Antihypertensive Combinations

This Professional Resource gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2016 ~ Resource #321047 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. Combination Single Pill Combination Availability Comments 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 Copyright 2016 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Professional Resource #321047: Page 2 of 5) Combination Single Pill Combination Availability Comments Preferred Combinations for Uncomplicated Hypertension, continued ACEI or ARB plus CCB c Benazepril/amlodipine (U.S.)(Lotrel, ACEI/ARB ameliorate calcium channel blocker-induced generics) 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, generics) Beta-blockers ameliorate thiazide-induced activation of reninangiotensin-aldosterone system. 1 Bisoprolol/hydrochlorothiazide (U.S.) (Ziac, generics) Additive blood pressure reduction. 1 Thiazides improve beta-blocker efficacy in African Americans. 1 Metoprolol tartrate/hydrochlorothiazide (U.S.)(Lopressor HCT, generics) Side effects (fatigue, sexual dysfunction, glucose intolerance) may be problematic. 1 Nadolol/bendroflumethiazide (U.S.)(Corzide, generics) 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. Copyright 2016 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Professional Resource #321047: Page 3 of 5) Combination Single Pill Combination Availability Comments 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], generics) Hydrochlorothiazide/triamterene (Maxzide [U.S.], Dyazide [U.S.], generics) Hydrochlorothiazide/spironolactone (Aldactazide, generics) 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. Copyright 2016 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(Professional Resource #321047: Page 4 of 5) Combination Single Pill Combination Availability Comments 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. Copyright 2016 by Therapeutic Research Center 3120 W. March Lane, Stockton, CA 95219 ~ Phone: 209-472-2240 ~ Fax: 209-472-2249 PharmacistsLetter.com ~ PrescribersLetter.com ~ PharmacyTechniciansLetter.com ~ NursesLetter.com

(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;4:42-50. 2. James PA, Oparil S, Carter BL, et al. 2014 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;311:507-20. 3. 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;370:829-40. 4. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-98. 5. Professional Resource, Atenolol for Hypertension. Pharmacist's Letter/Prescriber's Letter. January 2013. 6. 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;363:2022 31. 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 2001;358:1033-41. 8. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-28. 9. 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;32:569-88. 10. Chobanian AV. Does it matter how hypertension is controlled? N Engl J Med 2008;359:2485-8. 11. 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;367:2204-13. 12. Product information for Tekturna. Novartis Pharmaceuticals Corporation. East Hanover, NJ 07936. December 2015. 13. Product monograph for Rasilez. Novartis Pharmaceuticals Canada Inc. Dorval, QC H9S 1A9. May 2016. 14. Professional Resource, ACEI, ARB, and Aliskiren Comparison. Pharmacist s Letter/Prescriber s Letter. March 2016. 15. 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;92:532-6. 16. 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;265:3255-64. 17. 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;16:14-26. Cite this document as follows: Professional Resource, Antihypertensive Combinations. Pharmacist s Letter/Prescriber s Letter. October 2016. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 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

PL Detail-Document #280502 This Detail-Document accompanies the related article published in PHARMACIST S LETTER / PRESCRIBER S LETTER May 2012 Characteristics of the Various Statins Based on U.S. product labeling and relevant studies. Canadian product information given if differs significantly (e.g., more conservative) from U.S. (Full update November 2013) Drug a Atorvastatin (Lipitor, generics) Fluvastatin (Lescol, generics; Lescol XL) Potency (average decrease in LDL) 1,2,8 10 mg: 35-39% 20 mg: 43% 40 mg: 50% 80 mg: 55-60% 20 mg: 22% 40 mg: 25% 80 mg: 35% (as XL product) View our helpful PL Chart, Non-Statin Lipid-Lowering Agents Renal Liver Function Selected Drug Interactions Cost/month Considerations Monitoring c (U.S./ No dose adjustment necessary for reduced renal function. (Use 10 mg daily in patients with renal disease per Canadian labelling.) In severe renal impairment, use daily doses over 40 mg with caution. (Canadian labelling recommends not using if CrCl <30 ml/min.) Check liver function tests at baseline and when clinically indicated. 4 Check liver function tests at baseline (and 8 weeks after initiation or dosage increase, per Canadian labelling) and when clinically indicated. 4 Metabolized by CYP3A4, but less than lovastatin and simvastatin. Some drugs that significantly inhibit its metabolism through CYP3A4 inhibition include amiodarone, erythromycin, clarithromycin, telithromycin, itraconazole & other azoles, nefazodone, protease inhibitors, cyclosporine, and grapefruit juice; atorvastatin dose reduction or discontinuation may be recommended. Consider cautious dosing with niacin or fibrates (avoid gemfibrozil). Rifampin may increase or decrease levels, depending on timing. Metabolized primarily by CYP2C9. Few significant interactions with 2C9 inhibitors. 3 May be less likely to be involved in drug interactions. Use with phenytoin or glyburide can increase levels of both drugs. Consider dose reduction with niacin. Caution with fibrates (avoid gemfibrozil). Max dose 20 mg twice daily with cyclosporine or fluconazole. Rifampin decreases levels. Canada) b 10 mg: $7.08 (generic)/ $10.17 (generic) 80 mg XL: $162.24/ $49.39

(PL Detail-Document #280502: Page 2 of 9) Drug a Lovastatin (Mevacor, generics) Potency (average decrease in LDL) 1,2,8 10 mg: 21% 20 mg: 24-27% 40 mg: 30-31% 80 mg: 40-42% (as 40 mg BID) Renal Considerations If CrCl <30 ml/min, use daily doses over 20 mg with caution. Liver Function Selected Drug Interactions Cost/month Monitoring c (U.S./ Canada) b Check liver function tests at baseline (and periodically, per Canadian labelling [more frequent with 40 mg or more]) and when clinically indicated. 4 Metabolized by CYP3A4. Contraindicated with strong CYP3A4 inhibitors including erythromycin, clarithromycin, telithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, protease inhibitors, and nefazodone. Avoid grapefruit and cyclosporine (cyclosporine contraindicated [Canada]). Do not exceed 40 mg daily with amiodarone. Do not exceed 20 mg daily with diltiazem, verapamil, danazol, dronedarone, or niacin >1000 mg/day (Canada), or 40 mg daily with extendedrelease niacin (Niaspan). Consider dose reduction with ranolazine. Caution with fibrates (avoid gemfibrozil; do not exceed 20 mg daily with fibrates [Canada]). 40 mg: $<5 (generic)/ $29.11 (generic) Pitavastatin (Livalo) (U.S. only) 1 mg: 29% 2 mg: 36-39% 4 mg: 41-45% For glomerular filtration rate (GFR) 15-59 ml/min/1.73m 2, including hemodialysis, initial daily dose is 1 mg, max daily dose is 2 mg. Check liver function tests at baseline and when clinically indicated. 4 Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Contraindicated with cyclosporine. Limit dose to 1 mg daily with erythromycin or 2 mg daily with rifampin. Consider dosage reduction with niacin. Caution with fibrates (avoid gemfibrozil). 2 mg: $150

(PL Detail-Document #280502: Page 3 of 9) Drug a Pravastatin (Pravachol, generics) Rosuvastatin (Crestor, generics [Canada]) Potency (average decrease in LDL) 1,2,8 10 mg: 22% 20 mg: 29% 40 mg: 34% 80 mg: 37% 5 mg: 45% 10 mg: 46-49% 20 mg: 50-55% 40 mg: 55-63% Renal Considerations In significant renal impairment, start with 10 mg daily. (Canadian labelling advises caution with daily doses of 40 mg or more in renal impairment.) If CrCl <30 ml/min/1.73 m 2 (but not on hemodialysis), starting dose is 5 mg daily, maximum 10 mg daily. Rosuvastatin levels in hemodialysis patients are about 50% higher than levels in normal renal function. Liver Function Selected Drug Interactions Cost/month Monitoring c (U.S./ Canada) b Check liver function tests at baseline (and 12 weeks after initiation or dosage increase, per Canadian labelling), and when clinically indicated. 4 Check liver function tests at baseline (and 12 weeks after initiation, and before and 12 weeks after titration to 40 mg, per Canadian labelling), and when clinically indicated. 4 Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Do not exceed 20 mg once daily with cyclosporine. Do not exceed 40 mg once daily with clarithromycin. Caution with fibrates (avoid gemfibrozil). Consider dose reduction with niacin >1000 mg/day. Not significantly metabolized by cytochrome P450 and may be less likely to be involved in drug interactions. Substrate of transporter proteins OATP1B1 and BCRP. Drugs that may increase rosuvastatin levels include dronedarone and itraconazole. Caution with niacin. Limit to 10 mg with lopinavir/ritonavir or atazanavir/ritonavir. Use caution with other protease inhibitor/ritonavir combos. Protease inhibitor use discouraged in Canadian labelling. Canada: cyclosporine contraindicated. Rosuvastatin 40 mg contraindicated with fibrate or niacin. U.S.: max rosuvastatin dose 5 mg with cyclosporine, and 10 mg with gemfibrozil (avoid gemfibrozil preferred); caution with fenofibrate. 40 mg: $18.82 (generic)/ $18.65 (generic) 5 mg: $171.33/ $10.45 (generic)

(PL Detail-Document #280502: Page 4 of 9) Drug a Simvastatin (Zocor, generics) Potency (average decrease in LDL) 1,2,8 5 mg: 26% 10 mg: 29% 20 mg: 38% 40 mg: 30-41% 80 mg: 36-47% Renal Considerations In severe renal impairment, starting dose is 5 mg daily with close monitoring. (Per Canadian labelling, caution with doses >10 mg daily with severe renal impairment [CrCl <30 ml/min].) Liver Function Selected Drug Interactions Cost/month Monitoring c (U.S./ Canada) b Check liver function tests at baseline and when clinically indicated. 4 (Per Canadian labelling, for patients to be titrated to 80 mg, check prior to dosage increase, three months later, then periodically [e.g., semiannually] for the first year.) Metabolized by CYP3A4. Contraindicated with strong CYP3A4 inhibitors including erythromycin, clarithromycin, telithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, protease inhibitors, and nefazodone. Cyclosporine and danazol contraindicated. Avoid grapefruit. Do not exceed 20 mg daily with amiodarone, amlodipine, ranolazine, or lomitapide. Do not exceed 10 mg daily with diltiazem, verapamil, or dronedarone. Do not exceed 40 mg daily with extended-release niacin (Niaspan), in Chinese patients taking >1 g/day niacin, or with lomitapide in patients who have previously tolerated simvastatin 80 mg. Contraindicated with gemfibrozil. Caution with fibrates (do not exceed 10 mg with fenofibrate [Canada]). 20 mg: $<4 (generic)/ $20.26 (generic) a. The following product labeling was used for the above chart: Lipitor (October 2012), Lescol/Lescol XL (October 2012), Mevacor (October 2012), Livalo (October 2013), Pravachol (October 2012), Crestor (August 2013), Zocor (October 2013), Niaspan (March 2013), Lipitor Canada (May 2013), Lescol/Lescol XL Canada (September 2013), Mevacor Canada (April 2013), Pravachol Canada (January 2013), Crestor Canada (May 2013), Zocor Canada (March 2013). b. U.S. cost is wholesale average cost (WAC). Canadian cost is wholesale cost. Cost is for generic if available. c. Tell statin users to stop the statin and report symptoms of liver injury (e.g., jaundice, abdominal pain, etc) right away. Stop the statin in the event of evidence of liver injury (e.g., elevated direct bilirubin level, hepatomegaly, jaundice, increased prothrombin time). 5,6 If the statin cannot be excluded as a cause of liver injury, do not restart a statin. 5 But if elevated transaminase levels are the only problem, experts recommend continuing the statin. 5 There s no proof that dose reduction is necessary. 5 If transaminases exceed three times the upper limit of normal, repeat the test. 6 In asymptomatic patients with transaminases less than five times normal and no evidence of liver injury, the repeat test can be deferred for six months.

(PL Detail-Document #280502: Page 5 of 9) In the meantime, stop alcohol and hepatotoxic medications, encourage weight loss, and control diabetes. 7 consider decreasing the dose or stopping the statin. 6 If still elevated, rule out other causes and Abbreviations: ACS = acute coronary syndrome; CHD = coronary heart disease; HDL = high-density lipoprotein cholesterol; LDL = low-density lipoprotein cholesterol; MACE = major adverse cardiac event (cardiac death, non-fatal MI, or revascularization); MI = myocardial infarction; OATP = organic anion transporting polypeptide; PCI = percutaneous coronary intervention; TIA = transient ischemic attack. Evidence is Level A for all studies except CARDS, FLORIDA, TREADMILL [Level A/B] and GREACE and L-CAD [Level B]. Clinical Benefit of Statins (Study acronym in parentheses; FDA-labeled indications are underlined. Full update April 2012.) Atorvastatin (Lipitor) Primary prevention of CHD: Reduces non-fatal MI and fatal CHD, and stroke in patients with hypertension and total cholesterol <250 mg/dl (ASCOT). Primary prevention of CHD in diabetes: Reduces stroke and MI in patients with type 2 diabetes, an additional CHD risk factor, and LDL <160 mg/dl (CARDS). Secondary prevention of CHD: 80 mg/day reduced risk of major cardiovascular events in patients with CHD and LDL<130 mg/dl vs 10 mg. No overall mortality difference (TNT). Secondary prevention of CHD: 80 mg/day reduced risk of non-fatal cardiovascular events vs simvastatin 40-80 mg/day in patients with CHD and previous MI (mean LDL 121.5 mg/dl) (IDEAL). Secondary prevention of CHD:* Reduced risk of coronary morbidity and mortality, and stroke in open-label comparison with usual care of patients with LDL >100 mg/dl (GREACE). (*Note: GREACE not used to support this indication.) 80 mg/day begun within 1 to 4 days after ACS reduced recurrent ischemic events and stroke over 4 months (MIRACL). In ACS, intense lipid lowering (median LDL 62 mg/dl) lowers risk of death/major cardio events more than moderate lipid lowering (median LDL 95 mg/dl) (PROVE-IT). Regresses/slows progression of atherosclerosis (ASAP, ARBITER, REVERSAL). Unclear benefit in peripheral arterial disease (TREADMILL).

(PL Detail-Document #280502: Page 6 of 9) Fluvastatin (Lescol) Slows progression of atherosclerosis in patients with CHD and mild to moderate hypercholesterolemia (LCAS). Secondary prevention of CHD: Reduces need for revascularization. Dose of 40 mg twice daily reduced risk of MACE when begun within days after PCI in patients with average cholesterol levels (LIPS). Did not reduce MACE in renal transplant recipients, but secondary endpoints of cardiac death and MI were reduced (ALERT). No benefit for early treatment of ACS with 80 mg/day (FLORIDA). Lovastatin (Mevacor) Primary prevention of CHD: Reduces first acute coronary event, MI, unstable angina, and revascularization in patients with average LDL (AFCAPS/ TexCAPS). Slows progression of coronary atherosclerosis in CHD (CCAIT, FATS, MARS). Improvement also in carotid arteries (ACAPS). Pitavastatin (Livalo) Pitavastatin 4 mg and atorvastatin 20 mg similarly reduce nonculprit coronary plaque volume post-acs (JAPAN-ACS). Pravastatin (Pravachol) Primary prevention of CHD: Reduces cardiovascular death, MI, and revascularization in patients with high LDL and multiple risk factors (WOSCOPS). Secondary prevention of CHD: Reduces recurrent MI, coronary death, revascularization, and stroke/tia across range of cholesterol levels (CARE, LIPID). Slows progression of coronary atherosclerosis in CHD; improvement also in carotid arteries (REGRESS, PLAC I, PLAC II, KAPS). Failed to show benefit in hypertensive patients (ALLHAT-LLT), but result probably due to high non-study statin use in usual care group. Preliminary study found lower risk of MACE with early therapy of ACS (L-CAD). Reduced composite of coronary death, non-fatal MI, and stroke in high-risk patients >70 years old, but no benefit for stroke alone; result attributed to short study duration (PROSPER).

(PL Detail-Document #280502: Page 7 of 9) Rosuvastatin (Crestor) Regression of atherosclerosis with intensive statin therapy in patients with angiographic coronary disease. 40 mg/day reduced LDL (mean 60.8 mg/dl), raised HDL (mean 49.0 mg/dl), and reduced percent mean atheroma volume by 0.98% (ASTEROID). Slows progression of atherosclerosis (METEOR). Primary prevention of CAD: Reduces MI, stroke, and cardiovascular death in patients with LDL <130 mg/dl and hs-crp >2 mg/l (JUPITER). Simvastatin (Zocor) Primary and secondary prevention of CHD: Reduces risk of total mortality, non-fatal MI, stroke, and revascularization in patients at high risk of coronary events c, but with normal cholesterol (including LDL <100 mg/dl, women, diabetes, and peripheral arterial disease) (HPS). Secondary prevention of CHD: Reduces recurrent MI, coronary and total mortality, revascularization, and stroke in patients with high LDL (4S). Slows progression of atherosclerosis in patients with CHD and normal to high cholesterol (MAAS, SCAT). Combined with niacin reduces major coronary events in patients with CHD and HDL <35 mg/dl (HATS). Reduces vascular events (HPS) and development/progression of intermittent claudication (4S) in peripheral arterial disease. c. In patients with CHD or CHD risk-equivalent (diabetes, peripheral arterial disease, history of stroke or other cerebrovascular disease). Statin Clinical Trials 4S - Scandinavian Simvastatin Survival Study: Lancet 1994;344:1383-9. Am J Cardiol 1998;81:333-5. ACAPS - Asymptomatic Carotid Artery Progression Study: Circulation 1994;90:1679-87. AFCAPS/TEXCAPS - Air Force/Texas Coronary Atherosclerosis Prevention Study: JAMA 1998;279:1615-22. ALERT - Assessment of Lescol in Renal Transplantation Study: Lancet 2003;361:2024-31. ALLHAT-LLT - Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: JAMA 2002;288:2998-3007. ARBITER - Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: Circulation 2002;106:2055-60. ASAP - Atorvastatin versus Simvastatin on Atherosclerosis Prevention: Lancet 2001;357:577-81. ASCOT - Anglo-Scandinavian Cardiac Outcomes Trial: Lancet 2003;361:1149-58. ASTEROID - A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden: JAMA 2006;295:1556-65. CARDS - Collaborative Atorvastatin Diabetes Study. Lancet 2004;364:685-96. CARE - Cholesterol and Recurrent Events Trial: N Engl J Med 1996;335:1001-9. CCAIT - Canadian Coronary Atherosclerosis Intervention Trial: Circulation 1994;89:959-68. Circulation 1995;92:2404-10.

(PL Detail-Document #280502: Page 8 of 9) FATS - Familial Atherosclerosis Treatment Study: N Engl J Med 1990;323:1289-98. FLORIDA - Fluvastatin on Risk Diminishing after Acute Myocardial Infarction: [Abstract] Circulation 2000;102:2672d. GREACE - GREek Atorvastatin and Coronary-heart-disease Evaluation study: Curr Med Res Opin 2002;18:220-8. HATS - HDL Atherosclerosis Treatment Study: N Engl J Med 2001;345:1583-92. HPS - Heart Protection Study: Lancet 2002;360:7-22. Lancet 2003;361:2005-16. IDEAL - Incremental Decrease in End points through Aggressive Lipid lowering. JAMA 2005;294:2437-45. JAPAN-ACS - Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study. J Am Coll Cardiol 2009;54:293-302. JUPITER - Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. N Engl J Med 2008;359:2195-207. KAPS - Kuopio Atherosclerosis Prevention Study: Circulation 1995;92:1758-64. LCAS - Lipoprotein and Coronary Atherosclerosis Study: Am J Cardiol 1997;80:278-86. L-CAD - Lipid-Coronary Artery Disease Study: Am J Cardiol 2000;86:1293-8. LIPID - Long-term Intervention with Pravastatin in Ischaemic Disease: N Engl J Med 1998;339:1349-57. LIPS - Lescol Intervention Prevention Study: JAMA 2002;3215-22. MAAS - Multicentre Anti-Atheroma Study: Lancet 1994;344:633-8. MARS - Monitored Atherosclerosis Regression Study: Ann Intern Med 1993;119:969-76. METEOR - Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin: JAMA 2007;297:1344-53. MIRACL - Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering: JAMA 2001;285:1711-8. PLAC-I - Pravastatin Limitation of Atherosclerosis in the Coronary arteries (PLAC-I): J Am Coll Cardiol 1995;26:1133-9. PLAC-II - Pravastatin Limitation of Atherosclerosis in the Carotid arteries. Am J Cardiol 1995;75:455-9. PROSPER - Prevention of First Stroke: Lancet 2002;360:1623-30. PROVE-IT - Pravastatin or Atorvastatin Evaluation and Infection Therapy: New Engl J Med 2004;350 (early release). REGRESS - Regression Growth Evaluation Study: Circulation 1995;91:2528-40. REVERSAL - Reversal of Atherosclerosis with Aggressive Lipid Lowering. JAMA 2004;291:1071-80. SCAT - Simvastatin/Enalapril Coronary Atherosclerosis Trial: Circulation 2000;102:1748-54. TNT - Treating to New Targets. N Engl J Med 2005;352:1425-35. TREADMILL - Treatment of Peripheral Atherosclerotic Disease with Moderate or Intensive Lipid Lowering: Creager MA, et al [Abstract]. Presented at the 14th International Symposium on Drugs Affecting Lipid Metabolism, New York, September 9-13, 2001. Mohler E, et al. [Abstract]. Presented at the 75th Scientific Sessions of the American Heart Association, Chicago, November 17-20, 2002. WOSCOPS - West of Scotland Coronary Prevention Study: N Engl J Med 1995;333:1301-7. Users of this PL Detail-Document 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.

(Detail-Document #280502: Page 9 of 9) Levels of Evidence In accordance with the trend towards Evidence-Based Medicine, we are citing the LEVEL OF EVIDENCE for the statements we publish. Level Definition A High-quality randomized controlled trial (RCT) High-quality meta-analysis (quantitative systematic review) B Nonrandomized clinical trial Nonquantitative systematic review Lower quality RCT Clinical cohort study Case-control study Historical control Epidemiologic study C Consensus Expert opinion D Anecdotal evidence In vitro or animal study Adapted from Siwek J, et al. How to write an evidence-based clinical review article. Am Fam Physician 2002;65:251-8. Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS differences in transporter and metabolic enzyme functions. Pharmacol Ther 2006;112:71-105. 4. FDA. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. February 28, 2012. http://www.fda.gov/drugs/drugsafety/ucm293101.ht m. (Accessed March 16, 2012). 5. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol 2006;97:77C-81C. 6. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol 2006;97:89C-94C. 7. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002;123:1364-6. 8. Stone NJ, Robinson J, Lichtenstein C, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013. (Published ahead of print Nov 12). DOI: 10.1161/01.cir.0000437738.63853.7a. References 1. PL Detail-Document, Statin Dose Comparison (U.S.). Pharmacist s Letter/Prescriber s Letter. August 2009 (Full update June 2013). 2. PL Detail-Document, Statin Dose Comparison (Canada). Pharmacist s Letter/Prescriber s Letter. August 2009 (Last modified November 2011). 3. Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug-drug interactions and interindividual Cite this document as follows: PL Detail-Document, Characteristics of the Various Statins. Pharmacist s Letter/Prescriber s Letter. May 2012. Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2012 by Therapeutic Research Center Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com