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European Journal of Heart Failure 2003 5(3):271-279; doi:10.1016/S1388-9842(03)00006-0
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© 2003 European Society of Cardiology

Aspirin alters arterial function in patients with chronic heart failure treated with ACE inhibitors: a dose-mediated deleterious effect

Christophe Meunea,*, Isabelle Mahéa, Jean-Jacques Mouradb, Alain Cohen-Solalc, Bernard Levyd, Jean-Philippe Kevorkiana, Guillaume Jondeaue, Aïda Habibf, Marilyne Lebretf, Anne-Laure Knellwolfa, Guy Simoneaua, Charles Caulina and Jean-François Bergmanna

a Internal Medicine, Hospital Lariboisière Paris, France
b Internal Medicine, Hospital Saint-Michel Paris, France
c Department of Cardiology, Hospital Beaujon Clichy, France
d Functional Explorations, Hospital Lariboisière Paris, France
e Department of Cardiology, Hospital Ambroise Paré Boulogne, France
f Inserm 348, Hospital Lariboisière Paris, France

* Corresponding author. Department of Cardiology, Hospital Cochin, 27 rue du Faubourg Saint-Jacques, 75014 Paris Cedex, France. Tel.: +33-1-58-41-16-21; fax: +33-1-58-41-16-05. E-mail address: christophe.meune{at}cch.ap-hop-paris.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Clinical implications
 7. Conclusion
 References
 
Background: By inhibiting prostaglandin synthesis, aspirin can interfere with both arterial functional and angiotensin-converting enzyme inhibitor (ACEI) properties and be deleterious in chronic heart failure (CHF).

Aim: Our aim was to prospectively evaluate the effect of aspirin on arterial functional properties in CHF patients treated with ACEIs.

Methods and results: Over three consecutive treatment periods of 7 days, 18 patients received placebo, followed by aspirin 100 mg/day, and then aspirin 325 mg/day. Single blind prospective assessment of reflected wave and time reflection by radial applanation tonometry; pulse wave velocity; blood pressure; thromboxane B2 (TxB2) and prostaglandins in plasma and urine was performed. Aspirin 325 mg/day induced a significant increase in augmentation index of reflected wave (P<0.0001 and P=0.0013 vs. placebo and aspirin 100 mg, respectively) and a significant decrease in reflected wave traveling times (P=0.0007 vs. placebo). Aspirin 100 mg/day produced a similar, though non-significant, trend in these parameters compared with placebo. Both aspirin treatments produced a statistically significant decrease in serum TxB2 (P<0.0001) but did not have an effect on the metabolite of prostaglandin I2 (P=0.136).

Conclusion: This study demonstrates the existence of a dose-mediated deleterious effect of aspirin upon arterial functional properties in CHF patients treated with ACEI.

Key Words: Angiotensin-converting enzyme inhibitors • Aspirin • Heart failure • Bradykinin

Received June 26, 2001; Revised October 17, 2002; Accepted December 18, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Clinical implications
 7. Conclusion
 References
 
Over recent years, angiotensin-converting enzyme inhibitors (ACEIs) have proved to be highly effective in patients with chronic heart failure (CHF) [1,2]. Aspirin is widely used in coronary artery disease [3] and is often co-prescribed with ACEIs because ischemic heart disease is a common cause of CHF. Concerns have been raised about a possible deleterious effect of aspirin in CHF [4]. In fact, inhibition of cyclo-oxygenase (COX) by aspirin would cause a decrease in the formation of prostanoids leading to a possible direct deleterious arterial effect of aspirin [5] or an inhibition of ACEI efficacy [6]. Literature regarding the aspirin–ACEI interaction is inconclusive [7–10].

The aim of this dose-ranging study was to prospectively evaluate the effect of aspirin in CHF patients treated with ACEI, using applanation tonometry, a sensitive method of assessing the functional properties of arteries, and by measuring pulse wave velocity (PWV) and blood pressure. This is the first study to evaluate pharmacodynamic modifications in ACEI activity using several dosages of aspirin in CHF.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 5. Limitations of the...
 6. Clinical implications
 7. Conclusion
 References
 
2.1. Patient selection
We enrolled volunteer CHF patients aged over 35 years, who had been clinically stable for more than 3 weeks, and treated with ACEIs at the maximum tolerated dosage for more than 3 months. CHF was defined as investigators opinion and a left ventricular (LV) ejection fraction <=40% assessed by echocardiography.

Patients who had had an acute ischemic event during the last 3 weeks were not included. All vasodilator treatments (except ACEIs), as well as anti-inflammatory, antiplatelet and anticoagulant drugs were withdrawn at least 2 weeks before inclusion. All patients remained on constant therapy (including diuretics, ACEI and β-blockers) during the study.

The investigation conforms with the principles outlined in the Declaration of Helsinki and was approved by the ethics committee (Paris, St. Louis). All patients included gave written informed consent.

2.2. Protocol
This study was a prospective, dose-ranging, single centre, controlled, single blind (patient) trial, with intra-individual comparison. Two doses of aspirin, 100 mg and 325 mg/day were studied, in order to investigate a dose-mediated effect. These doses were chosen as they are currently recommended in patients with coronary artery disease, and 325 mg/day was the lowest dose ever used in a long-term post-infarction trial. The study comprised 3 treatment periods of 7 days each (placebo, followed by aspirin 100 mg/day, then by aspirin 325 mg/day), and 4 measurements (at inclusion and then on the 7th day of each treatment period). The first and second measurements were compared to assess reproducibility and stability during the placebo period. The third and fourth measurements determined the effect of the different doses of aspirin.

2.3. Treatments and compliance
All treatments were presented in similar capsules. At each visit patients were given their treatment for the following 7 days. Compliance was assessed by capsule count.

2.4. Assessment methods
We used radial applanation tonometry to assess the functional properties of the arterial system. Tonometry is a sensitive, non-invasive method, previously used to assess arterial pulse waveform [11]. The radial pressure wave was recorded with a high-fidelity strain-gauge transducer (Mikrotip pulse transducer SPT 301, Millar Instruments, Inc., Houston, TX) and a Canon Noteget III, PWV medical computer for mathematical analysis. We measured the height of the shoulder (Pi) and the height above the shoulder ({Delta}P) of the late systolic peak (Ppk; {Delta}P=Ppk–Pi) attributable to the return of wave reflections from reflected sites. The {Delta}P to radial pulse pressure ratio ({Delta}P:PP) defines an augmentation index (AI in %) (Fig. 1). AI is an estimation of the effect of wave reflection in central arteries and was the primary end-point. The other parameters measured were: the peak induced by the reflected wave (AG), the time from the foot of the pressure wave to the shoulder (Pi) which represents the traveling time of the reflected wave ({Delta}TP), aortic pulse pressure, the Buckberg index (defined as the ratio between diastolic and systolic area under the curve), and aortic pressure.


Figure 1
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  		Fig. 1 Applanation tonometry. PP, pulse pressure; {Delta}TP, travel time of reflected wave; LVET, LV ejection time; Pi, first systolic peak; Ppk, late systolic peak. Ppk–Pi/PP or augmentation index (AI) (%). Buckberg index, diastolic area under curve divided by systolic area under curve.

 
Applanation tonometry measurements were recorded automatically, the computer selected the analyzable curve without human intervention, therefore the record was blind to the treatment.

PWV assesses the functional properties of the large arteries and was determined using the foot-to-foot method (Fukuda TY-306 transducers and COMPLIOR 3.0) [12]. Briefly, transcutaneous recordings of pulse pressure waves were carried out simultaneously at the carotid and the femoral arteries, and the time delay between the bases of the two flow waves was measured and averaged over 15 cardiac cycles. PWV was then calculated as the distance between recording sites measured over the surface of the body, divided by the time delay [12]. Both examinations were performed by the same two experienced operators (CM, BL).

Blood pressure was determined using an automatic sphygmomanometer (Dinamap Pro 400, Critikon INC Créteil – France).

Serum assays included renin and aldosterone at rest and thromboxane B2 (TxB2) (stable metabolite of TxA2). TxB2 was assessed by enzyme immunoassay after blood coagulation [13,14].

Urinary 11-dehydro-TxB2 (urinary metabolite of TxB2) and 2,3-dinor 6-keto PGF1{alpha} (metabolite of prostacyclin PGI2) were measured by enzyme immunoassay [13,14] after extraction and separation by chromatography [15].

2.5. Statistical analysis
Eighteen patients were enrolled in order to detect a 5% increase in AI, with a 5% standard deviation (S.D.), a one-sided {alpha} risk of 0.05 and β risk of 0.1. All data are expressed as mean±S.D. Statistical analysis was performed using STATVIEW software (Abacus concept, Berkeley, USA, 1998). Reproducibility between day 0 and day 7 (placebo period) was assessed by intra-individual variability and according to the method of Bland and Altman [16]. The effects of aspirin were determined by a one-way ANOVA during the day 7–day 21 period, followed by multiple comparisons using a Bonferroni/Dunn test (aspirin 325 mg/day with aspirin 100 mg/day and placebo, aspirin 100 mg/day with placebo). An adjusted P<0.0167 value was thus required to establish a statistical difference between measurements.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 5. Limitations of the...
 6. Clinical implications
 7. Conclusion
 References
 
3.1. Study population
One patient was withdrawn during the placebo period due to an adverse event (macroscopic haematuria), results are therefore presented for 17 patients. Patient characteristics are summarized in Table 1.


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  		Table 1 Population characteristics

 
ACEI therapy consisted of enalapril 20 mg/day in 9 patients, 10 mg/day in 2, lisinopril 20 mg/day in 3, ramipril 10 mg/day in 2 and 2.5 mg/day in 1. Eleven patients had been treated with an ACEI for more than 2 years.

3.2. Reproducibility of measurements between day 0 and day 7 (placebo period)
For AI (primary end-point), values were 17.0±9.0% and 16.3±8.3% for placebo at day 0 and day 7, respectively (Table 2). Intra-individual variability was 14% for AI, 26% for AG and 7% for {Delta}TP. Fig. 2 represents the intra-individual difference between day 0 and day 7 for AI.


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  		Table 2 Applanation tonometry measurements and PWV values

 


Figure 2
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  		Fig. 2 Bland–Altman plots showing the intra-individual difference between day 0 and day 7 in augmentation index of reflected wave (AI). S.D., standard deviation.

 
Other criteria did not show any significant statistical difference between day 0 and day 7.

3.3. Comparisons between aspirin and placebo
The results of heart rate, applanation tonometry and pulse wave measurements are summarized in Table 2.

Aspirin 100 mg/day for 7 days produced a trend towards an increase in AI (P=0.041, NS for multiple comparison) and AG (P=0.18, NS) and a decrease in {Delta}TP (P=0.164, NS) compared with placebo.

Aspirin 325 mg/day induced a significant increase in AI (P<0.0001 and P=0.0013 vs. placebo and aspirin 100 mg, respectively) and AG (P<0.0001 and 0.0019, respectively) and a significant decrease in {Delta}TP (P=0.0007 vs. placebo).

Applanation tonometry did not demonstrate any statistically significant difference in duration of the reflected wave, aortic pulse pressure and aortic pressure between the three treatment groups (Table 2). Similarly, PWV measurements (P=0.70), heart rate (P=0.85), and blood pressure (P=0.34 for systolic and P=0.28 for diastolic) did not change significantly after aspirin therapy.

Plasma renin activity ranged from 11.9±16.7 ng/ml/H to 12.8±14.1 and 13.6±21.3 (P=0.83) and aldosterone from 213.5±165.7 pg/ml to 168.6±93.2 and 214.6±176.0 (P=0.13) over the three consecutive treatment periods.

Aspirin induced a significant lowering of TxB2 and 11-dehydro-TxB2 compared with placebo (P<0.0001 for both dosages) with no statistically significant difference between aspirin 325 mg and aspirin 100 mg (P=0.77 and 0.41, respectively) (Table 3). 2,3-Dinor 6-keto PGF1{alpha} was not significantly affected by aspirin therapy (P=0.136) (Table 3).


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  		Table 3 TxB2, 11-dehydro-TxB2 and 2,3-dinor 6-keto PGF1{alpha} results

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
5. Limitations of the...
 6. Clinical implications
 7. Conclusion
 References
 
The main finding of this study is that, compared to placebo and aspirin 100 mg/day, aspirin 325 mg/day administered for 1 week in CHF patients alters arterial functional properties, by increasing reflected wave amplitude and shortening reflection time as assessed by applanation tonometry. Aspirin 100 mg/day showed a similar trend, however, this was not significant.

Applanation tonometry is a recognized non-invasive method to evaluate large and small arterial properties. Measurements are highly reproducible [17] and correlate with invasive haemodynamic methods [18]. AI is of critical importance as it represents the effects of reflected wave in central arteries [19]. AI is increased in CHF because of peripheral vasoconstriction [20]. The presence of an early and heightened reflected wave (elevated AI and short {Delta}TP) is responsible for an increase in end systolic ventricular pressure and in LV after load and a decrease in diastolic aortic pressure [21,22]. Furthermore, in a recent study, increased AI was predictive of both all-cause and cardiovascular mortality, in end-stage renal failure patients [23]. Clinical studies have shown that AI can be reduced by ACEIs [19,24].

PWV evaluates the functional properties of the large arteries. The carotid-femoral PWV measurements represent aortic stiffness and are inversely correlated to arterial distensibility [17]. Recently, Blacher et al. demonstrated that a high PWV measurement was an independent predictor of cardiovascular risk and mortality in end-stage renal disease [12]. In our study, we did not observe any statistical significant variation in PWV after aspirin therapy. Theoretically, changes in PWV could be related to modifications in aortic smooth muscle cell tone, wall structure or blood pressure [19]. Since we did not observe any change in blood pressure, our results therefore show that aspirin treatment for 1 week did not change aortic elastic properties.

Interpretation of the applanation tonometry measurements is more relevant. Increased AI values can theoretically be attributed to higher PWV, a more proximal site of reflection, or increased reflection coefficient [22,25]. The observed decrease in {Delta}TP and increase in AI with constant PWV suggest that aspirin modified at least the arteriolar site of reflection by increasing vasoconstrictor tone in small peripheral arteries.

Our findings are in accordance with previous haemodynamic studies reporting an increase in LV filling pressure [6] and in vascular systemic resistance after aspirin therapy [6,10]. Another study of inhibition of arachidonic acid-induced vasodilatation after aspirin for 14 days, in CHF patients treated with ACEI [5] showed similar results.

Since we have not shown the effect of ACEIs on these measurements directly, our results could be attributed to a direct negative effect of aspirin and/or an interaction with ACEI. The theoretical basis for both hypotheses involves inhibition of vasodilator prostaglandins (such as PGI2 and PGE2), metabolites of the COX pathway [4]. The negative effect of inhibitors of prostaglandin synthesis in CHF patients has been widely documented with nonsteroidal anti-inflammatory drugs particularly in hyponatremic patients [26] but only a few studies have investigated a direct effect of aspirin. Venous arachidonic acid-induced vasodilatation was inhibited after a single oral dose of aspirin 1 g and preserved with 75 mg in a study of healthy subjects [27]. Whereas in another study, arterial induced vasodilatation was inhibited after 14 days of low dose of aspirin in CHF patients treated with ACEIs [5]. In a retrospective study, low-dose aspirin (75–150 mg) resulted in increased calf vascular resistance in CHF patients treated with ACEI [28].

The existence of an interaction between ACEI and aspirin may be another alternative. In fact, via inhibition of bradykinin breakdown [29], ACEIs enhance the formation of vasodilator prostaglandins via the COX pathway [30]. Aspirin inhibits the COX enzyme, and is therefore capable, in theory, of attenuating ACEI efficacy. Theoretically this inhibition of ACEI efficacy is dose-mediated [31] and chemical affinity of aspirin is more important for platelet COX than for tissular COX [32].

In a recent review of the ACEI–aspirin interaction [33], we listed 13 studies conducted in CHF with various dosages of aspirin, of which 9 demonstrated an inhibition of ACEI efficacy by aspirin.

In the present study, a significant effect on arterial properties was observed, but only with aspirin 325 mg/day. This is in agreement with a recent study where intermediate, but not low doses, of aspirin inhibited ACEI-induced cough [34]. In other studies there was an indication of a more frequent interaction with aspirin at dosages greater than 250 mg/day [33].

The plasma renin activity and aldosterone concentration did not show any statistically significant variation in our study, suggesting that aspirin did not interfere with the angiotensin pathway of ACEIs.

Our results showed no change in urinary 2,3-dinor 6-keto PGF1{alpha} and a decrease in the TxB2 concentration. Other studies analyzing PGI2 metabolite concentrations are also inconclusive [35] and duration of ACEI treatment appears to be a distinguishing feature among them [35]. In our study ACEI therapy was a long-term treatment. A possible interpretation could be either that the 2,3-dinor 6-keto PGF1{alpha} concentration does not reflect PGI2 levels possibly due to the existence of other metabolic pathways, or that PGI2 is not the major mediator of bradykinin action and that PGE2 is a more potent vasodilator [36].


   5. Limitations of the study
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitations of the...
6. Clinical implications
 7. Conclusion
 References
 
In order to limit the length of the study and thus ensure the clinical stability of our patients throughout study, we did not perform a randomized cross-over study with wash-out periods. This study design did not allow us to rule out a carry-over effect. Nevertheless, aspirin for 1-week is sufficient to achieve maximal lowering of Tx, and its effect on COX inhibition is dose dependant [31]. Therefore, we assumed that aspirin 325 mg/day should not have been influenced markedly by prior aspirin 100 mg/day, nor placebo.

Heart failure of ischaemic origin was less represented in our study than in the general CHF population but the withdrawal of aspirin for 3 weeks prior to the study required us to exclude subjects with recent ischaemic events.

The study design did not allow for assessment of the ACEI–aspirin interaction directly, as there was no group of patients without ACEIs. Since ACEIs are first-line treatment in CHF, withdrawal of ACEI treatment was considered unethical. The theoretical basis for both hypotheses involves bradykinin and prostaglandins. However, there are only minor data regarding a direct effect of aspirin on vascular tone, whereas an interaction has been demonstrated in a number of studies. Finally, in a randomized, double blind study, involving patients with CHF, Guazzi et al. [37] reported that aspirin 325 mg/day inhibited the improvement in pulmonary dynamics and function induced by ACEI, whereas it had no effect on patients not taking ACEI.

This study was conducted according to a single blind (patient) protocol and not double blind. However, applanation tonometry measurements were automatically recorded: the computer selected the analyzable curve, based on adequate amplitude and morphology, and calculated different parameters without human intervention so the report was blind to the treatment.

In our study, aspirin 100 mg/day resulted in a non statistically significant trend towards an effect. With a larger population, results may be different. Nevertheless, if large-scale studies are needed to observe minimal variations, this is an argument for the poor level of an interaction.


   6. Clinical implications
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Clinical implications
7. Conclusion
 References
 
Our study shows that aspirin 325 mg/day for 1 week results in increased vascular tone in CHF patients treated with ACEI compared with aspirin 100 mg/day or placebo. No formal conclusion can be drawn concerning long-term use. However, such a deleterious effect, if confirmed, could be a crucial issue because these two drugs are often co-prescribed in CHF and prostaglandins may play a more important role in CHF than in other diseases [27]. In a recent review [38], Hall reported that aspirin therapy is responsible for an inhibition of half of the efficacy of ACEI therapy and that in some patients with refractory heart failure, cessation of aspirin results in an improvement in the condition.

To address this issue, 3 prospective studies have evaluated the aspirin–ACEI interaction using clinical events as end-points. Aspirin was responsible for increased hospitalizations for heart failure compared with placebo [39,40] or warfarin [40] whereas it had no effect on clinical events in one study [41]. The WASH pilot study [40] did not show a statistically significant difference in mortality but the sample size did not allow any formal conclusion to be reached.

Finally, large ongoing studies with clinical end-points are needed, the Warfarin and Antiplatelet Trial in Chronic Heart failure (WATCH) study and Long Term Antithrombotic Study (HELAS) will try to answer this question.


   7. Conclusion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Clinical implications
 7. Conclusion
References
 
Our study shows that there is a dose-mediated alteration of arterial functional properties following 1 week of treatment with aspirin 325 mg/day in CHF patients treated with ACEI. Aspirin 325 mg/day for 1 week caused an increase in the reflected wave and shortened reflection time compared with aspirin 100 mg/day or placebo. This effect may be attributed to a direct effect of aspirin and/or an interaction with ACEIs. The clinical relevance of this deleterious effect of aspirin is of vital importance and needs to be studied in prospective long-term studies using the mortality end-point and focusing on several dosages of aspirin therapy. Meanwhile, we can recommend low doses of aspirin (100 mg/day) in patients with CHF who concomitantly need aspirin.


   Acknowledgements
 
The authors would like to thank Mrs Caillaud, Mrs Paplomatas, Mr Thoraval for technical assistance and Dr Martins for her help during the study.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 5. Limitations of the...
 6. Clinical implications
 7. Conclusion
 References
 

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