An initial phase I study in healthy volunteers showed the percentage of converting enzyme inhibition at peak activity and 24 hours after the administration of increasing doses of COVERSYL (0.5, 1, 2, 4, 6 and 8 mg). Based on these results, the percentage inhibition was equal to at least 50% of the predictive antihypertensive activity, thus defining the  minimal  active dose  at  2 mg  and  the 24-hour effective dose at
4 mg(1).

The dose-action  antihypertensive  curve   was   also   established  by a demonstration of   the  significant  relationship between plasma  concentrations,   levels   of   converting   enzyme inhibition,  and   a   decrease    in    blood    pressure.  The   potency of   action   of   COVERSYL 4 mg is greater than that of cilazapril and enalapril (2). Regardless of the dose administered (2-4-8-16 mg), COVERSYL exerts an antihypertensive effect on both systolic and diastolic arterial pressure over the 24-hour period (3).

Compared with placebo, continuous ambulatory blood pressure measurements have demonstrated a significant reduction in blood pressure over a 24-hour period and during the day; circadian alterations in blood pressure were not affected. In particular, the percentage of isolated values of SBP greater than 160 mm Hg fell from 20% to 6% and for DBP above 90 mm Hg from 61% to 37%, both results being statistically significant. No early morning hypertensive peak was seen under the trial conditions and the trough: peak ratio was 53% (4).

A comparative, double-blind crossover study of the duration of action of COVERSYL versus enalapril 10 mg, using continuous recording of arterial blood pressure, confirmed the residual effect/peak effect ratio. In this study, it was observed that the gross ratio was 78% for COVERSYL 4 mg and 55% for enalapril. When taken over 24 hours, compared with placebo, the figures were 100% for COVERSYL 4 mg and 71% for enalapril (5). These results have been confirmed by a second study (7).

In another comparative, double-blind study of COVERSYL, enalapril and captopril, a placebo-corrected residual effect/peak effect of 87% was observed for COVERSYL, 55% for enalapril, and 38% for captopril (6).

These results confirmed the 24-hour duration of action of COVERSYL, without any interference in circadian variations in blood pressure. The antihypertensive activity of COVERSYL protects patients from nocturnal hypotension, often responsible for silent myocardial ischemia, and from early-morning hypertensive crisis, which are the cause of many cerebrovascular accidents.

Moreover, these studies enabled COVERSYL to be registered in the USA: the FDA, (which requires a trough:peak ratio greater than 50% to validate single-dose registration), concluded that the residual effect:peak effect ratio for COVERSYL was between 75% and 100%.

References:

1. Luccioni R, Frances Y, Gass R, Gilgenkrantz JM. Evaluation de la relation dose-effet du perindopril dans le traitement de l'hypertension artérielle. Arch Mal Coeur Vaiss. 1989;82(suppl 1):43-50.
   
   
2. Louis WJ, Conway BS, Krum H, et al. Comparison of the pharmacokinetics and pharmacodynamics of perindopril, cilazapril and enalapril. Clin Exp Pharmacol Physiol. 1992;19 (suppl 19):55-60.
   
   
3. Myers MG. A dose-response study of perindopril in hypertension: effects on blood pressure 6 and 24 hours after dosing. Can J Cardiol. 1996; 12:1191-1196.
   
   
4. Santoni JP, Asmar RG, Bizot-Espiard JG, Safar M. Enregistrement ambulatoire de la pression artérielle lors d'un traitement par le perindopril. Effet sur la pression systolique et implications hémodynamiques. Arch Mal Coeur Vaiss. 1989;82(special 1):51-56.
   
   
5. Morgan T, Anderson A. Clinical efficacy of perindopril in hypertension. Clin Exp Pharmacol Physiol. 1992;19 (suppl 19):61-65.
   
   
6. Morgan T, Anderson A. Duration of antihypertensive effect of perindopril, enalapril and captopril. Hypertension 1993;21:568.
   
   
7. Anderson A, Morgan O, Morgan T. Effectiveness of blood pressure control with once daily administration of enalapril and perindopril. Am J Hypertens. 1994;7:371-373.

The antihypertensive action of COVERSYL is rapid: 65% of the maximum antihypertensive effect on diastolic blood pressure is seen after 11 days of treatment and 78% after 1 month of treatment (1). It acts both on systolic and diastolic arterial blood pressure, without interfering with the normal 24-hour variations (2). Its action covers the entire 24-hour period, as shown by the trough:peak ratio of between 75% and 100% (3-4).

The resulting clinical efficacy is characterized by a return to normal of blood pressure readings in 66% of the hypertensive patients treated with COVERSYL (single-drug therapy) at a dose of 4 or 8 mg. Comparative clinical studies with other antihypertensives (ACE - inhibitors, ß-blockers, calcium inhibitors, diuretics) show that the efficacy of COVERSYL is greater than or equal to that of the others (5-12, 14, 16, 18), particularly enalapril (19). The synergistic action of COVERSYL with diuretics allows a notable gain in efficacy of 15% when hypertension is resistant to single-drug therapy (5).

The antihypertensive efficacy of COVERSYL persists in the long term, without the development of pharmacological tolerance. In 215 patients monitored for 3 years, the fall in SBP was 31.0 ± 1.3 mm Hg and that in DBP 20.7 ± 0.7 mm Hg in the supine position. In the standing position, the fall in SBP was 28.9 ± 1.3 mm Hg and in DBP 19.6 ± 0.8 mm Hg; 56.3% of patients were normalized by single-drug therapy, 25.1% by two-drug therapy, and 10.7% by three-drug therapy (13).

The value of COVERSYL as a first-line treatment of hypertension is confirmed by pragmatic studies on large cohorts (47 351 patients). Under  conditions  of  current  medical  practice, 73%   of   patients normalized   by   COVERSYL   remained   under  single-drug  therapy
1 year into treatment (17).

1. Leary WP, Reyes AJ, Van der Byl K, Santoni JP. Time course of the hypotensive effect of the converting enzyme inhibitor perindopril. Curr Ther Res. 1989; 46:308-316.
   
   
2. Asmar RG, Pannier BM, Santoni JP, Safar ME. Angiotensin converting enzyme inhibition decreases systolic blood pressure more than diastolic pressure as shown by ambulatory blood pressure monitoring. J Hypertens. 1988;6(suppl 3):S79-S81.
   
   
3. Morgan T, Anderson A. Clinical efficacy of perindopril in hypertension. Clin Exp Pharmacol Physiol. 1992;19(suppl 19):61-65.
   
   
4. Myers MG. A dose-response study of perindopril in hypertension: effects on blood pressure 6 and 24 hours after dosing. Can J Cardiol. 1996;12:1191-1196.
   
   
5. Thurston H, Desche P. Assessment of antihypertensive efficacy of perindopril: results of double-blind multicenter studies versus reference drugs. J Cardiovasc Pharmacol. 1991;18 (suppl 7):S45-S49.
   
   
6. Lees KR, Reid JL, Scott MGB, Hosie J, Herpin D, Santoni JP. Captopril versus perindopril: a double blind study in essential hypertension. J Hum Hypertens. 1989;3:17-22.
   
   
7. Rorive G, Creytens G, Ruhwiedel M, Van de Voorde K. Etude comparative de l'efficacité et de la tolérance du perindopril, un nouvel inhibiteur de l'enzyme de conversion, et de l'aténolol, un bêta-bloquant. Rev Med Liège. 1990;17:62-68.
   
   
8. Morgan TO. Australian multicenter study of perindopril compared with atenolol in the management of hypertension. JAMA. 1990;6:18-22.
   
   
9. Villamil A, Weber C, Desche P, Bertolasi C. Antihypertensive effect and acceptability of perindopril, a 3-month double-blind trial versus atenolol in 40 patients with mild to moderate hypertension. Drug Invest. 1991;3:308-324.
   
   
10. Andrejak M, Santoni JP, Carre A, et al. A double blind comparison of perindopril and hydrochlorothiazide-amiloride in mild to moderate essential hypertension. Fundam Clin Pharmacol. 1991;5:185-192.
    
    
11. Morgan TO, Anderson A. Clinical efficacy of perindopril in hypertension. Clin Exp Pharmacol Physiol. 1992;19 (suppl 19):61-65.
    
    
12. Agabiti-Rosei E, Ambrosioni E, Finardi G, et al. Perindopril versus captopril: efficacy and acceptability in an Italian multicenter trial. Am J Med. 1992;92(suppl 4B):79S-83S.
    
    
13. Degaute JP, Leeman M, Desche P. Long term acceptability of perindopril: European Multicenter Trial on 856 patients. Am J Med. 1992;92 (suppl 4B):84S-90S.
    
    
14. Canadian Study Group on perindopril. Once-daily perindopril versus slow-release diltiazem in the treatment of mild to moderate essential hypertension. Can J Cardiol. 1994;10 (suppl D): 8D-12D.
    
    
15. Overlack A, Adamczack M, Bachmann W, et al. ACE inhibition with perindopril in essential hypertensive patients with concomitant diseases. The Perindopril Therapeutic Safety Collaborative Research Group. Am J Med. 1994;97:126-134.
    
    
16. Black HR, Saunders E. (COVERSYL 4 mg PE Study Group). Efficacy and safety of perindopril and hydrochlorothiazide in stage I-II hypertension. J Vasc Med Biol. 1994;5:191-198.
    
    
17. Poggi L, Renucci JF, Denolle T. Treatment of essential hypertension in general practice: an open-label study of 47351 French hypertensive patients treated for one year with perindopril. Can J Cardiol. 1994;10 (suppl D):21D-24D.
    
    
18. Alcocer L, Campos C, Bahena JH, et al. Clinical acceptability of ACE inhibitor therapy in mild to moderate hypertension: comparison between perindopril and enalapril. Cardiovasc Drugs Ther. 1995;9:431-436.
    
    
19. Yoshinaga K, Saruta T, Abe K, et al. Clinical evaluation of monotherapy with perindopril, an ACE inhibitor, in the treatment of essential hypertension: double-blind parallel comparison with enalapril. Rinsko Iyaku (J Clin Ther Med) 1997;13:4259-4297.
    

The direct and indirect hemodynamic studies with COVERSYL have shown evidence of an improvement in hemodynamic performance: decrease in pre- and afterload, fall in pulmonary pressures, reduced water/sodium retention, and an increase in arterial compliance and cardiac output. These changes are seen from a dose of 2 mg onwards  and  are  statistically  significant for 24 hours at the dose of
4 mg, indicating prescription of COVERSYL 4 mg as a single dose per day in treatment of cardiac failure (1-2).

The therapeutic efficacy of COVERSYL was demonstrated in 513 patients suffering from mild to moderate heart failure (class 2 = 69.8% and class 3 = 28.8% according to the classification of the NYHA) recruited into 3 therapeutic trials, two of which were of double-blind versus placebo design. The treatment, begun at a dose of 2 mg, did not exceed 4 mg per day and the duration of treatment was 6 months for 421 patients, 1 year for 352 patients and 30 months for 45 patients. Clinical improvement was seen from the first month of treatment onwards (8) and was characterized by statistically significant increases in the duration of stress tests, and improvement in NYHA classification at 6, 12, and 30 months 13. The efficacy of COVERSYL in cardiac failure is therefore of early onset and long-lasting.

Several specific studies observed the absence of first dose effect on arterial blood pressure when treatment started. By comparison with other ACE inhibitors (captopril 6.25 mg, lisinopril 2.5 mg, enalapril 2.5 mg) COVERSYL 2 mg reduces the risk of hypotension when treatment is started (3-12-16). Putative explanations of this original property are as follows: a difference in tissue penetration and interaction due to the drug's specificity; competition between the drug and prodrug resulting in progressive inhibition of converting enzyme.

A combination of these two mechanisms cannot be discounted.
Blood pressure safety of COVERSYL is confirmed as treatment is continued. A placebo-controlled trial showed that the efficacy of COVERSYL on parameters relating to the renin-angiotensin system was not accompanied by a significant decrease in blood pressure (14). In a study of patients who had recently undergone coronary bypass surgery, with moderate renal insufficiency and altered left ventricular function, the administration of COVERSYL altered hemodynamic function less than enalapril at a dose of 5 mg (17).

Clinical and laboratory acceptability of COVERSYL has been confirmed in the long term (9). The occurrence of adverse events noted in 30.3% of patients resulted in withdrawal from the trial in only 11.9% of cases (cough 6.3%, dizziness 4.1%, and tiredness 4.1% were the most frequent symptoms). No significant modification in renal function was observed: plasma creatinine and electrolytes remained stable, even in patients with simultaneous cardiac and renal insufficiency (4). Stabilisation of blood pressure, both initially and in the long term, contributes to the renal safety of COVERSYL in subjects with cardiac failure. Lastly, it has been shown that COVERSYL does not interact with digoxin (10).

In  conclusion,  the  therapeutic  efficacy  of  COVERSYL  on  the symptoms  and  signs  of  heart  failure,  and  its  good  safety  in terms of blood pressure and renal function, allow its prescription at optimal doses: 2 mg at  the  start  of  treatment, and an early switch to 4 mg  as  maintenance  therapy  in  a  single  daily  dose.  In practice, COVERSYL 4 mg is the only ACE inhibitor to be prescribed at the dosage recommended in heart failure, even in the elderly (18-19).

References:

1. Benetos A, Levy B, Asmar R, Safar M. Effets hémodynamiques du perindopril. Ann Cardiol Angeiol. 1989;38: 483-486.
   
   
2. Thuillez C, Richard C, Louestali H, et al. Systemic and regional hemodynamic effects of perindopril in congestive heart failure. J Cardiovasc Pharmacol. 1990;15:527-535.
   
   
3. Mac Fadyen RJ, Lees KR, Reid JL. Differences in first dose response to angiotensin converting enzyme inhibition in congestive heart failure: a placebo controlled study. Br Heart J. 1991;66:206-211.
   
   
4. Garnham SP, Blackwood RA, O'Donnell JG. et al. Perindopril in the treatment of congestive heart failure patients with impaired renal function. Cardiovasc Drugs Ther. 1991;5(suppl 3):331.
   
   
5. Richard C, Thuillez C, Deprez J, et al. Regional hemodynamic effects of perindopril in congestive heart failure. Am Heart J. 1993;126: 782-788.
   
   
6. Medvedev O, Gorodetskaya EA. Systemic and regional hemodynamic effets of perindopril in experimental heart failure. Am Heart J. 1993;126:764-769.
   
   
7. Flammang D, Waynberger M, Chassing A. Acute and long-term efficacy of perindopril in severe chronic congestive heart failure. Am J Cardiol. 1993; 71:48E-56E.
   
   
8. Lechat Ph, Garnham SP, Desche P, Bounhoure JP. Efficacy and acceptability of perindopril in mild to moderate chronic congestive heart failure. Am Heart J. 1993;126:798-806.
   
   
9. Desche P, Antony I, Lerebours G, Violet I, Robert S, Weber C. Acceptability of perindopril in mild-to-moderate chronic congestive heart failure. Results of a long-term open study in 320 patients. Am J Cardiol. 1993;71: 61E-68E.
   
   
10. Vandenburg MJ, Stephens JD, Resplandy G, Dews IM, Robinson J, Desche P. Digoxin pharmacokinetics and perindopril in heart failure patients. J Clin Pharmacol. 1993;33:146-149.
    
    
11. Squire IB, Mac Fadyen RJ, Reid JL, Devlin A, Lees KL. Differing early blood pressure and renin-angiotensin system responses to the first dose of angiotensin converting enzyme inhibitors in congestive heart failure. J Clin Pharmacol. 1996;27:657-666.
    
    
12. Squire IB, Violet I, Chiche M, Lerebours G. Acceptability of long-term perindopril in the treatment of mild to moderate chronic congestive heart failure. Clin Cardiol. 1996;19:9-15.
    
    
13. MacFadyen RJ, Barr CS, Sturrock NDC, Fenwick M, Struthers AD. Further evidence that chronic perindopril treatment maintains neurohormonal suppression but does not lower blood pressure in chronic cardiac failure. Br J Clin Pharmacol. 1997;44:69-76.
    
    
14. Haiat R, Piot O, Gallois H, Hanania G. Blood pressure response to the first 36 hours of heart failure therapy with perindopril versus captopril. J Cardiovasc Pharmacol. 1999;33:953-959.
    
    
15. Navookarasu NT, Rahman A, Abdullah I. First-dose response to angiotensin-converting enzyme inhibition in congestive cardiac failure: a Malaysian experience. Int J Clin Pract. 1999;53:25-30.
    
    
16. De Vries O, Jansen PAF, De Rooij S, Raymakers JA, Meyburg HWJ. Blood pressure reduction after the first dose of perindopril compared with captopril in elderly patients with heart failure. Age Ageing. 1999;28:94.
    
    
17. Manche A, Galea J, Busuttil W. Tolerance to ACE-inhibitors after cardiac surgery. Eur J Cardiothorac Surg. 1999;15:55-60.
    
    
18. Mair FS, Crowley TS, Bundred PE. Prevalence, aetiology and management of heart failure in general practice. Br J Gen Pract. 1996;46:77-79.
    
    
19. Farnsworth A. Angiotensin converting enzyme inhibitors in heart failure:target dose prescription in elderly patients. Age Ageing. 1998;27:653-654.

The efficacy and acceptability of COVERSYL have been fully demonstrated in hypertension affecting the elderly.

A multicenter, placebo-controlled trial involving 34 patients with a mean age of 84 years showed that the antihypertensive effect of COVERSYL was twice that of a placebo (1). In 91 placebo-resistant hypertensive patients with a mean age of 79 years, the efficacy of COVERSYL at the dose of 2 to 8 mg per day was expressed by the normalization of blood pressure figures in 88.8% of patients (2).

Results have been confirmed in a large number of patients aged over 70 (2927 cases), treated with COVERSYL for 6 months. The antihypertensive efficacy of COVERSYL seen in 90% of patients was accompanied by good safety/acceptability on the basis of both clinical and laboratory parameters: 6.1% of dropouts due to adverse events, no interference with carbohydrate and lipid metabolism, absence of impairment of renal function (3-5).

In a cohort study which recruited more than 2000 patients over 80 years old who were treated for 1 year, the adverse event frequency was 7% and only 4.1% led to dropouts(6).

The antihypertensive efficacy of COVERSYL in the elderly involves a 24-hour duration of action, without nocturnal hypotension and without early morning hypertensive peaks, as has been shown in studies with continuous monitoring of blood pressure. In addition, the effect of the properties of COVERSYL on the structure of the arterial wall (restoring the vascular lumen/wall thickness ratio, thus improving arterial compliance) provide the vascular protection needed in a population particularly exposed to myocardial infarction and cerebrovascular accidents.

Analysis of pharmacokinetic parameters in the elderly, in comparison with the younger adult, leads to recommendation of an initial daily dosage of 2 mg in elderly individuals aged over 70 years (8). Renal function, often impaired in such patients, should be regularly monitored, as is standard practice with this group of drugs.

The limited first-dose effect of COVERSYL 4 mg has been demonstrated in patients over 70 years of age (9).

A placebo-controlled clinical study is presently under way to investigate the effects of COVERSYL in 1000 patients over 70 years of age treated for 1 year for chronic heart failure demonstrated by echocardiography. The main criteria of efficacy are death or hospitalization due to worsening of heart failure. After 1 year of treatment, it is also planned to analyze quality of life, changes in cognitive function, and left ventricular function (10).

References:

1. Forette F, Claran JMC, Delesalle MC, Hervy MP, Bouchacourt P, Henry-Amar M, Santoni JP. Intérêt des inhibiteurs de l'enzyme de conversion chez le sujet âgé; l'exemple du perindopril. Arch Mal Cœur Vaiss. 1989;82:79-85.
   
   
2. Fressinaud P. Utilisation de COVERSYL au cours du traitement à long terme de l'hypertension du sujet âgé. Essai multicentrique en simple insu chez 91 patients. JAMA (French Ed Suppl) 1989; 46-47.
   
   
3. Plouin PF, Battaglia C, Alhenc-Gelas F, Corvol P. Are angiotensin converting enzyme inhibition and aldosterone antagonism equivalent in hypertensive patients over fifty? Am J Hypertens. 1991;4:356-362.
   
   
4. Fressinaud P. Berrut G, Gallois H. Activité antihypertensive, acceptabilité clinique et biologique du perindopril: principaux résultats chez 23 460 hypertendus légers à modérés traités pendant 6 mois en médecine générale. Ann Cardiol Angeiol. 1993;42:51-59.
   
   
5. Suraniti S, Berrut G, Marre M, Fressinaud P. Antihypertensive efficacy and acceptability of perindopril in elderly hypertensivepatients. Am J Cardiol. 1993; 71:28E-31E.
   
   
6. Speirs C, Wagniart F, Poggi L. Perindopril postmarketing surveillance: a 12 month study in 47 351 hypertensive patients. Br J Clin Pharmacol. 1998;46:63-70.
   
   
7. Woo J, Woo KS, Or KH, Cockram CS, Nicholls MG. A double-blind randomised comparison of perindopril and Ketanserin in the treatment of hypertension in elderly diabetic patients. Drugs Aging. 1993; 3:525-531.
   
   
8. Lees KR, Green ST, Reid JL. Influence of age on the pharmacokinetics and pharmacodynamics of perindopril. Clin Pharmacol Ther. 1988;44:418-25.
   
   
9. De Vries O, Jansen PAF, De Rooij S, Raymakers JA, Meyburg HWJ. Blood pressure reduction after the first dose of perindopril compared with captopril in elderly patients with heart failure. Age Ageing. 1999;28(suppl 2):94.
   
   
10. Cleland JGF, Tendera M, Adamus J, et al. On behalf of the PEP investigators. Perindopril for elderly people with chronic heart failure: the PEP-CHF Study. Eur J Heart Fail. 1999;1:211-217.
    

The efficacy and acceptability of COVERSYL in hypertensive diabetic patients have been demonstrated by the absence of changes in carbohydrate metabolism and by improvement in renal function.

In type 1 (insulin-dependent) diabetics, the antihypertensive efficacy of COVERSYL is characterized by a statistically significant reduction of 11% in systolic blood pressure (SBP) and 15% in diastolic blood pressure (DBP) from the first month of treatment onwards, reaching 14% for SBP and 18% for DBP respectively after 1 year of treatment. By the third month of treatment, 79.5% of the patients were normalized, with no cases of orthostatic hypotension and no reflex tachycardia in the standing position. The lack of disturbance of carbohydrate metabolism was shown by the absence of variations in postprandial glycemia, glucosuria, HbA1c and fructosamine. The absence of drug interactions was shown by maintenance of the same doses of insulin (1).

In type 2 (non-insulin-dependent) diabetics, COVERSYL restored normal blood pressure in 67% of the patients after 1 month of treatment and in 83% after 1 year (2). No modifications in insulin secretion or in tissue sensitivity to insulin were observed. Likewise, COVERSYL did not disturb and even improved, the lipid profile of type 2 diabetics (3).

In all diabetics, both type 1 and type 2, COVERSYL maintained renal function (creatininemia and kaliemia remain stable) and improved the signs of incipient nephropathy (reduction in microalbuminuria) (4). Improvement in microalbuminuria was confirmed in the long term (5). The mechanism of this effect has not been elucidated: the authors suggest reduction in intraglomerular pressure related to vasodilation of the artery due to converting enzyme inhibition.

Two histological studies conducted in type 1 and 2 diabetic patients with microalbuminuria showed that chronic treatment with COVERSYL (3 years and 2 years) delayed the progression of certain structural modifications in diabetic nephropathy (thickening of the basal membrane of the glomerulus and interstitial fibrosis) (8-9).

The  antihypertensive  efficacy  and  clinical  and  biological acceptability of COVERSYL in diabetics  have  been  confirmed  in  two cohorts of 2 916 and 6 137 patients treated for 6 months and 1 year respectively with COVERSYL under the conditions of daily practice in general medicine (6-7).

References:

1. Brichards SM, Santoni JP, Thomas JR, et al. Long term reduction of microalbuminuria after 1 year of angiotensin convertingenzyme inhibition by perindopril in hypertensive insulin-treated diabetic patients. Diabetes Metab. 1990;16: 30-36.
   
   
2. Jandrain B, Herbaut C, Depoorter JC, Van de Voorde K. Long-term (1 year) acceptability of perindopril in type II diabetic patients with hypertension. Am J Med. 1992;92(suppl 4B):91S-94S.
   
   
3. Bak JF, Gerdes LU, Sorensen NS, Pedersen O. Effects of perindopril on insulin sensitivity and plasma lipid profile in hypertensive non insulin dependent diabetic patients. Am J Med. 1992;92 (suppl 4B):69S-72S.
   
   
4. Melbourne Diabetic Nephropathy Study Group.Comparison between perindopril and nifedipine in hypertensive and normotensive diabetic patients with microalbuminuria. BMJ. 1991; 302:210-216.
   
   
5. Hermans MP, Brichard S, Colin I, Borgies P, Ketelslegers JM, Lambert AE. Long-term reduction of microalbuminuria after 3 years of angiotensin-converting enzyme inhibition by perindopril in hypertensive insulin-treated diabetic patients. Am J Med. 1992;92(suppl 48)4B 102S-107S.
   
   
6. Poggi L, Renucci JF, Denolle T. Treatment of essential hypertension in general practice: an open-label study of 47 351 French hypertensive patients treated for one year with perindopril. Can J Cardiol. 1994; 10 (suppl D):21D-24D.
   
   
7. Fressinaud P, Berrut G, Gallois H. Activité antihypertensive, acceptabilité clinique et biologique du perindopril: principaux résultats chez 23 460 hypertendus légers à modérés traités pendant 6 mois en médecine générale. Ann Cardiol Angeiol. 1993;42:51-59.
   
   
8. Nankervis A, Nicholls K, Kilmartin G, Allen P, Ratnaike S, Martin FIR. Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study. Metabolism. 1998; 47(12,Suppl 1):12-15.
   
   
9. Cordonnier DJ, Pinel N, Barro C, Zaoui P. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group. J Am Soc Nephrol. 1999;10:1253-1263.
   
   
10. Patel V, Rassam SMB, Chen HC, Jones M, Kohner EM. Effect of angiotensin-converting enzyme inhibition with perindopril and b-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects. Metabolism. 1998;47 (12;Suppl 1): 28-33.
    

The antihypertensive efficacy of COVERSYL enables normalization of blood pressure in the great majority of patients by single-drug therapy alone. In cases of hypertension resistant to single-drug therapy, combination of a diuretic with COVERSYL leads to synergism of antihypertensive activity which has been demonstrated experimentally. Hydrochlorothiazide was selected in these clinical trials since it is a reference diuretic. It resulted in normalization of a further 15% of patients (2).

In patients with heart failure, addition of COVERSYL to a standard digitalis-diuretic treatment did not lead to an excessive risk of hypotension, either at the time it was added or during continued treatment and did not alter renal function.

However, addition of an ACE inhibitor to ongoing diuretic treatment raises the question of a risk of acute renal insufficiency. The sodium depletion induced by a thiazide or loop diuretic stimulates the renin-angiotensin system. Prescription of an ACE inhibitor under such circumstances is associated with the risk of excessive hypotension and of renal hypoperfusion. This leads to the recommendation that COVERSYL be introduced at the dose of 2 mg, with regular monitoring of renal function before any increase in dosage is envisaged, in hypertensive patients previously treated with a diuretic. Furthermore, in patients with heart failure, temporary withdrawal of the diuretic 48 hours before introduction of COVERSYL at the dose of 2 mg is advisable to guard against a risk of a first-dose effect (5).

Potassium-sparing diuretics are not an alternative. Inhibition of the renin-angiotensin system leads to a decrease in aldosterone levels which favorizes the tubular reabsorption of potassium. ACE inhibitors may increase this effect of the diuretic and thereby lead to hyperkalemia. Analysis of variations in plasma potassium during long-term treatment with COVERSYL reveals a moderate increase in plasma potassium over the course of time (1.7% after 1 year of treatment, 2.6% after 2 years and 3.1% after 3 years in patients on single-drug therapy). Rare individual increases in plasma potassium, seen with COVERSYL, are corrected by the combined prescription of a thiazide diuretic (3). Thus, the combination of ACE inhibitors with a potassium-sparing diuretic should not be recommended from the outset. As stipulated in the drug data sheet, frequent monitoring of plasma potassium is essential if such a combination should prove necessary.

References:

1. Scalbert E, Abdon D, Devissaguet M, Juggi JS. Interaction between an angiotensin converting enzyme inhibitor, COVERSYL 4 mg, and a thiazide diuretic in the spontaneously hypertensive rat. Can J Cardiol. 1992;8:381-386.
   
   
2. Thurston H, Desche P. Assessment of antihypertensive efficacy of perindopril: results of double-blind multicenter studies versus reference drugs. J Cardiovasc Pharmacol. 1991;18 (suppl 7):S45-S49.
   
   
3. Degaute JP, Leeman M, Desche P. Long term acceptability of perindopril: European Multicenter Trial on 856 patients. Am J Med. 1992;92(suppl 4B:84S-90S.
   
   
4. Leary WP, Reyes AM, Van der Byl K. Interactions between different diuretics and between diuretics and other drugs on renal excretions in man: mechanisms and clinical implications. Prog Pharmacol Clin Pharmacol. 1992;9:317-360.
   
   
5. Mac Fadyen RJ, Barr CS, Sturrock NDC, Fenwick M, Struthers AD. Further evidence that chronic perindopril treatment maintains neurohormonal suppression but does not lower blood pressure in chronic cardiac failure. Br J Clin Pharmacol. 1997;44:69-76.

In patients with a history of Stroke or TIA, COVERSYL based treatment lead to a significant 28% reduction in recurrent stroke. (1) All types of stroke were prevented. Only 23 patients need to be treated for 5 years to prevent 1 stroke (2). Thus the PROGRESS study results suggest that all patients with a history of stroke should receive COVERSYL.

References:

1. PROGRESS Collaborative Group. Randomised trial of perindopril-based blood-pressure-lowering regimen among 6 105 patients with prior stroke or transient ischaemic attack. The Lancet. 2001; 358, 1033-1041.
   
   
2. GORELICK P B. Stroke prevention therapy beyond antithrombotics : unifying mechanisms in ischaemic stroke pathogenesis and implications for therapy. Stroke. 2002;33:862-875 .