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European Journal of Heart Failure 2004 6(7):909-916; doi:10.1016/j.ejheart.2004.02.005
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© 2004 European Society of Cardiology

Acute administration of diclofenac, but possibly not long term low dose aspirin, causes detrimental renal effects in heart failure patients treated with ACE-inhibitors

Tord Juhlina, Sven Björkmanb, Bodil Gunnarssonc, Åsa Fygeb, Bodil Rothb and Peter Höglundc,*

a Department of Cardiology, Malmö University Hospital Malmö, Sweden
b Hospital Pharmacy, Malmö University Hospital Malmö Sweden
c Department of Clinical Pharmacology, Lund University Hospital S-221 85, Lund, Sweden

* Corresponding author. Tel.: +46-46-177979; Fax: +46-46-176085 E-mail address: Peter.Hoglund{at}skane.se


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Background: Non-steroidal anti-inflammatory drugs (NSAID) or high doses of aspirin (acetylsalicylic acid) can exert detrimental effects on renal function and counteract the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with congestive heart failure.

Aims: The objective of our study was to evaluate the renal effects of low dose aspirin and the NSAID diclofenac in patients with congestive heart failure treated with ACE-inhibitors.

Methods: Ten patients on their individually titrated dose of ACE-inhibitors and low dose aspirin (≤125 mg daily) with stable congestive heart failure from coronary artery disease, entered an open investigation while on low dose aspirin, which was then discontinued. After one week wash-out they received an oral dose of 50 mg diclofenac potassium or placebo in a double-blind cross-over fashion with a one week wash-out period between treatments.

Results: Diclofenac caused significant (P<0.05) decreases in GFR, urine flow, osmolality clearance, and excretion rates of sodium and potassium compared to placebo and aspirin. At tmax for diclofenac or corresponding time for placebo diclofenac caused 40 (11–59)% (geometric mean and 95% confidence limits) reduction in GFR compared to placebo and 36 (5.4–56)% reduction to low-dose aspirin. No significant changes between low dose aspirin and placebo were found.

Conclusion: Acute administration of diclofenac, but not long term low dose aspirin, has profound impact on renal function in patients with heart failure treated with ACE-inhibitors and may cause worsened heart failure.

Key Words: ACE-inhibitors • NSAIDs • Heart failure • Renal function • Coronary artery disease • Aspirin

Received May 30, 2003; Revised December 19, 2003; Accepted February 23, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
The angiotensin-converting enzyme inhibitors (ACE-inhibitors) enalapril, captopril, ramipril, trandalopril and lisinopril have been demonstrated to produce beneficial effects and improve both function and survival in patients with congestive heart failure [1–6]. A further action of these drugs is an enhancement of renal function through reducing vasoconstricting factors and inhibiting the degradation of bradykinin. Bradykinin is a potent vasodilator, which, in part, acts through the enhancement of vasodilatory prostaglandin synthesis [7]. In conditions with activation of the neurohumoral systems, as congestive heart failure, the prostaglandins attenuate the effects of the vasoconstrictors and have an important part in maintaining renal hemodynamics. This mechanism is in part responsible for the beneficial effects of ACE-inhibitors in congestive heart failure [8].

The formation of prostaglandins can be blocked by inhibiting the enzyme cyclooxygenase [9]. Due to its effect on platelet aggregation the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) is now routinely used in patients with coronary artery disease [10], the most important causal factor of heart failure [11]. However, the concomitant use of prostaglandin synthesis inhibitors could attenuate the beneficial effects of ACE-inhibition. In accordance with this the SOLVD-study showed that, in contrast to the overall effect, enalapril had no beneficial effect on mortality among those treated with aspirin [12]. Also, a subgroup analysis from CONSENSUS II showed that the effect of enalapril was less favourable in aspirin treated patients [13]. The WASH-study, where patients with congestive heart failure treated with ACE-inhibitors were randomised to no anti-thrombotic 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 aspirin [14]. Alveolar-capillary membrane diffusing capacity, exercise performance and pulmonary gas exchange have been found to be improved with angiotensin-converting enzyme inhibitors and to be counteracted by aspirin in patients with heart failure [15,16]. High dose aspirin, 500 mg t.i.d, to patients with heart failure has been demonstrated to reduce renal sodium excretion [17]. The role of aspirin for patients with heart failure has therefore been questioned [18–21].

The aim of this study was to further investigate the negative influence on renal function of prostaglandin inhibition in patients with congestive heart failure treated with ACE-inhibitors. As a model drug we chose the NSAID diclofenac, which in an earlier study has been shown to decrease GFR by 35% in patients with a history of ureteral colic but normal renal function at the time of the study [22]. The primary objective was to study the influence of a single oral dose of diclofenac on GFR. Secondary objectives were to study the effects on urine flow, excretion rates of sodium and potassium, osmolality clearance and free water clearance. As secondary objectives we also studied the mentioned parameters for long term low dose acetylsalicylic acid compared with placebo.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
2.1. Study protocol
The study was of a double-blind, placebo-controlled cross-over design where all the patients received a single dose of diclofenac and placebo in a randomised order. Prior to this double-blind part of the study an open investigation with the patients on their usual daily dose of aspirin was performed. Aspirin was then discontinued at least 1 week prior to the first visit of the double-blinded part and between visits.

NSAIDs were not allowed during the study period. After 1 week wash-out they received a single oral dose of 50 mg diclofenac potassium or placebo in a double blind cross-over study with a 1 week wash-out period between the treatments.

The patients were assigned to the two possible treatment sequences of diclofenac and placebo according to a table of random numbers. Diclofenac potassium was given as Voltaren T® immediate-release tablets (Novartis). Fortuitously, the vitamin B complex tablets Polybion® (Merck) were found to have very similar shape, size and colour, and these were consequently used as placebo. Each tablet was packed in a paper envelope and taken by the subject without close inspection by the investigators. Randomisation and packaging of the drugs were performed by author SB, who did not participate in the experimental sessions.

The patients were requested to take no diuretics on the day of visit, while other drugs were taken as prescribed in the morning. Each patient had breakfast at home before arriving to the department at 07.30 when the study procedures were started. An intravenous indwelling catheter was inserted into both forearms, one to obtain blood and the other for administration of iohexol. Omnipaque® (Nycomed), 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 patients were slightly over-hydrated during study days; after having emptied the bladder a loading volume of 500 ml was given and then water volumes corresponding to voided urine during pre-determined intervals were given for 7 h. This total volume included clear soup served after 3 h.

The loading volume was given 1 h prior to the start of the experiment (start or time zero was when placebo or diclofenac was given). Urine was collected over 1 h prior to dose and over 6 h post dose in the following intervals: –1–0, 0–0.5, 0.5–1, 1–1.5, 1.5–2, 2–2.5, 2.5–3, 3–4, 4–5 and 5–6 h. The volume was noted and the urine was analysed for iohexol, sodium, potassium and osmolality.

Blood samples were obtained 30 min prior to dose and 15, 45, 75, 105, 135, 165, 210, 270 and 330 min post dose, i.e. at mid-time of the urine collection intervals. The samples were analysed for iohexol, sodium, potassium, creatinine and osmolality. Blood samples for analysis of diclofenac were obtained prior to dose and 5, 10, 15, 30, 45, 55, 65, 75, 90, 105, 120, 135, 150, 165, 180, 210, 240, 270, 300 and 330 min post dose. Blood pressure and pulse rates were measured prior to dose and 2, 4 and 6 h post-dose.

2.2. Patient population
The study comprised nine men and one woman, aged 50–78 (mean age 67±8.2), with stable chronic congestive heart failure due to ischemic heart disease treated with their individually titrated dose of ACE-inhibitors and low dose aspirin (≤125 mg daily). Three patients were treated with ramipril 2.5 mg/day, four with captopril (mean dose 69 mg/day, range 37.5–112.5), two with enalapril (mean dose 30 mg/day, range 20–40) and one patient with cilazapril 5 mg/day. The dose of acetylsalicylic acid ranged from 75 mg/day (n=8) to 125 mg/day (n=2). Five patients were in New York Heart Association (NYHA) class II and five in class III. All patients had additional cardiovascular medication, such as diuretics (n=8), digoxin (n=4), betablockers (n=5), long-acting nitroglycerin (n=6) and anticoagulants (n=3). All patients had left ventricular ejection fractions <40% (mean 32.5±5.0) determined by two-dimensional trace echocardiography. At the inclusion visit their blood pressure in standing was 110±19/76±12 mmHg, supine blood pressure was 116±19/77±7 mmHg and pulse rate was 74±11 bpm. Exclusion criteria were; unstable angina pectoris or myocardial infarction within the past 3 months; clinical decompensation; severe renal insufficiency (GFR<30 ml/min); severe heart failure (NYHA class IV); peptic ulcer; liver cirrhosis; intolerance to aspirin or NSAIDs or porphyria. At an entry visit medical history and written informed consent was obtained and a physical examination was made and inclusion and exclusion criteria were evaluated. The study was conducted in accordance with the Declaration of Helsinki and 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 Trelleborg Hospital Laboratory. Iohexol was determined in urine and serum by modifications of a published high-performance liquid chromatography (HPLC) method [23]. In brief, urine samples, 0.050 or 0.25 ml, were diluted to 1.25 ml with 0.1-M sodium phosphate solution, pH 3.2, and 10 or 20 µl of these mixtures were injected into the chromatograph. The 250x4 mm RP-18 column was eluted at 1.5 ml/min with the mobile phase 7.5% methanol in 0.1-M sodium phosphate solution, pH 3.2, and the detection wavelength was 265 nm. At a concentration of 0.80 mg/ml, the within-day coefficient of variation (C.V.) was 2.2% (n=8) and the between-day C.V. was 8.4% at 0.50 mg/ml (n=11) and 10% at 2.50 mg/ml (n=10). To each serum sample, 0.20 ml, was added 25 µl of iopentol solution (1.0 mg/ml in water) as internal standard and 0.8 ml of 5% perchloric acid. After centrifugation, 20 µl of the supernatant was injected into the chromatograph. The mobile phase was 5% acetonitrile in water, adjusted to pH 2.5 with 0.1-M hydrochloric acid. The detection wavelength was 254 nm. At a concentration of 40 µg/ml, the within-day C.V. was 1.3% (n=8) and the between-day C.V. was 3.4% (n=12).

Diclofenac was determined by a modification of a published HPLC procedure [24]. To each serum sample, 0.50 or 1.00 ml, were added 20 or 40 µl of carprofen solution (10 µg/ml in methanol) and 0.5 ml of 1.0-M phosphoric acid. The samples were then extracted with 5.0 ml of dichloromethane. The organic phase was evaporated and the residue taken up in 50 µl of mobile phase, of which 20 µl was injected into the chromatograph. The RP-18 column was eluted at 1.2 ml/min with 59% acetonitrile in water adjusted to pH 3.3 with acetic acid. The detection wavelength was 285 nm. The within-day C.V. was 2.3% at 0.050 µg/ml (n=6) and 2.4% at 0.50 µg/ml (n=6), and the between-day C.V. was 5.4% at 0.50 µg/ml (n=16).

2.4. Calculation of renal parameters
Urine flow was calculated from each sampling interval 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. Clearance of iohexol was calculated as the product of urine concentration and flow rate divided by the serum concentration and expressed in ml/min. GFR was determined as clearance of iohexol. 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 methods
The number of patients was based on the following assumptions: in an earlier study on healthy subjects [22] GFR fell from 113±22 ml/min to 73±22 ml/min after 50 mg diclofenac. The mean pre-study GFR was believed to be lower than 113 ml/min in this study but with a S.D. 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. If a constant R.S.D. of 20% was assumed a sample size of 10 should make it possible to detect a true difference of 23%.

As descriptive statistics mean±S.D. 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 after dose and one using the observations obtained at the time of maximum diclofenac concentration (Cmax) and the corresponding time during the two other occasions. The statistical model comprised treatments and treatment sequences as fixed effects, visit number and patient within sequence as random effects. As it turned out there were no sequence or period effects and the model was reduced to treatments and patient within sequence. The main variable (GFR) was analysed under the assumption of a constant relative standard deviation and, consequently, geometric least square means and 95% confidence limits are presented; for the other variables arithmetic least square means and 95% confidence limits are given. Statistical significance was accepted at P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
Observations at tmax or corresponding time after placebo treatment and low-dose aspirin showed that diclofenac caused significant decreases (P<0.05) in GFR, urine flow, osmolality clearance and excretion rates of sodium and potassium, but not in free water clearance, compared to placebo and low-dose aspirin. No significant changes between placebo and low-dose aspirin were found (Table 1). GFR diminished after diclofenac administration and reached its lowest mean value after 75 min. The effect lasted for approximately 3.5 h (Fig. 1a). The reduction was from 75±41 ml/min (mean±S.D.) to 43±24 ml/min after 75 min. Diclofenac caused 40 (11–59)% (geometric mean and 95% confidence limits) reduction in GFR compared to placebo and 36 (5.4–56)% reduction to low-dose aspirin. The urine flow started to decrease early after the dose and fell from 3.6±3.0 ml/min at 15 min to 1.6±2.0 ml/min after 165 min. The effect lasted throughout the examination day (Fig. 1b). The excretion rate of sodium was significantly reduced after the diclofenac dose and decreased from 131±76 µmol/min to 29±22 µmol/min after 165 min (Fig. 1c). The potassium excretion rates showed diminution from 72±54 µmol/min at 15 min to 19±12 µmol/min after 3.5 h (Fig. 1d). The osmolality clearance was reduced from 2.9±1.4 to 0.9±0.6 ml/min after 165 min (Fig. 1e). A non-significant change was found in free water clearance from 0.8±2.1 ml/min at 15 min to 0.6±1.8 ml/min after 105 min (Fig. 1f).


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  		Table 1 Slightly over-hydrated patients with congestive heart failure treated with ACE-inhibitors. Least square means and 95% confidence limits of observations at tmax for diclofenac or corresponding time after placebo treatment and low-dose aspirin (GFR are presented as geometric means and 95% confidence limits)

 


Figure 1
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  		Fig. 1 (a–f): Slightly over-hydrated patients with congestive heart failure treated with ACE-inhibitors. Observations in (a) GFR, (b) urine flow, (c) sodium excretion rate, (d) potassium excretion rate, (e) osmolality clearance and (f) free water clearance after continuous treatment with low-dose aspirin (triangle), a single dose of 50 mg diclofenac (square), and placebo (dot).

 
Least square means of the observations after dose showed that diclofenac caused significant decreases (P<0.05) in GFR, urine flow, excretion rates of sodium and potassium, osmolality clearance, and in free water clearance compared with placebo and low-dose aspirin. Both diclofenac and low-dose aspirin caused slight but significant (P<0.05) increases in serum creatinine. Diclofenac caused 15 (6.1–22)% reduction in GFR compared to placebo and 20 (12–27)% reduction to low-dose aspirin. Here, low-dose aspirin showed a significant decrease compared with placebo in the secondary objective osmolality clearance but an increase in free water clearance (Table 2).


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  		Table 2 Slightly over-hydrated patients with congestive heart failure treated with ACE-inhibitors. Least square means and 95% confidence limits of all observations after dose for diclofenac, placebo and low-dose aspirin (GFR are presented as geometric means and 95% confidence limits)

 
The plasma Cmax and tmax of diclofenac varied considerably between patients. The range of Cmax was 0.54–2.58 µg/ml (median 0.89 µg/ml) and the range of tmax was 30–330 min (median 75 min).

All 10 patients completed the study. No changes of blood pressure or pulse rate were observed. One of the patients experienced dyspnea at the end of one study day and was given furosemide intravenously.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
This study demonstrates that acute administration of diclofenac induces significant decreases in GFR, urine flow, excretion rates of sodium and potassium, osmolality clearance and free water clearance in patients with congestive heart failure treated with ACE-inhibitors. Further, diclofenac and aspirin caused small increases in serum creatinine in these patients with normal or slightly impaired renal function.

Indomethacin, another NSAID, has in previous studies been shown to attenuate the peripheral hemodynamic effect of the ACE-inhibitor captopril in patients with congestive heart failure [25]. In one earlier study where invasive hemodynamics measurements were performed, enalapril caused significant decreases in systemic vascular resistance, left ventricular filling pressure and total pulmonary resistance together with a significant increase in cardiac output. However, enalapril did not elicit any changes in any of these variables when given on the same day or the day after aspirin [26]. In that study, however, the dose of aspirin was higher, 350 mg, than we used: 75–125 mg. With this low dose we did not find any significant changes as a consequence of aspirin, except for a significant decrease in the secondary objective osmolality clearance but an increase in free water clearance. This is in agreement with previous studies with lower doses of aspirin having found no hemodynamic interaction [27,28]. A high dose of aspirin, e.g. 350 mg, reduces both prostacyclin and thromboxane production and inhibits synthesis of vasodilating prostaglandins but lower doses of aspirin suppress thromboxane production but spare prostacyclin synthesis [29]. The dose of aspirin in our study, 75–125 mg daily, taken approximately 1 h before the start of the experiment, was probably too low to affect renal prostacyclin synthesis which probably explains why aspirin did not elicit any significant changes though it has been shown that even low-dose aspirin inhibits arachidonic acid-induced vasodilatation in patients with heart failure treated with ACE-inhibitors [30].

The optimal dose for preventing coronary and cerebral thrombosis has long been a cause of debate. For patients with cerebrovascular disease the recommendations range from 30 to 1300 mg daily [31]. Since many patients suffer both from congestive heart failure and cerebrovascular disease the need for a high dose of aspirin may arise. The possibility of attenuation of the efficacy of ACE-inhibitors, and clinical deterioration, must then be taken into account.

The vasodilating prostaglandins PGI2 and PGE2 seem to contribute little to changes in vascular resistance under normal circumstances. However, in conditions with activation of neurohumoral systems, e.g. congestive heart failure, the prostaglandins play an important part in maintaining renal hemodynamics attenuating the effects of the vasoconstrictors. The mechanism is mainly through dilatation of the afferent arteriole [8]. ACE-inhibitors act as vasodilators and impede the degradation of the strong vasodilator bradykinin which augments its vasodilating effect by releasing prostaglandins [7]. This interference suggests that the vasodilating effect of ACE-inhibitors is in part mediated by prostaglandins. Patients with activated renin angiotensin system therefore depend upon prostaglandins in their renal function and treatment with cyclooxygenase inhibitors, like diclofenac, may cause deterioration in renal function. As part of the vasodilating properties from ACE-inhibitors arise from stimulation of the prostaglandins, cyclooxygenase inhibition may antagonise the effects of the ACE-inhibitors.

The prostaglandins also assist in excretion of free water through interfering with the action of antidiuretic hormone (ADH) and thereby limiting the ability of water reabsorption by the collecting duct [32]. Through their action to augment renal blood flow and glomerular filtration rate ACE-inhibitors increase the delivery of filtrate to more distal nephrons. The increase in water excretion seen with ACE-inhibitors is believed to be mediated by bradykinin via prostaglandins [33] though there is little evidence of a diuretic sparing effect of ACE-inhibitors [34]. Thus cyclooxygenase inhibitors can diminish water excretion and also here attenuate the efficacy of ACE-inhibitors. These effects can be expected to have contributed to the observed reduction in urine flow.

The doses of aspirin in the SOLVD- and CONSENSUS II-studies are not known and the doses for many patients were probably higher than our studied doses, 75–125 mg daily. Though we did not find any changes with low-dose aspirin our findings of impairment of renal function with a high dose of a cyclooxygenase-inhibitor in patients with congestive heart failure treated with ACE-inhibitors are in line with the results of the SOLVD-, CONSENSUS II- and the WASH-studies [12–14]. Further, the observed deterioration in renal function in our study was caused by a single dose of diclofenac and the renal effects of repeated dosing are not known. This question will be addressed in a future study.

Many people buy NSAIDs over the counter and the proportion of elderly patients taking NSAIDs has been estimated at 25% [35]. It seems probable that many of these patients suffer from congestive heart failure and are being treated with ACE-inhibitors. They therefore cause themselves the potential risk of counteraction of the efficacy of ACE-inhibitors.

Whether the renal effects of diclofenac are more pronounced than of other NSAIDs has been investigated earlier. Clinical studies have not found any difference [36], but theoretical considerations imply there could be a difference as diclofenac exhibits more effect on PGI2 than other tested NSAIDs [37,38].

A possible methodological weakness in this study was the urine collection by normal voiding. Urine can remain in the bladder despite emptying which could cause errors in volume measurements. From ethical considerations it is not acceptable and recruitment of patients to the study probably would have been more difficult if catheterisations were to be made.

In the study we were not able to separate effects depending on worsened heart failure from effects depending on counteraction of the renal effects of ACE-inhibition. This issue will be addressed in a future study with healthy volunteers with normal cardiac and renal functions, and with pharmacological activation of the renin angiotensin system.

In conclusion, our results show that acute administration of diclofenac, but not long term low-dose aspirin, deteriorated renal function in patients with coronary artery disease and heart failure treated with ACE-inhibitors. The treatment with cyclooxygenase-inhibitors may worsen heart failure and potentially counteract the efficacy of ACE-inhibitors. This counteraction must be taken into consideration in the management of patients with congestive heart failure.


   Acknowledgements
 
To Prof. Leif Erhardt and Associate Prof. Bo Israelsson, Department of Cardiology, Malmö University Hospital, for many fruitful discussions.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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 Eur J Heart FailHome page
T. Juhlin, B. A.G. Jonsson, and P. Hoglund
Renal effects of aspirin are clearly dose-dependent and are of clinical importance from a dose of 160 mg
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T. Juhlin, L. R. Erhardt, H. Ottosson, B. A.G. Jonsson, and P. Hoglund
Treatments with losartan or enalapril are equally sensitive to deterioration in renal function from cyclooxygenase inhibition
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