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European Journal of Heart Failure 2007 9(2):191-196; doi:10.1016/j.ejheart.2006.05.015
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© 2007 European Society of Cardiology

Treatments with losartan or enalapril are equally sensitive to deterioration in renal function from cyclooxygenase inhibition

Tord Juhlina, Leif R. Erhardta, Helene Ottossonb, Bo A.G. Jönssonb and Peter Höglundc,*

a Department of Cardiology, Malmö University Hospital Malmö, Sweden
b Department of Occupational and Environmental Medicine, Lund University Hospital Lund, 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: The beneficial effects of angiotensin converting enzyme (ACE)-inhibitors are in part mediated through the inhibition of the degradation of the vasodilator bradykinin. The bradykinin effect is counteracted by cyclooxygenase-inhibitors. Angiotensin receptor blockers (ARBs) do not affect bradykinin.

Aims: To test the hypothesis that renal counteraction from a cyclooxygenase-inhibitor, diclofenac, is different in subjects treated with an ACE-inhibitor, enalapril compared with an ARB, losartan.

Methods: Twelve elderly, healthy, slightly over-hydrated subjects received diclofenac orally after pre-treatment with a diuretic, bendroflumethiazide, and enalapril or bendroflumethiazide and losartan, in a double-blind cross-over fashion, with a wash-out period of at least 1 week.

Results: Diclofenac reduced GFR significantly from 81(64–98) ml/min at first observations after dose for enalapril to 29(16–42) and from 76(64–88) after losartan to 35(24–46). There was no significant difference between enalapril and losartan in GFR. Diclofenac induced decreases in urine flow, excretion rates and clearances of sodium, osmolality clearance and free water clearance, irrespective of treatment with enalapril or losartan. However, serum potassium and handling of potassium were significantly lower after losartan-treatment.

Conclusion: The negative renal effects of diclofenac administration in subjects with activation of the renin–angiotensin system and enalapril treatment are the same in subjects with activation of the renin–angiotensin system and losartan treatment.

Key Words: Heart failure • ACE-inhibition • Angiotensin receptor blockers • Cyclooxygenase inhibition • RAAS • Clinical trial • Renal function

Received November 2, 2004; Revised September 12, 2005; Accepted May 25, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
Several large-scale randomised controlled trials have established the role of angiotensin-converting enzyme (ACE)-inhibitors in the treatment of congestive heart failure [1-6]. Furthermore, the HOPE-study showed that ACE-inhibitors might also reduce the risk in patients who are at high risk of cardiovascular events but with normal left ventricular function [7]. ACE-inhibitors exert their effect by decreasing the production of angiotensin II and by inhibition of bradykinin degradation. Some of the vasodilating effects of ACE-inhibitors are believed to be mediated by bradykinin via an increase in prostaglandin synthesis. This effect is more marked in the kidney than in other vascular beds [8].

Angiotensin receptor blockers (ARBs) block the angiotensin II action at the AT1 receptor [9]. Theoretically, ARBs should offer a more absolute inhibition and exclude angiotensin II escape, (i.e. other enzymes capable of catalysing the conversion of angiotensin I to angiotensin II), thus offering more complete protection against the harmful effects of angiotensin II. ARBs have no influence on bradykinin [10]. Clinical trials have established ARBs as an alternative to ACE-inhibitors in congestive heart failure and after myocardial infarction but have not proven any superiority [11-13].

Cyclooxygenase (COX)-inhibitors inhibit the production of prostaglandins and therefore the concomitant use of cyclooxygenase-inhibitors, e.g. aspirin and non-steroidal anti-inflammatory drugs (NSAIDs), could attenuate the beneficial effects of ACE-inhibitors and patients may therefore not receive full advantage of ACE-inhibition [14].

It seems likely that ARBs do not interact with COX-inhibitors since ARBs do not inhibit the breakdown of bradykinin and consequently should not affect prostaglandin synthesis. There is only one study comparing the effects of cyclooxygenase-inhibitors on ACE-inhibitors and ARBs in patients with congestive heart failure, looking at the effects on exercise oxygen uptake and exercise tolerance [15] and one study in patients with hypertension [16]. The effects of COX-inhibitors together with ARBs on renal function have not been studied previously which is surprising knowing that the effect of bradykinin is more marked in the kidney than in other vascular beds [8].

We tested the hypothesis that the effects of cyclooxygenase-inhibitors on renal function are different between ACE-inhibitors and ARBs. We used a model, which has been used previously, in which the renin-angiotensin system is activated by pre-treatment with a diuretic, bendroflumethiazide [17]. The subjects were then randomised to receive the ACE-inhibitor enalapril or the ARB losartan in the first study period. After at least one-week wash-out, the second study period commenced and the alternate treatment was given.

The primary objective was to compare the effect of losartan and enalapril on GFR after a single oral dose of diclofenac. Secondary objectives were to study the effects on urine flow, excretion rates of sodium and potassium, clearances of sodium and potassium, osmolality clearance and free water clearance.


   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, randomised cross-over design where all the subjects received diclofenac after having received an ACE-inhibitor or an ARB.

The subjects received pre-treatment with a thiazide diuretic, bendroflumethiazide 5 mg, daily for 6 days (i.e. days –6 to –1), this drug was not given on study days. Subjects also received either the ACE-inhibitor, enalapril, 2.5 mg daily days –6, –5 and –4; 5 mg daily days –3 and –2; and 10 mg daily day –1 and on the study day, or the ARB, losartan 12.5 mg days –6, –5 and –4, 25 mg days –3 and –2, and 50 mg daily day –1 and on the study day. The subjects were in contact with one of the investigators (TJ) on days –3 and –1; if adverse events suggestive of too high dosage of enalapril or losartan, e.g. dizziness or tiredness, were reported, the dosage was lowered. Though the investigator did not know the subjects actual treatment the expected short-term adverse events were the same for enalapril and losartan.

Diclofenac was given as Voltaren T®(Novartis). Enalapril was administered as Renitec® (MSD) and losartan as Cozaar® (MSD). Each dose was individually packed and written information was included.

During the pre-treatment period the subjects filled in a study medication diary. The packages were returned on study days and the remaining tablets were counted.

On study days, each subject had breakfast at home before arriving at the department. There, they met one of the investigators who performed an examination to ensure that no contraindications had developed and they had not experienced any adverse events. Two intravenous indwelling catheters were used, one in each arm, one to obtain blood samples and one for the administration of iohexol. Blood was obtained for analysis of active renin and aldosterone. 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. At the end of each pre-defined 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 after 3 h was included. The loading volume was given 1 h prior to the administration of diclofenac. Urine was collected 1 h prior to dosing and over 6 h post dose at the following intervals: –60 to 0, 0-30, 30-60, 60-90, 90-120, 120-150, 150-180, 180-240, 240-300 and 300-360 min. The volumes were 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 the midpoints of the urine sampling intervals. The samples were analysed for iohexol, sodium, potassium, creatinine and osmolality. At the end of each study day the investigators questioned the subjects about any adverse events.

2.2. Study population
Inclusion criteria were male or female aged 50-80 years. Exclusion criteria were heart disease, severe renal insufficiency (known GFR<30 ml/min), peptic ulcer, liver cirrhosis, intolerance to iohexol, bendroflumethiazide, enalapril, losartan, NSAIDs or aspirin.

The study group consisted of twelve healthy elderly volunteers. There were six men and six women aged 58 to 79 years, mean 72±5.3 (SD).

All treatment considered necessary was allowed, but aspirin and NSAIDs were not allowed for a period of 5 days prior to and during each study day.

At the 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 monitored and performed in accordance with the 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 in the Department of Clinical Chemistry Malmö University Hospital. Active renin was analysed by a two-site direct immunoassay specific for active renin at the Department of Clinical Chemistry Malmö University Hospital [18]. The relevant reference interval corresponding to our subjects was 7-76 mU/l and the CV was 8% at 70 mU/l (n=27) and 5% at 270 mU/l (n=27). Aldosterone was analysed at the Department of Clinical Chemistry Malmö University Hospital. The relevant reference interval corresponding to our subjects was 0.09-0.74 nmol/l.

Iohexol was analysed at the Department of Occupational and Environmental Medicine Lund University Hospital. Plasma (40 µl) and urine (10 µl) was diluted 25 and 200 times, respectively with water. Xenetix 300 (Guerbet, Villepinte, France) was added as an internal standard (2 and 20 µg/sample for plasma and urine, respectively). Solid iohexol (batch 502090) from Nycomed (Staffanstorp, Sweden) was used for calibration standards. The analyses were performed with a Perkin Elmer Series 200 liquid chromatography system with autosampler (Applied Biosystems, Norfolk, CT, USA), coupled to an API 3000 triple quadrupole mass spectrometer (Applied Biosystems/MDS-SCIEX, Toronto, Canada) with a Turbo electrospray ion source operated in positive ion mode at 350 °C. The column was a Genesis C18 (50x2.1 mm) with a particle size of 4 µm (Jones, Lakewood, CO, USA). Aliquots of 5 µl samples were injected. The mobile phases were (A) water containing 0.5% acetic acid and (B) methanol containing 0.5% acetic acid. A gradient from 95% A up to 100% B was applied in 5 min. The declustering potential was 40 V. The fragments analysed were for iohexol m/z 822.0/603.2 at a collision energy of 37 V and for Xenetix m/z 836.0/734.0 at a collision energy of 30 V. The CV:s for control samples, prepared by addition of iohexol to blank plasma and urine, were 7% at 50 mg/l for plasma and 13% at 500 mg/l for urine.

2.4. Calculation of renal parameters
Urine flow was calculated from each sampling interval and expressed as ml/min. Excretion rates of sodium and potassium were expressed as µmol/min. Urine and serum osmolality were given as mOsm/kg. Clearances of iohexol and electrolytes were calculated as the products of urine concentrations and flow rates divided by the serum concentrations and expressed as 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 analysis
The number of subjects was based on the following assumptions: in an earlier study on healthy subjects [19] 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. If a constant relative standard deviation of 20% was assumed a sample size of 12 should make it possible to detect a true difference of 23%. In our earlier study in healthy subjects with activated renin-angiotensin system and treatment with ACE-inhibitors, GFR fell by 20%, from 60 to 48 ml/min, after 50 mg diclofenac. Without pre-treatment, GFR fell by 17% from 71 to 59 ml/min [17]. In our earlier study in patients with congestive heart failure GFR fell by 40%, from 51 ml/min to 31 after 50 mg diclofenac [20].

As descriptive statistics mean±SD are used. For statistical analysis the t-test procedure in SAS (version 8.2, SAS Institute, Cary, NC, USA) was used. The differences between enalapril and losartan at first observations after dose, at the lowest observations and differences between first observations and lowest observations after administration of diclofenac were calculated. The first observations after dose were chosen as the subjects were in steady-state after the water loading and diclofenac had not yet affected the results. The lowest observations represent the maximum effect of diclofenac and the differences between the first and the lowest observations represent the effect of diclofenac on treatment with enalapril and losartan, respectively.

Arithmetic 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
 
The treatments were generally well tolerated. No adverse effects were observed and the study subjects did not report any discomfort. Accordingly, all subjects received the planned doses of enalapril and losartan.

Mean active renin was 371, range 43-1219, mU/l after enalapril and 336, range 61-1146, mU/l after losartan and was thus higher than the reference interval (7-76) but the means were not significantly different. Two subjects were inside the reference interval after enalapril treatment and one subject after losartan. Aldosterone was within the reference intervals (0.09-0.74) after both enalapril, mean 0.15, range 0.08-0.28, nmol/l, and losartan, 0.20, range 0.08-0.48, nmol/l. The means were not significantly different.

Significant differences between first observations and the lowest observations after diclofenac administration were found for both enalapril and losartan in GFR, urine flow, excretion rates and clearances of potassium and sodium, osmolality clearance and free water clearance. As GFR was expected to decrease after diclofenac administration serum creatinine was consequently expected to increase. Therefore, for serum creatinine the highest observations were used and showed significant increases for both enalapril and losartan (Table 1).


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  		Table 1 Biochemical parameters in 12 elderly, healthy subjects pre-treated with a diuretic and then with enalapril or losartan (cross-over)

 
Diclofenac reduced GFR from 81(64-98) at first observations after dose for enalapril to 29(16-42) and from 76(64-88) after losartan to 35(24-46). Urine flow fell significantly from 4.4(3.5-5.2) ml/min to 0.5(0.0-1.1) after enalapril and from 4.1(3.1-5.1) to 0.5(0.3-3.8) ml/min after losartan. Potassium excretion rate was significantly diminished from 84(62-106) to 14(6-22) µmol/min and from 64(45-82) to 14(10-18) µmol/min after losartan. After enalapril, potassium clearance was significantly reduced from 19.2(14.5-23.9) ml/min to 3.3(1.5-5.0) and from 15.4(11.1-19.7) to 3.4(2.4-4.5) ml/min after losartan. In Fig. 1A-D the mean values for each time-point for these variables are given.


Figure 01
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  		Fig. 1 A-D: Elderly, healthy, slightly over-hydrated subjects with activated renin-angiotensin system from short-term pre-treatment with diuretics and treatment with enalapril (square) or losartan (dot). Observations in (A) GFR, (B) urine flow, (C) potassium excretion rate and (D) sodium excretion rate after a single dose of 50 mg diclofenac.

 
The first observations after dose showed that serum potassium was significantly higher after treatment with enalapril, mean difference 0.3 (0.1-0.4) mmol/l. Also the potassium excretion rate was significantly higher with enalapril, mean difference 20 (1-39) µmol/min. No other significant differences were found.

At the lowest observations after diclofenac administration a significant difference was observed in serum potassium. After treatment with enalapril, serum potassium was 0.2 (0.1-0.4) mmol/l higher.

Significant differences between the first observations and the lowest observations after diclofenac administration were found in potassium excretion rate and potassium clearance. Pre-treatment with enalapril caused a higher excretion rate and clearance than losartan. The difference in excretion rate was 20 (3-38) µmol/min. Potassium clearance was 3.9 (0.1-7.7) ml/min higher with enalapril. No other significant differences were found.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
This study demonstrates that the cyclooxygenase-inhibitor diclofenac induced significant decreases in GFR, urine flow, excretion rates and clearances of sodium and potassium, osmolality clearance and free water clearance in elderly healthy volunteers with activated renin-angiotensin system from pre-treatment with diuretics, irrespective of treatment with enalapril or losartan. There was no significant difference in the response in GFR between enalapril and losartan following acute administration of diclofenac. Nor, were there any significant differences in the secondary objectives; urine flow, excretion rate and clearance of sodium, osmolality clearance and free water clearance. Thus, the data reject our pre-specified hypothesis. However, serum potassium and handling of potassium were significantly lower after losartan-treatment.

The significant differences in serum potassium and potassium excretion rate were not unexpected findings as ARBs are believed to reduce the risk of hyperkalaemia compared with ACE-inhibitors [21,22]. The differential effect on serum potassium is believed to be related to a relatively smaller reduction of the aldosterone levels with ARB-treatment [22]. We did not observe any significant differences in aldosterone after pre-treatment with ACE-inhibitors or ARBs but there was a non-significant (p=0.061) trend to higher aldosterone levels after ARB-treatment, but the study was underpowered to test for differences in aldosterone levels. Prostaglandins decrease aldosterone [23] but there is no reason the effects of COX-inhibition should be different between an ACE-inhibitor and an ARB. In addition, blood for analysis of active renin and aldosterone was obtained before administration of diclofenac.

The results in GFR, urine flow and sodium handling are however surprising knowing the difference between ARBs and ACE-inhibitors. We expected diclofenac, which inhibits the prostaglandin system, to interact with the renal effects of ACE-inhibitors but not with the renal effects of ARBs. Under normal circumstances the prostaglandins contribute little to changes in the renal circulation but they play an important part in maintaining renal haemodynamics attenuating the effects of the vasoconstrictors in conditions with activation of neurohumoral systems, e.g. congestive heart failure. The mechanism is mainly through dilation of the afferent arteriole [24]. Both ACE-inhibitors and ARBs have effects on the renal circulation as they dilate the efferent arteriole [21]. From studies with the bradykinin antagonist HOE 140 it has been assumed that bradykinin also contributes to the reduction in efferent arterial tone [25]. From our findings this does not seem to be the case. Our findings with the same decrease in GFR and urine flow could be a direct renal effect caused by vasoconstriction induced by diclofenac. The fact that part of the prostaglandin-induced vasodilation is mediated through bradykinin does not seem to be of more importance than the effects on the efferent arteriole. In which case, the renal effects are not related to bradykinin.

In patients with congestive heart failure the beneficial effects of ACE-inhibitors on respiratory function and exercise oxygen uptake have been found to be antagonised by aspirin [26,27]. These parameters have also been studied with an ARB. Losartan and enalapril were found to cause a similar improvement in exercise oxygen uptake and exercise tolerance. These effects were counteracted by aspirin when obtained with enalapril but not with losartan. The authors concluded that ARBs may represent an advancement in the treatment of congestive heart failure because their effect on exercise oxygen uptake is similar to that of ACE-inhibitors but is not antagonised by aspirin [15].

A possible explanation for these unexpected results may be stimulation of the AT2 receptor in the kidney by selective AT1 receptor blockade, causing an AT2 mediated vasodilation of the afferent arteriole [28]. As the mechanism for this is via endothelium-derived release of bradykinins and prostaglandins [29], a possible interaction between cyclooxygenase-inhibitors and ARBs can be suspected. Also, in line with these observations, losartan has been shown to increase bradykinin levels in hypertensive patients and this could account for the lack of difference in our study [30].

The concomitant use of ACE-inhibitors and aspirin has been questioned since trials have shown a negative interaction between ACE-inhibitors and aspirin [31-33]. One could speculate that these negative effects could be avoided if the ACE-inhibitor was changed to an ARB. Our results do not support this speculation at least not for short-term treatment with 50 mg losartan compared with 10 mg enalapril.

In conclusion, our results show that the negative renal effects caused by acute administration of diclofenac in elderly healthy volunteers, with normal cardiac and renal function, with activated renin-angiotensin system from pre-treatment with diuretics and enalapril are the same after pre-treatment with diuretics and losartan. Thus, losartan is equally as sensitive to cyclooxygenase-inhibitors as enalapril. Treatment with cyclooxygenase-inhibitors may worsen heart failure and potentially counteract the effect of both ACE-inhibitors and ARBs such as losartan. This effect must be taken into consideration when treating patients with congestive heart failure.


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

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