Antihypertensive Combinations

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1 This Professional Resource gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2016 ~ Resource # Antihypertensive Combinations At least 75% of patients need two or more antihypertensives to reach their blood pressure goal. Initiating therapy with two antihypertensives should be considered for patients who are 20 mmhg above their systolic goal or 10 mmhg above their diastolic goal. 1 Using two appropriately chosen antihypertensives can lower blood pressure more and help patients reach blood pressure goals sooner, with fewer side effects and at lower doses, than using a single drug. 1 Certain combinations are preferred, acceptable, or not preferred based on efficacy, cardiovascular outcomes, side effects, and adherence. 1 This chart provides efficacy, cardiovascular outcomes, side effects, and single pill (i.e., fixed-dose combo) availability information for preferred, acceptable, and nonpreferred combinations. It also provides information to assist in matching patients to a particular preferred or acceptable combination. When choosing a combination, note that pivotal studies showing clinical benefit of treating hypertension included a thiazide. 2 Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker. a. Dihydropyridine CCBs = amlodipine, felodipine, nifedipine, nisoldipine. b. The thiazides chlorthalidone and indapamide provide better 24-hour blood pressure control than hydrochlorothiazide, and were used in pivotal outcomes studies (e.g., ALLHAT, SHEP, ADVANCE). 1,3,10,15,16 c. Position paper does not distinguish between dihydropyridine and nondihydropyridine CCB. d. Combination not specifically addressed in position paper. Preferred Combinations for Uncomplicated Hypertension ACEI or ARB plus diuretic b All ARBs and most ACEIs available in Reduces risk of hypokalemia. 1 combination with hydrochlorothiazide. ACEI/ARB ameliorates diuretic-induced activation of the reninangiotensin-aldosterone All ACEI/hydrochlorothiazide combos available generically in U.S. system. Additive blood pressure reduction. 1 Olmesartan/amlodipine/ hydrochlorothiazide (U.S.)(Tribenzor) d Outcomes data for ACEI/thiazide combination (e.g., reduces stroke, heart failure, mortality, diabetes complications). 3,4,7 Perindopril/indapamide (Canada)(Coversyl Plus) Consider for chronic renal insufficiency, 9,17 diabetes, 17 or history of stroke or transient ischemic attack. 7,9,17 Valsartan/amlodipine/hydrochlorothiazide (U.S.)(Exforge HCT) d Azilsartan/chlorthalidone (Edarbyclor) d

2 (Professional Resource #321047: Page 2 of 5) Preferred Combinations for Uncomplicated Hypertension, continued ACEI or ARB plus CCB c Benazepril/amlodipine (U.S.)(Lotrel, ACEI/ARB ameliorate calcium channel blocker-induced edema. 1 Olmesartan/amlodipine (U.S.)(Azor) Also counteract dihydropyridine calcium channel blockerinduced Olmesartan/amlodipine/ sympathetic stimulation (e.g., tachycardia). 1 hydrochlorothiazide (U.S.)(Tribenzor) d Additive blood pressure reduction. 1 Trandolapril/verapamil (Tarka, generics Dihydropyridine outcomes data are primarily with amlodipine. 8 [U.S.]) Consider for chronic renal insufficiency, 17 diabetes, 9,17 history Valsartan/amlodipine (U.S.)(Exforge, generics; also available with hydrochlorothiazide as Exforge HCT, generics d of stroke or transient ischemic attack, 17 and high-risk coronary artery disease (ACEI plus dihydropyridine [not short-acting nifedipine]). 9 Perindopril/amlodipine (Prestalia [U.S.], Viacoram [Canada]) Telmisartan/amlodipine (Twynsta, generics [U.S.]) Acceptable Combinations for Uncomplicated Hypertension: Consider based on patient factors (e.g., comorbidities, antihypertensive response history, contraindications/potential safety issues with preferred agents, cost). Thiazide b plus beta-blocker Atenolol/chlorthalidone (Tenoretic, Beta-blockers ameliorate thiazide-induced activation of reninangiotensin-aldosterone system. 1 Bisoprolol/hydrochlorothiazide (U.S.) (Ziac, Additive blood pressure reduction. 1 Thiazides improve beta-blocker efficacy in African Americans. 1 Metoprolol tartrate/hydrochlorothiazide (U.S.)(Lopressor HCT, Side effects (fatigue, sexual dysfunction, glucose intolerance) may be problematic. 1 Nadolol/bendroflumethiazide (U.S.)(Corzide, Beta-blockers seem less effective than other antihypertensive classes for improving outcomes in hypertension (most data are Propranolol/hydrochlorothiazide (U.S.) from studies using atenolol). 5 Pindolol/hydrochlorothiazide (Canada)(Viskazide) Reserve for patients with hypertension plus another condition that would benefit from a beta-blocker (e.g., heart failure, post- MI, angina, etc). 5,9,17 See our charts, Target Doses of Meds for Systolic Heart Failure and Target Doses of Post-MI Medications, for evidence-based choices.

3 (Professional Resource #321047: Page 3 of 5) Acceptable Combinations for Uncomplicated Hypertension, continued Thiazide b plus CCB c Olmesartan/amlodipine/ hydrochlorothiazide (Tribenzor [U.S.]) d Blood pressure reduction not additive. 1 Valsartan/amlodipine/ hydrochlorothiazide (Exforge HCT [U.S.] d VALUE study: amlodipine plus hydrochlorothiazide reduced cardiovascular events as well as valsartan plus hydrochlorothiazide. 6 Neither drug offsets the side effects of the other. 1 Thiazide b plus aliskiren Aliskiren/hydrochlorothiazide (Tekturna HCT [U.S.], Rasilez HCT [Canada]) Aliskiren reduces risk of hypokalemia. 1 Ameliorates thiazide-induced activation of the reninangiotensin-aldosterone system. 1 Additive blood pressure reduction. 1 Thiazide b plus potassium-sparing diuretic Hydrochlorothiazide/amiloride (Midamor [Canada], Hydrochlorothiazide/triamterene (Maxzide [U.S.], Dyazide [U.S.], Hydrochlorothiazide/spironolactone (Aldactazide, Spironolactone, amiloride, or triamterene offsets thiazideinduced potassium loss. 1 Blood pressure reduction variable. 1 Risk of hyperkalemia in patients with CrCl 50 ml/min or less. 1 No outcomes data. Beta-blocker plus None Additive blood pressure reduction. 1 dihydropyridine CCB a No outcomes data. 1 Reserve for patients with hypertension plus another condition that would benefit from a beta-blocker (e.g., heart failure, post- MI, angina, etc). 5,9,17 See our charts, Target Doses of Meds for Systolic Heart Failure and Target Doses of Post-MI Medications, for evidence-based choices. Aliskiren plus CCB c None No outcomes data. Reserve aliskiren for patients who can t take an ACEI or ARB.

4 (Professional Resource #321047: Page 4 of 5) Not Preferred Combinations for Uncomplicated Hypertension ACEI plus ARB None Combination provides little additional blood pressure lowering with more adverse effects than monotherapy and no cardiovascular outcomes benefit. 1,14 Not recommended per Canadian guidelines. 9 May have role in systolic heart failure. 1,14 Aliskiren plus ARB or ACEI None Combination provides little additional blood pressure lowering with more adverse effects than monotherapy, and no cardiovascular outcomes data in hypertesion. 1,14 ACEI or ARB plus betablocker Nondihydropyridine CCB (i.e., verapamil, diltiazem) plus beta-blocker Aliskiren added to ACEI or ARB in patients with diabetes plus renal impairment and/or cardiovascular disease increased risk of hyperkalemia and hypotension. 11 Avoid combo in patients with diabetes or moderate to severe renal impairment. 12,13 Consider a preferred ACEI or ARB combo first. Nebivolol/valsartan (Byvalson) d Combination provides little additional blood pressure lowering. 1 Combination is appropriate for systolic heart failure or post- MI. 1 See our charts, Target Doses of Meds for Systolic Heart Failure and Target Doses of Post-MI Medications, for evidence-based choices. None Risk of heart block and bradycardia. 1 Methyldopa plus beta-blocker None Risk of heart block and bradycardia. 1 Abrupt discontinuation can cause hypertensive crisis. 1 Clonidine plus beta-blocker None Risk of heart block and bradycardia. 1 Abrupt discontinuation can cause hypertensive crisis. 1 Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

5 (Professional Resource #321047: Page 5 of 5) Project Leader in preparation of this professional resource: Melanie Cupp, Pharm.D., BCPS References 1. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens 2010;4: James PA, Oparil S, Carter BL, et al evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311: Patel A, ADVANCE Collaborative Group, MacMahon S, et al. 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 2007;370: Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358: Professional Resource, Atenolol for Hypertension. Pharmacist's Letter/Prescriber's Letter. January Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363: 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 2001;358: Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359: Leung AA, Nerenberg K, Daskalopoulou SS, et al. Hypertension Canada s 2016 Canadian Hypertension Education Program guidelines for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2016;32: Chobanian AV. Does it matter how hypertension is controlled? N Engl J Med 2008;359: Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367: Product information for Tekturna. Novartis Pharmaceuticals Corporation. East Hanover, NJ December Product monograph for Rasilez. Novartis Pharmaceuticals Canada Inc. Dorval, QC H9S 1A9. May Professional Resource, ACEI, ARB, and Aliskiren Comparison. Pharmacist s Letter/Prescriber s Letter. March Radevski IV, Valtchanova ZP, Candy GP, et al. Comparison of indapamide and low-dose hydrochlorothiazide monotherapy in black patients with mild to moderate hypertension. S Afr Med J 2002;92: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265: Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) 2014;16: Cite this document as follows: Professional Resource, Antihypertensive Combinations. Pharmacist s Letter/Prescriber s Letter. October Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2016 by Therapeutic Research Center Subscribers to the Letter can get professional resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com

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