Treating Microalbuminuria

Transcription

1 Background Diabetic nephropathy is the most common cause of end stage renal disease (ESRD). In diabetes, high blood glucose causes glomerular hyperfiltration and triggers inflammation, oxidative damage, fibrosis, and activation of the renin-angiotensin-aldosterone system (RAAS). Not surprisingly, RAAS blockers (e.g., angiotensin converting enzyme inhibitors [ACEIs], angiotensin receptor blockers (ARBs]) have been studied to prevent progression of diabetic nephropathy. 1 Microalbuminuria, defined as 30 to 299 mg albumin/g creatinine (Canada: 2 mg/mmol to 20 mg/mmol in men or 2.8 to 28 in women) in a random urine sample, is associated with nephron damage and cardiovascular disease. 1-3 Treatment of microalbuminuria with ACEIs or ARBs has been shown to reduce the risk of progression from micro- to macroalbuminuria. 4-6 This article addresses the question of whether treating microalbuminuria with a RAAS blocker prevents the hard clinical endpoints of ESRD and cardiovascular events. Reducing Microalbuminuria: Association with Clinical Endpoints ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial) enrolled patients with atherosclerosis, or diabetes with target organ damage. In ONTARGET, achieving a blood pressure of <130/80 mmhg was associated with a lower risk of microalbuminuria or macroalbuminuria, and even conversion to normoalbuminuria, vs achieving a blood pressure of <140/90 mmhg. However, tight control (<130/80 mmhg) did not reduce cardiovascular events more than achieving a blood pressure of <140/90 mmhg. 7 The primary renal outcome of ONTARGET was a composite of dialysis, creatinine doubling, or death. The combination of telmisartan (Micardis) plus ramipril (Altace) increased the risk of the primary outcome vs either drug alone. PL Detail-Document # This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER April 2012 Treating Microalbuminuria This was despite the combination s superiority over ramipril alone at reducing progression from microalbuminuria to macroalbuminuria. 8 The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) study included almost 7000 patients with diabetes. Patients were randomized to benazepril (Lotensin) plus amlodipine (Norvasc) or benazepril plus hydrochlorothiazide. Benazepril/amlodipine was more effective at reducing cardiovascular events compared to benazepril/hydrochlorothiazide. However, only benazepril/hydrochlorothiazide was associated with reduction of microalbuminuria. 9 In ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation), patients with type 2 diabetes were randomized to perindopril/indapamide (Coversyl Plus, Canada) or placebo. Although active treatment was effective for preventing onset of microalbuminuria, preventing progression of microalbuminuria to macroalbuminuria, and even regression of albuminuria, it did not prevent development of ESRD. 10 The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints) study set out to determine if aliskiren (Tekturna) 300 mg once daily added to an ACEI or ARB would reduce renal and cardiovascular morbidity and mortality in patients with type 2 diabetes at high event risk. The study included patients with albuminuria, microalbuminuria, or cardiovascular disease. 11 In an interim analysis of the ALTITUDE trial, patients receiving the combination had a higher risk of nonfatal stroke, end-stage renal disease, renal death, hyperkalemia, and hypotension. Most patients baseline blood pressure was controlled. 12 Based on these results, the U.S. manufacturer is recommending against the use of aliskiren with an ACEI or ARB in patients with diabetes. 12 Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~ ~

2 Novartis Pharmaceuticals Canada is also recommending against use of aliskiren with an ACEI or ARB in patients with diabetes. 13 Once additional analysis of ALTITUDE is complete, Health Canada will update the product monograph in In the ROADMAP (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention) trial, olmesartan (Benicar) was studied to prevent microalbuminuria in normoalbuminuric diabetic patients. Microalbuminuria onset was delayed, but cardiovascular events were increased. 14 In the BENEDICT-B (Bergamo Nephrologic Diabetes Complications Trial-B) study, trandolapril (Mavik) alone was compared to verapamil/trandolapril in hypertensive diabetic patients with microalbuminuria. There was no placebo group. Both treatments were similar in regard to progression to macroalbuminuria, regression to normoalbuminuria, and occurrence of major cardiovascular events. Patients who regressed to normoalbuminuria had fewer cardiovascular events vs those who did not regress. This effect was seen independent of treatment group. Patients who regressed had higher blood pressure, better glycemic control, shorter duration of diabetes, and lower urinary albumin excretion at baseline. 15 Commentary In the U.S., annual screening for microalbuminuria in patients 18 through 75 years of age with diabetes is one component of the Centers for Medicare and Medicaid Services (CMS) Physician Quality Reporting diabetes measures group. 16 In addition, private insurers are increasingly pursuing diabetes measures for their pay for performance programs. 17 Annual screening is also recommended by diabetes guidelines. 3,18 But what do you do with the test result? Macroalbuminuria is diagnosed if the patient has 300 mg albumin/g creatinine or greater (Canada: over 20 mg/mmol in men or over 28 mg/mmol in women) on spot urine collection. 17,18 The American Diabetes Association recommends that the diagnosis only be made if two of three tests within a three to six month period are abnormal. 18 If the patient has macroalbuminuria, an ACEI or ARB is indicated to reduce the risk of progression to ESRD [Evidence level A; high-quality randomized (PL Detail-Document #280412: Page 2 of 4) controlled trials]. 19,20 Canadian guidelines (and other experts) suggest checking an albumin/creatinine ratio every six months in patients with macroalbuminuria. 17 Diabetes guidelines also recommend an ACEI or ARB for normotensive diabetes patients with microalbuminuria. 3,18 However, current evidence does not support it. ACEIs and ARBs also have not been shown to prevent slow nephropathy progression in normotensive/normoalbuminuric patients with diabetes. 21 To reduce the risk or slow the progression of nephropathy, address glucose control as well as blood pressure. 18,22,23 For patients with diabetes and hypertension, a target blood pressure of <130/80 mmhg is recommended. 19,23 The recent ACCORD blood pressure study suggests that achieving an average systolic blood pressure of around 119 mmhg doesn t reduce overall cardiovascular outcomes compared to an average systolic blood pressure of about 133 mmhg [Evidence level A; high-quality RCT]. 24 However, this lower blood pressure was associated with a reduced risk of stroke and macroalbuminuria. 24 In the absence of macroalbuminuria, don t feel that you must use an ACEI or ARB for blood pressure control. 25 That being said, ACEIs and ARBs have been shown to reduce cardiovascular morbidity and mortality in hypertensive patients with and without diabetes. 3,24,26,27 In addition, ACEIs and ARBs are among the first-line options for hypertension, even for patients without compelling indications. 28,29 Although an ACEI/ARB combination can reduce proteinuria, it can actually increase risk of cardiovascular death, renal events, and hyperkalemia. 7,30,31 Adding aliskiren to an ACEI or ARB might increase cardiovascular and renal events in patients with diabetes and should be avoided until more is known. 7,10 In addition to blood pressure control, focus on other interventions to reduce cardiovascular risk, such as reaching lipid goals and smoking cessation, for all patients with diabetes, regardless of proteinuria. 18 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 Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~ ~

3 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. 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: Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. Choudhury D, Tuncel M, Levi M. Diabetic nephropathy a multifaceted target of new therapies. Discov Med 2012;10: Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007;2: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Chronic kidney disease in diabetes. Can J Diabetes 2008;32(Suppl 1):S (Accessed March 14, 2012). 4. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355: Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345: Makino H, Haneda M, Babazono T, et al. Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes. Diabetes Care 2007;30: Mancia G, Schumacher H, Redon J, et al. Blood pressure targets recommended by guidelines and (PL Detail-Document #280412: Page 3 of 4) incidence of cardiovascular and renal events in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Circulation 2011;124: Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372: Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010;56: De Galen BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduced renal events in type 2 diabetes. J Am Soc Nephrol 2009;20: Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009;24: Novartis Pharmaceuticals Corporation. Direct Healthcare Professional Communication on potential risks of cardiovascular and renal adverse events in patients with type 2 diabetes and renal impairment and/or cardiovascular disease treated with aliskiren (Tekturna) tablets and aliskirencontaining combination products. January %20Dear_HCP_Letter_ _with%20Te k-val%20pis_vf.pdf. (Accessed March 12, 2012). 13. Health Canada. Rasilez (aliskiren) and Rasilez HCT (aliskiren/hydrochlorothiazide)-potential risks of cardiovascular and renal adverse events in patients with type 2 diabetes-for health professionals. January 20, (Accessed March 12, 2012). 14. Haller H, Ito S, Izzo JL, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364: Ruggenenti P, Fassi A, Ilieva AP, et al. Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. J Hypertens 2011;29: Centers for Medicare and Medicaid Services physician quality reporting system (physician quality reporting) measures groups specifications manual. ualrptg_measuresgroups_specificationsmanual_ pdf?agree=yes&next=Accept. (Accessed March 12, 2012). 17. Kuritzky L. Type 2 diabetes mellitus: improving key performance measures. December 22, (Accessed March 13, 2012). 18. American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2012;35:S11-S63. Copyright 2012 by Therapeutic Research Center P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~ ~

4 (PL Detail-Document #280412: Page 4 of 4) 19. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993;329: Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 2009;361: American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 2002;25(Suppl 1):S28-S KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease (2007). ne_diabetes/. (Accessed March 12, 2012). 24. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362: Sica D. Are there pleiotropic effects of antihypertensive medications or is it all about the blood pressure in the patient with diabetes and hypertension? J Clin Hypertens 2011;13: ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker versus diuretic: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002;288: 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: Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289(19): The Canadian Hypertension Society Canadian Hypertension Education Program recommendations for management of hypertension. gl/2012completecheprecommendationsen.pdf. (Accessed March 14, 2012). 30. Kunz R, Friedrich C, Wolbers M, Mann JF. Metaanalysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008;148: Imai E, Chan JC, Ito S, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia 2011;54: Cite this document as follows: PL Detail-Document, Treating Microalbuminuria. Pharmacist s Letter/Prescriber s Letter. April Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) 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 or

5 Detail-Document # R October 2010 ~ Volume 26 ~ Number Antihypertensive Combinations (Last modified January 2012) 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 less side effects and at lower doses, than using a single drug. 2 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. Abbreviations: ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker. a. Dihydropyridine CCBs = amlodipine, felodipine, nifedipine, nisoldipine. b. The thiazide chlorthalidone provides better 24-hour blood pressure control than hydrochlorothiazide, and was used in pivotal outcomes studies (e.g., ALLHAT, SHEP). 2,10 c. Guideline does not distinguish between dihydropyridine and nondihydropyridine CCB. d. Combination not specifically addressed in guideline. Combination Single Pill Combination Availability Comments Preferred Combinations for Uncomplicated Hypertension ACEI or ARB plus diuretic b All ARBs and most ACEI available in Reduces risk of hypokalemia. 1 combination with hydrochlorothiazide. ACEI/ARB ameliorates diuretic-induced activation of the All ACEI/hydrochlorothiazide combos renin-angiotensin-aldosterone system. Additive blood available generically in U.S. pressure reduction. 1 Losartan/hydrochlorothiazide available Outcomes data for ACEI/thiazide combination (e.g., generically in U.S. reduces stroke, heart failure, mortality, diabetes Olmesartan/amlodipine/ complications). 2-4 hydrochlorothiazide (Tribenzor [U.S.]) d Good option for chronic renal insufficiency. 2 Perindopril/indapamide (Coversyl Plus ARBs second-line (less outcomes data, especially in [Canada]) comorbidities or high cardiac risk). 2.9 Valsartan/amlodipine/hydrochlorothiazide (Exforge HCT [U.S.]) d Azilsartan/chlorthalidone (Edarbyclor [U.S.]) Copyright 2010 by Therapeutic Research Center ~ P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~

6 (Detail-Document #261001: Page 2 of 5) Combination Single Pill Combination Availability Comments Preferred Combinations for Uncomplicated Hypertension, continued ACEI or ARB plus CCB c Benazepril/amlodipine (Lotrel, generics [U.S.]) ACEI/ARB ameliorate calcium channel blocker-induced edema. 1 Enalapril/felodipine (Lexxel [U.S.]) Also counteract dihydropyridine calcium channel blockerinduced Olmesartan/amlodipine/ sympathetic stimulation (e.g., tachycardia). 1 hydrochlorothiazide (Tribenzor [U.S.]) d Additive blood pressure reduction. 1 Ramipril/felodipine Dihydropyridine outcomes data is primarily with (Altace Plus Felodipine [Canada]) amlodipine. 8 Trandolapril/verapamil (Tarka) ARBs second-line (less outcomes data, especially in Valsartan/amlodipine (Exforge [U.S.]; comorbidities or high cardiac risk). 2.9 also available with hydrochlorothiazide as Exforge HCT d [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 renin-angiotensin-aldosterone system. 1 Atenolol/hydrochlorothiazide (U.S.) Additive blood pressure reduction. 1 Bisoprolol/hydrochlorothiazide (Ziac, generics [U.S.]) Thiazides improve beta-blocker efficacy in African Americans. 1 Metoprolol/hydrochlorothiazide Side effects (fatigue, sexual dysfunction, glucose (Lopressor HCT, generics [U.S.]) intolerance) may be problematic. 1 Nadolol/bendroflumethiazide (Corzide, Beta-blockers seem less effective than other generics [U.S.]) antihypertensive classes for improving outcomes in Propranolol/hydrochlorothiazide hypertension (most data is from studies using atenolol). 5 (Inderide, generics [U.S.]) Reserve for patients with hypertension plus another Pindolol/hydrochlorothiazide (Viskazide [Canada]) condition that would benefit from a beta-blocker (e.g., heart failure, post-mi, angina, etc). 5 Thiazide b plus CCB c Aliskiren/amlodipine/ Blood pressure reduction not additive. 1 hydrochlorothiazide (Amturnide [U.S.]) d VALUE study: amlodipine plus hydrochlorothiazide Olmesartan/amlodipine/ hydrochlorothiazide (Tribenzor [U.S.]) d reduced cardiovascular events as well as valsartan plus hydrochlorothiazide. 6 Valsartan/amlodipine/ hydrochlorothiazide (Exforge HCT [U.S.] d Neither drug offsets the side effects of the other. 1 Copyright 2010 by Therapeutic Research Center ~ P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~

7 (Detail-Document #261001: Page 3 of 5) Combination Single Pill Combination Availability Comments Acceptable Combinations for Uncomplicated Hypertension, continued Thiazide b plus aliskiren Aliskiren/hydrochlorothiazide (Tekturna HCT [U.S.], Rasilez HCT [Canada]) Aliskiren reduces risk of hypokalemia. 1 Aliskiren/amlodipine/ hydrochlorothiazide (Amturnide [U.S.]) d Ameliorates thiazide-induced activation of the reninangiotensin-aldosterone system. 1 Additive blood pressure reduction. 1 Thiazide b plus potassium-sparing diuretic Hydrochlorothiazide/amiloride (Midamor, 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 a condition that would benefit from a beta-blocker (e.g., heart failure, post-mi, angina, etc). 5 Aliskiren plus CCB c Aliskiren/amlodipine (Tekamlo [U.S.]) Aliskiren/amlodipine/ hydrochlorothiazide (Amturnide [U.S.]) d Aliskiren ameliorates amlodipine-induced edema. 7 No outcomes data. Rese ARB. 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 Not recommended per Canadian guidelines. 9 May have role in systolic heart failure, or nondiabetic renal disease with proteinuria. 1,14 Copyright 2010 by Therapeutic Research Center ~ P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~

8 (Detail-Document #261001: Page 4 of 5) Combination Single Pill Combination Availability Comments Not Preferred Combinations for Uncomplicated Hypertension, continued Aliskiren plus ARB or ACEI Aliskiren/valsartan (Valturna [U.S.]) Valturna approval based on an 8-week hypertension study. 13 Additional blood pressure lowering of 30% with aliskiren/arb combo vs monotherapy. 1 No outcomes data. 1 Use of aliskiren with maximal dose of ACEI not adequately studied. 12 Aliskiren added to ACEI or ARB in patients with diabetes and high cardiovascular and renal risk increased the risk of nonfatal stroke, end stage renal disease, renal death, and hyperkalemia. Avoid combo in patients with diabetes. 11,15 Consider a preferred ACEI or ARB combo first. ACEI or ARB plus beta-blocker None Combination provides little additional blood pressure lowering. 1 Combination is appropriate for systolic heart failure or post-mi. 1 Nondihydropyridine CCB (i.e., verapamil, diltiazem) plus betablocker 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 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. Copyright 2010 by Therapeutic Research Center ~ P.O. Box 8190, Stockton, CA ~ Phone: ~ Fax: ~

9 (Detail-Document #261001: Page 5 of 5) Project Leader in preparation of this Detail- Document: 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: National Heart, Lung, and Blood Institute. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). full.pdf. (Accessed August 2, 2010). 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: 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: PL Detail-Document, Beta-blockers for Hypertension: Help or Harm? Pharmacist's Letter/Prescriber's Letter. December 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: Prescribing information for Tekamlo. Novartis Pharmaceuticals Corporation. East Hanover, NJ August 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: CHEP recommendations for the management of hypertension. /images/stories/dls/2011gl/_2011completecheprec ommendationsen_.pdf. (Accessed February 10, 2012). 10. Chobanian AV. Does it matter how hypertension is controlled? N Engl J Med 2008;359: Novartis Pharmaceuticals Corporation. Direct Healthcare Professional Communication on potential risks of cardiovascular and renal adverse events in patients with type 2 diabetes and renal impairment and/or cardiovascular disease treated with aliskiren (Tekturna) tablets and aliskiren-containing combination products. January %20Dear_HCP_Letter_ _with%20 Tek-Val%20PIs_vf.pdf. (Accessed January 10, 2012). 12. Product information for Tekturna. Novartis Pharmaceuticals Corporation. East Hanover, NJ October Product information for Valturna. Novartis Pharmaceuticals Corporation. East Hanover, NJ October PL Detail-Document, Combination Therapy for Hypertension. Letter. October (Last modified January 2012). 15. Health Canada. Rasilez (aliskiren) and Rasilez HCT (aliskiren/hydrochlorothiazide)-potential risks of cardiovascular and renal adverse events in patients with type 2 diabetes-for health professionals. January 18, (Accessed January 25, 2012). Cite this Detail-Document as follows: PL Detail-Document, Antihypertensive Combinations. Ph Letter/Pre. October 2010 (last modified January 2012). Evidence and Advice You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2010 by Therapeutic Research Center Subscribers to and can get Detail-Documents, like this one, on any topic covered in any issue by going to or