European Journal of Heart Failure 3 Ž2001. 203᎐207

Aspirin does not influence the effect of angiotensin-converting enzyme inhibition on left ventricular ejection fraction 3 months after acute myocardial infarction

b

a Department of Cardiology, Ulle¨ ˚ al Uni¨ ersity Hospital, Oslo, Norway Medical Department, Central Hospital of Møre and Romsdal, Oslo, Norway c Research Forum, Ulle¨ ˚ al Uni¨ ersity Hospital, Oslo, Norway

Received 10 April 2000; received in revised form 11 August 2000; accepted 12 October 2000

Abstract The aim of the present study was to evaluate the possible interaction between chronic aspirin therapy and angiotensin-converting enzyme inhibitor ŽACE-I. on left ventricular ejection fraction ŽLVEF. in patients surviving an acute myocardial infarction ŽAMI.. Forty-two patients with reduced LVEF were recruited from the warfarin aspirin reinfarction study ŽWARIS-II., a randomized, open study comparing enteric coated aspirin Ž160 mgrd., warfarin ŽINR 2.8᎐4.2. and the combination of aspirin Ž75 mgrd. and warfarin ŽINR 2.0᎐2.5. on mortality, reinfarction and stroke after AMI. LVEF and relevant biochemical measurements were performed before discharge and after 3 months. The overall LVEF increased during the study period from median 35 to 39% Ž P - 0.001.. There was no difference between patients on aspirin and warfarin regarding the main end point, LVEF. Furthermore, neither endothelin-1 nor ANP showed significant differences between the treatment groups. A possible interaction between ACE-I and aspirin might theoretically lead to reduced levels of renin activity in patients on aspirin, but we did not find any such inter-group difference. In conclusion, we did not find evidence of interaction between ACE-I and low-dose aspirin. 䊚 2001 European Society of Cardiology. All rights reserved. Keywords: Angiotensin-converting enzyme inhibitor; Aspirin; Myocardial infarction; Interaction; Left ventricular ejection fraction

1. Introduction Angiotensin-converting enzyme inhibitors ŽACE-I. have contributed radically to the treatment of patients with severe heart failure, with respect to survival as well as amelioration of symptoms w1᎐3x. They are efficacious vasodilators by reduction of angiotensin II and norepinephrine w4x. In addition, ACE-I reduce the degradation of bradykinin, a potent vasodilator,

U

Corresponding author. Tel: q47-22-11-80-80; fax: q47-22-1179-65.

which also augments the synthesis of prostacyclin w5,6x, contributing to the vasodilatory effect. Coronary heart disease is the cause of heart failure in many patients. Aspirin is widely used in secondary prevention after acute myocardial infarction ŽAMI. and has been shown to reduce mortality and morbidity through inhibition of platelet aggregation w7x. Aspirin blocks the enzyme cyclooxygenase, thereby inhibiting the synthesis of the aggregatory and vasoconstrictory thromboxane, but also the antiaggregatory and vasodilatory prostaglandins. Even the small doses of aspirin used today may, to some degree, affect the synthesis of prostaglandins w8,9x.

1388-9842r01r$20.00 䊚 2001 European Society of Cardiology. All rights reserved. PII: S 1 3 8 8 - 9 8 4 2 Ž 0 0 . 0 0 1 3 8 - 0

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Mette Hurlen a,U , Torstein Hole b, Ingebjørg Seljeflot c , Harald Arnesen a

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M. Hurlen et al. r European Journal of Heart Failure 3 (2001) 203᎐207

2. Methods The 42 patients were recruited from the warfarin aspirin reinfarction study ŽWARIS-II., a national multicenter study including 3630 patients with AMI. WARIS-II is a randomized, open study comparing enteric coated aspirin Ž160 mgrd., warfarin ŽINR 2.8᎐4.2. and the combination of aspirin Ž75 mgrd. and warfarin ŽINR 2.0᎐2.5. on mortality, reinfarction and stroke after AMI w20x. The present substudy was performed in two of the study centers, Ulleval ˚ University Hospital, Oslo, and Central Hospital of Møre ˚ and Romsdal, Alesund. The inclusion criteria were LVEF- 40% or heart failure during hospital stay leading to initiation of ACE-I before discharge. Patients meeting these criteria were enrolled successively into the substudy according to a preformed study protocol. During the study period, captopril was given to 15 patients, nine on aspirin and six on warfarin Žmean daily dosage 47 mg and 50 mg, respectively, n.s., 12 patients received enalapril, seven on aspirin and five on warfarin Žmean daily dosage 9.6 mg and 8.0 mg, respectively, n.s.. and finally, 15 patients received lisinopril, 11 in the aspirin group and 4 in the warfarin group Žmean daily dosage 7.95 mg and 8.75 mg, respectively, n.s... The choice of

ACE-I and titration of dosage was made on an individual basis. A panel of laboratory measurements was included in 19 of the patients. LVEF, as well as biochemical measurements, were performed before discharge from hospital Ž‘baseline’. and after 3 months. The ‘baseline’ measurements were usually undertaken 6 days after the AMI and 1᎐2 days after randomization in WARIS-II. LVEF was determined by gated radionuclide ventriculography according to standard procedure w21x. Plasma for determination of the prostacyclin ŽPGI2. metabolite 6-keto PGF-1␣ , endothelin-1 ŽET-1., ANP and pro-ANP was prepared from 10 ml ice-chilled vacutainer tubes ŽBecton Dickinson. containing 0.34 molrl EDTA-K3, kept on ice and centrifuged at 4⬚C and 3000 g for 20 min. All samples were kept at y70⬚C until analysis. 6-keto PGF-1␣ was analyzed using a commercial enzyme immunoassay system Žcode RPN 221, Amersham International plc.. Serum for Thromboxane B2 ŽTXB2. was collected in Vacutainer 䊛 tubes without anticoagulants and kept at 25⬚C for 1 h before centrifugation Ž2500 g for 15 min.. The samples were frozen and stored at y70⬚C until analysis. The assays were performed using a commercial EIA-kit Žcode RPN 220, Amersham International plc, Amersham, UK.. Atrial natriuretic peptide ŽANP. was measured in EDTA plasma using the radioimmunoassay RIK 8798 from Peninsula Laboratories, San Carlos, CA, USA Žalfa-atrial natriuretic polypeptide 1᎐28 Žhuman, canine.. Extraction was performed with C18 columns ŽBond᎐Elut 䊛 , 3 ccr200 mg, Varian sample preparation products, Harbor City, CA, USA.. The columns were pre-treated with sequential washing in 100% trifluoroacetic acid ŽTFA, HPLC grade. Ž1 ml, once. followed by 1% TFA Ž3 ml, 3 times.. Plasma samples Ž1 ml. were acidified with 1 ml 1% TFA and clarified by centrifugation at 17 400 g for 20 min at 4⬚C. The clarified plasma samples were loaded onto the pretreated C18 columns. The columns were slowly washed with 1% TFA Ž3 ml = 2. discarding the wash. The ANP1-28 polypeptide was eluted with 3 ml 60% acetonitrile ŽHPLC grade in 1% TFA. and the eluants collected in polypropylene tubes. The eluants were evaporated to dryness by nitrogen gas at 37⬚C and the dried extracts stored at y70⬚C for maximum 1 week before further analysis. The extracts were reconstructed in 0.5 ml assay buffer, and the radioimmunometric assay was performed according to the manufacturer’s instructions. Pro-ANP was performed by radioimmunoassay w22x. Renin activity: 4 ml blood was sampled in tubes containing 0.1 ml 0.4 molrl BAL Ž2,3 dimercap-

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Theoretically, the effect of ACE-I may be reduced by aspirin and the hemodynamic status of the patients may be adversely affected. This theory was supported by subgroup analyses of the results from studies of left ventricular dysfunction w10x, the AIRE study w11x and Consensus II w12x, where there was a trend toward less benefit of enalapril in patients using aspirin at baseline. Recent subgroup analyses from the WASH study and the HOPE study w13x also add evidence to the theory. Short-term studies on hemodynamic parameters and vasoactive substances have been contradictory w14᎐19x. Most have used a single dose of either drug. The reports on the effect of acetylsalisylic acid vary from little effect to significant attenuations of hemodynamic improvement. As yet, there are no prospective studies on the impact of chronic low-dose aspirin therapy on the effect of ACE-inhibitors on clinical endpoints or left ventricular function in patients with heart failure. The aim of the present study was to evaluate the possible interaction between chronic aspirin therapy and ACE-I on left ventricular ejection fraction ŽLVEF. in patients surviving an AMI. In order to elucidate possible mechanisms of drug interaction, biochemical analyses were included in the study protocol.

M. Hurlen et al. r European Journal of Heart Failure 3 (2001) 203᎐207

205

Table 1 Baseline characteristics according to antithrombotic treatment groups. Use of medication refers to treatment during hospitalization and the clinical parameters to the last measurements before randomizationa

a

Pvalue

Aspirin Ž n s 13.

59 Ž43᎐74. 35

57 10

59 13

62 12

0.29 0.55

3245 9 11 12 0 8 6

1730 10 13 10 0 15 9

2720 12 12 9 1 8 8

0.09 0.45 0.99 0.19 0.32 0.02 0.75

110

120

115

0.81

75 Ž70, 80. 72 Ž62, 82.

70 70

75 70

76 70

0.73 0.50

35 Ž28, 38.

36

34

33

0.26

2782 Ž880, 4332. 31 36 31 1 31 23

115 Ž119, 130.

SBP s systolic blood pressure, DBPs diastolic blood pressure, LVEFs left ventricular ejection fraction

topran-1-ol.; and 0.2 ml 0.25 molrl EDTA in water. The tubes were turned upside down 5 times for adequate mixing and put in ice water for 10 min. After centrifugation renin activity was measured by radioimmunoassay. Enzyme immunoassays were used for determination of ET-1 ŽParameter Human Endothelin-1 Immunoassay, R and D Systems Europe, Abington, Oxon, UK. Žreference values 0.3᎐0.9 pgrml.. Plasma was extracted according to the recommendation of the manufacturer: 1 ml of plasma; and 1.5 ml of a mixture of acetonr1 M HClrH 2 O Ž40:1:5. were mixed in polypropylene tubes and centrifuged for 20 min at 2000 g at 40⬚C. The supernatant was decanted into polypropylene tubes and dried in a centrifugal evaporator overnight. The pellet was reconstituted in 0.25 ml sample diluent and the immunoassay was performed. Statistical analyses: For comparison of demographic baseline data Kruskal Wallis test and chi-square tests were performed. Relative changes in LVEF and

biochemical measurements were analyzed as delta values and with Mann᎐Whitney test. A P-value 0.05 was considered statistically significant.

3. Results The baseline characteristics are shown in Table 1. The mean age was 59 years Ž43᎐74.. There were 35 males and 7 females. The groups were quite comparable with respect to baseline characteristics, LVEF, initial and follow-up treatment except for the use of ACE-I before randomization, which was given to all patients in the warfarin group. Because there were no inter-group differences between the two aspirin groups in any measurement, they were combined for further statistical analyses. The overall LVEF increased during the study period from median 35 to 39% Ž P- 0.001. ŽTable 2.. Simultaneously, there was a borderline significant in-

Table 2 Left ventricular ejection fraction ŽLVEF. and some biochemical measurements at baseline and 3 months after the AMI in the total population. Median values Ž25, 75% quartiles . are given

LVEF Ž%. Ž n s 42. ANP Žpgr100 ␮l. Ž n s 19. Renin activity Žnmolrlrt. Ž n s 18. Endothelin-1 Žpgrml. Ž n s 19.

Baseline

After 3 months

P-value Žchange from baseline .

35 Ž28, 38. 46.0 Ž24.4, 80.2. 1.75 Ž0.28, 3.36. 1.28 Ž 1.03, 1.53.

39 Ž33, 46. 43.8 Ž19.2, 72.0. 2.05 Ž0.80, 3.90. 1.09 Ž0.86, 1.36.

- 0.001 0.21 0.15 0.03

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Age, years, Mean Žrange. Males, no CK max, Url, median Ž25, 75% tile. Thrombolysis Aspirin Beta blockers Calcium antagonists ACE-I Diuretics SBP, mmHg, median Ž25, 75% tile. DBP, mmHg, median Ž25, 75% tile. Pulse, bpm LVEF, %, median Ž25, 75% tile.

Warfarin Ž n s 15.

Aspirin q warfarin Ž n s 14.

All patients Ž n s 42.

M. Hurlen et al. r European Journal of Heart Failure 3 (2001) 203᎐207

206

Table 3 Changes during the study period according to antithrombotic treatment Baseline

After 3 months

6 keto PGF 1 A Žpgrml.

Aspirin Ž n s 27. Warfarin Ž n s 15. Aspirin Ž n s 13. Warfarin Ž n s 6.

35 Ž33,39. 34 Ž29, 45. U 125 Ž95, 125. Ž 289 230, 444.

40 Ž30, 50. 36 Ž35, 49. 134 Ž105, 148. 299 Ž265, 476.

TXB2 Žngrml.

Aspirin Ž n s 13. Warfarin Ž n s 6.

4 Ž2,6. 47 Ž16, 133.

ANP Žpgr100 ␮l.

Aspirin Ž n s 13. Warfarin Ž n s 6.

54.0 Ž 22.9, 81.6. 30.9 Ž 23.7, 72.6.

Renin activity Žnmolrlrt. Ž n s 18.

Aspirin Ž n s 12. Warfarin Ž n s 5.

Endothelin-1 Žpgrml.

Aspirin Ž n s 13. Warfarin Ž n s 6.

LVEF Ž%.

U

U

4 Ž2,6. 394 Ž340, 493.

p-value Ždiff. in rel. changes from baseline .

0.73 0.79

0.007

47.6 Ž18.6, 72.3. 27.2 Ž20.0, 53.5.

0.54

1.5 Ž0.2, 3.0. 1.8 Ž0.9, 3.9.

2.1 Ž0.2, 3.4. 2.8 Ž1.5, 5.9.

0.71

1.30 Ž1.05, 1.55. 1.17 Ž0.99, 1.51.

1.09 Ž0.95, 1.26. 1.18 Ž0.69, 1.63.

0.41

Statistically significant intergroup differences at baseline are indicated by U . Median values Ž25, 75% quartiles . are given.

crease in the metabolite of PGI2, 6-keto PGF-1␣ , from median 155 to 168 pgrml Ž Ps 0.06. and in TXB2 from median 6.5 to 7.0 ngrml Ž Ps 0.007. Žnot shown in the table.. ANP was slightly, non-significantly reduced, whereas renin activity tended to increase, also non-significantly. Endothelin-1 showed a significant decrease from median 1.28 to 1.09 pgrml Ž Ps 0.03.. There was a high degree of correlation between ANP and pro-ANP on both first and second measurement Ž r s 0.82 and 0.96, respectively, P- 0.001.. In the following, only the ANP results are presented. The comparison of these parameters in patients treated with aspirin vs. warfarin alone is shown in Table 3. It emerges that there was no difference between patients on aspirin and warfarin regarding the main end point, LVEF. Furthermore, the biochemical parameters showed no significant differences between the treatment groups, except for TXB2, which increased during the study period from median 47 to 394 ngrml on warfarin and remained low Ž4 ngrml. on aspirin.

4. Discussion There was an overall increase in LVEF during the first 3 months after the AMI, probably due to initial myocardial stunning. This finding is in accordance with previous studies in post-infarction patients with reduced LVEF treated with ACE-I w23,24x. This increase, however, was equal in patients on aspirin and warfarin. Thus, the improvement in left ventricular function did not seem to be affected by the potential

interaction between ACE-I and aspirin. The increase in TXB2 reflects the fact that aspirin was given to most patients initially and discontinued in approximately one third after randomization. This is clearly illustrated in the warfarin group, which had intermediate values at baseline after aspirin therapy in the acute phase. Small doses of aspirin have been thought to suppress TXB2 and spare prostacyclin w25,26x. In our study, the stable metabolite of PGI2, 6-keto PGF 1␣ , was suppressed in patients on aspirin as compared to patients on warfarin, indicating that even these small doses of aspirin Ž75᎐160 mg. are not completely prostacyclin sparing, as shown also by others w8,9x. At baseline, where samples were usually taken 1᎐2 days after randomization, it had already increased substantially in the warfarin group, showing that prostacyclin regenerates faster than TXB2, possibly mainly by contribution from the endothelium. An increase in renin activity during the study period might be expected on treatment with ACE-I, but in the present study the increase was non-significant, probably because the majority of patients had already received ACE-I therapy for some days before baseline sampling. However, there was no inter-group difference. A possible interaction between ACE-I and aspirin might theoretically lead to reduced levels of renin activity in patients on aspirin. This was not demonstrated in our study. The levels of endothelin-1 decreased during the 3 months period. This may be due to the acute phase reaction at baseline, an effect of ACE-I per se w27x or as an expression of the improved LVEF w28x. We did not find evidence of interaction between

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Treatment

M. Hurlen et al. r European Journal of Heart Failure 3 (2001) 203᎐207

Acknowledgements We wish to thank Torstein Lyberg and Ann Christin Lindgaard for performing the ANP analyses and Christian Hall for the pro-ANP analyses. References w1x Consensus Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987; 316: 1429᎐1435. w2x The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293᎐302. w3x Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303᎐310. w4x Riegger GA, Kochsiek K. Vasopressin, renin, and norepinephrine levels before and after captopril administration in patients with congestive heart failure due to idiopathic dilated cardiomyopathy. Am J Cardiol 1986;58Ž3.:300᎐303. w5x Van Wijngaarden J, Tio RA, Van Gilst WH et al. Basic pharmacology of ACE-inhibitors with respect to ischaemic heart disease: prostaglandins and bradykinin. Eur Heart J 1990;11ŽB.:84᎐93. w6x Schror ¨ K. Converting enzyme inhibitors and the interaction between kinins and eicosanoids. J Cardiovasc Pharmacol 1990;15Žsuppl 6.:S60᎐S68. w7x Antiplatelet Trialists Collaboration. Collaborative overview of randomized trials of antiplatelet therapy. ŽI. Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. B M J 1994;308:81᎐106. w8x Weksler BB, Pett SB, Alonso D et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 1983;308:800᎐805. w9x De Caterina R, Giannessi D, Bernini W, Lazzerini G, Laverazzi M, Stragliotto E. A prostacyclin-sparing effect of indobufen vs. aspirin. Thromb Haemost 1996;75:510᎐514. w10x Pitt B, Yusuf S. Studies of left ventricular dysfunction ŽSOLVD.: subgroup results Žabstract .. J Am Coll Cardiol 1992;19:215A. for the SOLVD investigators.

w11x The Acute Infarction Ramipril Efficacy ŽAIRE. Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardinal infarction with clinical evidence of heart failure. Lancet 1993; 342: 821᎐828. w12x Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the co-operative new scandinavian enalapril survival study II ŽConsensus II.. Am J Cardiol 1997;79:115᎐119. w13x Jones CG, Cleland JGF. Meeting report-the LIDO, HOPE, MEXCON and WASH studies. Eur J Heart Failure 1999;1:425᎐431. w14x Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992;20:1549᎐1555. w15x Van Wijngaarden J, Smit AJ, Van Gilst WH et al. Effects of acetylsalicylic acid on peripheral hemodynamics in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol 1994;23Ž2.: 240᎐245. w16x Sioufi A, Pommier F, Gauducheau N, Godbillon J, Choi L, John V. The absence of a pharmacokinetic interaction between aspirin and the angiotensin-converting enzyme inhibitor benazepril in healthy volunteers. Biopharm drug disposition 1994;15:451᎐461. w17x Baur LH, Schipperheyn JJ, van der Laarse A et al. Combining salicylate and enalapril in patients with coronary artery disease. Br Heart J 1995;73:227᎐236. w18x Nishimura H, Kubo S, Ueyama M, Kubota J, Kawamura K. Peripheral hemodynamic effects of captopril in patients with congestive heart failure. Am Heart J 1989;117:100᎐105. w19x Guazzi M, Marenzi G, Alimento M, Contini M, Agostoni P. Improvement of alveolar-capillary mambrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin. Circulation 1997;95:1930᎐1936. w20x Hurlen M, Smith P, Arnesen H. Effects of warfarin, aspirin and the two combined on mortality and thrombo-embolic morbidity after myocardial infarction. The WARIS-II study design. Scand Cardiovasc J 2000;34:168᎐171. w21x Zaret BL, Wackers FJ, Soufer R et al. Nuclear cardiology. In: Braunwald E, editor. Heart disease. A textbook of cardiovascular medicine.. Philadelphia: WB Saunders Company, 1992:276᎐311. w22x Sharpe N, Murphy J, Smith H, Hannan S. Preventive treatment of asymptomatic left ventricular dysfunction following myocardial infarction. Eur Heart J 1990;11ŽB.:147᎐156. w23x Oldroy KG, Pye MP, Ray SG et al. Effects of early captopril administration on infarct expansion, left ventricular remodeling and exercise capacity after acute myocardial infarction. Am J Cardiol 1991;68:713᎐718. w24x Sundsfjord JA, Thibault G, Larochelle P, Cantin M. Identification and plasma concentrations of the N-terminal fragment of proatrial natriuretic factor in man. J Clin Endocrin Metab 1988;66:605᎐610. w25x Vial JH, Mc Leod LJ, Roberts MS et al. Selective inhibition of platelet cyclooxygenase with controlled release, low dose aspirin. Aust NZ J Med 1990;20:652᎐656. w26x Clarke RJ, Mayo G, Price P et al. Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin. N Engl J Med 1991;325:1137᎐1141. w27x Desideri G, Ferri C, Bellini C, De Mattia G, Santucci A. Effects of ACE inhibition on spontaneous and insulin-stimulated endothelin-1 secretion. Diabetes 1997;46:81᎐86. w28x Tomuda H. Plasma endothelin-1 in acute myocardial infarction with heart failure. Am Heart J 1993;125:667᎐672.

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ACE-I and low-dose aspirin on our main outcome LVEF. Naturally, the observation time was only 3 months, but any clinically interesting interaction would probably have influenced the increase in LVEF. Concerning the biochemical variables, the expected influence of aspirin on TXB2 and 6-keto PGF 1␣ production was the only difference found between the treatment groups with and without aspirin. Of course, the limited number of patients undergoing biochemical analyses may have contributed to the lack of visualization of potential minor differences. Until long-term prospective studies on hard end points have been performed, we do not find reason to avoid the combination of ACE-I with aspirin during the first months after AMI.

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