Perindopril Explained

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.^[1]

As a long-acting ACE inhibitor, it works by relaxing blood vessels and decreasing blood volume. As a prodrug, perindopril is hydrolyzed in the liver to its active metabolite, perindoprilat. It was patented in 1980 and approved for medical use in 1988.^[2]

Perindopril is taken in the form of perindopril arginine (with arginine, trade names include Coversyl, Coversum) or perindopril erbumine (with erbumine (tert-Butylamine), trade name Aceon). Both forms are therapeutically equivalent and interchangeable,^[3] but the dose prescribed to achieve the same effect differs between the two forms. It is also often combined with another medication, sometimes in the same tablet (see below).

Medical uses

Perindopril shares the indications of ACE inhibitors as a class, including essential hypertension, stable coronary artery disease (reduction of risk of cardiac events in patients with a history of myocardial infarction and/or revascularization), treatment of symptomatic coronary artery disease or heart failure, and diabetic nephropathy.^[4]

Combination therapy

With indapamide

See main article: Perindopril/indapamide. In combination with indapamide, perindopril has been shown to significantly reduce the progression of chronic kidney disease and renal complications in patients with type 2 diabetes.^{[5] [6]} In addition, the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) found that whilst perindopril monotherapy demonstrated no significant benefit in reducing recurrent strokes when compared to placebo, the addition of low dose indapamide to perindopril therapy was associated with larger reductions in both blood pressure lowering and recurrent stroke risk in patients with pre-existing cerebrovascular disease, irrespective of their blood pressure.^{[7] [8]} There is evidence to support the use of perindopril and indapamide combination over perindopril monotherapy to prevent strokes and improve mortality in patients with a history of stroke, transient ischaemic attack or other cardiovascular disease.^{[7] [9]}

With amlodipine

The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BLA) was a 2005 landmark trial that compared the effects of the established therapy of the combination of atenolol and bendroflumethiazide to the new drug combination of amlodipine and perindopril (trade names Viacoram, AceryCal etc.).^[10] The study of more than 19 000 patients world-wide was terminated earlier than anticipated because it clearly demonstrated a statistically significant improvement in mortality and cardiovascular outcomes with the newer treatment. The combination of amlodipine and perindopril remains in the current treatment guidelines for hypertension and the outcomes of the ASCOT-BLA trial paved the way for further research into combination therapy and newer agents.^[11]

Contraindications

• Children
• Pregnancy
• Lactation
• Situations where a patient has a history of hypersensitivity
• Kidney failure

Precautions

• Assess kidney function before and during treatment where appropriate.
• Renovascular hypertension
• Surgery/anesthesia
• An analysis on the PROGRESS trial showed that perindopril has key benefits in reducing cardiovascular events by 30% in patients with chronic kidney disease defined as a CrCl <60ml/min.^[12] A 2016 and 2017 meta-analysis review looking at ACE inhibitors demonstrated a reduction in cardiovascular events but also slowed the decline of renal failure by 39% when compared to placebo.^[13] These studies included patients with moderate to severe kidney disease and those on dialysis.
• Its renoprotective benefits of decreasing blood pressure and removing filtration pressure is highlighted in a 2016 review.^[14] ACE inhibitor can result in an initial increase of serum creatinine, but mostly returns to baseline in a few weeks in majority of patients.^[15] It has been suggested that increased monitoring, especially in advanced kidney failure, will minimise any related risk and improve long-term benefits.^[16]
• Use cautiously in patients with sodium or volume depletion due to potential excessive hypotensive effects of renin-angiotensin blockade causing symptomatic hypotension.^[4] Careful monitoring or short-term dose reduction of diuretics prior to commencing perindopril is recommended to prevent this potential effect.^[4] A diuretic may later be given in combination if necessary; potassium-sparing diuretics are not recommended in combination with perindopril due to the risk of hyperkalaemia.^[4]
• Combination with neuroleptics or imipramine-type drugs may increase the blood pressure lowering effect. Serum lithium concentrations may rise during lithium therapy.

Side effects

Side effects are mild, usually at the start of treatment; they include:

• Cough
• Fatigue
• Weakness/Asthenia
• Headache
• Disturbances of mood and/or sleep

Less often

• Taste impairment
• Epigastric discomfort
• Nausea
• Abdominal pain
• Rash

Reversible increases in blood urea and creatinine may be observed. Proteinuria has occurred in some patients. Rarely, angioneurotic edema and decreases in hemoglobin, red cells, and platelets have been reported.

Composition

Each tablet contains 2, 4, or 8 mg of the tert-butylamine salt of perindopril. Perindopril is also available under the trade name Coversyl Plus, containing 4 mg of perindopril combined with 1.25 mg indapamide, a thiazide-like diuretic.

In Australia, each tablet contains 2.5, 5, or 10 mg of perindopril arginine. Perindopril is also available under the trade name Coversyl Plus, containing 5 mg of perindopril arginine combined with 1.25 mg indapamide and Coversyl Plus LD, containing 2.5 mg of perindopril arginine combined with 0.625 mg indapamide.

The efficacy and tolerability of a fixed-dose combination of 4 mg perindopril and 5 mg amlodipine, a calcium channel antagonist, has been confirmed in a prospective, observational multicenter trial of 1,250 hypertensive patients.^[17] A preparation of the two drugs is available commercially as Coveram.

Society and culture

Trade names

Perindopril is available under the following brand names among others:

Marketing

On 9 July 2014, the European Commission imposed fines of €427,700,000 on Laboratoires Servier and 5 companies which produce generics due to Servier's abuse of their dominant market position, in breach of European Union Competition law. Servier's strategy had included acquiring the principal source of generic production of Perindopril and entering into several pay-for-delay agreements with potential generic competitors.^[18]

Further reading

• Wang JG, Pimenta E, Chwallek F . Comparative review of the blood pressure-lowering and cardiovascular benefits of telmisartan and perindopril . Vascular Health and Risk Management . 10 . 189–200 . 2014 . 24741317 . 3983078 . 10.2147/VHRM.S59429 . free .
• Shirley M, McCormack PL . Perindopril/amlodipine (Prestalia(®)): a review in hypertension . American Journal of Cardiovascular Drugs . 15 . 5 . 363–370 . October 2015 . 26341621 . 10.1007/s40256-015-0144-1 . 40807688 .
• Bertrand ME, Vlachopoulos C, Mourad JJ . Triple Combination Therapy for Global Cardiovascular Risk: Atorvastatin, Perindopril, and Amlodipine . American Journal of Cardiovascular Drugs . 16 . 4 . 241–253 . August 2016 . 27256435 . 10.1007/s40256-016-0175-2 . 13318472 .
• Ancion A, Tridetti J, Nguyen Trung ML, Oury C, Lancellotti P . A Review of the Role of Bradykinin and Nitric Oxide in the Cardioprotective Action of Angiotensin-Converting Enzyme Inhibitors: Focus on Perindopril . Cardiology and Therapy . 8 . 2 . 179–191 . December 2019 . 31578675 . 6828891 . 10.1007/s40119-019-00150-w .

Notes and References

1. Web site: Consumer Medicine Information, GenRx Perindopril . Clinical Resources, Medicine information for health professionals . Royal Australian College of General Practitioners . dead . https://web.archive.org/web/20070901023153/http://www.racgp.org.au/cmi/gxcperin.pdf . 2007-09-01.
2. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006. John Wiley & Sons. 9783527607495. 467. en .
3. Web site: PBS For Health Professionals . Pharmaceutical Benefits Scheme . 2008 . Australian Government Department of Health and Ageing . 2008-09-04 . dead . https://web.archive.org/web/20081030010429/http://www.pbs.gov.au/html/healthpro/search/results?term=perindopril&scope=PBS+STATIC&form-type=simple . 2008-10-30.
4. Web site: Australian Medicines Handbook. amhonline.amh.net.au. 2020-05-10.
5. Netchessova TA, Shepelkevich AP, Gorbat TV . NIKA Study Group . Efficacy of single-pill perindopril/indapamide in patients with hypertension and type 2 diabetes . High Blood Pressure & Cardiovascular Prevention . 21 . 1 . 63–69 . March 2014 . 24357222 . 10.1007/s40292-013-0036-x . 20819715 .
6. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B . 6 . Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial . Lancet . 370 . 9590 . 829–840 . September 2007 . 17765963 . 10.1016/s0140-6736(07)61303-8 . 21153924 .
7. ((PROGRESS Collaborative Group)) . Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack . Lancet . 358 . 9287 . 1033–1041 . September 2001 . 11589932 . 10.1016/s0140-6736(01)06178-5 . 2001 Sep 29 . 10053225 .
8. Post-stroke antihypertensive treatment study. A preliminary result . Chinese Medical Journal . 108 . 9 . 710–717 . September 1995 . 8575241 . PATS Collaborating Group .
9. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ . 6 . Treatment of hypertension in patients 80 years of age or older . The New England Journal of Medicine . 358 . 18 . 1887–1898 . May 2008 . 18378519 . 10.1056/NEJMoa0801369 . free .
10. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J . 6 . Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial . Lancet . 366 . 9489 . 895–906 . September 2005 . 16154016 . 10.1016/S0140-6736(05)67185-1 . 26084146 .
11. Web site: Hypertension clinical information and guidelines . Australia . The Heart Foundation . 2020-05-10 . 2020-05-14 . https://web.archive.org/web/20200514021049/https://www.heartfoundation.org.au/conditions/hypertension . dead .
12. Perkovic V, Ninomiya T, Arima H, Gallagher M, Jardine M, Cass A, Neal B, Macmahon S, Chalmers J . 6 . Chronic kidney disease, cardiovascular events, and the effects of perindopril-based blood pressure lowering: data from the PROGRESS study . Journal of the American Society of Nephrology . 18 . 10 . 2766–2772 . October 2007 . 17804673 . 10.1681/ASN.2007020256 . free .
13. Liu Y, Ma X, Zheng J, Jia J, Yan T . Effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular events and residual renal function in dialysis patients: a meta-analysis of randomised controlled trials . BMC Nephrology . 18 . 1 . 206 . June 2017 . 28666408 . 5493067 . 10.1186/s12882-017-0605-7 . free .
14. Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, Zhao N, Liu L, Lv J, Zhang H, Wang H . 6 . Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials . American Journal of Kidney Diseases . 67 . 5 . 728–741 . May 2016 . 26597926 . 10.1053/j.ajkd.2015.10.011 . free .
15. Garlo KG, Bates DW, Seger DL, Fiskio JM, Charytan DM . Association of Changes in Creatinine and Potassium Levels After Initiation of Renin Angiotensin Aldosterone System Inhibitors With Emergency Department Visits, Hospitalizations, and Mortality in Individuals With Chronic Kidney Disease . JAMA Network Open . 1 . 7 . e183874 . November 2018 . 30646338 . 6324397 . 10.1001/jamanetworkopen.2018.3874 .
16. Ohkuma T, Jun M, Rodgers A, Cooper ME, Glasziou P, Hamet P, Harrap S, Mancia G, Marre M, Neal B, Perkovic V, Poulter N, Williams B, Zoungas S, Chalmers J, Woodward M . 6 . Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus . Hypertension . 73 . 1 . 84–91 . January 2019 . 30571562 . 10.1161/HYPERTENSIONAHA.118.12060 . free . 58547523 . 10044/1/66141 .
17. Bahl VK, Jadhav UM, Thacker HP. Management of Hypertension with the Fixed Combination of Perindopril and Amlodipine in Daily Clinical Practice: Results from the STRONG Prospective, Observational, Multicenter Study. American Journal of Cardiovascular Drugs May 22, 2009; 9 (3): 135-42 Link text
18. Web site: Antitrust: Commission fines Servier and five generic companies for curbing entry of cheaper versions of cardiovascular medicine . European Commission . 9 July 2014 .