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Special Alerts
Angiotensin II Receptor Blockers (ARBs) and Cancer Risk
June 2011
The U.S. Food and Drug Administration (FDA) has notified healthcare providers of the results from an ongoing review of ARB use and cancer risk. In June 2010, a published meta-analysis of 5 clinical trials reported a statistically significant increased risk of developing cancer in patients who received treatment with ARBs compared to those who did not. The FDA has completed a meta-analysis of 31 trials to further investigate the association between ARB use and cancer risk. The results of the FDA meta-analysis, along with other available data, have found no evidence for an increased risk of cancer with ARB use.
For additional information, see http://www.fda.gov/Drugs/DrugSafety/ucm257516.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(kan de SAR tan)
Generic Available (U.S.)
No
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Alone or in combination with other antihypertensive agents in treating essential hypertension; treatment of heart failure (NYHA class II-IV)
Pregnancy Risk Factor
C (1st trimester); D (2nd and 3rd trimesters)
Pregnancy Considerations
Medications which act on the renin-angiotensin system are reported to have the following fetal/neonatal effects: Hypotension, neonatal skull hypoplasia, anuria, renal failure, and death; oligohydramnios is also reported. These effects are reported to occur with exposure during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Angiotensin receptor blockers should be discontinued as soon as possible once pregnancy is detected.
Lactation
Enters breast milk/contraindicated
Contraindications
Hypersensitivity to candesartan or any component of the formulation; severe hepatic impairment and/or cholestasis; pregnancy; breast-feeding
Warnings/Precautions
Boxed warnings:
• Pregnancy: See “Special populations” below.
Concerns related to adverse effects:
• Hyperkalemia: May occur; risk factors include renal dysfunction, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium containing salts. Use cautiously, if at all, with these agents and monitor potassium closely.
• Renal function deterioration: May be associated with deterioration of renal function and/or increases in serum creatinine, particularly in patients with low renal blood flow (eg, renal artery stenosis, heart failure) whose glomerular filtration rate (GFR) is dependent on efferent arteriolar vasoconstriction by angiotensin II; deterioration may result in oliguria, acute renal failure, and progressive azotemia. Small increases in serum creatinine may occur following initiation; consider discontinuation only in patients with progressive and/or significant deterioration in renal function.
Disease-related concerns:
• Aortic/mitral stenosis: Use caution in patients with significant aortic/mitral stenosis.
• Heart failure: Use caution when initiating in heart failure; may need to adjust dose, and/or concurrent diuretic therapy, because of candesartan-induced hypotension.
• Hepatic impairment: Use caution in patients with moderate hepatic impairment. Contraindicated in severe hepatic impairment and/or cholestasis.
• Hypovolemia: Avoid use or use a smaller dose in patients who are volume depleted; correct depletion first.
• Renal artery stenosis: Use candesartan with caution in patients with unstented unilateral/bilateral renal artery stenosis. When unstented bilateral renal artery stenosis is present, use is generally avoided due to the elevated risk of deterioration in renal function unless possible benefits outweigh risks.
• Renal impairment: Use with caution with pre-existing renal insufficiency and severe renal impairment.
Concurrent drug therapy issues:
• Angiotensin-converting enzyme (ACE) inhibitors: Although concurrent therapy with an ACE inhibitor may be rational in select patients, concurrent use may increase the risk of clinically-significant adverse events (eg, renal dysfunction, hyperkalemia).
Special populations:
• Pregnancy: [U.S. Boxed Warning]: Based on human data, drugs that act on the angiotensin system can cause injury and death to the developing fetus when used in the second and third trimesters. Angiotensin receptor blockers should be discontinued as soon as possible once pregnancy is detected.
Other warnings/precautions:
• Anesthesia/surgery: Hypotension may occur during major surgery and anesthesia; use cautiously before, during, and immediately after such interventions.
Adverse Reactions
Cardiovascular: Angina, hypotension (CHF 19%), MI, palpitation, tachycardia
Central nervous system: Dizziness, lightheadedness, drowsiness, headache, vertigo, anxiety, depression, somnolence, fever
Dermatologic: Angioedema, rash
Endocrine & metabolic: Hyperglycemia, hyperkalemia (CHF <1% to 6%), hypertriglyceridemia, hyperuricemia
Gastrointestinal: Dyspepsia, gastroenteritis
Genitourinary: Hematuria
Neuromuscular & skeletal: Back pain, CPK increased, myalgia, paresthesia, weakness
Renal: Serum creatinine increased (up to 13% in patients with CHF with drug discontinuation required in 6%)
Respiratory: Dyspnea, epistaxis, pharyngitis, rhinitis, upper respiratory tract infection
Miscellaneous: Diaphoresis increased
<1%, postmarketing, and/or case reports: Abnormal hepatic function, agranulocytosis, anemia, hepatitis, hyponatremia, leukopenia, neutropenia, pruritus, renal failure, renal impairment, rhinitis, sinusitis, thrombocytopenia, urticaria; rhabdomyolysis has been reported (rarely) with angiotensin-receptor antagonists
Metabolism/Transport Effects
Substrate of CYP2C9 (minor); Inhibits CYP2C8 (weak), 2C9 (weak)
Drug Interactions
ACE Inhibitors: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of ACE Inhibitors. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Eplerenone: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Lithium: Angiotensin II Receptor Blockers may increase the serum concentration of Lithium. Management: Lithium dosage reductions will likely be needed following the addition of an angiotensin II receptor antagonist. Risk D: Consider therapy modification
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: Angiotensin II Receptor Blockers may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Potassium-Sparing Diuretics: Angiotensin II Receptor Blockers may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Sodium Phosphates: Angiotensin II Receptor Blockers may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with ARBs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
Tolvaptan: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Trimethoprim: May enhance the hyperkalemic effect of Angiotensin II Receptor Blockers. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).
Mechanism of Action
Candesartan is an angiotensin receptor antagonist. Angiotensin II acts as a vasoconstrictor. In addition to causing direct vasoconstriction, angiotensin II also stimulates the release of aldosterone. Once aldosterone is released, sodium as well as water are reabsorbed. The end result is an elevation in blood pressure. Candesartan binds to the AT1 angiotensin II receptor. This binding prevents angiotensin II from binding to the receptor thereby blocking the vasoconstriction and the aldosterone secreting effects of angiotensin II.
Pharmacodynamics/Kinetics
Onset of action: 2-3 hours
Peak effect: 6-8 hours
Duration: >24 hours
Distribution: Vd: 0.13 L/kg
Protein binding: 99%
Metabolism: To candesartan by the intestinal wall cells
Bioavailability: 15%
Half-life elimination (dose dependent): 5-9 hours
Time to peak: 3-4 hours
Excretion: Urine (26%)
Clearance: Total body: 0.37 mL/kg/minute; Renal: 0.19 mL/kg/minute
Dosage
Adults: Oral:
Hypertension: Usual dose is 4-32 mg once daily; dosage must be individualized. Blood pressure response is dose related over the range of 2-32 mg. The usual recommended starting dose of 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. It can be administered once or twice daily with total daily doses ranging from 8-32 mg. Larger doses do not appear to have a greater effect and there is relatively little experience with such doses.
Congestive heart failure: Initial: 4 mg once daily; double the dose at 2-week intervals, as tolerated; target dose: 32 mg
Note: In selected cases, concurrent therapy with an ACE inhibitor may provide additional benefit.
Elderly: No initial dosage adjustment is necessary for elderly patients (although higher concentrations (Cmax) and AUC were observed in these populations), for patients with mildly impaired renal function, or for patients with mildly impaired hepatic function.
Dosage adjustment in hepatic impairment:
Mild hepatic impairment: No initial dosage adjustment required
Moderate hepatic impairment: Consider initiation at lower dosages (AUC increased by 145%).
Severe hepatic impairment and/or cholestasis: Contraindicated
Monitoring Parameters
Supine blood pressure, electrolytes, serum creatinine, BUN, urinalysis, symptomatic hypotension, and tachycardia; in CHF, serum potassium during dose escalation and periodically thereafter
Patient Education
Take with or without food. This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause dizziness, fainting, lightheadedness, postural hypotension, nausea, or vomiting. Report chest pain or palpitations; unusual weight gain or swelling of ankles and hands; persistent fatigue; unusual flu or cold symptoms or dry cough; respiratory difficulty; swelling of eyes, face, or lips; skin rash; muscle pain or weakness; or unusual bleeding (blood in urine).
Geriatric Considerations
High concentrations occur in the elderly compared to younger subjects. AUC may be doubled in patients with renal impairment. No initial dose adjustment necessary since repeated dose did not demonstrate accumulation of drug or metabolites in elderly.
Additional Information
May have an advantage over losartan due to minimal metabolism requirements and consequent use in mild-to-moderate hepatic impairment
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearls/Comments: In patients on chronic angiotensin receptor blocker (ARB) therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; however, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent. Episodes of intraoperative hypotension may be managed by fluid administration and/or modest doses of alpha-adrenergic agents. Severe hypotension may occur in patients who are sodium- and/or volume-depleted; initiate lower doses and monitor closely when starting therapy in these patients. ARB therapy may elicit an increase in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema and therefore should be avoided.
Evidence-Based Information: The angiotensin II receptor antagonists have similar indications as ACE inhibitors. In heart failure, the angiotensin II antagonists are especially useful in providing an alternative therapy in those patients who have intractable cough due to ACE inhibitor therapy. Candesartan has been studied as an alternative therapy in chronic heart failure patients who cannot tolerate an ACE-I (CHARM-Alternative) and as an added therapy in heart failure patients who are maintained on an ACE-I (CHARM-Added). In both studies, the combined endpoint of cardiovascular death or heart failure hospitalizations was significantly improved over the placebo-treated group.
Cardiovascular Considerations
Congestive Heart Failure: Currently, the use of angiotensin II receptor blockers (ARBs) should not supersede angiotensin converting enzyme inhibitors (ACEIs) in the treatment of congestive heart failure. One may be considered, however, when an ACEI cannot be tolerated. Because they are angiotensin II blockers rather than inhibitors of ACE, ARBs do not cause increases in bradykinin levels. ELITE II (Pitt, 2000) compared losartan (50 mg/day) with captopril (150 mg/day) in a heart failure population (mean EF 31%). There were 280 deaths in the losartan group and 250 in the captopril group. Mortality was insignificantly higher for losartan (17.7% vs 16% for captopril). The secondary endpoint (sudden cardiac death or resuscitated cardiac arrest) favored captopril, but the improvement did not achieve statistical significance. The discontinuation rate for adverse events was significantly lower for losartan. In the doses used, losartan appears to be less effective or as effective as captopril.
CHARM-Alternative is a prospective, randomized trial (Granger, 2003) in ACE inhibitor-intolerant patients with CHF. Patients were randomized to candesartan (target dose: 32 mg/day; mean dose at 6 months: 23 mg/day) or placebo. Baseline characteristics included NYHA Class II or III (97% of patients), and mean LVEF 30%. Therapy included beta-blocker (55%), diuretic (86%), spironolactone (24%), and digitalis (46%). During a 33-month follow-up, the combined primary endpoint (CV death or heart failure hospitalizations) was significantly reduced in the candesartan group mainly because of reduced hospitalization. Death due to cardiovascular disease was not significantly different. There were significantly more MIs (75) in the candesartan group than in the placebo group (48). Candesartan was discontinued because of hypotension, renal dysfunction, and hyperkalemia.
Congestive Heart Failure: Concomitant ACE-I Therapy: The Val-HeFT study (Cohn, 2001) randomized CHF patients maintained on standard therapy to valsartan (320 mg/day; mean dose 254 mg/day) or placebo. The primary outcome was mortality and a combined endpoint of morbidity and mortality (cardiac arrest, hospitalization for CHF, need for intravenous inotrope or vasodilator). Patients (5010 in number) with predominately NYHA class II or III heart failure (85% on diuretic; 67% on digoxin; 35% on beta-blocker; ~93% on ACEI; 5% on spironolactone) were randomized to valsartan or placebo. The mean duration of follow-up was 23 months. Overall mortality was similar in both groups. The incidence of combined endpoints was lower with valsartan than placebo (p=.009) primarily because of decreased heart failure hospitalizations in the valsartan group. In a posthoc analysis of the endpoints in subgroups defined by baseline treatments (ACEI or beta-blockers), valsartan had a positive effect on patients receiving neither or one of these drugs. A higher incidence of mortality was seen in patients receiving valsartan in combination with an ACEI and a beta-blocker.
CHARM-Added trial is a prospective, randomized trial (McMurray, 2003) evaluating the addition of candesartan therapy (target dose: 32 mg/day; mean dose at 6 months: 24 mg/day) to CHF patients maintained on an ACEI. Baseline characteristics: NYHA class II (24%), class III (73%), and mean LVEF 28%. Baseline therapy was similar to CHARM-Alternative except all patients were maintained on an ACEI and ~55% were on a beta-blocker. The median duration of follow-up was 41 months. The combined primary endpoint (CV death or heart failure hospitalizations) was significantly reduced in the candesartan group.
Hypertension: According to the 2003 JNC 7 guidelines for the treatment of hypertension, most patients with hypertension will require treatment with at least 2 antihypertensives. First-line therapy for hypertension is a diuretic (eg, hydrochlorothiazide or chlorthalidone). When a diuretic cannot be used or when a compelling indication exists for another drug, other types of antihypertensives may be used (eg, ACEIs, ARBs, beta-blockers, CCBs). Angiotensin II receptor blockers are among the multiple choices of agents that have shown benefit in a number of different patient subtypes. Compelling indications for an ARB include patients with heart failure, diabetes, or chronic kidney disease. The LIFE trial (Dahlof, 2002) confirmed that ARB (losartan 50-100 mg daily) was better tolerated than a beta-blocker (atenolol), and resulted in significant reduction in mortality, angina, or HF hospitalization (primary endpoint). Stroke and new-onset diabetes were significantly reduced in the losartan treatment group.
Treatment should be targeted to a goal blood pressure of <140/90 mm Hg. If diabetes or renal disease coexists, the blood pressure goal should be <130/80 mm Hg.
Myocardial Infarction: The 2004 ACC/AHA STEMI guidelines suggest an angiotensin receptor blocker should be administered to STEMI patients who are intolerant of ACE inhibitors and who have either clinical or radiological signs of heart failure or LVEF <0.4. The OPTIMAAL trial evaluated whether losartan (50 mg/day) would be superior or noninferior to captopril (150 mg/day) in post-MI patients. They were randomized to one of two treatments and followed up for 2.7 years. There was no difference between the two treatment groups (499 deaths in losartan group; 447 deaths in the captopril-treated group). The VALIANT trial compared the effects of valsartan, captopril, and the combination in patients who had suffered a recent MI (0.5 to 10 days prior) complicated by left ventricular systolic dysfunction (Pfeffer, 2003). The primary endpoint was mortality from any cause. Mortality in the valsartan group and the valsartan-captopril group was similar to the captopril group alone. Valsartan was found to be noninferior to captopril in this patient population. Combining valsartan with captopril increased the rate of adverse events without improving survival. Hypotension and renal dysfunction were more common in the valsartan group. Cough, rash, and taste disturbances were more common in the captopril group.
Cautions: Similar to ACE inhibitors, pre-existing volume depletion caused by diuretic therapy may potentiate hypotension in response to angiotensin II antagonists. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the lack of effect on the response to bradykinin, angiotensin receptor blockers are less likely to be associated with nonrenin-angiotensin effects such as cough and angioedema. The angiotensin II antagonists do not cause increases in levels of bradykinin as the ACEIs do.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness or drowsiness; may rarely cause anxiety or depression
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Evaluate renal status and history prior to beginning treatment. Assess for potential interactions (eg, increased risk for hypotension, hyperkalemia). Assess results of laboratory tests (electrolytes, serum creatinine, BUN, urinalysis). Monitor for reduced hypertension. Monitor for tachycardia, CNS changes, hyperglycemia, and hypotension prior to treatment, when changing dose, and throughout therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral, as cilexetil:
Atacand®: 4 mg, 8 mg, 16 mg, 32 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Atacand)
4 mg (30): $78.99
8 mg (30): $80.99
16 mg (30): $82.99
32 mg (30): $105.99
References
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2011,” Diabetes Care, 2011, 34(Suppl 1):11-61.
Anderson JL, Adams CD, Antman EM, et al, “ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration With the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine,” J Am Coll Cardiol, 2007, 50(7):e1-e157.
Antman EM, Anbe SC, Alpert JS, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),” Circulation, 2004, 110(5):588-636. Available at http://www.circulationaha.org/cgi/content/full/110/5/588
Antman EM, Hand M, Armstrong PW, et al, “2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines,” J Am Coll Cardiol, 2008, 51(2):210-49.
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):2560-71.
Cohn JN and Tognoni G, “Valsartan Heart Failure Trial Investigators. A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure,” N Engl J Med, 2001, 345(23):1667-75.
Conlin P, Moore T, Swartz S, et al, “Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients,” Hypertension, 2000, 36(3):461-5.
Dahlof B, Devereux RB, Kjeldsen SE, et al, “Cardiovascular Morbidity and Mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): A Randomised Trial Against Atenolol,” Lancet, 2002, 359(9311):995-1003.
Dickstein K and Kjekshus J, “Effects of Losartan and Captopril on Mortality and Morbidity in High-Risk Patients After Acute Myocardial Infarction: The OPTIMAAL Randomised Trial. Optimal Trial in Myocardial Infarction With Angiotensin II Antagonist Losartan,” Lancet , 2002, 360(9335):752-60.
Epstein BJ and Gums JG, “Angiotensin Receptor Blockers Versus ACE Inhibitors: Prevention of Death and Myocardial Infarction in High-Risk Populations,” Ann Pharmacother, 2005, 39(3):470-80.
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(9386):772-6.
Hamroff G, Katz SD, Mancini D, et al, “Addition of Angiotensin II Receptor Blockade to Maximal Angiotensin-Converting Enzyme Inhibition Improves Exercise Capacity in Patients With Severe Congestive Heart Failure,” Circulation, 1999, 99(8):990-2.
Hunt SA, Abraham WT, Chin MH, et al, “2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation,” J Am Coll Cardiol, 2009, 53(15):e1-e90.
“K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Kidney Disease Outcome Quality Initiative,” Am J Kidney Dis, 2002, 39(2 Suppl 2):1-246. Available at http://www.kidney.org/professionals/KDOQI/guidelines_ckd/toc.htm
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.
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McKelvie RS, Yusuf S, Pericak D, et al, “Comparison of Candesartan, Enalapril, and Their Combination in Congestive Heart Failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study: The RESOLVD Pilot Study Investigators,” Circulation, 1999, 100(10):1056-64.
McMurray JJ, Ostergren J, Swedberg K, et al, “Effects of Candesartan in Patients With Chronic Heart Failure and Reduced Left-Ventricular Systolic Function Taking Angiotensin-Converting-Enzyme Inhibitors: The CHARM-Added Trial,” Lancet, 2003, 362(9386):767-71.
Morsing P, Adler G, Brandt-Eliasson U, et al, “Mechanistic Differences of Various AT1-Receptor Blockers in Isolated Vessels of Different Origin,” Hypertension, 1999, 33(6):1406-13.
Pfeffer MA, McMurray JJ, Velazquez EJ, et al, “Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both,” N Engl J Med, 2004, 350(2):203.
Pitt B, Poole-Wilson PA, Segal R, et al, “Effect of Losartan Compared With Captopril on Mortality in Patients With Symptomatic Heart Failure: Randomised Trial - The Losartan Heart Failure Survival Study ELITE II,” Lancet, 2000, 355(9215):1582-7.
Reif M, White WB, Fagan TC, et al, “Effects of Candesartan Cilexetil in Patients With Systemic Hypertension. Candesartan Cilexetil Study Investigators,” Am J Cardiol, 1998, 82(8):961-5.
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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(7):627-36.
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International Brand Names
Lexi-Comp.com
Last full review/revision June 2011
Content last modified June 2011
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