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European Journal of Heart Failure 2007 9(2):197-201; doi:10.1016/j.ejheart.2006.06.003
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© 2007 European Society of Cardiology

Effects of aspirin and clopidogrel on plasma brain natriuretic peptide in patients with heart failure receiving ACE inhibitors

Christophe Meunea,*, Karim Wahbia, Yvonne Fullab, Alain Cohen-Solalc, Denis Duboca, Isabelle Mahéd, Guy Simoneaud, Jean-François Bergmannd, Simon Webera and Stéphane Moulyd

a Department of Cardiology, Cochin Hospital Paris, France
b Department of Nuclear Medicine, Cochin Hospital Paris, France
c Department of Cardiology, Beaujon Hospital Clichy, France
d Department of Internal Medicine-Therapeutic Research Unit, Lariboisière Hospital Paris, France

* Corresponding author. Department of Cardiology, Cochin Hospital, 27 rue du fg Saint-Jacques, 75014 Paris, France. Tel.: +33 1 58 41 22 80; fax: +33 1 58 41 16 05. E-mail address: christophe.meune{at}cch.ap-hop-paris.fr


   Abstract
Top
 Abstract
1. Materials and methods
 2. Results
 3. Discussion
 4. Conclusion
 References
 
Background: By inhibiting prostaglandins, aspirin may be deleterious in heart failure (HF) and/or may counteract angiotensin-converting enzyme (ACE) inhibitor efficacy. Conversely, clopidogrel has no effect on prostaglandin metabolism.

Aim: To investigate the effect of aspirin and clopidogrel on brain natriuretic peptide (BNP) levels in HF patients treated with ACE inhibitors.

Methods: 36 patients with stable HF (65±13 years, 24 males/12 females, NYHA class II to IV, ejection fraction <40%, 13 with coronary disease, all treated with ACE inhibitors) were enrolled in this prospective, double-blind study and randomised to aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days. BNP was determined at day 0 and day 14.

Results: 19 patients were randomised to aspirin and 17 to clopidogrel. Baseline characteristics were similar in both groups. BNP levels increased in the aspirin group from day 0 to day 14 (107±103 to 144±149 pg/ml, p=0.04) whereas clopidogrel had no effect (104±107 and 97±99 pg/ml respectively, p=0.61).

Conclusion: This study demonstrates an adverse effect of aspirin 325 mg/day on BNP plasma levels in HF patients treated with ACE inhibitors. In contrast clopidogrel 75 mg/day had no effect.

Key Words: Angiotensin converting enzyme inhibitor • Aspirin • Brain natriuretic peptide • Clopidogrel

Received June 30, 2005; Revised January 18, 2006; Accepted June 12, 2006

Heart failure is a syndrome characterized by haemodynamic impairment and neurohumoral activation [1]. The magnitude of neurohormone activation is known to be an important prognostic factor and the most effective therapies are those which lessen it [2,3]. Angiotensin-converting enzyme inhibitors (ACE inhibitors) are considered as first line therapy in chronic heart failure (CHF) related to left ventricular (LV) systolic dysfunction [4]. Since the effects of ACE inhibitors may result from both inhibition of angiotensin II generation and inhibition of bradykinin breakdown (which results in nitric oxide and vasodilator prostaglandin (PG) synthesis), they may be affected by administration of cyclooxygenase (COX) inhibitors, including aspirin [5-7]. Indeed, there is pharmacological evidence that aspirin may be deleterious in CHF patients treated with ACE inhibitors; and that this effect may be dose-dependent and more common in patients with advanced disease [7,8]. CHF is mainly of ischaemic origin and is characterized by a prothrombotic state; antiplatelet or antithrombotic agents may thus be warranted [9,10]. Since most of the studies which evaluated the effect of aspirin in CHF patients treated with ACE inhibitors were retrospective, used surrogated end-points, or investigated single administration of aspirin or of ACE inhibitors, no formal conclusions can be drawn about this interaction [7,11-13].

B-type natriuretic peptide (BNP) has emerged in recent years as an important diagnostic and prognostic marker in CHF. BNP plasma levels are related to ventricular wall stress: an increase in BNP generally reflects an increase in LV filling pressures and is associated with advanced CHF [2,14-17].

The aim of our prospective, double-blind study was to compare the effect of aspirin and clopidogrel, an adenosine diphosphate (ADP) receptor inhibitor with no known effect on PG metabolism, on BNP levels in CHF patients treated with ACE inhibitors.


   1. Materials and methods
Top
 Abstract
 1. Materials and methods
2. Results
 3. Discussion
 4. Conclusion
 References
 
Thirty-seven patients with stable CHF aged 18 to 85 years, in NYHA class II to IV, with documented reduced LV ejection fraction <40% (determined by either echocardiography or radionuclide ventriculography) on constant dose CHF treatment for more than 3 weeks were recruited. Additional criteria included treatment with an ACE inhibitor at maximal tolerated dosage for more than 3 months. All vasodilator treatments (except ACE inhibitors), as well as anti-inflammatory, anticoagulant and antithrombotic agents had to be withdrawn at least 2 weeks before entry in the study. Based on previous studies which investigated patients with acute heart failure, patients with baseline BNP plasma level >400 pg/ml were excluded from the study [17]. The investigation conforms with the principles outlined in the Declaration of Helsinki. The protocol was approved by the local ethics committee and all patients gave informed consent.

This was a prospective, randomised, double-blind study. On day 0, after baseline BNP measurement, patients were randomised to receive either aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days.

Patients were asked to take the study medication at breakfast each morning. All evaluations were performed 3-4 h after dosing.

Blood samples for BNP measurements were collected in EDTA-containing tubes at randomisation (day 0) and repeated at day 14. Patients rested supine for >30 min before blood collection via an indwelling venous cannula. Immediately after collection, the blood was centrifuged at 4 °C for 10 min and the plasma stored at –80 °C until assay.

BNP was determined using a radioimmunoassay (Shionoria-BNP, Cisbio international, Gif sur Yvette, France) as previously described [18]. Briefly, this method utilizes two specific monoclonal antibodies against BNP, one recognizing the carboxy-terminal sequence and the other the ring structure of human BNP. The analytical performance of the Shionoria BNP method has been evaluated in our laboratory. The intra-assay coefficient of variation was 15% and 9% for low and high concentrations respectively. The detection limit of the assay was 2 pg/ml. The mean linearity was 104%, with a linearity range between 2 and 2000 pg/ml. The mean accuracy was 106%. Normal BNP measurements are <30 pg/ml according to the manufacturer and optimal diagnostic threshold value in acute dyspnoea is 60 pg/ml in our experience.

Based upon previous results [8,19], in order to detect a 25% relative variation in BNP measurement after aspirin treatment, with a 20% standard deviation ({alpha}=0.05, β=0.1, bilateral test), 17 patients had to be enrolled in each group.

All values are expressed as mean±S.D. Differences between groups were investigated using Student's t-test for comparison of normally distributed continuous variables and chi-square analysis for differences in frequency. Since BNP values may not be normally distributed, Wilcoxon signed rank test, a non-parametric test, was used to determine the effect of treatment in each group. A p value<0.05 was necessary for statistical significance in all comparisons (Statview software, Abacus concept, Berkeley, USA).


   2. Results
Top
 Abstract
 1. Materials and methods
 2. Results
3. Discussion
 4. Conclusion
 References
 
None of the 37 patients included in this prospective study experienced any adverse events during the 2-week run-in period without antithrombotic therapy. One patient did not complete the protocol for personal reasons and was excluded. Results are presented for 36 patients, 19 randomised to receive aspirin and 17 to clopidogrel for 14 days.

Baseline characteristics are given in Table 1; no difference between the groups was observed, although there was a trend for fewer patients treated with beta-blockers, higher creatinine levels, and higher baseline heart rate in patients randomised to aspirin (Table 1). None of the patients had implantable devices, including cardioverter defibrillators or cardiac pace-makers. Recommended dosages for ACE inhibitors were defined as: perindopril 4 mg/day, enalapril and lisinopril 20 mg/day, or ramipril 10 mg/day, Based on these dosages, eight patients (42%) in the aspirin group were being treated with the recommended dose, 5 with half of the recommended dose and 6 with a quarter, compared with 9 (53%), 7 and 1 patients respectively in the clopidogrel group (p=0.143). The duration of ACE inhibitor treatment was 15.5±30.2 months in the aspirin group and 10.7±14.7 months in the clopidogrel group (p=0.558). In all patients, both ACE inhibitors and beta-blockers were prescribed at the maximum tolerated dosage. Additionally, 8/19 patients in the aspirin group versus 5/17 in the clopidogrel group were prior aspirin users (p=0.429) (aspirin was withdrawn 2 weeks before enrolment).


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  		Table 1 Baseline characteristics

 
As shown in Table 2, plasma BNP values were similar in the aspirin and clopidogrel group at baseline (107±103 versus 104±107 pg/ml, p=0.553). From day 0 to day 14, BNP levels increased significantly in the aspirin group (from 107±103 to 144±149 pg/ml, p=0.044) but remained unchanged in the clopidogrel group (from 104±107 to 97±99 pg/ml, p=0.605) (Fig. 1). However, the difference in BNP values between the groups at day 14 was not significant (144±148.7 versus 97±99.2 pg/ml, p=0.373). Fluid status, estimated by weight, and plasma creatinine measurements did not change significantly during the aspirin/clopidogrel treatment. BNP levels increased after aspirin in patients with higher baseline BNP levels (from 172±111 to 241±157 pg/ml, p=0.038 in patients with baseline BNP over the median 88pg/ml value, and remained unchanged in the other patients) (Fig. 1).


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  		Table 2 BNP measurements at baseline and after 14 days aspirin or clopidogrel treatment

 


Figure 01
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  		Fig. 1 Plasma BNP measurements at baseline and after aspirin or clopidogrel treatment.

 

   3. Discussion
Top
 Abstract
 1. Materials and methods
 2. Results
 3. Discussion
4. Conclusion
 References
 
In our study, aspirin 325 mg/day administered for 14 days in CHF patients treated with ACE inhibitors increased plasma BNP levels. In contrast, clopidogrel had no effect.

BNP is mainly produced by ventricular myocytes in response to volume expansion and pressure overload, so BNP changes may be attributed to haemodynamic deterioration and/or renal fluid retention [7,15,20]. Neither weight nor plasma creatinine measurements changed significantly during the study. Combined with our previous results demonstrating an increase in peripheral arterial tone after aspirin treatment in CHF patients, these results support the concept that aspirin induces a sustained peripheral vasoconstriction which may affect filling pressure [8,19]. The clinical relevance of a 36±69 pg/ml increase (34% relative increase) in BNP levels cannot be derived from our study. However, in the Val-HeFT study, mean BNP at baseline was 181 pg/ml and a 44 pg/ml difference between valsartan and placebo was noted (immunoradiometric assay Shionogi, Shering CIS). This relative increase in BNP was associated with increased mortality and the occurrence of a first morbid event [3,16]. Although a subgroup analysis was not planned in our study, we observed that BNP levels increased after aspirin solely in patients with higher baseline BNP levels. This suggests that patients with more advanced disease may be more susceptible to the effect of aspirin; the impact of aspirin in patients with less advanced CHF may not be consistent [7].

Theoretically, this effect of aspirin may be a direct effect or a counteraction of ACE inhibitors, as both mechanisms involve PG [6,7]. Some studies have demonstrated a direct vascular effect of low and intermediate dose aspirin in CHF [20,21]. Inhibition of ACE inhibitor efficacy has been more extensively demonstrated using a variety of assessment criteria, including cardiac output and vascular resistance [7,11,22]. In our study, we hypothesized a deleterious interaction between aspirin and ACE inhibitors in CHF and investigated patients treated with ACE inhibitors; our results suggest less benefit from ACE inhibition in the presence of aspirin. Some studies have investigated this possible interaction using clinical endpoints, but most are retrospective or observational studies, so that no formal conclusion can be made [7,13]. In a meta-analysis, Teo et al. observed a clinical benefit of ACE inhibitor therapy irrespective of aspirin co-administration in CHF, but also a negative interaction between both drugs for myocardial infarction and death [12]. In the WASH pilot study, a prospective double-blind study, aspirin 300 mg/day resulted in an increased rate of hospitalisation for heart failure when compared to warfarin or to no antiplatelet therapy (64% versus 47% and 48% respectively, p=0.044) [23]. The WATCH trial, comparing aspirin to clopidogrel in CHF was stopped early due to a withdrawal of funding by the sponsor and therefore was not powered to demonstrate a difference on the primary end-point, a composite of mortality, stroke, and myocardial infarction; however fewer patients were hospitalised for heart failure in the warfarin group compared to the aspirin group (27% reduction, p=0.01) [24,25]. A meta-analysis shows that the results of WASH and WATCH are consistent (ref [25]). The recently published HELAS study of 197 patients with chronic heart failure treated with aspirin, warfarin or placebo, showed that embolic events were rare in these patients and there was no evidence of a difference in outcome between the treatment groups [26].

The prognostic importance of plasma BNP measurement has been determined in various studies [2,3,14,16]. In a recent study, a BNP-guided approach was associated with a significant reduction in cardiovascular events when compared to conventional management not using natriuretic peptides [27-29].

Our results did not show an effect of clopidogrel on BNP; this, combined with its demonstrated effect on platelet aggregation in CHF [30], suggests that clopidogrel may represent a safer approach in CHF patients treated with ACE inhibitors. This potential role for thienopyridine derivatives has already been suggested in two studies [11,31]. However, in one of these studies, the authors investigated the effect of ticlodipine, which is now very rarely prescribed [11], and in the second study, the authors measured peak VO2 but only investigated the effect of a single dose of aspirin or clopidogrel [31]. Finally, in a previous study, we demonstrated a neutral effect of clopidogrel on vascular function in CHF patients using applanation tonometry, an accurate method of assessing peripheral arterial vasoconstrictor tone [19]. Thus, our current results confirm and further reinforce our previous studies by showing a differential effect on BNP, an important prognostic factor in CHF.

There are several limitations to our study. Patients with coronary artery disease were under-represented in our study compared to the general CHF population. The risk of a possible deleterious effect of aspirin is even more pertinent in these patients with both CHF and ischaemic disease and we cannot be sure that our results would have been the same if our analysis had focused on these patients. Intra-individual variation may be important to consider when serial measurements of BNP are performed [32], but since we did not have a placebo group, we cannot be certain that such variations did not account in part for our results. However, since there was no significant variation in the clopidogrel group, we can assume that results in the aspirin group were mainly due to the effect of aspirin rather than from intra-individual variation. In this study we demonstrated a difference in BNP values within groups but not between groups; power calculations were based on the hypothesis of a negative effect of aspirin in its group and our study solely planned to demonstrate such an effect. Our study may be underpowered. A cross-over study may have increased statistical power but could have been complicated by order or period effects. Although baseline characteristics were similar in each group, our sample size precludes subgroup analysis of potentially important factors such as beta-blocker treatment and prior aspirin treatment. Lastly, we investigated the effect of aspirin 325 mg/day and our findings cannot be generalized to lower dosages. Aspirin 325 mg has been a common choice in randomised trials of aspirin that have suggested efficacy and is still widely prescribed [33,34]. Some pharmacodynamic studies suggest a similar effect of lower aspirin dosage [7,20,21,35]; this requires further investigation using clinical end-points and/or pertinent surrogate endpoints. However, the WATCH study used 162 mg/day of aspirin and reported no less adverse effect than in WASH (dose 300 mg/day).


   4. Conclusion
Top
 Abstract
 1. Materials and methods
 2. Results
 3. Discussion
 4. Conclusion
References
 
Our study demonstrates an adverse effect of aspirin (325 mg/day) but not clopidogrel (75 mg/day) for 14 days on plasma BNP levels in CHF patients. Whether this difference is clinically relevant can not be ascertained by our study but may help explain the apparent adverse effect of aspirin in two substantial randomised trials. The results of a third substantial trial are awaited (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial).


   References
Top
 Abstract
 1. Materials and methods
 2. Results
 3. Discussion
 4. Conclusion
 References
 

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