Clinical and Investigative Medicine

 

Acetylsalicylic acid (Aspirin) test for the diagnosis of renovascular hypertension

Jerzy Gluszek
Anna Posadzy-Malaczynska, MD, PhD
Andrzej Tykarski, MD, PhD
Danuta Pupek-Musialik
Maria Gracz, MSc
Hanna Kara-Perz, MD

Clin Invest Med 1997;20(3):171-175.

[résumé]

From the Department of Arterial Hypertension, Institute of Cardiology, K. Marcinkowski University School of Medical Sciences, Poznan, Poland.

(Original manuscript submitted Mar. 19, 1996; received in revised form Feb. 11, 1997; accepted Feb. 25, 1997)

Reprint requests to: Jerzy Gluszek, Department of Arterial Hypertension, Institute of Cardiology, K. Marcinkowski University School of Medical Sciences, Dluga 1/2, 61­848 Poznan, Poland

Contents

Abstract

Objective: To determine whether the administration of acetylsalicylic acid (ASA, also known as Aspirin) differentiates patients with renovascular hypertension from those with essential hypertension, in order to provide a simple alternative to more expensive forms of diagnosis for this condition.

Design: Trial of ASA test in patients with previously diagnosed essential and renovascular hypertension.

Setting: Inpatient department of an academic health sciences centre in Poznan, Poland.

Patients: Forty patients with essential hypertension and 21 patients with renovascular hypertension.

Interventions: Patients were given an intravenous injection of ASA (10 mg/kg body weight), blood pressure was measured and blood was sampled and assayed for plasma renin activity (PRA) before and 30 minutes after the injection.

Results: ASA infusion in patients with renovascular hypertension resulted in a decrease in PRA from 15.2 (standard deviation [SD] 12.4) ng/mL per hour to 7.2 (SD 9.8) ng/mL per hour, whereas in patients with essential hypertension the initial PRA was significantly lower before ASA administration and did not change afterward. In patients with renovascular hypertension, the mean systolic, diastolic and arterial pressure decreased significantly (p < 0.001) after ASA infusion, but these did not change in patients with essential hypertension. Based on the criterion of 4 mm Hg as a detectable decrease in mean blood pressure, the sensitivity of the ASA test was 95.0% and the specificity 82.5%; its positive predictive value was 74% and its negative predictive value 97%.

Conclusion: The precise measurement of blood pressure during the ASA test may provide a useful method of differentiating between patients with renovascular and essential hypertension.

Résumé

 Objectif : Déterminer si l'administration d'acide acétylsalicylique (ASA, aussi appelé Aspirine) différencie les patients atteints d'hypertension artérielle rénovasculaire de ceux qui souffrent d'hypertension artérielle essentielle, afin d'offrir une solution de rechange simple à des moyens plus coûteux de diagnostiquer ce problème.

Conception : Essai de l'ASA chez des patients chez lesquels on avait déjà diagnostiqué une hypertension essentielle et une hypertension rénovasculaire.

Contexte : Service interne d'un centre universitaire des sciences de la santé à Poznan, Pologne.

Patients : Quarante patients souffrant d'hypertension essentielle et 21 patients souffrant d'hypertension rénovasculaire.

Interventions : On a injecté aux patients de l'ASA (10 mg/kg de masse corporelle) par voie intraveineuse, mesuré la tension artérielle, prélevé et analysé des spécimens de sang et déterminé l'activité rénine plasmatique (ARP) avant l'injection et 30 minutes après.

Résultats : L'injection d'ASA à des patients atteints d'hypertension rénovasculaire a entraîné une baisse de l'ARP qui est passée de 15,2 (écart type [ET] 12,4) ng/mL par heure à 7,2 (ET 9,8) ng/mL par heure, tandis que chez les patients atteints d'hypertension essentielle, l'ARP initiale était beaucoup plus basse avant l'administration d'ASA et n'a pas changé après l'injection. Chez les patients atteints d'hypertension rénovasculaire, les tensions systolique, diastolique et artérielle moyenne a diminué considérablement (p < 0,001) après l'injection d'ASA, mais elles n'ont pas changé chez les patients atteints d'hypertension essentielle. Si l'on se fonde sur le critère de 4 mm Hg comme baisse détectable de la tension artérielle moyenne, la sensibilité du test à l'ASA s'est établie à 95,0 % et sa spécificité, à 82,5 %. Sa valeur prédictive positive a été de 74 % et sa valeur prédictive négative, de 97 %.

Conclusion : La mesure précise de la tension artérielle au cours du test à l'ASA peut fournir un moyen utile de différencier les patients atteints d'hypertension rénovasculaire de ceux qui sont atteints d'hypertension essentielle.

[ Top of document ]

Introduction

Renovascular hypertension is an important form of arterial hypertension which, if diagnosed early, can be completely cured. However, a precise method of diagnosing renovascular hypertension requires sophisticated and expensive equipment. For the initial diagnosis, renography with the use of captopril is often employed.1­4 This procedure is straightforward and the interpretation of the results easy, but it requires a relatively expensive camera. Another method, involving comparing the values for plasma renin activity (PRA) in renal veins, is invasive and inconvenient as a screening test.5,6 The captopril test proposed by Müller and associates7 has become widely recognized, but it requires evaluation of the PRA in blood from peripheral veins. Diagnosis based solely on blood pressure has high rates of false-positive and false-negative results.

It was recently reported by Imanishi and associates8,9 that it is possible to diagnose renovascular hypertension on the basis of blood pressure, PRA and prostaglandin concentration after an intravenous injection of acetylsalicylic acid (ASA, also known as Aspirin). This study referred to earlier reports on the participation of prostaglandins in the control of renin release10 and earlier experimental and clinical observations of blood pressure after administration of nonsteroidal anti-inflammatory drugs.

In patients with renovascular hypertension, ASA suppresses renin release from the stenotic kidney by inhibiting renal prostaglandin synthesis, resulting in lowered blood pressure.11­13 In contrast, in patients with essential hypertension, the inhibition of cyclo-oxygenase by nonsteroidal anti-inflammatory drugs results in a further increase in blood pressure.14­17 In one of Imanishi's studies,9 the diagnosis of renovascular hypertension was based on measurement of blood pressure, PRA and prostaglandin concentration in blood. To date, the diagnostic value of the ASA test in differentiating between patients with renovascular and essential hypertension, on the basis of measurement of the aforementioned parameters, has not been evaluated. The aim of this study was to apply the ASA test to differentiate between patients with essential and renovascular hypertension on the basis of precise measurements of blood pressure.

[ Top of document ]

Materials and methods

Forty patients (21 men and 19 women, mean age 40.7 SD 9.3 years) with essential hypertension and 21 patients (9 men and 12 women, mean age 41.4 SD 9.2 years) with renovascular hypertension were examined. The body weight of the patients with essential hypertension (mean 78.5 SD 14.1 kg) was not significantly different from that of the patients with renovascular hypertension (mean 71.5 SD 11.0 kg). The patients with essential hypertension had longer histories of illness than the patients with renovascular hypertension (3.2 SD 2.4 years v. 1.2 SD 1.0 year, respectively). Ten patients with renovascular hypertension had a diagnosis of fibromuscular dysplasia, and 11 patients had a diagnosis of atherosclerosis of the renal artery. All patients were admitted to the inpatient Department of Arterial Hypertension, Institute of Cardiology, K. Marcinkowski University School of Medical Sciences in Poznan, Poland, with suspected renal arterial stenosis. All patients had a serum creatinine level lower than 106 µmol/L and did not have peptic ulcer, diabetes mellitus, hematuria or proteinuria. A history of gastrointestinal bleeding was considered a contraindication to the ASA test. Digital subtraction angiography (DSA) was performed in all patients with renovascular and essential hypertension. The contrast medium for DSA was injected intra-arterially (in the femoral artery). Radiographs (anterior-posterior and oblique) were evaluated by 2 independent and experienced radiologists. No computer-assisted assessment of the degree of stenosis was carried out. Renal arterial stenosis of 75% or more of the diameter has been considered critical in patients with renovascular hypertension. No radiologically detectable changes in the renal arteries were found in the patients with essential hypertension. The diagnosis of renovascular hypertension was confirmed by 2 of the following tests: the captopril test proposed by Müller and associates, renography with the use of captopril or regression of hypertension after angioplasty of the renal artery. Nine patients underwent renal angioplasty and, in all of these patients, diastolic blood pressure dropped to or below 90 mm Hg, without antihypertensive treatment. Four patients had a reconstructive operation in another centre, and we did not follow them. The remaining patients decided against surgery after DSA. Angiotensin-converting-enzyme (ACE) inhibitors and diuretics were withdrawn from all patients 10 days before the study, and other antihypertensive medication was ceased 1 day before the study in all but 10 patients. These 10 patients continued to receive small doses of ß-adrenergic blocking agents and isosorbide dinitrates. After 1 hour's rest in a horizontal position, patients had their blood pressure measured 3 times at 3-minute intervals, and the patients' blood was sampled and assayed for PRA. ASA (Aspégic from Laboratoires Synthélabo, France) was then injected intravenously in a dose of 10 mg/kg body weight. Blood pressure was measured 24, 27 and 30 minutes after the injection. The patients remained in the same position, their blood was again sampled, and PRA was determined by radioimmunoassay. Blood pressure in each patient was expressed as a mean of 3 measurements before and 3 measurements after the injection of ASA. In addition, the mean blood pressure was calculated with the use of the following formula: diastolic blood pressure plus one-third of the difference between systolic and diastolic blood pressure. Not all of the evaluated parameters had a normal distribution; therefore, we used Wilcoxon's test for the analysis.

[ Top of document ]

Results

In the patients with renovascular hypertension, a statistically significant decrease in systolic blood pressure (from mean 165.0 SD 21.0 mm Hg to mean 150.1 SD 23.9 mm Hg, p < 0.001) and in diastolic blood pressure (from mean 106.2 SD 14.5 mm Hg to mean 97.5 SD 12.5 mm Hg, p < 0.001) was observed after the ASA injection. No significant change in systolic and diastolic blood pressure was recorded in the patients with essential hypertension (systolic: mean 158.0 SD 22.9 mm Hg v. mean 159.5 SD 22.1 mm Hg; diastolic: mean 100.7 SD 14.1 mm Hg v. mean 103.0 SD 15.8 mm Hg). Figs. 1 and 2 show the changes in blood pressure in all of the patients with renovascular and essential hypertension. If one accepts as the differentiating criterion a decrease in blood pressure of 10/5 mm Hg, then the sensitivity and specificity of the test are 80% and 82% for systolic and 80% and 85% for diastolic blood pressure, respectively. The mean blood pressure decreased significantly in all of the patients with renovascular hypertension. The decrease ranged from 1 to 26 mm Hg, with the mean fall being 11.1 SD 5.8 mm Hg (Fig. 3). In 25 of the patients with essential hypertension, the mean blood pressure either did not change or increased after ASA infusion; in 7 patients, the decrease in blood pressure was equal to or larger than 4 mm Hg (Fig. 3). Thus, if one accepts a decrease in mean blood pressure of 4 mm Hg or more as a differentiating criterion, 1 result was false-negative, 20 were true-positive, 7 were false-positive and 33 were true-negative. The calculated sensitivity of the ASA test was 95.0% and its specificity 82.5%; its positive predictive value was 74% and its negative predictive value 97%. PRA decreased significantly (p < 0.001), from mean 15.2 SD 12.4 ng/mL per hour to 7.18 SD 9.8 ng/mL per hour in patients with renovascular hypertension. The mean change in PRA was mean 8.0 SD 9.3 ng/mL per hour. The normal range of PRA in our laboratory is 0 to 7 ng/mL per hour. In patients with essential hypertension, the initial value of PRA was much lower (mean 4.0 SD 5.9 ng/mL per hour, p < 0.01) than in patients with renovascular hypertension, and it did not change significantly after ASA infusion (mean 3.84 SD 6.22 ng/mL per hour, for a mean change of 0.16 SD 0.93 ng/mL per hour).

[ Top of document ]

Discussion

The results of our study confirm the earlier report by Imanishi and associates9 that intravenous ASA injection causes different responses in PRA and blood pressure in patients with essential hypertension than in those with renovascular hypertension. Our study comprised a much larger number of patients than the earlier study. The decrease in blood pressure in patients with renovascular hypertension is probably caused by inhibition of prostaglandin IgE (PGE) synthesis and the release of renin from the ischemic kidney, in confirmation of Imanishi's suggestion. In the patients with renovascular hypertension, a highly significant decrease in PRA was observed, whereas in the patients with essential hypertension there was no significant decrease in PRA.

Our study was designed to make the ASA test easy to perform by general practitioners and to eliminate the risk to the patient of increased blood pressure. To keep their blood pressure controlled, the patients remained on their usual diet and received hypotensive medication (except ACE inhibitors and diuretics, which were stopped). A more rigorous low-sodium diet and long-term withdrawal of diuretics would probably have increased the sensitivity and specificity of the ASA test. On the basis of our results, we feel that the ASA test is useful as a screening test to differentiate between patients with renovascular and essential hypertension, provided that the small changes in blood pressure are precisely evaluated. A decrease in mean blood pressure as a result of the test warrants application of further diagnostic procedures for renovascular hypertension. In light of our results, an increase in blood pressure excludes the diagnosis of renovascular hypertension.

The diagnosis of renovascular hypertension on the basis of blood pressure in the captopril test proposed by Müller and associates is biased. The use of the Müller and associates test in our study showed that the diagnostic efficiency of the captopril test is high if changes in PRA activity are taken into account; when only blood pressure is taken into account, the sensitivity of the test is 37.5% and its specificity 92.1%. According to our observations, evaluation of blood pressure in the ASA test is much more reliable than in the captopril test.

No side effects were observed after intravenous ASA injection. In particular, we did not observe any dangerous decrease in blood pressure in patients with renovascular hypertension; however, we have observed such a decrease after the captopril test, and this has also been reported by Hansen, Garsdal and Fruegaard.18

[ Top of document ]

Conclusion

The precise evaluation of blood pressure after an ASA injection constitutes a very simple and useful tool for differentiating between patients with essential hypertension and those with renovascular hypertension.

References
  1. Setaro JF, Chen CC, Hoffer PB, Black HR. Captopril renography in the diagnosis of renal artery stenosis and the prediction of improvment with revascularization. Am J Hypertens 1991;4:698S-705S.
  2. Geyskes GG, Oei HY, Puylaest CBAJ, Dorhout Mees EJ. Renovascular hypertension identifed by captopril-induced changes in the renogram. Hypertension 1987;9:451-8.
  3. Sfakianakis GN, Bourgoigne JJ. Renographic diagnosis of renovascular hypertension with angiotensin converting enzyme inhibition and furosemide. Am J Hypertens 1991;4:706S-710S.
  4. Elliott WJ, Martin WB, Murphy MB. Comparison of two noninvasive screening tests for renovascular hypertension. Arch Intern Med 1993;153:755.
  5. Working Group on Renovascular Hypertension. Detection, evaluation, and treatment of renovascular hypertension. Final report. Arch Intern Med 1987;147:820-9.
  6. Laragh JH. The pathophysiology and diagnosis of renovascular hypertension. In: Glorioso N, Laragh JH, editors. Renovascular hypertension. New York: Raven Press; 1987:37-257.
  7. Müller FB, Sealey JE, Case DB, Atlas SA, Pickering TG, Pecker MS, et al. The captopril test for identifying renovascular disease in hypertensive patients. Am J Med 1986;80:633-44.
  8. Imanishi M, Ohta M, Kawamura M, Akabane S, Mtsushima Y, Kuramochi M, et al. Aspirin test for differentiation of unilateral renovascular hypertension from hyperreninemic essential hypertension. Am J Hypertens 1991;4:761-8.
  9. Imanishi M, Ohta M, Akabane M, Matsushima Y, Koiima S, Kuramochi M, et al. Aspirin injection test to predict angioplasty outcome in unilateral renovascular hypertension: preliminary report. Clin Invest Med 1991;14:566-73.
  10. Jackson EK, Branch RA, Oates JA. Participation of prostaglandins in the control of renin release. In: Oates JA, editor. Prostaglandins and the cardiovascular system. New York: Raven Press; 1982:255-76.
  11. ;deJong PE, Donker AJM, van der Wall E, Erkelens DW, van der Hem GK, Doorenbos H. Effect of indomethacin in two siblings with renin-dependent hypertension, hyperaldosteronism and hypokalemia. Nephron 1980;25:47-52.
  12. Jackson EK, Oates JA, Branch RA. Indomethacin decreases arterial blood pressure and plasma renin activity in rats with aortic ligation. Circ Res 1981;49:180-5.
  13. Imanishi M, Kawamura M, Akabane S, Matsushima Y, Kuramochi M, Ito K, et al. Aspirin lowers blood pressure in patients with renovascular hypertension. Hypertension 1989;14:461-8.
  14. Ylitalo P, Pitkajarvi T, Metsa-Ketela T, Vapaatalo H. The effect of inhibition of prostagalndin synthesis on plasma renin activity and blood pressure in essential hypertension. Prostaglandins Med 1978;1:479-88.
  15. Safar ME, Hornych AF, Levenson JA. Central haemodynamics and plasma prostaglandin E2 in borderline and sustained essential hypertensive patients before and after indomethacin. Clin Sci 1981;61:323S-325S.
  16. Ballermann BJ, Leverson DJ, Brenner BM. Renin, angiotensin, kinins, prostaglandins, and leukotriens. In: Brenner BM, Rector FC, editors. The kidney. Philadelphia: WB Saunders, 1986:281-340.
  17. Stoff JS. Prostaglandins and hypertension. Am J Med 1986;80(suppl 1A):56-61.
  18. Hansen PB, Garsdal P, Fruegaard P. The captopril test for identification of renovascular hypertension: value and immediate adverse effects. J Intern Med 1990;228:159-63.

| CIM: June 1997 / MCE : juin 1997 |
CMA Webspinners / >