Scand J Rheumatol 1991; Suppl. 91: 3 7 4 4

Maintenance of Blood Pressure Control in Elderly Hypertensives on Ketoprofen

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Y. WEISS,') A. CHENARD, J.M. DE KERMADEC, F. TERTRAIN, and M. ABITEBOUL ')Service de Me'decine Interne, Centre hospitalier de Meaux, F-77104 MEAUX, France

In elderly patients, nonsteroidal anti-inflammatory drugs (NSAIDs) are often used concomitantly with antihypertensive agents. It is therefore important to assess the potential for interactions between NSAIDs and these agents. In a double-blind, placebo-controlled study. 40 elderly hypertensive patients treated with acebutolol or atenolol, together with frusemide. were randomized to receive either ketoprofen, 200 mg/day (50 mg q.i.d.), or matching placebo for 7 days. Arterial blood pressure and heart rate were monitored for a 24-hour period at baseline and at the end of treatment. Standard sphygmomanometric measurements of blood pressure and heart rate were conducted twice a day during the study. No clinically significant side effects or blood pressure or heart rate alterations were observed during the trial. The results indicate that ketoprofen does not interfere with blood pressure control in elderly hypertensive patients being treated with a combination of beta-blockers and diuretics.

Key words: Ketoprofen, antihypertensive, interaction, elderly, NSAID, beta-blocker, frusemide

Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive agents are often used concomitantly, especially in the elderly population. In the United States, it has been estimated that between 12 and 20 million patients are taking both NSAIDs and antihypertensive medications (1). NSAIDs have been reported to enhance the vasoconstrictor response to pressor hormones (2) and to decrease the synthesis of vasodilatory prostaglandins (3). Clinically significant interactions between NSAIDs and antihypertensive drugs, resulting in loss of blood pressure control, have been found to occur with indomethacin (4.5). ibuprofen (2). piroxicam and naproxen (3). However, this type of interaction has not been found with sulindac (3). Due to the selective nature of this interaction, each NSAID should be studied to determine its effect on antihypertensive therapy. No data have been reported on the effect of the NSAID ketoprofen on blood pressure control. Therefore, a randomized, doubleblind, parallel-group, placebo-controlled study was conducted to assess the potential interaction between the propionic acid derivative ketoprofen and the combination of a beta-adrenergic blocking agent and frusemide in elderly patients with established hypertension and rheumatic disease. Grants: Supported by a grant from Rh&e-Poulenc Rorer

38 Y. Weiss, A. Chenard, J.M. De Kermadec, F. Tertrain, M. Abiteboul

Materials and Methods

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Patients Forty inpatients, aged 60 years or older, with documented mild-to-moderate primary hypertension (< 180/90 mm Hg) that was well controlled by treatment with either atenolol or acebutolol in combination with frusemide were enrolled in the study. All patients had previously been treated with NSAIDs for osteoarthritis. Exclusion criteria included gastroduodenal ulcer or previous history of gastroduodenal ulcer, hypersensitivity to aspirin or NSAIDs, renal insufficiency (serum creatinine > 150 pmol/L) and treatment with anticoagulants. Written consent was obtained from all patients prior to enrollment.

Study Design The study had a randomized, double-blind, parallel-group, placebo-controlled design. Following enrollment, patients. were treated with either atenolol (100 mg/day) or acebutolol (200-400 mgday) together with frusemide (20 mg/day) and randomly assigned to receive either ketoprofen (50 mg q.i.d.) or matching placebo (q.i.d.) for 7 days. A total of four capsules of ketoprofen or placebo were taken each day - one in the morning, one at midday and two in the evening. Except for other antihypertensive drugs or NS AIDS, other treatments were allowed provided they remained stable throughout the study. Patients were allowed to take paracetamol (up to 4 &day) for the relief of pain. Patients received a standardized diet, with a daily intake of 4 to 6 g of sodium. Twenty-four-hour ambulatory blood pressure monitoring (using a Nippon Collin monitoring device) was performed before patient randomization (day 0) and again at the end of the study (day 7). Measurements of systolic, diastolic, and mean arterial blood pressure as well as heart rate were recorded at 30-minute intervals during each 24-hour period, using both the Korotkoff and oscillometric methods (6). Standard sphygmomanometric measurements of supine systolic and diastolic blood pressures and heart rate were performed at 8 a.m. and 8 p.m. on days 1 through 7 of the study. Various biological parameters, including a complete blood count and urine electrolytes, were also evaluated on day 0 and day 7. Throughout the study, any intercurrent illnesses and adverse events were recorded.

Statistical Analysis The number of patients enrolled in the study was calculated so that a difference of 10 mm Hg in the mean systolic blood pressure between the two treatment groups could be detected at the P = 0.05 level, assuming that the standard deviation of systolic blood pressure is 9 mm Hg in elderly hypertensive patients treated with beta-blockers or diuretics (7). The two treatment groups were compared using bilateral unpaired t-tests for continuous variables and with chi-square tests or Fisher’s exact tests for contingency tables. The measurements made during each 24-hour ambulatory blood pressure monitoring period were averaged to determine: (1) mean day values (i.e., mean of the values measured between 8 a.m. and 10 p.m.);

Maintenance of Blood Pressure Control in Elderly Hypertensives on Ketoprofen 39

Table I: Demographic and clinical characteristics.of randomized patients.

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Treatment group Ketoprofen (n = 20)

Placebo (n = 20)

Age (years)

75.6 f 1.9

79.1 f 1.6

Height (cm)

163.6 f 1.4'

158.9 f 1.8

Weight (kg)

69.3 f 2.9

61.9 f 2.6

Male/female

5/15

4/16

Duration of hypenension (years)

17.5 f 1.7

21.6 f 2.0

Duration of osteoarthritis (years)

14.3 f 1.9

18.9 f 2.2

Pta expressed as mean f SEM

P c 0.05 (bilateral unpaired t-test)

(2) mean night values (mean of the values measured between 10 p.m. and 8 a.m.); and (3) mean 24-hour values (mean of values measured over the entire 24-hour period). Each of the four variables measured during 24-hour ambulatory blood pressure monitoring (i.e., systolic, diastolic, mean arterial blood pressures and heart rate) by each of the two (Korotkoff and oscillometric) methods were averaged in this fashion. For each patient, the difference between the initial value (day 0) and the final value (day 7) for each of these variables was computed. The differences were analyzed using two-way analysis of variance (treatment group, type of beta-blocker). The correlation between the two methods (Korotkoffand oscillometric) was determined, and the mean square regression line computed for the 24-hour measurements at day 0. The standard sphygmomanometric blood pressure measurements (days 1-7) were analyzed using three-way analysis of variance (time, treatment group, type of betablocker). The same type of analyses were performed on biological parameter measurements. Statistical significance was assessed at the 0.05 level.

Results Demographics Forty patients were enrolled in the study, 20 in each treatment group. Compliance with the study regimen was excellent, except for 1 patient in the placebo group, who dropped out after 1 day due to lack of compliance. Twenty-nine patients were treated with atenolol (ketoprofen 13, placebo 16) and 11 received acebutolol (ketoprofen 7, placebo 4). Except for the patient who dropped out due to lack of compliance, all enrolled patients completed the study according to the protocol and were included in the analyses. The demographic and clinical characteristics of the two treatment groups are summarized in Table I. There were no statistically significant differences between the two groups, with the exception of patient height. The two treatment groups also were well matched for the type of beta-blocker used, the frequency of previous NSAID

40 Y . Weiss, A, Chenard, J . M . De Kermadec, F. Tertrain, M. Abiteboul

Table 11: Mean ( SEM) baseline 24-hour, daytime (8 a.m.-10 p.m.) and nighttime (10 p.m.-8 a.m.) blood pressure (BP) measurements of patients as measured by both the Korotkoff and oscillomeaic methods. Blood pressures are expressed in mm Hg and heart rate is expressed in beats/min. Treatment group Ketoprofen (n = 20)

(n = 20)

Placebo

148.5 f 7.1

141.6 f 4.2

76.4 f 3.0

12.8 f 2.6

Mean BP

101.2 f 4.7

95.7 f 3.3

Heart rate

63.4 It 2.3

61.4 f 1.9

141.8 f 7.0

140.9 f 4.0

76.3 -+ 3.1

12.1 f 2.4

Mean BP

101.2 f 4.6

95.1 f 3.1

Heart rate

64.2 f 2.4

61.8 f 1.9

151.3 f 7.9

144.5 f 5.3

16.9 f 3.3

74.1 f 3.2

Mean BP

101.3 f 5.2

91.4 f 5.3

Heart rate

61.8 f 2.2

60.3 ? 2.0

147.3 f 6.7

142.3 f 4.0

77.4 f 3.4

12.6 f 2.8

Mean BP

115.4 f 5.6

108.1 f 3.9

Heart rate

64.5 f 2.2

62.4 f 1.8

146.9 f 6.5

141.7 k 3.9

77.2 f 3.5

72.8 f 2.8

Mean BP

114.9 f 5.4

108.1 f 3.9

Hean rate

64.5 f 2.4

61.8 f 1.9

150.5 i 7.6

143.3 f 5.2

78.4 f 3.8

72.5 f 3.3

Mean BP

118.6 f 6.8

110.4 f 4.8

Heart rate

61.8 f 2.0

60.1 f 1.8

KOROTKOFF

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24-hour

- Systolic BP Diastolic BP

Day

- Systolic BP Diastolic BP

Night

- Systolic BP Diastolic BP

OSCILLOMETRIC 24-hour

- Systolic BP Diastolic BP

Day

- Systolic BP Diastolic BP

Night

- Systolic BP

Diastolic BP

treatment, and clinical examination abnormalities. Mean baseline blood pressure and heart rate readings over the 24-hour monitoring period as well as mean values during the day and during the night confirmed good blood pressure control, with no significant differences between the two treatment groups (Table 11). The two groups were also well matched for the frequency of abnormal systolic blood pressure (> 140 mm Hg),

Maintenance of Blood Pressure Control in Elderly Hypertensives on Ketoprofen

41

diastolic blood pressure (> 90 mm Hg) and global blood pressure (> 140/90 mm Hg) values recorded during each of the three periods of time.

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Blood Pressure Control The differences in mean blood pressure parameters between day 0 and day 7, assessed by 24-hour ambulatory monitoring, are summarized in Table 111. These differences were in no case statistically significant or different from zero. In general, the observed values tended to decrease after one week of combined treatment. In addition, there were no significant differences between the two treatment groups in the daily frequencies of abnormal blood pressure values (Table IV). The results of 24-hour ambulatory blood pressure monitoring were corroborated by those of the standard sphygmomanometric measurements performed twice daily on day 1 through day 7 (Fig. 1).

Safety Clinical and biological tolerance of the drug combinations evaluated was excellent. No adverse event was reported during the study, and no clinically significant change in biological parameter values was observed, including plasma creatinine and potassium levels.

E E

0 Systolic BP: Ketoprofen 0 Systolic BP: Placebo A Diastolic BP: Ketoprofen

u)

u)

E

n

100

A Diastolic BP: Placebo

0

0 0

Z

80 60 1

2

3

4

5

6

7

Day Figure 1: Mean morning (8 a.m.) sphygrnomanometric blood pressure (BP) readings during the 7-day study. Bars represent 95% confidence intervals.

8

42 Y. Weiss,A. Chenard, J.M. De Kermadec, F. Tertrain, M. Abiteboul

Table Iff: Differences between mean (SEM)blood pressure values and heart rate values measured at baseline (day 0) and after 1 week of treatment (day 7). Blood pressure (BP) differences are expressed in mm Hg and heart rate differences in beatdmin. Treatment group Ketoprofen (n = 20)

Placebo (n = 20)

KOROTKOFF 24-hour

- Systolic BP

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Night

* 2.7

-0.3 f 1.3

Mean BP

-0.6 f 3.2

1.8 f 1.8

Heart rate

0.1 f 1.4

0.4 k 1.1

4.1 f 4.0

0.7 f 3.0

Diastolic BP

-0.4 f 2.4

-1.3 f 1.4

Mean BP

-1.3 f 3.3

0.4 f 2.1

Heart rate

-0.2 f 1.6

-0.6 f 1.1

5.5 f 3.2

6.6 f 3.2

Diastolic BP

2.8 f 2.8

2.6 f 1.7

Mean BP

0.9 f 3.5

4.4 f 2.0

Heart rate

1.0 f 1.5

2.2 f 1.1

3.5 f 3.9

3.6 f 2.3

Diastolic BP

1.6 f 1.8

0.9 f 1.3

Mean BP

3.3 f 3.2

3.2 f 2.1

Heart rate

-0.3 f 1.3

-0.1 f 1.0

2.9 f 4.1

2.3 f 2.5

Diastolic BP

0.5 f 2.0

0.3 f 1.5

Mean BP

3.0 f 3.2

1.8 f 2.4

Heart rate

-0.6 f 1.4

-0.8 f 1.0

5.9 f 4.6

6.2 f 2.9

Diastolic BP

4.4 f 2.3

2.9 f 1.5

Mean BP

5.8 f 4.2

6.0 f 2.2

Heart rate

0.8 f 1.4

1.4 f 1.0

- Systolic BP ’

2.5

0.5 f 2.3

Diastolic BP

Day

4.6 f 3.9

- Systolic BP

OSCILLOMETRIC 24-hour

Day

Night

- Systolic BP

- Systolic BP

- Systolic BP

Maintenance of Blood Pressure Control in Elderly Hypertensives on Keioprofen

43

Table N: Changes in the frequencies of abnormal blood pressure (BP) values. The results are. expressed in 9%. Treatment group Ketoprofen (n = 20)

(n = 20)

Placebo

SBP > 140

5.4 f 5.0

0.6 f 5.0

DBP > 90

-0.1 f 6.1

-1.9 f 2.6

Both

1.5 f 6.2

-1.6 f 2.6

SBP > 140

6.5 f 5.3

0.4 f 5.6

DBP > 90

0.2 f 6.2

-3.1 f 3.2

Both

1.9 f 6.5

-2.9 f 3.2

SBP> 140

3.8 f 5.8

3.4 f 5.5

DBP > 90

-0.6 f 7.6

2.9 f 4.0

1.7 f 7.4

2.6 f 3.7

KOROTKOFF

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24-hour

Day

Night

-

-

-

Both

OSCILLOMETRIC 24-hour

Day

Night

DBP > 90

2.1 f 5.2

* 4.3 4 . 9 * 3.1

Both

2.3 f 5.2

-1.1 f 3.0

SBP> 140

4.0 f 5.2

2.1 f 4.2

DBP > 90

0.6 f 5.5

-2.1 f 3.7

Both

1.0 f 5.6

-2.2 f 3.6

1.0 f 6.6

9.9 f 6.0

DBP > 90

7.0 f 6.4

0.7 It 2.7

Both

7.0 f 6.4

0.7 f 2.7

- SBP> 140

-

- SBP> 140

3.1 f 5.2

4.5

Discussion Various NSAlDs have shown to reduce the effectiveness of antihypertensive treatment in hypertensive patients (2-5). However, it appears that certain NSAIDs do not interact with antihypertensives (3). This study was designed to determine whether ketoprofen has an effect on blood pressure control. Elderly patients were evaluated since this population is frequently treated with both antihypertensive agents and NSAIDs. This group is also at risk for drug interactions. The study was conducted on inpatients in order to optimize compliance with the protocol. The study was limited to predefined antihypertensive treatments in order to limit bias due to unbalanced distribution of antihypertensive treatments between the two treatment groups. The multiple measurements obtained for each patient on each day of the study added considerable power to the ability to ascertain changes in blood pressure during the study (8). No effect on blood pressure control was found in these well-controlled hypertensive patients when ketoprofen was added to the antihypertensive therapy, which combined

44

Y. Weiss, A. Chenard, J.M. De Kermudec, F . Tertruin, M. Abiteboul

a beta-blocker (atenolol or acebutolol) and a diuretic (frusemide). The results of the study indicated that ketoprofen did not have an effect on blood pressure control. These results are of particular interest since ketopmfen, which is known as a safe and potent NSAID (9,10), is frequently prescribed to the elderly. In summary, this double-Wind, placebo-controlled study has indicated no interaction between ketoprofen and the combination of a beta-blocker and frusemide in elderly hypertensive patients.

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References 1. Houston MC. Nonsteroidal anti-vlflammatory drugs andantihypertensives. Am J Med 1991; 9O(Suppl 5A):42S47S. 2. Kenneth LR, Colleen CD. Saul SB. Ibuprofen interferes with the efficacy of antihypertensive drugs. Ann Intern Med 1987; 107:628-35. 3. Wong DG,Spence JD, Laniki L, Freeman D, McDonald JWD. Effect of nonsteroidal anti-inflammatory drugs on control of hypertension by beta-blockersand diuretics. Lancet 1986; 1:997-1001. 4. Patak RV, Mookerjee BK, Bentzel CJ. Hysert PE et al. Antagonism of the effects of furosemide by indomethacin in normal and hypertensive men. Prostaglandins 1975; 10649-59. 5. Ylitalo P, Pitkgjwi T, Pyykonen ML, Nurmi AK et al. Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol. Clin Pharmacol Ther 1985; 38~443-9. 6. Weber MA, Deanna GC, Graettinger WF, Lipson JL. Characterizationof antihypertensivetherapy by whole-day blood pressure monitoring. JAMA 1988; 259:3281-5. 7. Watkins J, Abbott E, Hensky C, Webster J, Dollery C. Alteration of hypotensive effect of propanolol and thiazide diuretics by indomelhacin. Br Med J 1980; 281:702-5. 8. Ylitalo P, Pitkiijlirvi T, Pyykbnen ML, Nurmi AK, SeppWA E. Vapaatalo H. Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol. Clin Pharmacol Ther 1985; 38:443-9. 9. Le M t X. Safety of ketoprofen in the elderly: A prospective study on 20.000 patients. Scand J Rheumatol 1989; (suppl 83):21-7. 10. De Bono GG.Pearlgood M. General practice trials: A reappraisal in the light offindings of a general practice study of Oruvail. Br J Clin Pract 1986; 40(10):421-8.

Maintenance of blood pressure control in elderly hypertensives on ketoprofen.

In elderly patients, nonsteroidal anti-inflammatory drugs (NSAIDs) are often used concomitantly with antihypertensive agents. It is therefore importan...
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