Ambulatory blood pressure and heart rate monitoring were used for comparing the antihypertensive effect of a 1-week treatment with enalapril and lisinopril 10 mg once daily (double-blind crossover placebo-controlled d y ). Twelve outpatients with mild to moderate hypertension were treated. Both drugs had a significant and identical hypotensive effect. Neither drug affected the diurnal rhythm of blood pressure or heart rate. Therefore the two drugs are equipotent antihypertensive agents. Both drugs inhibited ACE activity to a highly significant extent, but in this regard lisinopril was more effective than enalapril. However, lisinopril's greater ACE inhibition was not accompanied by a greater hypotensive effect. The clinical value of this difference is not yet established

Cocco, G.

Hari, Jürg J.

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m.card io l .  14,881-884 (1991) Different Hernodynamic (24-H Ambulatory Blood Pressure Monitoring) a d  Renin-Inhibiting Effect of a 1-Week Treatment with Enalapril and Lisinopril G.COKO, M.D. (F.E.s.c.), J. HARI, PH.D. minfelden, Switzerland Summary: Ambulatory blood pressure and heart rate monitoring were used for comparing the antihypertensive effect of a 1 -week treatment with enalapril and lisinopril 10 mg once daily (double-blind crossover placebo-controlled d y ) .  Welve outpatients with mild to moderate hyper- tension were treated. Both drugs had a significant and identical hypotensive effect. Neither drug affected the diur- nal rhythm of blood pressure or heart rate. Therefore the two drugs are equipotent antihypertensive agents. Both drugs inhibited ACE activity to a highly significant extent, but in this regard lisinopril was more effective than en- alapril. However, lisinopril's greater ACE inhibition was not accompanied by a greater hypotensive effect. The clin- ical value of this difference is not yet established. Key words: ACE inhibitors, enalapril, lisinopril, 24-h ambulatory blood pressure monitoring Introduction Enalapril, the prodrug of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat,' is used in the treat- ment of hypertension. Lisinopril is the lysine analog of enalaprilat* and is also an ACE inhibit~r.~ Unlike enalapril, ~~~ ~ ~ ~ Address for reprints: G .  Cocco. M.D. PO. Box 214 CH-4103 Rheinfelden Switzerland Received: February 14, 1991 Accepted with revision: June 5, 1 9 9 1  lisinopril is directly active? There is also evidence to sug- gest that lisinopril produces more prolonged inhibition of plasma ACE5 and has a longer-lasting antihypertensive effect than enalapril.6 The antihypertensive effect of single doses of enalapril and lisinopril is known,7 but it is con- ceivable that the response might be different after several days of active therapy. To our knowledge, direct compara- tive data from treatment more than one day were unavail- able. On the other hand, it was conceivable that, enalapril and lisinopril being long-acting ACE inhibitors, there could be a greater response as plasma and tissue concen- trations rise over time. Our study was planned to clarify this question. Material and Method Twelve outpatients (5 males and 7 females) aged be- tween 44 and 66 years were selected and treated. All had mild to moderate essential hypertension (duration 2 to 4 years). Their antihypertensive therapy was stopped be- cause of insufficient effect or side effects: the patients were without treatment for 2 to 3 weeks. No other drugs were used and no contraindications to ACE inhibitors were pre- sent. The study was approved by the ethical committee and all patients gave informed consent. No patient was with- drawn before receiving the test medications because of normalization of blood pressure (BP). The test medications were placebo, enalapril, and lisinopril, 10 mg/day given as monotherapy once a day between 7:OO and 8:OO a.m. Treatment was given according to a randomized, double- blind, crossover design. Each test medication was given for a double-blind period of 7 days, followed by a single- blind placebo period of 4 days before the next crossover. Fixed dose regimens are necessary for research purposes; on the other hand, they are not likely to be adequate for the long-term treatment of hypertension: therefore, the duration of the treatment with the individual test medica- tions was limited to 7 days. Hypmtension was defined by a mean diastolic BP of between 95 and 115 mmHg, this 882 Clin. Cardiol. Vol. 14, November 1991 being the mean value of a 24-h ambulatory blood pressure monitoring (ABPM). Routine prestudy clinical laboratory tests were either normal or the abnormalities were clini- cally irrelevant. Blood samples and laboratory plus renin estimations were taken 24 h after the last dose of the 1- week treatment periods and 40 h before the ABPM. Base- line measurements of BP were obtained from the same ann throughout using simultaneously a mercury sphygmo- manometer and a Disetronic CH-Druck@ equipment.8 Afterward, BP and heart rate (HR) were automatically measured with the CH-Druck equipment: two times per hour between 8:OO and 22:OO h (daily period) and once per hour between 22:OO and 8:OO h (night period). Again at the end of the ABPM, BF and HR were checked simultane- ously. The mean difference between manual and CH- Druck BP was less than 3 mmHg (range: -2 to +2 mmHg for systolic B P  0 + 3 mmHg for diastolic BP). ABPM was obtained 24 to 26 h after the last dose and during the last 24-h period of the 1 -week treatment periods. Adverse events were recorded in response to the question: “Have you had any symptoms or problems since your last visit?’ All data were analyzed by means of a paired f-test and by calculation of the area under the curve (AUC) of the ABPM. Both methods gave identical statistical values. The presentation of the clinical data (figures) was better with the paired t-test analysis and therefore this method was used for presentation of the results. Results The portable automatic CH-Druck equipment was well accepted by the patients and functioned optimally. All patients ended the study with complete ABPM profiles. Systolic Blood Pressure Pretreatment values were similar: placebo 170.7f6.8; enalapril 176.5f9.5; lisinopril 176k7.9 mmHg (mean_+ SD). Placebo had no effect. As shown in Figure 1, both drugs reduced systolic BP 5.5 h postdosing (hollow area, ~ 0 . 0 5 ) .  The hypotensive effect was slightly faster with enalapril (2.5 h: 165.859.3) than with lisioopril (5.0 h: 165.1 f 14.1). Nonetheless the global hypotensive effect was similar for enalapril and lisinopril. The hypotensive effect was also similar at the 24th h (enalapril: 162.0f6.9, lisin- opril: 160. I k6.2). The diurnal rhythm was not changed. Diastolic Blood Pressure The pretreatment values were similar: placebo 102.3k 3.2; enalapril 104.8f3.8; lisinopril 108.8k5.4 mmHg. Placebo had no effect. As shown in Figure 2, the hypoten- sive effect was similar for both drugs and was significant 6 h postdosing: enalapril 99.1 k8.5, lisinopril 97.3f4.8 mmHg (hollow area of Fig. 2, ~ ~ 0 . 0 5 % ) .  The circadian rhythm was not affected. Time of day FIG. 1 Systolic blood pressure mean of 12 patients. + SBP plac bo; -E- SBP lisinopril; +- SBP enalapril. Light-shaded area: I difference between treatment; dark-shaded area: No difference b tween lisinopd and placebo, but enalapril different from placebo I lisinopril; white area: no difference between treatments but both re imens differ from placebo. r-test (@%) at each time point. Heart Rate Neither placebo nor the test dwgs affected HR to ar significant extent (Fig. 3). Renin As shown in Figure 4, basal values were similar for i treatment periods: placebo 3.0f0.3; enalapril 2.9f0. lisinopril 2.8f0.2 ng/ml. Placebo had no effect. As ev dence for the ACE inhibition, serum renin levels increw significantly ( ~ 4 . 0 1 )  after both enalapril and lisinopn However, the effect of lisinopril was significantly great1 than that of endapril: 4.7 10.3 after enalapril; 6.6f0.4 aft1 lisinopril (pcO.01). Side Effects Few side effects were observed. One patient complaine of mild nausea at Day 2 with both drugs. Another patier complained of mild headache with enalapril on Day : Drug-related effects on the laboratory results were nc detectable. Discussion Oftice blood pressures have been the primary basis fc the physician’s decisions in the diagnosis and treatment c hypertension. In some patients, however, the office pre! G. Cocco and J. Hari: Ambulatory BP effects of enalapril and lisinopril 883 Time of day FK;. 2 Diastolic blood pressure mean of 12 patients. - DBP place- bo; + DBP lisinopril; *DBP enalapril. Shaded area: no differ- ence between treatments as well as no difference compared with placebo; white area: significant difference between placebo and both yeatments; no difference between lisinopril and enalapril. r-test (p<5%) at each time point. sures may be misleading. ABPM offers complementary relevance to the value of office blood pressures and may improve treatment9. lo by providing information about the risk of developing clinical complications of hypertension.” 90 85 k Time of day FIG. 3 Heart rate mean of 12 patients. - HR placebo; + HR lisinopril; * HR enalapril. No difference between treatments (t-test NS). 4 I ” Placebo Lisinopril Enalapril FIG. 4 Serum renin levels mean of 12 patients: lbefore  dose.; 0 2 4  h after dose. Basal values: no difference; enalapril vs. baseline: pCo.01; lisinopril vs. baseline: p4.01; lisinopril vs. enalapril: pd.01. Our study confirms the optimal function of the CH-Druck equipment and ABPM was important in assessing the anti- hypertensive effects of the tested drugs. Our data confirm the results of the single dose study by Dews er ~ z f . : ~  while both drugs were equally effective and potent for the treat- ment of hypertension, the greater renin-inhibiting effect of lisinopril was not reflected by a greater antihypertensive effect. The antihypertensive effect of enalapril and lisino- pril was similar (duration and magnitude) and persisted for 24 h. The diurnal profile of BP and HR were not affected by treatment. On the other hand, our data do not confirm the results of the single dose study by Millar er aL,6 where the antihypertensive effect of lisinopril was longer than that of enalapril. Obviously, the response of the drugs is different on repeated treatment. We used a fixed dose, and therefore our data are not sufficient for judging the effect of different doses. In spite of a similar antihypertensive effect, the renin in- hibiting effect of lisinopril was superior. Clearly, the phys- iologic effects of enalapril and lisinopril (and all known ACE inhibitors) are not clearly related to plasma renin alone. Indeed it has been known for some time that re- sponses of patients with hypertension to ACE inhibitors cannot be predicted by renin profiling alone.’)-l6 Brady- kinin, prostacyclin, and other humoral factors may play an important role in the pharmacologic effect of renin Renin inhibitors seem to be effective in pre- venting progression of ventricular dysfunction and may delay or prevent the appearance of heart failure:l7, I *  the full effect of these drugs, however, develops slowly and it may take more than 12 weeks to become maximal. Ob- viously our data from a 1-week treatment cannot be extrap- olated for the long-term treatment of patients with heart failure and, as Sir Arthur Conan Doyle said, “It is a capital mistake to theorize before one has data.” However, since the greater renin-inhibiting effect of lisinopril is not ac- companied by a greater antihypertensive effect, it would be interesting to compare their long-term effect in the mat- ment of heart failure. + 884 Clin. Cardiol. Vol. 14, November 1991 References 1 2. 3. 4. 5. 6. 7. 8. Cooper WD, Sheldon D, Kimber GR, lsitt VL, Currie WJC: Post-marketing surveillance of elanapril: Experience in 11700 hypertensive patients in general practice. J R. CON Gen Pract 37,346 (1987) Wu MT, Douglas AW, Ondeyka DL: Synthesis of N-((S)-l-car- boxy-3-phenylpropyl]-L-lysyl proline (lisinopril). J Pharm Sci 74.352 (1985) Bull HG, Thornberry NA, Cordes EH: Inhibition of rabbit lung angiotensin converting enzyme by N-[(S)- 1 -carboxy-3-phenyl- propyl]-~-alanyl-~-proline and N-[(S)- 1 -carboxy-3-phenyl- propyll-L-lysyl-proline. J Biol Chem 260,2952 (1985) Ulm EH. Hichens M, Gomez HJ: Enalapril maleate and a lysine analogue (MK-521) disposition in man. Br JPharmacol14.357 (1982) Bodsman GP, Zabludowski JR, Zoccali C: Enalapril (MK-421) and its lysine analogue (MK-521): A comparison of acute and chronic effect on blood pressure, renin-angiotensin system and sodium excretion in normal man. Br J Clin Pharmacol17,233 (1984) Millar JA, Derkx FH. McLean K, Reid JL: Pharmacodynamics of converting enzyme inhibition: The cardiovascular, endocrine and autonomic effects of MK42l(endapril) and MK-521. Br J Clin Phurmacol14,347 (1982) Dews I, Wiseman WT, Al-Khawaja I, Stephens J, Vanden-Burg M: A comparison of single doses of lisinopril and endapril in hypertension. J Human Hypertens 3.35 (1989) CH-DRUCK. Operating Manual. Disetronic Medical Systems. CH-3401 Burgdorf 9. Perloff D, Sokolow M: The representative blood pr Usefulness of office. basal, home, and ambulatory re Cardiovasc Med 3,655 (1978) 10. Locw F, Gauthey L, Donath R, Petitot C. Herrmann F, Ja Combes B: Monitoring tensionnel chez des hypertend trait& par nicardipine ou nifedipine h 1iMration pro Schweiz Med Wschr 120, 1887 (I 990) 11. ACEIine 8, 1-6 (1991) 12. Imae Y, Abe K. Seino M: Atxenuation of pressor resp norepinephrine and pitnssin and potentiation of pres sponses to angiotensin I1 by captopril in human subjec pertension 4,444 (1982) 13. Zusman RM: Renin and non-renin-mediated antihypen action of converting enzyme inhibitors. Kidney Int 2 (1984) 14. Moore TJ, Crantz FR, Hollenberg NK: Contribution of I glandins to the antihypertensive effect and angioconveni zyme inhibition by captopril. Hyperrension 2,236 (1980 15. Cohen ML, Kurz KD: Angiotensin converting enzyme tion in tissue from spontaneously hypertensive rats aftel ment with captopril or MK42 1. J Phamcol  E*p Ther 2 (1982) 16. Swales JD: The renin-angiotensin system in hypertensi The Renin-Angiotensin Sysrem (Ed. Robertson JIS). Me Co., Inc.. Gower Medical Publ. Ltd., 4.4.1 (1985) 17. NichoUs MG. The renin-angiotensin system in cardiac fail1 The Renin-Angiotensin System. (Ed. Robertson JIS). Me Co., Inc.. Gower Medical Publ. Ltd.. 5,5.1 (1985) 18. Cleland JGF: ACE inhibitors in mild heart failure: First4 second-line therapy? Eur Heart J 11 (suppl D), 53 (1990) 

Different haemodynamic (24-h ambulatory blood-pressure monitoring) and rennin-inhibiting effect of a 1 week treatment with enalapril and lisinopril

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Different haemodynamic (24-h ambulatory blood-pressure monitoring) and rennin-inhibiting effect of a 1 week treatment with enalapril and lisinopril

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