Therapeutic Class Overview Angiotensin-Converting Enzyme (ACE) Inhibitors Single Entity Agents Therapeutic Class Overview/Summary: The renin-angiotensin-aldosterone system (RAAS) is the most important component in the homeostatic regulation of blood pressure.1,2 Excessive activity of the RAAS may lead to hypertension and disorders of fluid and electrolyte imbalance.3 Renin catalyzes the conversion of angiotensinogen to angiotensin I. Angiotensin I is then cleaved to angiotensin II by angiotensin- converting enzyme (ACE). Angiotensin II may also be generated through other pathways (angiotensin I convertase).1 Angiotensin II can increase blood pressure by direct vasoconstriction and through actions on the brain and autonomic nervous system.1,3 In addition, angiotensin II stimulates aldosterone synthesis from the adrenal cortex, leading to sodium and water reabsorption. Angiotensin II exerts other detrimental cardiovascular effects including ventricular hypertrophy, remodeling and myocyte apoptosis.1,2 The ACE inhibitors block the conversion of angiotensin I to angiotensin II, and also inhibit the breakdown of bradykinin, a potent vasodilator.4 Evidence-based guidelines recognize the important role that ACE inhibitors play in the treatment of hypertension and other cardiovascular and renal diseases. With the exception of Epaned® (enalapril solution) and Qbrelis® (lisinopril solution), all of the ACE inhibitors are available generically. Table 1. Current Medications Available in Therapeutic Class5-19 Generic Food and Drug Administration Approved Dosage Generic (Trade Name) Indications Form/Strength Availability Benazepril Hypertension Tablet: (Lotensin®*) 5 mg 10 mg 20 mg 40 mg Captopril* Diabetic nephropathy, heart failure, hypertension, Tablet: left ventricular dysfunction post-myocardial 12.5 mg infarction 25 mg 50 mg 100 mg Enalapril Asymptomatic left ventricular dysfunction, heart Solution: (Vasotec®*, failure, hypertension 1 mg/mL Epaned®) Tablet: 2.5 mg 5 mg 10 mg 20 mg Enalaprilat* Hypertension Injection: 1.25 mg/mL Fosinopril* Heart failure, hypertension Tablet: 10 mg 20 mg 40 mg Lisinopril Acute myocardial infarction to improve survival, Solution: (Prinivil®*, heart failure, hypertension 1 mg/mL Qbrelis®, Zestril®*) Tablet: 2.5 mg 5 mg 10 mg 20 mg Page 1 of 6 Copyright 2016 • Review Completed on 09/13/2016 Therapeutic Class Overview: angiotensin-converting enzyme (ACE) inhibitors-single entity Generic Food and Drug Administration Approved Dosage Generic (Trade Name) Indications Form/Strength Availability 30 mg 40 mg Moexipril* Hypertension Tablet: 7.5 mg 15 mg Perindopril Hypertension, stable coronary artery disease to Tablet: (Aceon®*) reduce the risk of cardiovascular mortality or 2 mg nonfatal myocardial infarction 4 mg 8 mg Quinapril Heart failure, hypertension Tablet: (Accupril®*) 5 mg 10 mg 20 mg 40 mg Ramipril Heart failure post myocardial infarction, Capsule: (Altace®*) hypertension, reduce the risk of myocardial 1.25 mg infarction, stroke and death from cardiovascular 2.5 mg causes 5 mg 10 mg Trandolapril Heart failure post-myocardial infarction, Tablet: (Mavik®*) hypertension, left ventricular dysfunction post- 1 mg myocardial infarction 2 mg 4 mg *Generic available in at least one dosage form or strength. Evidence-based Medicine Angiotensin-converting enzyme (ACE) inhibitors have been shown to be effective for coronary artery disease and to reduce the risk of cardiovascular mortality, myocardial infarction and stroke.19-30 Clinical Trials have demonstrated the efficacy of ACE inhibitors in reducing mortally associated with congestive heart failure.31-47 ACE inhibitors have demonstrated efficacy for the treatment for hypertension and for the use in diabetic nephropathy.48-79 Key Points within the Medication Class According to Current Clinical Guidelines:80-97 o Treatment guidelines for the management of stable angina recommend angiotensin- converting enzyme (ACE) inhibitors in patients with a left ventricular ejection fraction <40% and in those with hypertension, diabetes or chronic kidney disease. ACE inhibitors are also recommended in patients at lower risk (mildly reduced or normal left ventricular ejection fraction) in whom cardiovascular risk factors remain well controlled and revascularization has been performed. o Treatment guidelines for the management of unstable angina/non-ST elevation myocardial infarction recommend the use of ACE inhibitors in the first 24 hours in patients with or without pulmonary congestion or left ventricular ejection fraction of <40%. ACE inhibitors are recommended in patients with heart failure, left ventricular dysfunction, diabetes or hypertension. In addition, ACE inhibitors are a reasonable for patients with heart failure and left ventricular ejection fraction >40% and patients without hypertension or diabetes. The guidelines are similar for the management of ST-elevation myocardial infarction. o Treatment guidelines recommend ACE inhibitors in patients who are at risk for the development of heart failure. ACE inhibitors are recommended for the management of heart failure in patients who have cardiac structural abnormalities or remodeling who have not Page 2 of 6 Copyright 2016 • Review Completed on 09/13/2016 Therapeutic Class Overview: angiotensin-converting enzyme (ACE) inhibitors-single entity developed heart failure symptoms, especially in patients with reduced left ventricular ejection fraction and a history of myocardial infarction. o Treatment guidelines for hypertension recommend the use of ACE inhibitors as a first line option in all patients as well as in hypertensive patients with certain compelling indications including heart failure, post-myocardial infarction, left ventricular dysfunction, high coronary disease risk, diabetes, chronic kidney disease, and recurrent stroke prevention. o Treatment guidelines for the management of hypertension in patients with diabetes recommend a regimen including an ACE inhibitor. In patients with known cardiovascular disease, a regimen including an ACE inhibitor should be used to reduce the risk of cardiovascular events. In patients with type 1 diabetes, with hypertension and any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. In patients with type 2 diabetes, hypertension and microalbuminuria, ACE inhibitors have been shown to delay the progression to macroalbuminuria. Other Key Facts: o Clinical trials have not demonstrated significant differences when ACE inhibitors were compared to angiotensin II receptor blockers. o With the exception of Epaned® (enalapril solution) and Qbrelis® (lisinopril solution), all of the ACE inhibitors are available generically. References 1. Saseen JJ, Carter BL. Hypertension. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 6th edition. New York (NY): McGraw-Hill; 2005. p. 185-217. 2. Parker RB, Patterson JH, Johnson JA. Heart failure. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 6th edition. New York (NY): McGraw-Hill; 2005. p. 219-60. 3. Reid IA. Vasoactive peptides. In: Katzung BG, editor. Basic and clinical pharmacology [monograph on the Internet]. 11th ed. New York (NY): McGraw-Hill: 2009 [cited 2011 Mar 25]. Available from: http://online.statref.com. 4. Benowitz NL. Antihypertensive agents. In: Katzung BG, editor. Basic and clinical pharmacology [monograph on the Internet]. 11th ed. New York (NY): McGraw-Hill: 2009 [cited 2011 Mar 25]. Available from: http://online.statref.com. 5. Drug Facts and Comparisons 4.0 [database on the Internet]. St. Louis: Wolters Kluwer Health, Inc.; 2014 [cited 2014 Apr 18]. Available from: http://online.factsandcomparisons.com. 6. Micromedex® Healthcare Series [database on the Internet]. Greenwood Village (CO): Thomson Reuters (Healthcare) Inc.; Updated periodically [cited 2014 Apr 18]. Available from: http://www.thomsonhc.com/ 7. Lotensin® [package insert]. Suffern (NY): Novartis Pharmaceuticals Corporation; 2015 Jul. 8. Captopril [package insert]. Morgantown (WV): Mylan Pharmaceuticals Inc.; 2015 Jun. 9. Epaned® [package insert]. Greenwood Villaige (Co): Silvergate Pharmaceuticals, Inc.; 2016 Jan. 10. Vasotec® [package insert]. Bridgewater (NJ): Valeant Pharmaceuticals North America, LLC; 2015 Aug. 11. Fosinopril [package insert]. Fort Lauderdale (FL): Andrx Pharmaceuticals, Inc.; 2004 Jan. 12. Prinivil® [package insert]. Whitehouse Station (NJ): Merck&Co., Inc.; 2015 Aug. 13. Qbrelis® [package insert]. Greenwood Village (CO): Silvergate Pharmaceuticals, Inc.; 2016 Jul. 14. Zestril® [package insert]. Wilmington (DE): AstraZeneca Pharmaceuticals, LP; 2014 Jun. 15. Moexipril [package insert]. Mahwah (NJ): Glenmark Pharmaceuticals, Inc.; 2014 Dec. 16. Perindopril [package insert]. Baltimore (MD): Lupin Pharmaceuticals, Inc.; 2010 Jan. 17. Accupril® [package insert]. New York (NY): Pfizer Inc; 2015 Sep. 18. Altace® [package insert]. Bristol (TN): King Pharmaceuticals; 2015 Sep. 19. Mavik® [package insert]. North Chicago (IL): AbbVie, Inc.; 2016 Jan. 20. Swedberg K, Held P, Kjekshus J, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction results of the cooperative New Scandinavian enalapril survival study II (CONSENSUS II). N Engl J Med. 1992 Sep 3;327(10):678-84. 21. Pitt B, Reichek N, Willenbrock R, Zannad F, Philips RA, Roniker B, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril