouseffectson this pathway leading to p-receptor down-regulation.6-14This loss of p-receptor function or number subsequentlydeprivesthe heart of its ability to respondto inotropic support explaining the clinical findings that plasma norepinephrine concentration correlates with prognosis5J5and that progressiveheart failure occursdespitetherapy with therapeutic regimens that do not influence, or that increase,sympatheticdrive. Furthermore, enhanced &receptor down-regulation resulting from exogenousinotrope therapy would explain the frequent occurrence of tachyphylaxis to such agents,’2 and would also explain why no inotrope improves,and why someworsen,prognosis.16-18 Conversely, angiotensin-converting enzyme inhibitors have been shownto improve prognosis;I9this may be due, at least in part, to their ability to provide vasodilatation associated with reduced, rather than increased,sympathetic drive with a consequentrestoration of b-receptor function.20 Similarly, the apparent paradoxic useof P antagonistsin severeheart failure aimed at protecting P-receptorfunction has beenshownto have beneficial effectsin selected groupsof patients.21-23However,removal of sympathetic support when pure B antagonistsare being administered to patients with heart failure is potentially hazardous. Xamoterol is a cardioselective/31partial agonist with 43%of the intrinsic sympathomimeticactivity of the full agonist isoprenaline.24This novel profile providesthe potential to modulate the cardiac responsesto variations in sympathetic tone. At relatively low levels of sympathetic tone, such as at rest in mild to moderate heart failure, occupancyof the /3receptorby xamoterol should result in a net agonist effect. However, at higher levelsof sympathetic tone, occurring during exercise,a net antagonist effect should predominatebecauseof competitive inhibition of norepinephrine at the receptor level. This study reports the hemodynamiceffectsof xamoterol in patients with mild to moderate heart failure at rest and during exercise, and was designed to determine whether this profile of net agonism/antagonism, dependent on the
T
background level of sympathetic tone, occurs.The effects of xamoterol on ventricular arrhythmias and its potential to prevent the development of tachyphylaxis resultant on the stabilization of P-receptor stimulation is also examined. METHODS Patknts The study group consistedof 30 patients (27 men, 3 women, mean age 60 f 2 years, range 40 to 73 years) with mild to moderate heart failure (New York Heart Association class II [n = 131;class III [n = 171) due to ischemic (24 patients) or cardiomyopathic (6 patients) heart disease.During the study, concomitant therapy with xamoterol consisted of digoxin (12 patients), vasodilators (nitrates, calcium channel antagonists or ACE inhibitors, 16 patients) and diuretics (frusemide and/or amiloride, 28 patients). All patients underwent a symptom-limited exercise test on a bicycle ergometer 1 to 2 weeksbeforetheir initial hemodynamicstudy to determine their exercisecapacity. The initial work load of 25 watts was maintained for 3 minutes and then increasedby 25 watts every 3 minutes. The patients were selectedon their ability to completea minimum of 3 minutes of this exercise protocol with dyspnea as their limiting symptom.
STUDY PROTOCOL Initial invasive hemodynamic assessm enk A thermodilution Swan-Ganz catheter was inserted through the right subclavian vein and an intraarterial cannula was sited percutaneously into the right brachial artery. All hemcdynamic measurementswere obtained with the patient in a semirecumbentposition at 25” from the vertical. Hemodynamic variables at rest were recorded 1 hour after catheter insertion. ’ The patient then performed a symptom-limited bicycle exercisetest, with hemodynamic variables recorded during the last 30 secondsof each stage.Left ventricular ejection fraction wasmeasuredby radionuclide technetium-99m scanningat rest and during the last 2 minutes of each 3-minute exercisestage.Thermodilution cardiac output was determined in triplicate. The patients were then allowed to rest for 4 hours and at the endof this period hemodynamicmeasurementsat rest were recordedagain, before and 15 minutes after intravenous (i.v.) administration of xamoterol, 0.2 mg/kg. The exercisetest was then repeated as mentioned before. Chronic oral dosing: After theseinitial hemodynamic assessmentsthe patients .were entered into a (i-month, placebo-controlled,double-blind, crossoverstudy of oral xamoterol, 200 mg twice daily. Final hemodynamic assesAt the end of the chronic oral dosing phase, and after a 72-hour washout period, the hemodynamic assessments at rest and during exercise before and after i.v. administration of xamoterol, 0.2 mg/kg, were repeatedin the same manner as mentioned. Twenty-four-hour
ambulatory
electrocardiography:
Ambulatory electrocardiographic monitoring (Oxford Medilog 4000 II) wasperformedin all patients beforethe initial hemodynamic assessmentand repeatedin the last week of eachtreatment phaseduring oral therapy. Mean
hourly heart rates over the 24-hour period were obtained directly from computer analysis (Oxford Medilog 4500). The mean hourly ventricular ectopic frequency and arrhythmia classification were analyzed by direct visual analysis of each 24hour disclosure. Statistical analysis: The significance of differences was analyzed using Student’s I test for paired observations. Values are expressedas mean f standard error of the mean; p
