Expert Rev Cardiovasc Ther. 2005 Jan;3(1):15-29.
Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril.
Ferrari R.
University of Ferrara, Department of Cardiology, Arcispedale S Anna, Corso Giovecca 203, 44100 Ferrara, Italy.

Perindopril is a long-acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensinII and potentiating bradykinin. Its efficacy, safety and tolerability are well established in the treatment of hypertension and heart failure. Moreover, large morbidity-mortality trials, such as the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) and Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS), have shown that antihypertensive treatment with perindopril reduces and prevents cardiovascular disease in a large range of patients with vascular diseases, whether hypertensive or not. Thus, the outcome of these and other trials support the concept of cardiovascular protective properties of angiotensin-converting enzyme inhibition with perindopril in addition to the obvious blood-pressure-lowering effect. Considering its properties and the gathered clinical evidence on efficacy and tolerability, perindopril fulfils the criteria of the latest guidelines for hypertension and cardiovascular disease management [1] and should therefore be considered as a first-line antihypertensive agent, forming a consistent part of the comprehensive strategy against hypertension and related cardiovascular complications..

Lancet. 2003 Sep 6;362(9386):782-8.
Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
Fox KM; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators.
Cardiology Department, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK.

Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events. We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure. METHODS: We recruited patients from October, 1997, to June, 2000. 13655 patients were registered with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run-in period of 4 weeks, in which all patients received perindopril, 12218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4.2 years, and the primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. Analysis was by intention to treat. FINDINGS: Mean age of patients was 60 years (SD 9), 85% were male, 92% were taking platelet inhibitors, 62% beta blockers, and 58% lipid-lowering therapy. 603 (10%) placebo and 488 (8%) perindopril patients experienced the primary endpoint, which yields a 20% relative risk reduction (95% CI 9-29, p=0.0003) with perindopril. These benefits were consistent in all predefined subgroups and secondary endpoints. Perindopril was well tolerated. INTERPRETATION: Among patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcome. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. Treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.

Clin Ther. 2003 Jul;25(7):2006-21
A randomized, double-blind, controlled, parallel-group comparison of perindopril and candesartan in hypertensive patients with type 2 diabetes
Derosa G, Cicero AF, Ciccarelli L, Fogari R
Department of Internal Medicine and Therapeutics, University of Pavia, IRCCS Policlinico S. Matteo, Pavia, Italy.

BACKGROUND: When choosing an antihypertensive drug for patients with hypertension and diabetes mellitus (DM), the metabolic side effects, possibility of improving some metabolic parameters, and need for adequate blood pressure control must all be considered.OBJECTIVE: The goal of this study was to compare the impacts of perindopril and candesartan on blood pressure, glucose metabolism, serum lipid profile, and metabolic parameters in patients with mild hypertension and type 2 DM during therapy and after a 1-month washout period.METHODS: Type 2 DM patients with mild hypertension and good glucose control who were not taking hypercholesterolemic drugs were enrolled. Perindopril 4 mg QD or candesartan 16 mg QD was administered for 12 months in this randomized, double-blind, controlled, parallel-group clinical trial. Fasting plasma glucose (FPG), fasting plasma insulin (FPI), glycosylated hemoglobin, homeostasis model assessment (HOMA) index, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, triglycerides, lipoprotein(a) (Lp[a]), plasminogen activator inhibitor 1 (PAI-1), homocysteine, body mass index (BMI), and albumin excretion rate (AER) were assessed.RESULTS: Ninety-six patients (49 women and 47 men; mean [SD] ages, 53 [10] years [perindopril] and 55 [9] years [candesartan]) were enrolled. Mean (SD) body weight, height, and BMI were 78.2 (9.4) kg, 1.69 (0.05) m, and 27.2 (2.0) kg/m(2) in the perindopril group and 77.5 (8.6) kg, 1.70 (0.06) m, and 26.8 (2.5) kg/m(2) in the candesartan group. A significant change occurred from baseline to month 12 during treatment with perindopril in SBP and DBP (both P < 0.01), FPG (P < 0.05), FPI (P < 0.05), TC (P < 0.05), LDL-C (P < 0.05), Lp(a) (P < 0.05), PAM (P < 0.05), and AER (P < 0.05). Significant changes from baseline to month 12 occurred with candesartan in SBP and DBP (both P < 0.01) and AER (P < 0.05). The HOMA index was significantly lower at month 12 in the perindopril group than in the candesartan group (P < 0.05). When we interrupted perindopril and candesartan therapy for a 1-month washout period, changes in SBP and DBP values were significant compared with month 12 in both groups (all P < 0.05). Changes in TC and LDL-C from month 12 to the end of washout were significant only in the perindopril group (both P < 0.05).CONCLUSIONS: Perindopril and candesartan both effectively lowered blood pressure in this group of patients with mild hypertension and type 2 DM. Perindopril showed an improvement on some metabolic parameters compared with candesartan. However, the inclusion/exclusion criteria could limit the ability to extrapolate the results to a general population.

Kidney Int Suppl. 2003 Feb;(83):S66-73
Reduction in natural death and renal failure from a systematic screening and treatment program in an Australian Aboriginal community
Hoy WE, Wang Z, Baker PR, Kelly AM
Menzies School of Health Research, Darwin, Northern Territory, Australia

BACKGROUND: Australian Aborigines in remote areas are experiencing an epidemic of renal and cardiovascular disease. In November 1995, we introduced a renal and cardiovascular treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated end-stage renal disease (ESRD) of 2760 per million. Our previous study described an estimated 50% reduction in renal failure and all-cause natural deaths in the treatment group through December 31, 1998. We now describe a reduction in these events through mid 2000. METHODS: People eligible for treatment were those with confirmed hypertension, diabetics with microalbuminuria or overt albuminuria, and people with overt albuminuria, regardless of blood pressure and diabetes. Treatment centered around the use of perindopril (Coversyl, Servier), with additional agents as needed to reach defined blood pressure goals, attempts at control of glucose and lipid levels, and health education. Two hundred and sixty-seven people, or 30% of the adult population, have been enrolled, with mean follow up of 3.39 years. Rates of terminal endpoints were compared on an intention-to-treat basis with those of 327 historical controls matched for baseline disease severity, who were followed for a mean of 3.18 years in the pre-treatment program era, against a background of no treatment or inconsistent changing treatment. RESULTS: Terminal events occurred in 38 controls and 23 people in the treatment group. The estimated rate of natural deaths in the treatment group was 50% that of the controls, (P=0.012); the rate of renal deaths was 47% (P=0.038) and the rate of non-renal deaths was 54% that of controls (P=0.085). Survival benefit in the treatment group was observed at all levels of overt albuminuria, in non-diabetics and diabetics, in normotensive as well as hypertensive people, and in people who had been taking angiotensin converting enzyme-inhibitors (ACEi) in the pre-program era, as well as those who had not. Benefit was absent among the low death rates of people without overt albuminuria, and questionable among people with glomerular filtration rates (GFRs) <60 mL/min. The number of people needed to treat (NNT) to avoid one terminal event of natural causes was calculated at only 11.6. CONCLUSIONS: Falling rates of deaths and renal failure in the whole community support marked benefit of the program. Millions of dollars have been saved, based on avoidance of dialysis alone, but the reduction in premature death is the greater benefit. Chronic disease programs like this are enormously effective, and should be introduced into to all high-risk communities as a matter of urgency.

Drug information

Generic name: perindopril
Product Brand Names: Coverex ®, Coversyl ®

1. What are ACE inhibitors, and how do they work? Angiotensin II is a very potent chemical that causes the muscles surrounding blood vessels to contract and thereby narrows the blood vessels. The narrowing of the vessels increases the pressure within the vessels and can cause high blood pressure (hypertension). Angiotensin II is formed from angiotensin I in the blood by the enzyme, angiotensin converting enzyme (ACE). ACE inhibitors are medications that slow (inhibit) the activity of the enzyme, which decreases the production of angiotensin II. As a result, the blood vessels enlarge or dilate, and the blood pressure is reduced. This lower blood pressure makes it easier for the heart to pump blood and can improve the function of a failing heart. In addition, the progression of kidney disease due to high blood pressure or diabetes is slowed.

2. For what conditions are ACE inhibitors used? ACE inhibitors are used for controlling blood pressure, treating heart failure and preventing kidney damage in people with hypertension or diabetes. They also benefit patients who have had heart attacks. In studies, individuals with hypertension, heart failure, or prior heart attacks who were treated with an ACE inhibitor lived longer than patients who did not take an ACE inhibitor. Because they prevent early death resulting from hypertension, heart failure or heart attacks, ACE inhibitors are one of the most important group of drugs. Some individuals with hypertension do not respond sufficiently to ACE inhibitors alone. In these cases, other drugs are used in combination with ACE inhibitors.

3. Are there any differences among the different types of ACE inhibitors? ACE inhibitors are very similar. However, they differ in how they are eliminated from the body and their doses. Some ACE inhibitors need to be converted into an active form in the body before they work. In addition, some ACE inhibitors may work more on ACE that is found in tissues than on ACE that is present in the blood. The importance of this difference or whether one ACE inhibitor is better than another, has not been determined.

4. What are the side effects of ACE inhibitors? ACE inhibitors are relatively well-tolerated by most individuals. Nevertheless, they are not free of side effects, and some patients should not use ACE inhibitors. ACE inhibitors usually are not prescribed for pregnant patients because they may cause birth defects. Individuals with severe kidney problems and people who have had a severe reaction to ACE inhibitors probably should avoid them. The most common side effects are cough, elevated blood potassium levels, low blood pressure, dizziness, headache, drowsiness, weakness, abnormal taste (metallic or salty taste), and rash. It may take up to a month for coughing to subside, and if one ACE inhibitor causes cough it is likely that the others will too. The most serious, but rare, side effects of ACE inhibitors are kidney failure, allergic reactions, a decrease in white blood cells, and swelling of tissues (angioedema).

5. With which drugs do ACE inhibitors interact? ACE inhibitors have few interactions with other drugs. Since ACE inhibitors may increase blood levels of potassium, the use of potassium supplements, salt substitutes (which often contain potassium), or other drugs that increase the body's potassium may result in excessive blood potassium levels. ACE inhibitors also may increase the blood concentration of lithium (Eskalith) and lead to an increase in side effects from lithium. There have been reports that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, indomethacin, and naproxen may reduce the effects of ACE inhibitors; however, there is no conclusive evidence that this interaction, if it exists, is important.

6. What ACE inhibitors are available? The following is a list of the ACE inhibitors that are available in the United States:

captopril (Capoten), benazepril (Lotensin), enalapril (Vasotec), lisinopril (Prinivil, Zestril) fosinopril (Monopril), ramipril (Altace), perindopril (Coverex), quinapril (Accupril), moexipril (Univasc), and trandolapril (Mavik).

Caution! Before starting to take this medicine, it is vital that you should consult your doctor! Do not use it on your own initiative, without medical advice.

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COVEREX
Generic name: Perindopril
Other brand name: Coversyl

ACE inhibitors belong to the class of medicines called high blood
pressure medicines (antihypertensives).

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4 mg	30 tab	USD 25.00

PERINDOPRIL brand name: Coverex

Perindopril

PERINDOPRIL
brand name: Coverex