Azilsartan (Monograph)

Brand name: Edarbi
Drug class: Angiotensin II Receptor Antagonists
VA class: CV805
Chemical name: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester-1-[[2′-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1′-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid, potassium salt
Molecular formula: C₃₀H₂₃KN₄O₈
CAS number: 863031-24-7

Medically reviewed by Drugs.com on Nov 25, 2024. Written by ASHP.

Warning

May cause fetal and neonatal morbidity and mortality if used during pregnancy.¹ ²⁵ ²⁶ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
If pregnancy is detected, discontinue as soon as possible.¹ ²⁵

Introduction

Angiotensin II receptor (AT₁) antagonist (i.e., angiotensin II receptor blocker, ARB).¹ ⁴

Uses for Azilsartan

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).¹ ³ ⁴ ⁵ ⁶ ¹²⁰⁰

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ¹²⁰⁰ While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ¹²⁰⁰ ¹²¹³

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).⁵⁰¹ ⁵⁰² ⁵⁰³ ⁵⁰⁴ ⁵¹⁵ ¹²⁰⁰ ¹²⁰¹

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.¹²⁰⁰ (See Table 1.)

Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

Table 1. ACC/AHA BP Classification in Adults1200
Category	SBP (mm Hg)		DBP (mm Hg)
Normal	<120	and	<80
Elevated	120–129	and	<80
Hypertension, Stage 1	130–139	or	80–89
Hypertension, Stage 2	≥140	or	≥90

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP.¹²⁰⁰ However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.⁵⁰¹ ⁵⁰³ ⁵⁰⁴ ⁵⁰⁵ ⁵⁰⁶ ⁵⁰⁷ ⁵⁰⁸ ⁵¹⁵ ⁵²³ ⁵²⁶ ⁵³⁰ ¹²⁰⁰ ¹²⁰¹ ¹²⁰⁷ ¹²⁰⁹ ¹²²² ¹²²³ ¹²²⁹

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BPs to achieve with drug therapy and/or nonpharmacologic intervention) <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.¹²⁰⁰ In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg.¹²⁰⁰ These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.¹²⁰⁰ ¹²⁰² ¹²¹⁰

Previous hypertension guidelines generally have based target BP goals on age and comorbidities.⁵⁰¹ ⁵⁰⁴ ⁵³⁶ Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients⁵⁰¹ ⁵⁰⁴ ⁵³⁶ compared with those recommended by the 2017 ACC/AHA hypertension guideline.¹²⁰⁰

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the current ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.¹²²² ¹²²³ ¹²²⁴ ¹²²⁹

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient’s BP treatment goal.¹²⁰⁰ ¹²²⁰ ¹²²⁹

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors.¹²⁰⁰ ¹²⁰⁷ ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.¹²⁰⁰

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).¹²⁰⁰

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.¹²⁰⁰

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.¹²⁰⁰

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP.¹²⁰⁰ Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.¹²⁰⁰

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.⁵⁰¹ ⁵⁰⁴ ¹²⁰⁰ However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.¹²⁰⁰

Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in hypertensive patients with diabetes mellitus or CKD; 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.⁵⁰¹ ⁵⁰² ⁵⁰⁴ ⁵²³ ⁵²⁴ ⁵²⁷ ⁵³⁴ ⁵³⁵ ⁵³⁶ ⁵⁴³ ¹²⁰⁰ ¹²¹⁴ ¹²¹⁵

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria^{† [off-label]} 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.¹² ¹³ ¹⁵ ¹⁶ ¹⁷ ⁵³⁵ ⁵³⁶ ¹²³²

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure^{† [off-label]}.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 considered reasonable alternative therapy for those patients in whom an ACE inhibitor or ARNI is inappropriate.⁵²⁴ ⁸⁰⁰ (See Sensitivity Reactions under Cautions.)

No additional therapeutic benefit when angiotensin II receptor antagonist used in combination with an ACE inhibitor.¹ ¹¹⁹

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

Azilsartan Dosage and Administration

General

BP Monitoring and Treatment Goals

Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.¹²⁰⁰
If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.¹²¹⁶
If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic).¹²⁰⁰ ¹²¹⁶ Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved with 2 antihypertensive agents, add a third drug.¹²⁰⁰ ¹²¹⁶ ¹²²⁰

Administration

Oral Administration

Administer orally once daily without regard to meals.¹

Must be dispensed and stored in the original manufacturer’s container.¹

Dosage

Available as azilsartan kamedoxomil (the potassium salt of azilsartan medoxomil); dosage expressed in terms of azilsartan medoxomil.¹

Adults

Hypertension

Oral

Usual dosage: Manufacturer states 80 mg once daily.¹ Some experts state 40–80 mg once daily.¹²⁰⁰ Consider initial dosage of 40 mg once daily in patients receiving high dosages of diuretics.¹

Special Populations

Hepatic Impairment

No adjustment of initial azilsartan medoxomil dosage necessary in patients with mild to moderate hepatic impairment.¹ Not studied in patients with severe hepatic impairment.¹

Renal Impairment

No adjustment of initial azilsartan medoxomil dosage necessary in patients with mild to severe renal impairment or end-stage renal disease.¹

Geriatric Patients

No adjustment of initial azilsartan medoxomil dosage is necessary.¹

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of azilsartan therapy or initiate therapy using lower initial dosage (40 mg once daily).¹

Cautions for Azilsartan

Contraindications

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

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when drugs that act directly on the renin-angiotensin system (e.g., angiotensin II receptor antagonists, ACE inhibitors) are used during the second and third trimesters of pregnancy.¹ ²⁵ Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.¹ ACE inhibitors also reported to increase the risk of major congenital malformations when administered during the first trimester of pregnancy.²⁵ ²⁶ Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.¹

Discontinue azilsartan as soon as possible when pregnancy is detected, unless continued use is considered life-saving.¹ ²⁵ ²⁶ Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.¹ ²⁷

Sensitivity Reactions

Angioedema, pruritus, and rash reported during postmarketing experience.¹

Other Warnings and Precautions

Hypotension

Possible symptomatic hypotension, particularly in volume- and/or salt-depleted patients (e.g., those treated with diuretics).¹ (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

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, renal artery stenosis, or volume depletion.¹

Increases in BUN and S_Cr possible in patients with renal artery stenosis.¹

Specific Populations

Pregnancy

Category D.¹

Can cause fetal and neonatal morbidity and death when administered to a pregnant woman.¹ (See Boxed Warning.)

Lactation

Azilsartan is distributed into milk in rats; not known whether azilsartan is distributed into human milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

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

Safety and efficacy of azilsartan not established in pediatric patients.¹

Geriatric Use

Increased incidence of elevated S_Cr in patients ≥75 years of age.¹ No other differences in safety or efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Data lacking in patients with severe hepatic impairment.¹

Renal Impairment

Increased incidence of abnormally high S_Cr in patients with moderate to severe renal impairment.¹

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

Black Patients

BP reduction with azilsartan monotherapy decreased by about 50% in black patients compared with patients of other races.¹ (See Hypertension under Uses.)

Common Adverse Effects

Diarrhea;¹ ³ less common adverse effects include hypotension/orthostatic hypotension,¹ nausea,¹ asthenia,¹ fatigue,¹ ³ ⁵ muscle spasm,¹ dizziness,¹ ³ ⁴ ⁵ postural dizziness,¹ cough.¹

Drug Interactions

Metabolized principally by CYP2C9.¹

Specific Drugs

Drug	Interaction	Comments
ACE inhibitors	Increased risk of renal impairment, hyperkalemia, and hypotension¹	Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly¹
Aliskiren	Increased risk of renal impairment, hyperkalemia, and hypotension¹ ⁵⁵⁰	Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly¹ ⁵⁵⁰ Concomitant use contraindicated in patients with diabetes mellitus¹ ⁵⁵⁰ Avoid concomitant use in patients with GFR <60 mL/minute¹ ⁵⁵⁰
Amlodipine	Pharmacokinetic interactions unlikely¹
Angiotensin II receptor antagonists	Increased risk of renal impairment, hyperkalemia, and hypotension¹	Generally, avoid concomitant use; monitor BP, renal function, and electrolytes if used concomitantly¹
Antacids	Pharmacokinetic interactions unlikely¹
Chlorthalidone	Pharmacokinetic interactions unlikely¹ Greater reversible increases in S_Cr possible¹
Digoxin	Pharmacokinetic interactions unlikely¹
Diuretics, potassium-sparing	Possible increase in serum potassium concentrations⁹	Avoid concomitant administration⁹
Fluconazole	Pharmacokinetic interactions unlikely¹
Glyburide	Pharmacokinetic interactions unlikely¹
Hydrochlorothiazide	Greater reversible increases in S_Cr possible¹
Ketoconazole	Pharmacokinetic interactions unlikely¹
Lithium	Increased serum lithium concentrations and lithium toxicity reported with concomitant angiotensin II receptor antagonist therapy¹	Monitor serum lithium concentrations during concomitant therapy¹
Metformin	Pharmacokinetic interactions unlikely¹
NSAIAs, including selective cyclooxygenase-2 (COX-2) inhibitors	Possible deterioration of renal function, including possible acute renal failure, in patients who are geriatric, volume-depleted, or have compromised renal function; effects usually reversible¹ Possible attenuation of azilsartan antihypertensive effect¹	Periodically monitor renal function¹
Pioglitazone	Pharmacokinetic interactions unlikely¹
Potassium supplements and potassium-containing salt substitutes	Possible increase in serum potassium concentrations⁹	Avoid concomitant administration⁹
Warfarin	Pharmacokinetic interactions unlikely¹

Azilsartan Pharmacokinetics

Absorption

Bioavailability

Azilsartan medoxomil (prodrug) is rapidly and completely hydrolyzed to azilsartan during absorption in the GI tract.¹

Absolute bioavailability of azilsartan is about 60%.¹

Peak plasma azilsartan concentration generally reached 1.5–3 hours following oral administration.¹

Increases in AUC are dose proportional following single or multiple doses of azilsartan medoxomil in the range of 20–320 mg.¹

Steady-state concentrations of azilsartan are achieved within 5 days.¹

Onset

Most of the antihypertensive effect of azilsartan occurs within 2 weeks.¹

Food

Food does not affect bioavailability of azilsartan.¹

Special Populations

Modest increases in peak plasma azilsartan concentration and AUC reported in geriatric patients and in patients with mild to severe renal impairment or mild to moderate hepatic impairment; no dosage adjustment required.¹ Not studied in patients with severe hepatic impairment.¹

Distribution

Extent

Azilsartan crosses the placenta and is distributed in the fetus in rats.¹

A minimal amount of azilsartan-associated radioactivity crosses the blood-brain barrier in rats.¹

Azilsartan is distributed into milk in rats; not known whether azilsartan is distributed into human milk.¹

Plasma Protein Binding

>99%.¹

Elimination

Metabolism

Azilsartan medoxomil undergoes rapid and complete hydrolysis to azilsartan.¹

Azilsartan is metabolized primarily by CYP2C9.¹

Azilsartan is metabolized to 2 primary metabolites, both of which are inactive; metabolite M-II (the major metabolite) is formed by O-dealkylation, and metabolite M-I (the minor metabolite) is formed by decarboxylation.¹

Systemic exposures to M-II and M-I are approximately 50% and <1%, respectively, that of azilsartan.¹

Elimination Route

Radiolabeled azilsartan medoxomil is eliminated mainly in feces (55%) and urine (42%, with 15% as azilsartan).¹

Half-life

Approximately 11 hours.¹

Stability

Storage

Oral

Tablets

25ºC (may be exposed to 15–30ºC).¹ Dispense and store in tightly closed original container; protect from light and moisture.¹

Actions

Azilsartan medoxomil, a prodrug, is hydrolyzed to azilsartan during absorption.¹ ³¹
Azilsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.¹
Azilsartan should not affect bradykinin levels.¹

Advice to Patients

Risk of hypotension.² Importance of lying down and informing clinician immediately if lightheadedness or dizziness occurs.²
Importance of storing azilsartan medoxomil in the original container, tightly closed and protected from light and moisture.²
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; importance of discussing other options for hypertension treatment if pregnancy occurs.² Importance of informing women of childbearing potential of risk of serious harm or death in the fetus and infant if azilsartan is used during the second or third trimester of pregnancy.¹ ² (See Fetal/Neonatal Morbidity and Mortality under Cautions.) All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.¹
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements.²
Importance of informing patients of other important precautionary information.¹ (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.

Azilsartan Kamedoxomil
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	40 mg (of azilsartan medoxomil)	Edarbi	Arbor
		80 mg (of azilsartan medoxomil)	Edarbi	Arbor

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

References

1. Arbor Pharmaceuticals. Edarbi (azilsartan medoxomil) tablets prescribing information. Atlanta, GA; 2014 Jul.

2. Arbor Pharmaceuticals. Edarbi (azilsartan medoxomil) tablets patient information. Atlanta, GA; 2014 Jul.

3. White WB, Weber MA, Sica D et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011; 57:413-20. https://pubmed.ncbi.nlm.nih.gov/21282560

4. Bakris GL, Sica D, Weber M et al. The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure. J Clin Hypertens. 2011; 13:81-8.

5. Sica D, White WB, Weber MA et al. Comparison of the novel angiotensin II receptor blocker azilsartan medoxomil vs valsartan by ambulatory blood pressure monitoring. J Clin Hypertens. 2011; 13:467-72.

6. Anon. Azilsartan medoxomil (Edarbi): the eighth ARB. Med Lett Drugs Ther. 2011; 53:39-40.

8. Food and Drug Administration. Angiotensin receptor blockers (ARBs): drug safety communication--drug safety review completed. Rockville, MD; 2011 Jun 2. From FDA website. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm219185.htm

9. Song JC, Singh P, Fung WF. Focus on azilsartan: a next-generation angiotensin II receptor blocker for the treatment of hypertension. 2010; 45:342-9. Accessed 2011 Dec 8. http://formularyjournal.modernmedicine.com/formulary/Modern+Medicine+Now/Focus-on-Azilsartan-A-next-generation-angiotensin-/ArticleStandard/Article/detail/700419

12. 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. https://pubmed.ncbi.nlm.nih.gov/8413456

13. Remuzzi G. Slowing the progression of diabetic nephropathy. N Engl J Med. 1993; 329:1496-7. https://pubmed.ncbi.nlm.nih.gov/8413463

15. Kaplan NM. Choice of initial therapy for hypertension. JAMA. 1996; 275:1577-80. https://pubmed.ncbi.nlm.nih.gov/8622249

16. 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. https://pubmed.ncbi.nlm.nih.gov/8295285

17. Fournier A. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1994; 330:937. https://pubmed.ncbi.nlm.nih.gov/8114873

18. 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.

19. Anon. Drugs for hypertension. Med Lett Drugs Ther. 2001; 43:17-22. https://pubmed.ncbi.nlm.nih.gov/11242494

20. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. https://pubmed.ncbi.nlm.nih.gov/10818056

21. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. https://pubmed.ncbi.nlm.nih.gov/10818055

23. 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. https://pubmed.ncbi.nlm.nih.gov/10977801

25. Food and Drug Administration. FDA public health advisory: angiotensin-converting enzyme inhibitor (ACE inhibitor) drugs and pregnancy. From FDA website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm102981.htm

26. 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. https://pubmed.ncbi.nlm.nih.gov/16760444

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

28. 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

29. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070221/ https://pubmed.ncbi.nlm.nih.gov/20542468

30. Sica DA. Angiotensin receptor blockers and the risk of malignancy: a note of caution. Drug Saf. 2010; 33:709-12. https://pubmed.ncbi.nlm.nih.gov/20701404

31. Nissen SE. Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Lancet Oncol. 2010; 11:605-6. https://pubmed.ncbi.nlm.nih.gov/20542469

32. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the management of chronic heart failure in the adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committees to Revise the 199t Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2001. From ACC website http://www.cardiosource.com

119. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.

120. Food and Drug Administration. FDA drug safety communication: ongoing safety review of the angiotensin receptor blockers and cancer. Rockville, MD; 2010 Jul 15. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070221/ https://pubmed.ncbi.nlm.nih.gov/20542468

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

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. https://pubmed.ncbi.nlm.nih.gov/21123111

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. https://pubmed.ncbi.nlm.nih.gov/21358417

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

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. https://pubmed.ncbi.nlm.nih.gov/21612311

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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104607/ https://pubmed.ncbi.nlm.nih.gov/21633727

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. https://pubmed.ncbi.nlm.nih.gov/24352797

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. https://pubmed.ncbi.nlm.nih.gov/23817082

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. https://pubmed.ncbi.nlm.nih.gov/24243703

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. https://pubmed.ncbi.nlm.nih.gov/24341872

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. https://pubmed.ncbi.nlm.nih.gov/24424788

506. Mitka M. Groups spar over new hypertension guidelines. JAMA. 2014; 311:663-4. https://pubmed.ncbi.nlm.nih.gov/24549531

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

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

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. https://pubmed.ncbi.nlm.nih.gov/19139601

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

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.

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.

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. https://pubmed.ncbi.nlm.nih.gov/22052934

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; :. https://pubmed.ncbi.nlm.nih.gov/24788967

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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695607/

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. https://pubmed.ncbi.nlm.nih.gov/13678868

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. https://pubmed.ncbi.nlm.nih.gov/24641124

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. https://pubmed.ncbi.nlm.nih.gov/24145991

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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929429/ https://pubmed.ncbi.nlm.nih.gov/23684145

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 Int Suppl. 2012: 2: 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. https://pubmed.ncbi.nlm.nih.gov/22555213

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

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. 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; 37:2129-200. https://pubmed.ncbi.nlm.nih.gov/27206819

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. https://pubmed.ncbi.nlm.nih.gov/25176015

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. https://pubmed.ncbi.nlm.nih.gov/26992459

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; 134:e282-93.

1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018; 71:el13-e115. https://pubmed.ncbi.nlm.nih.gov/29133356

1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med. 2018; 378:497-499. https://pubmed.ncbi.nlm.nih.gov/29341841

1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med. 2018; 168:351-358. https://pubmed.ncbi.nlm.nih.gov/29357392

1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press. 2018; 27:62-65. https://pubmed.ncbi.nlm.nih.gov/29447001

1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017; 166:430-437. https://pubmed.ncbi.nlm.nih.gov/28135725

1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015; 373:2103-16. https://pubmed.ncbi.nlm.nih.gov/26551272

1213. Reboussin DM, Allen NB, Griswold ME et al. Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018; 71:2176-2198. https://pubmed.ncbi.nlm.nih.gov/29146534

1214. American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetes 2018. Diabetes Care. 2018; 41:S86-S104. https://pubmed.ncbi.nlm.nih.gov/29222380

1215. de Boer IH, Bangalore S, Benetos A et al. Diabetes and hypertension: a position statement by the American Diabetes Association. Diabetes Care. 2017; 40:1273-1284. https://pubmed.ncbi.nlm.nih.gov/28830958

1216. Taler SJ. Initial treatment of hypertension. N Engl J Med. 2018; 378:636-644. https://pubmed.ncbi.nlm.nih.gov/29443671

1218. Messerli FH, Bangalore S, Bavishi C et al. Angiotensin-converting enzyme inhibitors in hypertension: to use or not to use?. J Am Coll Cardiol. 2018; 71:1474-1482. https://pubmed.ncbi.nlm.nih.gov/29598869

1219. Karmali KN, Lloyd-Jones DM. Global risk assessment to guide blood pressure management in cardiovascular disease prevention. Hypertension. 2017; 69:e2-e9. https://pubmed.ncbi.nlm.nih.gov/28115516

1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA. 2017; 318:2132-2134. https://pubmed.ncbi.nlm.nih.gov/29159416

1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med. 2018; 178:755-7. https://pubmed.ncbi.nlm.nih.gov/29710197

1223. LeFevre M. ACC/AHA hypertension guideline: What is new? What do we do?. Am Fam Physician. 2018; 97(6):372-3. https://pubmed.ncbi.nlm.nih.gov/29671534

1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. https://www.jwatch.org/na45778/2017/12/28/nejm-journal-watch-general-medicine-year-review-2017

1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA. 2018; 319(2):115-6. https://pubmed.ncbi.nlm.nih.gov/29242891

1232. American Diabetes Association. 10. Microvascular complications and foot care: standards of medical care in diabetes 2018. Diabetes Care. 2018; 41:S105-S118. https://pubmed.ncbi.nlm.nih.gov/29222381

1233. Remuzzi G, Macia M, Ruggeneti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J Am Soc Nephrol. 2006; 17(Suppl 2 ):S90-7. https://pubmed.ncbi.nlm.nih.gov/16565256

1234. Haller H, Ito S, Izzo JL Jr. et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med. 2011; 364:907-17. https://pubmed.ncbi.nlm.nih.gov/21388309