Skip to Content

Irbesartan

Class: Angiotensin II Receptor Antagonists
VA Class: CV805
Chemical Name: 2-Butyl-3-[[2′(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one
Molecular Formula: C25H28N6O3S•½C4H4 O4
CAS Number: 138402-11-6
Brands: Avapro

Medically reviewed on February 5, 2018

Warning

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 26 71 72 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue as soon as possible.1 26 72

Introduction

Angiotensin II receptor (AT1) antagonist (i.e., angiotensin II receptor blocker, ARB).1 2 4 5 6 21 22 23

Uses for Irbesartan

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 3 4 5 6 14 15 16 17 18 21 22 23 500

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Angiotensin II receptor antagonists or ACE inhibitors may be preferred in hypertensive patients with diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or post-MI.500 501 502 504 520 523 524 527 534 535 536 543

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.500 501 504 However, diminished response to an angiotensin II receptor antagonist is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Diabetic Nephropathy

Management of diabetic nephropathy manifested by elevated Scr and proteinuria (urinary protein excretion >300 mg daily) in patients with type 2 diabetes mellitus and hypertension.1

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.49 51 52 53 520 535 536

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure.524 528 800

Because of their established benefits, ACE inhibitors have been the preferred drugs for inhibition of the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced left ventricular ejection fraction (LVEF); 524 however, some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.701 702 703 800

Angiotensin II receptor antagonists may be used as an alternative for those patients in whom an ACE inhibitor or ARNI is inappropriate.524 800

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.800

Irbesartan Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

  • Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Oral Administration

Administer orally once daily without regard to meals.1 21

Dosage

Adults

Hypertension
Irbesartan Therapy
Oral

JNC 8 expert panel recommends initial dosage of 75 mg once daily and target dosage of 300 mg once daily based on dosages used in randomized controlled studies.501

Manufacturer recommends initial dosage of 150 mg once daily in adults without intravascular volume depletion.1 In adults with depletion of intravascular volume, the usual initial dosage is 75 mg once daily.1 24

Manufacturer states usual dosage is 150–300 mg once daily; no additional therapeutic benefit with higher dosages or with twice-daily dosing.1

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Irbesartan/Hydrochlorothiazide Fixed-combination Therapy
Oral

Manufacturer states fixed-combination preparation can be used for initial treatment of hypertension in patients who are likely to need multiple drugs to achieve their BP goals.26 Consider potential benefits and risks of initiating therapy with the fixed combination.26

If BP is not adequately controlled by monotherapy with irbesartan or hydrochlorothiazide, can switch to fixed-combination tablets (irbesartan 150 mg and 12.5 mg hydrochlorothiazide; then irbesartan 300 mg and hydrochlorothiazide 12.5 mg), administered once daily.26 Can increase dosage to irbesartan 300 mg and hydrochlorothiazide 25 mg daily, if needed, to control BP.26

In patients receiving fixed-combination tablets as initial therapy, the usual starting dosage is irbesartan 150 mg and hydrochlorothiazide 12.5 mg once daily.26 May increase dosage after 1–2 weeks of therapy to a maximum of irbesartan 300 mg and hydrochlorothiazide 25 mg once daily.26

Diabetic Nephropathy
Oral

Initial dosage of 75 mg once daily used in clinical trial.1 Increase dosage to target maintenance dosage of 300 mg once daily.1 No data available on effects of lower dosages.1

Special Populations

Hepatic Impairment

No initial dosage adjustments necessary.1 26

Renal Impairment

No initial dosage adjustments necessary.1 26

Irbesartan/hydrochlorothiazide fixed combination not recommended in patients with severe renal impairment.26

Geriatric Patients

No initial dosage adjustments necessary.1 26

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy using lower initial dosage (75 mg once daily).1 24 26 Fixed-combination tablets containing irbesartan and hydrochlorothiazide are not recommended as initial therapy in patients with intravascular volume depletion.26

Cautions for Irbesartan

Contraindications

  • Known hypersensitivity to irbesartan or any ingredient in the formulation.1 26

    Concomitant use of irbesartan and aliskiren in patients with diabetes mellitus.1 26 550 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible reduction in fetal renal function and increase in fetal and neonatal morbidity and mortality when drugs that act on the renin-angiotensin system (e.g., angiotensin II receptor antagonists, ACE inhibitors) are used during the second and third trimesters of pregnancy.1 26 (See Boxed Warning.) Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.1 26 Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.1 26

Discontinue irbesartan as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.1 72 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.13

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible;1 26 not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.544 545 73

Other Warnings and Precautions

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those receiving diuretics or undergoing dialysis).1 26 (See Volume- and/or Salt-depleted Patients under Dosage and Administration.)

Transient hypotension is not a contraindication to additional doses; may reinstate therapy cautiously after BP is stabilized (e.g., with volume expansion).1 26

Malignancies

In July 2010, FDA initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis found a modest but statistically significant increase in risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist compared with control.120 121 123 126 However, subsequent studies, including a larger meta-analysis conducted by FDA, have not shown such risk.126 127 128 129 Based on currently available data, FDA has concluded that angiotensin II receptor antagonists do not increase the risk of cancer.126

Renal Effects

Possible oliguria, progressive azotemia, and, rarely, acute renal failure and/or death in patients with severe heart failure.1 26

Increases in BUN and Scr possible in patients with renal artery stenosis, chronic kidney disease, or volume depletion.1 26

Use of Fixed Combinations

When used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.26

Specific Populations

Pregnancy

Category D.1 26 (See Boxed Warning.)

May cause fetal and neonatal morbidity and mortality when administered to a pregnant woman.1 26 Discontinue as soon as possible when pregnancy is detected.1 26 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 26 Discontinue nursing or the drug.1 26

Pediatric Use

If oliguria or hypotension occurs in neonates with a history of in utero exposure to irbesartan, support BP and renal function; exchange transfusions or dialysis may be required.1 26 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Dosages of up to 4.5 mg/kg once daily did not appear to effectively lower BP in pediatric patients 6–16 years of age.1 Not studied in children <6 years of age.1

Safety and efficacy of the fixed-combination preparation containing irbesartan and hydrochlorothiazide not established.26

Geriatric Use

No substantial differences in safety or efficacy of irbesartan monotherapy or fixed-combination containing irbesartan and hydrochlorothiazide relative to younger adults, but increased sensitivity cannot be ruled out.1 26

Renal Impairment

Use with caution.1

Deterioration of renal function may occur.1 26 (See Renal Effects under Cautions.)

Use of irbesartan in fixed combination with hydrochlorothiazide is not recommended in patients with severe renal impairment.26

Black Patients

BP reduction may be smaller in black patients than in patients of other races.1 26 69 70 (See Hypertension under Uses.)

Common Adverse Effects

Diarrhea, dyspepsia/heartburn, fatigue in patients with hypertension; also, dizziness, orthostatic dizziness, and orthostatic hypotension in patients with diabetic nephropathy.1

Interactions for Irbesartan

Metabolized principally by CYP2C9.1 26 Does not substantially induce or inhibit CYP1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.1 26

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased irbesartan metabolism) with CYP2C9 inhibitors.1 26

Specific Drugs

Drug

Interaction

Comments

ACE Inhibitors

Increased risk of renal impairment, hyperkalemia, and hypotension1 26

Generally avoid concomitant use1 26

Monitor BP, renal function, and electrolytes if used concomitantly1 26

Aliskiren

Increased risk of renal impairment, hyperkalemia, and hypotension1 26 550

Generally avoid concomitant use1 26

Monitor BP, renal function, and electrolytes if used concomitantly1 26 550

Concomitant use contraindicated in patients with diabetes mellitus1 26 550

Avoid concomitant use in patients with GFR<60 mL/minute1 26 550

Angiotensin II receptor antagonists

Increased risk of renal impairment, hyperkalemia, and hypotension1 26

Generally avoid concomitant use1 26

Monitor BP, renal function, and electrolytes if used concomitantly1 26

Digoxin

Pharmacologic and/or pharmacokinetic interactions unlikely1 26

Diuretics, potassium-sparing

Possible hyperkalemia1 26

Monitor serum potassium concentrations1 26

Hydrochlorothiazide

Pharmacokinetic interactions unlikely1 26

Additive hypotensive effects1 26

Lithium

Elevations in lithium concentrations and lithium toxicity reported1 26

Carefully monitor serum lithium concentrations 1 26 `

Nifedipine

Decreased irbesartan metabolism in vitro; alteration of irbesartan pharmacokinetics not observed in vivo1 26

NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors

Possible deterioration of renal function in geriatric, volume-depleted, or renally impaired patients1 26

Possible reduced antihypertensive effects1

Monitor renal function periodically1

Salt substitutes, potassium-containing

Possible hyperkalemia1 26

Monitor serum potassium concentrations1 26

Tolbutamide

Possible decreased irbesartan metabolism26

Warfarin

Pharmacologic and/or pharmacokinetic interaction unlikely1 26

Irbesartan Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration generally achieved 1.5–2 hours after oral dose.1 Absolute bioavailability is about 60–80%.1 26

Onset

Antihypertensive effect evident within 2 weeks, with maximum BP reduction after 2–4 weeks.1 26

Food

Food does not affect bioavailability.1 26

Distribution

Extent

Crosses the placenta and is distributed in the fetus in animals.1 26

Crosses the blood-brain barrier poorly, if at all, in animals.1 15

Distributed into milk in rats; not known whether distributed into human milk.1 26

Plasma Protein Binding

90% (principally albumin and α1-acid glycoprotein).1 26

Elimination

Metabolism

Undergoes hepatic metabolism by glucuronide conjugation and oxidation (principally by CYP2C9) to inactive metabolites.1 26

Elimination Route

Eliminated in urine and feces (via bile).1 26

Half-life

Terminal elimination half-life: 11–15 hours.1

Special Populations

Not removed by hemodialysis.1 26 Pharmacokinetics not substantially altered by hemodialysis or renal impairment.1 26

Stability

Storage

Oral

Tablets

15–30°C.1 26

Actions

  • Blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.1 21 22 23 26

  • Does not interfere with response to bradykinins and substance P.1 5 6 21

  • Does not share the ACE inhibitor common adverse effect of dry cough.1 5 6 21 26

Advice to Patients

  • Risks of use during pregnancy.1 26

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 26

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 26

  • Importance of informing patients of other important precautionary information.1 26 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Irbesartan

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

75 mg

Avapro

Sanofi-Aventis

150 mg

Avapro

Sanofi-Aventis

300 mg

Avapro

Sanofi-Aventis

Irbesartan Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

150 mg with Hydrochlorothiazide 12.5 mg

Avalide

Sanofi-Aventis

300 mg with Hydrochlorothiazide 12.5 mg

Avalide

Sanofi-Aventis

AHFS DI Essentials. © Copyright 2018, Selected Revisions February 5, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Sanofi-Aventis. Avapro (irbesartan) tablets prescribing information. Bridgewater, NJ; 2016 Jul.

2. van den Meiracker AH, Admiraal PJJ, Janssen JA et al. Hemodynamic and biochemical effects of the AT1 receptor antagonist irbesartan in hypertension. Hypertension. 1995; 25:22-9. http://www.ncbi.nlm.nih.gov/pubmed/7843749?dopt=AbstractPlus

3. Ellis ML, Patterson JH. A new class of antihypertensive therapy: angiotensin II receptor antagonists. Pharmacotherapy. 1996; 16:849-60. http://www.ncbi.nlm.nih.gov/pubmed/8888079?dopt=AbstractPlus

4. Bauer JH, Reams GP. The angiotensin II type 1 receptor antagonists: a new class of antihypertensive drugs. Arch Intern Med. 1995; 155:1361-8. http://www.ncbi.nlm.nih.gov/pubmed/7794084?dopt=AbstractPlus

5. Burnier M, Buclin T, Biollaz J et al. Pharmacokinetic-pharmacodynamic relationships of three angiotensin II receptor antagonists in normal volunteers. Kidney Int. 1996; 49(Suppl 55):S-24–S-29.

6. Velasquez MT. Angiotensin II receptor blockers: a new class of hypertensive drugs. Arch Fam Med. 1996; 5:351-356. http://www.ncbi.nlm.nih.gov/pubmed/8640326?dopt=AbstractPlus

7. Anon. Valsartan for hypertension. Med Lett Drugs Ther. 1997; 39:43-4. http://www.ncbi.nlm.nih.gov/pubmed/9137296?dopt=AbstractPlus

8. Pitt B, Segal R, Martinez FA et al for the ELITE study investigators. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997; 349:747-52. http://www.ncbi.nlm.nih.gov/pubmed/9074572?dopt=AbstractPlus

10. Anon. Drugs for hypertension. Med Lett Drugs Ther. 1995; 37:45-50. http://www.ncbi.nlm.nih.gov/pubmed/7760767?dopt=AbstractPlus

13. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull. 1992; 22:2.

14. Pool JL, Guthrie RM, Littlejohn T et al. The antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension. Am J Hypertens. 1996; 9:152A.

15. Fogari R, Zanchetti A, Moran S et al et al. Once-daily irbesartan provides full 24-hour ambulatory blood pressure control. J Hypertens. 1997; 15(Suppl 4):S113.

16. Stumpe KO, Haworth D, Höglund C et al et al. Comparison of the angiotensin II receptor antagonist, irbesartan, and atenolol for the treatment of hypertension. J Hypertens. 1997; 15(Suppl 4):S115.

17. Larochelle P, Flack JM, Hannah S et al et al. Irbesartan versus enalapril in severe hypertension. Am J Hypertens. 1997; 10:131A.

18. Mimran A, Ruilope L, Kerwin L et al et al. Comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of hypertension. J Hypertens. 1997; 15(Suppl 4):S117.

19. Cazaubon C, Gougat J, Bousquet F et al. Pharmacological characterization of SR 47436, a new nonpeptide AT1 subtype angiotensin II receptor antagonist. J Pharmacol Exp Ther. 1993; 265: 826-34. http://www.ncbi.nlm.nih.gov/pubmed/8496828?dopt=AbstractPlus

21. Anon. Irbesartan for hypertension. Med Lett Drugs Ther. 1998; 40:18-9. http://www.ncbi.nlm.nih.gov/pubmed/9465857?dopt=AbstractPlus

22. Kossler-Taub K, Littlejohn T, Elliott W et al. Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan, in mild-to-moderate hypertension. Am J Hypertens. 1998; 11:445-53. http://www.ncbi.nlm.nih.gov/pubmed/9607383?dopt=AbstractPlus

23. Larochelle P, Flack JM, Marbury TC et al. Effects and tolerability of irbesartan versus enalapril in patients with severe hypertension. Am J Cardiol. 1997; 80:1613-5. http://www.ncbi.nlm.nih.gov/pubmed/9416950?dopt=AbstractPlus

24. Bristol-Myers Squibb Company. Princeton, NJ: Personal communication.

25. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol. 1999; 83:9-38A.

26. Sanofi-aventis. Avalide (irbesartan-hydrochlorothiazide) tablets prescribing information. Bridgewater, NJ; 2016 Feb.

27. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. http://www.ncbi.nlm.nih.gov/pubmed/10818056?dopt=AbstractPlus

28. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. http://www.ncbi.nlm.nih.gov/pubmed/10818055?dopt=AbstractPlus

29. Merck & Co, Inc. Results of second heart-failure study with Cozaar presented at American Heart Association scientific sessions. West Point, PA; 1999 Nov 10. Press release from Yahoo web site. http://news.yahoo.com

30. Food and Drug Administration. Avapro (irbesartan) and Avalide (irbesartan/hydrochlorothiazide) tablets [May 9, 2000: Bristol-Myers Squibb]. MedWatch drug labeling changes. Rockville, MD; May 2000. From FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm172834.htm

31. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. http://www.ncbi.nlm.nih.gov/pubmed/10977801?dopt=AbstractPlus

32. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998; 351:1755-62. http://www.ncbi.nlm.nih.gov/pubmed/9635947?dopt=AbstractPlus

33. Pitt B, Segal R, Martinez FA et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997; 349:747-52. http://www.ncbi.nlm.nih.gov/pubmed/9074572?dopt=AbstractPlus

38. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001. From ACC website. Accessed July 25, 2002. http://www.cardiosource.org/Science-And-Quality/Practice-Guidelines-and-Quality-Standards.aspx

40. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001; 345:1667-75. http://www.ncbi.nlm.nih.gov/pubmed/11759645?dopt=AbstractPlus

41. Novartis. Diovan (valsartan) tablets prescribing information. East Hanover, NJ; 2002 Jul.

42. Williams CL, Hayman LL, Daniels SR et al. Cardiovascular health in childhood: a statement for health professional from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2002; 106:143-60. http://www.ncbi.nlm.nih.gov/pubmed/12093785?dopt=AbstractPlus

43. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345:851-60. http://www.ncbi.nlm.nih.gov/pubmed/11565517?dopt=AbstractPlus

44. Blankfield RP. Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med. 2002: 346;705. Letter.

45. Lewis EJ. Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med. 2002: 346;706. Letter.

46. Williams MA, Fleg JL, Ades PA et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients ≥ 75 years of age). An American Heart Association Scientific Statement from the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac rehabilitation, and Prevention. Circulation. 2002; 105:1735-43. http://www.ncbi.nlm.nih.gov/pubmed/11940556?dopt=AbstractPlus

47. 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; 345:861-9. http://www.ncbi.nlm.nih.gov/pubmed/11565518?dopt=AbstractPlus

48. Parving HH, Lehnert H, Bröchner-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; 345:870-6. http://www.ncbi.nlm.nih.gov/pubmed/11565519?dopt=AbstractPlus

49. Remuzzi G. Slowing the progression of diabetic nephropathy. N Engl J Med. 1993; 329:1496-7. http://www.ncbi.nlm.nih.gov/pubmed/8413463?dopt=AbstractPlus

51. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. http://www.ncbi.nlm.nih.gov/pubmed/8622249?dopt=AbstractPlus

52. Viberti G, Mogensen CE, Groop LC et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994; 271:275-9. http://www.ncbi.nlm.nih.gov/pubmed/8295285?dopt=AbstractPlus

53. Fournier A. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1994; 330:937. http://www.ncbi.nlm.nih.gov/pubmed/8114873?dopt=AbstractPlus

54. Kasiske VL, Kalil RSN, Ma JZ et al. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med. 1993; 118:129-138. http://www.ncbi.nlm.nih.gov/pubmed/8416309?dopt=AbstractPlus

55. Björck S, Mulec H, Johnsen SA et al. Renal protective effect of enalapril in diabetic nephropathy. BMJ. 1992; 304:339-43. http://www.ncbi.nlm.nih.gov/pubmed/1540729?dopt=AbstractPlus

56. Cook J, Daneman D, Spino M et al. Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus. J Pediatr. 1990; 117:39-45. http://www.ncbi.nlm.nih.gov/pubmed/2196359?dopt=AbstractPlus

57. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993; 329:1456-62. http://www.ncbi.nlm.nih.gov/pubmed/8413456?dopt=AbstractPlus

58. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA. 2002; 288:3039-60. http://www.ncbi.nlm.nih.gov/pubmed/12479770?dopt=AbstractPlus

59. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981-97. http://www.ncbi.nlm.nih.gov/pubmed/12479763?dopt=AbstractPlus

66. Morgensen CE, Neldman S, Tikkanen I et al. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000; 321:1440-4. http://www.ncbi.nlm.nih.gov/pubmed/11110735?dopt=AbstractPlus

67. Frohlich ED. Treating hypertension—what are we to believe? N Engl J Med. 2003; 348:639-401.

68. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004; 114(Suppl 2):555-76. http://www.ncbi.nlm.nih.gov/pubmed/15286277?dopt=AbstractPlus

69. Wright JT, Dunn JK, Cutler JA et al. Outcomes in hypertensive black and nonblack patients treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005; 293:1595-607. http://www.ncbi.nlm.nih.gov/pubmed/15811979?dopt=AbstractPlus

70. Neaton JD, Kuller LH. Diuretics are color blind. JAMA. 2005; 293:1663-6. http://www.ncbi.nlm.nih.gov/pubmed/15811986?dopt=AbstractPlus

71. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006; 354:2443-51. http://www.ncbi.nlm.nih.gov/pubmed/16760444?dopt=AbstractPlus

72. Food and Drug Administration. FDA public health advisory: angiotensin-converting enzyme inhibitor (ACE inhibitor) drugs and pregnancy. 2006 June 7. From FDA website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm053113.htm

73. Howes LG, Tran D. Can angiotensin receptor antagonists be used safely in patients with previous ACE inhibitor-induced angioedema? Drug Saf. 2002; 25:73-6.

120. Food and Drug Administration. FDA drug safety communication: ongoing safety review of the angiotensin receptor blockers and cancer. Rockville, MD; 2010 Jul 15. From FDA website (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm218845.htm).

121. Sipahi I, Debanne SM, Rowland DY et al. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010; 11:627-36. http://www.ncbi.nlm.nih.gov/pubmed/20542468?dopt=AbstractPlus

122. Nissen SE. Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Lancet Oncol. 2010; 11:605-6. http://www.ncbi.nlm.nih.gov/pubmed/20542469?dopt=AbstractPlus

123. Sica DA. Angiotensin receptor blockers and the risk of malignancy: a note of caution. Drug Saf. 2010; 33:709-12. http://www.ncbi.nlm.nih.gov/pubmed/20701404?dopt=AbstractPlus

126. Food and Drug Administration. FDA drug safety communication: No increase in risk of cancer with certain blood pressure drugs-angiotensin receptor blockers (ARBs). Rockville, MD; 2011 Jun 2. Available from FDA website. Accessed 2011 Jun 15. http://www.fda.gov/Drugs/DrugSafety/ucm257516.htm

127. Bangalore S, Kumar S, Kjeldsen SE et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol. 2011; 12:65-82. http://www.ncbi.nlm.nih.gov/pubmed/21123111?dopt=AbstractPlus

128. ARB Trialists Collaboration. Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138,769 individuals. J Hypertens. 2011; 29:623-35. http://www.ncbi.nlm.nih.gov/pubmed/21358417?dopt=AbstractPlus

129. Pasternak B, Svanström H, Callréus T et al. Use of angiotensin receptor blockers and the risk of cancer. Circulation. 2011; 123:1729-36. http://www.ncbi.nlm.nih.gov/pubmed/21482967?dopt=AbstractPlus

130. Volpe M, Morganti A. 2010 Position Paper of the Italian Society of Hypertension (SIIA): Angiotensin Receptor Blockers and Risk of Cancer. High Blood Press Cardiovasc Prev. 2011; 18:37-40. http://www.ncbi.nlm.nih.gov/pubmed/21612311?dopt=AbstractPlus

131. Siragy HM. A current evaluation of the safety of angiotensin receptor blockers and direct renin inhibitors. Vasc Health Risk Manag. 2011; 7:297-313. http://www.ncbi.nlm.nih.gov/pubmed/21633727?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3104607&blobtype=pdf

132. Granger CB, McMurray JJ, Yusuf S et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003; 362:772-6. http://www.ncbi.nlm.nih.gov/pubmed/13678870?dopt=AbstractPlus

500. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). Bethesda, MD: National Institutes of Health; 2004 Aug. (NIH publication No. 04-5230.)

501. 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. http://www.ncbi.nlm.nih.gov/pubmed/24352797?dopt=AbstractPlus

502. Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013; 31:1281-357. http://www.ncbi.nlm.nih.gov/pubmed/23817082?dopt=AbstractPlus

503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension. 2014; 63:878-85. http://www.ncbi.nlm.nih.gov/pubmed/24243703?dopt=AbstractPlus

504. 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. http://www.ncbi.nlm.nih.gov/pubmed/24341872?dopt=AbstractPlus

505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med. 2014; 160:499-503. http://www.ncbi.nlm.nih.gov/pubmed/24424788?dopt=AbstractPlus

506. Mitka M. Groups spar over new hypertension guidelines. JAMA. 2014; 311:663-4. http://www.ncbi.nlm.nih.gov/pubmed/24549531?dopt=AbstractPlus

507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA. 2014; 311:474-6. http://www.ncbi.nlm.nih.gov/pubmed/24352710?dopt=AbstractPlus

508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA. 2014; 311:477-8. http://www.ncbi.nlm.nih.gov/pubmed/24352759?dopt=AbstractPlus

511. JATOS Study Group. Principal results of the Japanese trial to assess optimal systolic blood pressure in elderly hypertensive patients (JATOS). Hypertens Res. 2008; 31:2115-27. http://www.ncbi.nlm.nih.gov/pubmed/19139601?dopt=AbstractPlus

515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med. 2014; 81:178-88. http://www.ncbi.nlm.nih.gov/pubmed/24591473?dopt=AbstractPlus

520. American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014; 37 Suppl 1:S14-80. http://www.ncbi.nlm.nih.gov/pubmed/24357209?dopt=AbstractPlus

523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012; 126:e354-471. http://www.ncbi.nlm.nih.gov/pubmed/23166211?dopt=AbstractPlus

524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013; 128:e240-327. http://www.ncbi.nlm.nih.gov/pubmed/23741058?dopt=AbstractPlus

525. Smith SC, Benjamin EJ, Bonow RO et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011; 124:2458-73. http://www.ncbi.nlm.nih.gov/pubmed/22052934?dopt=AbstractPlus

526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2014; :. http://www.ncbi.nlm.nih.gov/pubmed/24788967?dopt=AbstractPlus

527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013; 127:e362-425. http://www.ncbi.nlm.nih.gov/pubmed/23247304?dopt=AbstractPlus

528. Pfeffer MA, Swedberg K, Granger CB et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003; 362:759-66. http://www.ncbi.nlm.nih.gov/pubmed/13678868?dopt=AbstractPlus

530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich). 2014; 16:246-8. http://www.ncbi.nlm.nih.gov/pubmed/24641124?dopt=AbstractPlus

534. Qaseem A, Hopkins RH, Sweet DE et al. Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013; 159:835-47. http://www.ncbi.nlm.nih.gov/pubmed/24145991?dopt=AbstractPlus

535. Taler SJ, Agarwal R, Bakris GL et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. Am J Kidney Dis. 2013; 62:201-13. http://www.ncbi.nlm.nih.gov/pubmed/23684145?dopt=AbstractPlus

536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Inter. 2012: 2(suppl): 337-414.

541. Perk J, De Backer G, Gohlke H et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012; 33:1635-701. http://www.ncbi.nlm.nih.gov/pubmed/22555213?dopt=AbstractPlus

543. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. K/DOQI Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease (2002). From National Kidney Foundation website. http://www.kidney.org/professionals/kdoqi/guidelines_commentaries.cfm

544. Kirk JK. Therapy with angiotensin II receptor antagonists. Clin Geriatrics. From the MultiMedia Health Care website: (http://www.mmhc.com/cg/articles/CG0004/kirk.html).

545. Papademetriou V, Reif M, Henry D et al. Combination therapy with candesartan cilexetil and hydrochlorothiazide in patients with systemic hypertension. J Clin Hypertens. 2000; 2:372-8.

550. US Food and Drug Administration. FDA Drug Safety Communication: new warning and contraindication for blood pressure medicines containing aliskiren (Tekturna). Rockville, MD; 2012 April 20. From FDA website. http://www.fda.gov/Drugs/DrugSafety/ucm300889.htm

701. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016; :. http://www.ncbi.nlm.nih.gov/pubmed/27206819?dopt=AbstractPlus

702. McMurray JJ, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014; 371:993-1004. http://www.ncbi.nlm.nih.gov/pubmed/25176015?dopt=AbstractPlus

703. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther. 2016; 41:119-27. http://www.ncbi.nlm.nih.gov/pubmed/26992459?dopt=AbstractPlus

800. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016; :. http://www.ncbi.nlm.nih.gov/pubmed/27208050?dopt=AbstractPlus

Hide