European Journal of Heart Failure 10 (2008) 892 – 898 www.elsevier.com/locate/ejheart

Renal effects of aspirin are clearly dose-dependent and are of clinical importance from a dose of 160 mg Tord Juhlin a , Bo A.G. Jönsson b , Peter Höglund c,⁎ a

b

Department of Cardiology, Malmö University Hospital, Malmö, Sweden Department of Occupational and Environmental Medicine, Lund University Hospital, Lund, Sweden c Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden Received 3 July 2007; received in revised form 5 December 2007; accepted 24 June 2008

Abstract Background: High doses of aspirin counteract the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors. It is not known how low-dose aspirin, with concomitant ACE-inhibitor treatment, affects renal function. Aim: To study renal effects of different doses of aspirin in elderly healthy volunteers who had an activated renin–angiotensin system. Methods: Sixteen subjects each received two different doses of aspirin (0 and160 mg or 80 and 320 mg) after pre-treatment with bendroflumethiazide and enalapril, in a randomised double-blind, cross-over fashion. Results: Least square means of the observations 30 to 180 min after dosing, showed that urine flow, GFR, excretion rates of sodium, osmolality clearance and free water clearance were significantly decreased in a dose-dependent manner. Urine flow, sodium excretion rate and free water clearance were significantly lower with 320 mg aspirin vs. 0 mg and 80 mg, and GFR was significantly lower with 320 mg vs. 80 mg. Urine flow, sodium excretion rate, free water and osmolality clearance was significantly lower with aspirin 160 mg vs. 0 mg. Conclusion: The dose-dependent renal effects of aspirin are of clinical importance from a dose of 160 mg. The adverse influence of aspirin doses higher than 80 mg should be taken into consideration in patients with heart failure. © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. Keywords: Heart failure; ACE-inhibition; Aspirin; RAAS; Clinical trial; Renal function

1. Introduction Aspirin is recommended widely for the treatment of ischaemic heart disease [1], and exerts its effect on thrombocytes through blockade of the enzyme cyclooxygenase and thus inhibits prostaglandin synthesis [2]. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce morbidity and mortality in patients with left ventricular dysfunction, with or without heart failure [3]. ACE-inhibitors also have proven benefit in ⁎ Corresponding author. Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, Sweden. Tel.: +46 46 177979; fax: +46 46 176085. E-mail address: [email protected] (P. Höglund).

patients with normal left ventricular function but at risk for cardiovascular events [4]. Besides reducing angiotensin II, ACE-inhibitors also reduce the degradation of the potent vasodilator bradykinin, which elicits further vasodilatory function by enhancing production of prostaglandins [5]. The concomitant use of aspirin and ACE-inhibitors is common since ischaemic heart disease is one of the most common underlying causes of heart failure [6]. Thus the counteracting effect of aspirin on ACE-inhibitors could be of great importance for many patients with heart failure, since aspirin may neutralise the clinical benefits of ACEinhibitors. Large clinical trials have reported reduced benefit from treatment with ACE-inhibitors among patients taking aspirin [7,8] and therefore the role of aspirin for patients with heart

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T. Juhlin et al. / European Journal of Heart Failure 10 (2008) 892–898

failure has been questioned [9–11]. The exact doses of aspirin in these studies are not known. We have previously shown that acute administration of the cyclooxygenaseinhibitor diclofenac, but not long-term low-dose aspirin (median dose 75 mg), caused significant reductions in urine flow and glomerular filtration rate (GFR) [12]. A retrospective study of patients with chronic heart failure reported a dose-related adverse effect of aspirin on survival [13]. Haemodynamic studies have also led to the suggestion that higher doses of aspirin would be required to achieve inhibition of bradykinin induced vasodilation [14]. However, the highest dose which does not cause negative renal effects is not known. Therefore, we performed a study to examine the effects on renal function of different low doses of aspirin. We chose a model with activation of the renin–angiotensin system from pre-treatment with diuretics in elderly, healthy volunteers treated with ACE-inhibitors. This model has many advantages and has been used successfully before [15,16]. The primary objective was to study the influence on urine flow. Secondary objectives were to study the effects on GFR, excretion rates of sodium and potassium, osmolality clearance and free water clearance. 2. Material and methods 2.1. Study protocol The study was a double-blind, cross-over design. Subjects were divided into two groups and each group received two different doses of aspirin in a randomised order. All subjects were pre-treated with the thiazide diuretic bendroflumethiazide, administered as 5 mg daily for 6 days i.e. days-6 to -1, bendroflumethiazide was not given on study days. All subjects were also pre-treated with the ACEinhibitor enalapril, administered as 2.5 mg daily on days-6, -5 and -4; 5 mg daily on days-3 and -2; and 10 mg daily on day-1 and on the study days. The subjects were in contact with one of the investigators on days-3 to -1; if any adverse events suggestive of too high a dose, e.g. dizziness or tiredness, were reported, the dose was lowered for that subject. The volunteers were randomised into two groups (n = 8 per group). The first group received aspirin doses of 0 mg (placebo) and 160 mg. The second group received doses of 80 mg and 320 mg. The doses were given in a randomised order with at least 14 days wash-out between treatments. The same pretreatment was given before each dose of aspirin. The randomisation procedure was performed by one of the investigators (PH) who was blinded to the recruitment of the subjects. Aspirin was given as Trombyl® tablets 160 mg (Pharmacia). Bromhexine hydrochloride in the form of Bisolvon® 8 mg (Boehringer Ingelheim) tablets were used as placebo, since Bisolvon® is not known to affect renal function or interact with aspirin or ACE-inhibitors according to the SPC and a Medline search. Each drug was of a similar

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shape, size and colour. To give the correct doses and to preserve the blinding procedure, each dosage regimen consisted of 1 whole tablet and 2 half tablets. Therefore the 0 mg dose was administered as 1 whole and 2 half Bisolvon® tablets. For the 80 mg dose we administered 1 half Trombyl® tablet, 1 half and 1 whole Bisolvon® tablets; 160 mg was given as 1 whole Trombyl® tablet and 2 half Bisolvon® tablets. For 320 mg we used 1 whole and 2 half Trombyl® tablets. The tablets were halved and weighed by an investigator who did not meet the subjects. On study days, each subject had breakfast at home before coming to the department. On arrival one of the investigators performed a clinical examination to ensure that no contraindications were present. Two intravenous indwelling catheters were used, one in each arm, one to obtain blood samples and one for administration of iohexol. Omnipaque ® (Nycomed), containing 647 mg/ml iohexol, was diluted in saline giving a solution with a concentration of iohexol of 64.7 mg/ml. After initial measurements, the infusion of iohexol was started. Over 10 min 647 mg of iohexol was infused using an infusion pump followed by 3.45 mg/min for the rest of the examination day. The subjects were slightly over-hydrated during study days; after having emptied the bladder, a loading volume of 500 ml of drinking water was given. At the end of each pre-defined urine collection interval a volume of water corresponding to the urine volume collected in that interval plus 40 ml/h to compensate for perspiration was given. Clear soup was included after 3 h. The loading volume was given 1 h prior to the administration of aspirin. Urine was collected over 1 h prior to dosing and over 6 h post dosing in the following intervals:−60–0, 0–30, 30–60, 60–90, 90–120, 120–150, 150–180, 180–240, 240–300 and 300–360 min. Urine volumes were recorded and the urine was analysed for iohexol, sodium, potassium and osmolality. Blood samples were obtained 30 min prior to dosing, then at 15, 45, 75, 105, 135, 165, 210, 270 and 330 min post dose. The samples were analysed for iohexol, sodium, potassium, creatinine and osmolality. Blood samples for analyses of acetylsalicylic acid and salicylic acid were obtained prior to the dose and 10, 20, 30, 45, 60, 75, 90, 105, 120, 140, 160, 180, 210, 240, 300 and 360 min post dose. 2.2. Study population The inclusion criteria were male or female subjects aged 50–80 years. Exclusion criteria were heart disease, severe renal insufficiency (known GFRb 30 ml/min), peptic ulcer, liver cirrhosis, intolerance to bendroflumethiazide, intolerance to enalapril or any other ACE-inhibitor, intolerance to iohexol, NSAIDs or aspirin. A total of 16 subjects were included, 13 were women and three men. Ages ranged from 55–79 years (mean 68 ± 6.8). The group that received the 0 and 160 mg doses comprised seven women and one man aged 55–75 years (mean 66 ± 7.6). The group with the 80 and 320 mg doses comprised six women and two men aged 60–79 years (mean 69 ± 6.8).

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Concomitant medication considered necessary during the study was allowed. Aspirin or NSAIDs were however not allowed five days prior to and during each study day. On entering the study written informed consent and a medical history were obtained. A physical examination was performed and inclusion and exclusion criteria were evaluated. The study was monitored and performed in accordance with ICH-GCP and conducted in accordance with the Declaration of Helsinki. It was approved by the ethics committee of Lund University, Lund, Sweden, and by the Swedish Medical Products Agency. 2.3. Biochemical analyses Sodium, potassium, creatinine and osmolality in serum, and sodium, potassium and osmolality in urine, were analysed by standard methods at the Department of Clinical Chemistry Malmö University Hospital. Acetylsalicylic acid and salicylic acid were analysed by high-performance liquid chromatography (HLPC) at the Department of Clinical Chemistry Uddevalla Hospital using a previously described method [17]. The ranges of detection were 10–1000 μmol/l. Iohexol was analysed using a previously described method [16]. 2.4. Calculation of renal parameters Urine flow was calculated from each sampling interval and expressed as ml/min. GFR was determined as clearance of iohexol and was calculated as the product of urine concentration and flow rate divided by the serum concentration and expressed as ml/min. Urinary excretion rates of sodium and potassium were expressed as μmol/min. Urine and serum osmolality were given as mOsm/kg. Osmolality clearance was calculated as the product of urine osmolality and flow rate divided by the serum osmolality. Free water clearance was calculated as urine flow minus osmolality clearance. 2.5. Statistical analysis The number of subjects included in the study was based on the following assumptions: in an earlier study on healthy subjects [18] GFR fell from 113 ± 22 ml/min to 73 ± 22 ml/

min after 50 mg diclofenac. With a standard deviation of 22 ml/min we would be able to detect a true difference of 25 ml/min in GFR with a power of 80% and a two-sided significance level of 0.05. In our earlier study in healthy subjects with an activated renin–angiotensin system and treatment with ACE-inhibitors, GFR fell by 20%, from 60 ml/min to 48, after 50 mg diclofenac [15]. Our previous studies have shown that the variability in urine flow is less than that for GFR [12,15]. Consequently, even if we had no previous information on the size of an effect of these parameters from the various low doses of aspirin tested we anticipated the sample size of eight plus eight subjects should be sufficient for the detection of a clinically relevant effect. As descriptive statistics mean ± SD are used. For statistical analysis the MIXED procedure in SAS (version 8.2, SAS Institute, Cary, NC, USA) was used. Two sets of analyses were performed: one with a repeated measures design using all observations between 30 and 180 min after dose and one using the observations obtained at 75 min. This time period represents observations where we see drug effects, since the renal effects from low-dose aspirin have a short duration. The latter time point was chosen as the maximum concentration of acetylsalicylic acid was reached after 60 min and the maximum effect was estimated to occur in the observation period immediately thereafter. Arithmetic least square means and 95% confidence limits are given. Statistical significance was accepted at p b 0.05. 3. Results All subjects received the planned doses of diuretics and ACE-inhibitors as the pre-treatment was well tolerated. No adverse effects were reported after the aspirin doses. The time profiles of acetylsalicylic acid above a concentration of approximately 40 μmol/l exhibited a pattern suggestive of zero order elimination and thus the areas under the concentration versus time curves showed non-linear increase by dose. Observations of urine flow, GFR, excretion rate of sodium, osmolality clearance and free water clearance 75 min after dosing diminished in a dose-dependent manner. Urine flow, sodium excretion rate and free water clearance were significantly lower with 320 mg aspirin vs. placebo and 80 mg aspirin. GFR was significantly lower with 320 mg vs.

Table 1 Urine flow, excretion rates of electrolytes, osmolality clearance and free water clearance measured 75 min after dosing with different aspirin doses (0, 80, 160 and 320 mg) in elderly, healthy volunteers with an activated renin–angiotensin system and treated with ACE-inhibitors (means and 95% confidence limits)

Urine flow (ml/min) GFR (ml/min) Sodium excretion rate (μmol/min) Potassium excretion rate (μmol/min) Osmolality clearance (ml/min) Free water clearance (ml/min) *p b 0.05 vs. placebo (aspirin 0 mg). p b 0.05 vs. aspirin 80 mg.

♦

0 mg

80 mg

160 mg

320 mg

5.5(4.0–7.1) 84(68–99) 109(85–133) 53(30–76) 2.1(1.6–2.6) 3.4(2.2–4.7)

4.9(3.3–6.5) 85(69–100) 83(59–107) 72(49–95) 2.2(1.7–2.6) 2.8(1.5–4.0)

4.0(2.4–5.5)* 80(65–95) 58(34–82)* 44(21–67)* 1.7(1.2–2.2)* 2.0(0.7–3.4)*

2.8(1.2–4.4)*♦ 74(58–89)♦ 33(10–57)*♦ 56(33–79) 1.5(1.0–1.9) 1.4(0.1–2.6)*♦

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GFR, excretion rate of sodium, osmolality clearance and free water clearance (Fig. 1a–b). However, statistical significance was only shown for dose comparisons of aspirin 320 mg vs. placebo and 80 mg in urine flow, sodium excretion rate and osmolality clearance and vs. placebo in free water clearance. Statistical significance was also reached for dose comparisons of 160 mg aspirin vs. placebo in sodium excretion rate and free water clearance. With placebo the urine flow was 5.3(3.9–6.6), with 80 mg aspirin 4.7(3.3–6.1), with 160 mg it was reduced to 4.1(2.7–5.5) and with 320 mg it was further reduced to 3.2(1.8–4.5) (Table 2). No significant differences were found between 80 mg aspirin and placebo. 4. Discussion

Fig. 1. (a) Urine flow and (b) GFR, after different doses of aspirin; 0 mg (empty circles), 80 mg (filled circles), 160 mg (filled diamonds) and 320 mg (filled squares) in elderly, healthy subjects with an activated renin– angiotensin system and treated with ACE-inhibitors.

80 mg aspirin. Urine flow, sodium excretion rate, osmolality clearance and free water clearance were also significantly lower with the 160 mg aspirin dose than placebo. Urine flow decreased from 5.5(4.0–7.1) ml/min with placebo to 4.9 (3.3–6.5) with 80 mg aspirin, to 4.0(2.4–5.5) with 160 mg and to 2.8(1.2–4.4) ml/min with 320 mg aspirin (Table 1). Least square means of the observations 30 to 180 min after dosing showed dose-dependent decreases in urine flow,

In this study we have demonstrated that the adverse renal effects from acute administration of low doses of aspirin to subjects treated with ACE-inhibitors after activation of their renin–angiotensin systems are clearly dose-dependent, and are of clinical relevance even after a single aspirin dose as low as 160 mg. However, the effect on GFR is short-lasting and of a magnitude that is probably only of minor clinical importance. Observations from large-scale clinical trials with ACEinhibitors have led to the suspicion that aspirin may neutralise the clinical benefits from treatment with ACEinhibitors. A subgroup analysis from CONSENSUS II found evidence of an interaction between the ACE-inhibitor enalapril and aspirin. The effect of enalapril was less favourable among patients taking aspirin than among patients not taking aspirin at baseline. Aspirin antagonised the effect of enalapril on mortality at the end of the study [7]. In the SOLVD-trial there was less benefit with enalapril among patients taking aspirin; enalapril was shown to be almost inactive in patients taking aspirin [8]. The HOPE-trial observed a highly significant interaction. In the absence of aspirin, ramipril reduced the primary composite endpoint by 40%, but among those patients taking aspirin only by 15% [4]. The WASH-study, in which patients with heart failure treated with ACE-inhibitors were randomised to no antithrombotic therapy, warfarin or aspirin, showed a trend to excess mortality and a significant increase in the risk of hospitalisation for heart failure in patients randomised to

Table 2 Urine flow, excretion rates of electrolytes, osmolality clearance and free water clearance measured 30 to 180 min after dosing with different aspirin doses (0, 80, 160 and 320 mg) in elderly, healthy volunteers with an activated renin–angiotensin system and treated with ACE-inhibitors (least square means and 95% confidence limits)

Urine flow (ml/min) GFR (ml/min) Sodium excretion rate (μmol/min) Potassium excretion rate (μmol/min) Osmolality clearance (ml/min) Free water clearance (ml/min) *p b 0.05 vs. placebo (aspirin 0 mg). p b 0.05 vs. aspirin 80 mg.

♦

0 mg

80 mg

160 mg

320 mg

5.3(3.9–6.6) 86(73–99) 106(84–127) 46(28–64) 2.1(1.7–2.5) 3.2(2.0–4.3)

4.7(3.3–6.1) 87(74–100) 82(61–103) 63(44–81) 2.1(1.7–2.5) 2.6(1.5–3.8)

4.1(2.7–5.5) 80(67–93) 61(40–83)* 40(21–58) 1.7(1.3–2.1) 2.0(0.9–3.2)*

3.2(1.8–4.5)*♦ 76(63–90) 44(23–66)*♦ 53(35–71) 1.5(1.2–1.9)*♦ 1.6(0.5–2.7)*

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aspirin [19]. An observational study of patients with symptomatic heart failure requiring hospitalisation showed an increased incidence of early readmissions for heart failure among subjects treated with ACE-inhibitors and aspirin compared with those only treated with ACE-inhibitors [20]. In the WATCH-study, patients with heart failure and left ventricular ejection fraction b 35% were included and randomised to treatment with warfarin, clopidogrel 75 mg/ day or aspirin 162 mg/day. Due to poor recruitment rates the study was stopped when only 1587 of the planned 4500 patients had been enrolled. There was no difference between the treatment groups for all cause mortality, non-fatal myocardial infarction or stroke, but in the warfarin group compared with aspirin 27% fewer patients were hospitalised for heart failure. Thus, if 17 patients are treated with aspirin, 162 mg/day, instead of warfarin there will be one further hospitalisation due to heart failure. There were also fewer hospitalisations for heart failure with clopidogrel [21]. A retrospective study of patients hospitalised with a principal discharge diagnosis of chronic heart failure and treated with ACE-inhibitors, studied patients in three treatment groups. Group 1 had no aspirin treatment; group 2 had an aspirin dose ≤160 mg and group 3 had 325 mg or more aspirin. After an average follow-up of 37.6 months, survival was similar in groups 1 and 2, but was significantly worse in group 3 compared with groups 1 and 2. Thus, administration of high doses of aspirin was associated with reduced survival [13]. Our finding of a dose-dependent adverse effect on renal function is in accordance with this study. Several mechanistic studies have been performed to investigate the interaction between ACE-inhibitors and aspirin. In an invasive study of central haemodynamics, enalapril caused significant decreases in systemic vascular resistance, left ventricular filling pressures and total pulmonary resistance together with a significant increase in cardiac output. When enalapril was given on the same day or the day after 350 mg aspirin, it abolished the enalaprilinduced changes in these variables [22]. In another study, ticlopidine, an antiplatelet agent which does not interact with prostaglandin synthesis, reduced systemic vascular resistance more effectively with enalapril than when enalapril was given in combination with 325 mg aspirin [23]. In an evaluation of haemodynamic status in patients with chronic heart failure undergoing treatment with ACEinhibitors after a single dose of 236 mg aspirin, no discernible effect was observed after addition of aspirin. Aspirin significantly reduced plasma TXB2-levels, but vasodilating PGI2 was not significantly reduced. The authors concluded that the aspirin dose used (236 mg) preferentially blocks formation of the vasoconstricting TXA2 and that deterioration of the haemodynamic status of patients with heart failure is less likely after addition of low-dose aspirin but that higher doses may be deleterious [24]. Aspirin 325 mg/day for one week was shown to alter arterial function, assessed by applanation tonometry, com-

pared with placebo and aspirin 100 mg/day in patients with chronic heart failure treated with ACE-inhibitors. Thus the alteration in arterial function was dose-mediated [25]. However, using venous occlusion plethysmography, even 75 mg aspirin was shown to inhibit the acute arterial and venous vasodilator response to the ACE-inhibitor captopril in patients with chronic heart failure [26]. It has been suggested that ACE-inhibitors exert some of their benefits in heart failure by improving alveolar– capillary membrane diffusing capacity and pulmonary gas exchange. These effects have been shown to be counteracted by 325 mg aspirin [27,28]. The antiplatelet agent clopidogrel, which does not interact with prostaglandin synthesis, was compared with aspirin in patients with heart failure treated with ACE-inhibitors. A significant increase in mean VO2max was seen in patients receiving clopidogrel in combination with an ACE-inhibitor compared to those receiving aspirin plus an ACE-inhibitor [29]. In a study of patients with heart failure receiving ACEinhibitors, an adverse effect of aspirin 325 mg/day on plasma brain natriuretic peptide levels was demonstrated; however, in contrast clopidogrel 75 mg/day had no effect [30]. In hypertension, the blood pressure lowering effect of ACE-inhibitors seems to be blunted by aspirin in a dosedependent manner. The effects of aspirin 100 mg and 300 mg were studied in hypertensive patients treated with ACEinhibitors. No interaction was noted with 100 mg aspirin but a significant interaction was observed with 300 mg aspirin [31]. Whether the renal effects of low-dose aspirin in patients with heart failure treated with ACE-inhibitor are dosedependent, has not been studied previously. High dose aspirin, 500 mg t.i.d., administered to patients with heart failure has been shown to reduce renal sodium excretion [32]. Our study is the first to show that the adverse renal effects of aspirin, in ACE-inhibitor treated subjects with an activated renin–angiotensin system, are clearly dose-dependent and significant even after a single dose of 160 mg aspirin. In our previous study of patients with heart failure treated with ACE-inhibitors and continuous aspirin, median dose 75 mg/day, we did not find any clinically relevant negative renal effects compared with placebo on a group level [12]. However, we do not know the lowest dose causing clinical deterioration at the individual level. In the present study, there were no significant differences between placebo and 80 mg aspirin, but there was a trend towards an adverse effect. Aspirin 75 mg has been shown to be sufficient to block the vasodilator response to the prostacyclin precursor arachidonic acid in patients with heart failure [33] meaning that for some patients even low-dose aspirin can cause harmful vasoconstrictor effects. Therefore, it seems unwise to argue that low-dose aspirin is safe for the individual patient with heart failure treated with ACEinhibitors. Adding low doses of aspirin may cause vasoconstriction and oedema. In previous observational studies showing the lack of a negative interaction between

T. Juhlin et al. / European Journal of Heart Failure 10 (2008) 892–898

aspirin and ACE-inhibitors, the doses of aspirin used are not known [34,35]. Using healthy subjects at an age comparable to the average patient with heart failure has many advantages. We were able to separate the effects dependant on worsened heart failure from those dependant on counteraction of the renal effects of ACE-inhibition. It was also easier to recruit healthy subjects for the study and we could avoid the potentially dangerous effects of water loading and worsened renal function like fluid congestion and pulmonary oedema. In our opinion this model is a useful tool for studying pharmacological effects on renal function in heart failure. Our model is, however, based on acute administration and we do not know if the effects are true for long-term treatment with aspirin, though the results are in line with previous clinical observations and trials. We based our sample size on data from studies with diclofenac. The effects with aspirin were smaller and of shorter duration than we had expected, with more subjects we could have shown even clearer results. In conclusion, our results show that aspirin deteriorated renal function in a dose-dependent manner in elderly healthy volunteers with an activated renin–angiotensin system from pre-treatment with diuretics, who were also being treated with ACE-inhibitors. However, the lowest dose which does not cause adverse effects for the individual patient cannot be determined in advance and the risk that aspirin may neutralise the clinical benefits of ACE-inhibitors must be taken into consideration even with low-dose aspirin. References [1] Awtry EH, Loscalzo J. Aspirin. Circulation 2000;101:1206–18. [2] Fitzgerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacycline and thromboxane and platelet function during chronic administration of aspirin in men. J Clin Invest 1983;71: 676–88. [3] Lonn EM, Yusuf S, Jha P, et al. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994;90:2056–69. [4] The Heart Outcomes Prevention and Evaluation Investigators. Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342: 145–53. [5] Blais Jr C, Drapeau G, Raymond P, et al. Contribution of angiotensinconverting enzyme to the cardiac metabolism of bradykinin: an interspecies study. Am J Physiol 1997;273:H2263–2H271. [6] Parmley WW. Pathophysiology of congestive heart failure. Am J Cardiol 1985;56:7A–711. [7] Nguyen KN, Aursnes I, Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II. Am J Cardiol 1997;79:115–9. [8] Al-Khadra AS, Salem DN, Rand WM, Udelson JE, Smith JJ, Konstam MA. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) trial. J Am Coll Cardiol 1998;31:419–25. [9] Cleland JG, Bulpitt CJ, Falk RH, et al. Is aspirin safe for patients with heart failure? Br Heart J 1995;74:215–9. [10] Hall D. Controversies in heart failure. Are beneficial effects of angiotensin-converting enzyme inhibitors attenuated by aspirin in patients with heart failure? Cardiol Clin 2001;19:597–603.

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