VA Class:CV805
Valsartan is an angiotensin II type 1 (AT1) receptor antagonist (also referred to as an angiotensin II receptor blocker [ARB]).1,2,3,4,5,6,7,8,9,10,37,116 Valsartan also is commercially available in fixed combination with sacubitril, a neprilysin inhibitor. (See the monograph on Sacubitril and Valsartan in 24:32.92.)
Valsartan is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension.1,2,3,4,5,6,8,9,37,116,134,1200 Efficacy of valsartan for the management of hypertension has been established by controlled studies of 8-12 weeks' duration in patients with hypertension of mild to moderate severity in outpatient settings.2,3,4 The efficacy of valsartan for long-term use (i.e., exceeding 12 weeks) has been established in noncontrolled, follow-up studies in which the drug was used for up to 2 years without apparent loss of clinical effect.1 Clinical studies have shown that the hypotensive effect of usual dosages of valsartan in patients with mild to moderate hypertension is greater than that of placebo and comparable to that of usual dosages of amlodipine, enalapril, lisinopril, or hydrochlorothiazide.1,2,3,4,10
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics); data from clinical outcome trials indicate that lowering blood pressure with any of these drug classes can reduce the complications of hypertension and provide similar cardiovascular protection.501,502,503,504,1200 However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines.501,502,503,504,1200 This variability is due, in part, to differences in the guideline development process and the types of studies (e.g., randomized controlled studies only versus a range of studies with different study designs) included in the evidence reviews.501,502,503,515,1200 Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501,502,503,504,515,1200,1201 Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.71,109,501,502,523,1202
Worldwide, hypertension is the most common modifiable risk factor for cardiovascular events and mortality.1205 The lifetime risk of developing hypertension in the US exceeds 80%, with higher rates observed among African Americans and Hispanics compared with whites or Asians.1200 The systolic blood pressure and diastolic blood pressure values defined as hypertension in adults (see Blood Pressure Classification under Uses: Hypertension) in a 2017 multidisciplinary guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations1200 (subsequently referred to as the 2017 ACC/AHA hypertension guideline in this monograph) are lower than those defined in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines,500 which results in an increase of approximately 14% in the prevalence of hypertension in the US.1200,1222 However, this change in definition results in only a 2% increase in the percentage of patients requiring antihypertensive drug therapy because nonpharmacologic treatment is recommended for most adults now classified by the 2017 ACC/AHA hypertension guideline as hypertensive who would not meet the JNC 7 definition of hypertension.500,1200,1222 Among US adults receiving antihypertensive drugs, approximately 53% have inadequately controlled blood pressure according to current ACC/AHA treatment goals.1206
Cardiovascular and Renal Sequelae
The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.71,109,502,1200 The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors.71,1200 It is important that very high blood pressure be managed promptly to reduce the risk of target organ damage.1200 The higher the blood pressure, the more likely the development of myocardial infarction (MI), heart failure, stroke, and renal disease.502,1200 For adults 40-70 years of age, each 20-mm Hg increment in systolic blood pressure or 10-mm Hg increment in diastolic blood pressure doubles the risk of developing cardiovascular disease across the entire blood pressure range of 115/75 to 185/115 mm Hg.1200,1238 For those older than 50 years of age, systolic blood pressure is a much more important risk factor for developing cardiovascular disease than is diastolic blood pressure.502 The rapidity with which treatment is required depends on the patient's clinical presentation (presence of new or worsening target organ damage) and the presence or absence of cardiovascular complications; the 2017 ACC/AHA hypertension guideline states that treatment of very high blood pressure should be initiated within 1 week.1200
Accurate blood pressure measurement is essential for the proper diagnosis and management of hypertension.1200,1225,1226 Error in measuring blood pressure is a major cause of inadequate blood pressure control and may lead to overtreatment.1225,1226 Because a patient's blood pressure may vary in an unpredictable fashion, a single blood pressure measurement is not sufficient for clinical decision-making.1200 An average of 2 or 3 blood pressure measurements obtained on 2-3 separate occasions using proper technique should be used to minimize random error and provide a more accurate blood pressure reading.1200 Out-of-office blood pressure measurements may be useful for confirming and managing hypertension.1200 The 2017 ACC/AHA hypertension guideline document (available on the ACC and AHA websites) should be consulted for key steps on properly measuring blood pressure.1200
According to the 2017 ACC/AHA hypertension guideline, blood pressure in adults is classified into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension.1200 (See Table 1.) The 2017 ACC/AHA hypertension guideline lowers the blood pressure threshold used to define hypertension in the US; previous hypertension guidelines (JNC 7) considered adults with systolic blood pressure of 120-139 mm Hg or diastolic blood pressure of 80-89 mm Hg to have prehypertension, those with systolic blood pressure of 140-159 mm Hg or diastolic blood pressure of 90-99 mm Hg to have stage 1 hypertension, and those with systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 100 mm Hg or higher to have stage 2 hypertension.500,1200 The blood pressure definitions in the 2017 ACC/AHA hypertension guideline are based upon data from studies evaluating the association between systolic blood pressure/diastolic blood pressure and cardiovascular risk and the benefits of blood pressure reduction.1200 Individuals with systolic blood pressure and diastolic blood pressure in 2 different categories should be designated as being in the higher blood pressure category.1200
Category | SBPc (mm Hg) | DBPd (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 |
aSource: 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.
bIndividuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher blood pressure category (i.e., elevated BP).
The blood pressure thresholds used to define hypertension, when to initiate drug therapy, and the ideal target blood pressure values remain controversial.505,506,507,508,515,523,530,1200,1201,1207,1209,1222,1223,1229 The 2017 ACC/AHA hypertension guideline recommends a blood pressure goal of less than 130/80 mm Hg in all adults who have confirmed hypertension and known cardiovascular disease or a 10-year atherosclerotic cardiovascular disease (ASCVD) event risk of 10% or higher; the ACC/AHA guideline also states that this blood pressure goal is reasonable to attempt to achieve in adults with confirmed hypertension who do not have increased cardiovascular risk.1200 The lower blood pressure values used to define hypertension and the lower target blood pressure goals outlined in the 2017 ACC/AHA hypertension guideline are based on clinical studies demonstrating a substantial reduction in the composite end point of major cardiovascular disease events and the combination of fatal and nonfatal stroke when a lower systolic blood pressure/diastolic blood pressure value (i.e., 130/80 mm Hg) was used to define hypertension.521,1210,1223 These lower target blood pressure goals also are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210 A linear relationship has been demonstrated between cardiovascular risk and blood pressure even at low systolic blood pressures (e.g., 120-124 mm Hg).1200,1207 The 2017 ACC/AHA hypertension guideline recommends estimating a patient's ASCVD risk using the ACC/AHA Pooled Cohort equations (available online at [Web], which are based on a variety of factors including age, race, gender, cholesterol levels, statin use, blood pressure, treatment for hypertension, history of diabetes mellitus, smoking status, and aspirin use.1200,1202 While the 2017 ACC/AHA hypertension guideline has lowered the threshold for diagnosing hypertension in adults, the threshold for initiating drug therapy has only been lowered for those patients who are at high risk of cardiovascular disease.1200,1222 Clinicians who support the 2017 ACC/AHA hypertension guideline believe that these recommendations have the potential to increase hypertension awareness, encourage lifestyle modification, and focus antihypertensive drug initiation and intensification in those adults at high risk for cardiovascular disease.1227
The lower blood pressure goals advocated in the 2017 ACC/AHA hypertension guideline have been questioned by some clinicians who have concerns regarding the guideline's use of extrapolated observational data, the lack of generalizability of some of the randomized trials (e.g., SPRINT) used to support the guideline, the difficulty of establishing accurate representative blood pressure values in typical clinical practice settings, and the accuracy of the cardiovascular risk calculator used in the guideline.1224,1229 Some clinicians state the lower blood pressure threshold used to define hypertension in the 2017 ACC/AHA hypertension guideline is not fully supported by clinical data, and these clinicians have expressed concerns about the possible harms (e.g., adverse effects of antihypertensive therapy) associated with classifying more patients as being hypertensive.1222,1223,1229 Some clinicians also state that using this guideline, a large number of young, low-risk patients would need to be treated in order to observe a clinical benefit,1200,1224 while other clinicians state that the estimated gains in life-expectancy attributable to long-term use of blood pressure-lowering drugs are correspondingly greater in this patient population.1200
In clinical trials, antihypertensive therapy has been found to reduce the risk of developing stroke by about 34-40%, MI by about 20-25%, and heart failure by more than 50%.71,90,500,1235 In a randomized, controlled study (SPRINT) that included hypertensive patients without diabetes mellitus who had a high risk of cardiovascular disease, intensive systolic blood pressure lowering of approximately 15 mm Hg was associated with a 25% reduction in cardiovascular disease events and a 27% reduction in all-cause mortality.1210,1219 However, the exclusion of patients with diabetes mellitus, prior stroke, and those younger than 50 years of age may decrease the generalizability of these findings.1210 Some experts estimate that if the systolic blood pressure goals of the 2017 ACC/AHA hypertension guideline are achieved, major cardiovascular disease events may be reduced by an additional 340,000 and total deaths by an additional 156,000 compared with implementation of the JNC 8 expert panel guideline goals but these benefits may be accompanied by an increase in the frequency of adverse events.1228 While there was no overall difference in the occurrence of serious adverse events in patients receiving intensive therapy for blood pressure control (systolic blood pressure target of less than 120 mm Hg) compared with those receiving less intense control (systolic blood pressure target of less than 140 mm Hg) in the SPRINT study, hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure occurred in substantially more patients receiving intensive therapy.1210
In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease.66,67,1236,1237,1239,1240 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.66,67 Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure.1236,1237 The ALLHAT investigators suggested that the observed differences in cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.1236,1237 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)
General Considerations for Initial and Maintenance Antihypertensive Therapy
Nonpharmacologic measures (i.e., lifestyle/behavioral modifications) that are effective in lowering blood pressure include weight reduction (for those who are overweight or obese), dietary changes to include foods such as fruits, vegetables, whole grains, and low-fat dairy products that are rich in potassium, calcium, magnesium, and fiber (i.e., adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), sodium reduction, increased physical activity, and moderation of alcohol intake.1200 Such lifestyle/behavioral modifications, including smoking cessation, enhance antihypertensive drug efficacy and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.502,504,1200 Lifestyle/behavioral modifications without antihypertensive drug therapy are recommended for individuals classified by the 2017 ACC/AHA hypertension guideline as having elevated blood pressure (systolic blood pressure 120-129 mm Hg and diastolic blood pressure less than 80 mm Hg) and in those with stage 1 hypertension (systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg) who do not have preexisting cardiovascular disease or an estimated 10-year ASCVD risk of 10% or greater.1200
Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation while also considering cardiovascular risk factors.61,66,67,71,109,502,1200,1201 Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., lifestyle modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors, especially increased cardiovascular risk, requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.504,505,506,507,508,515,523,530,1200,1201,1207,1209 Recommendations generally are based on specific blood pressure levels shown in clinical studies to produce clinical benefits and can therefore vary depending on the studies selected for review.502,504,505,507,1200
The 2017 ACC/AHA hypertension guideline and many experts currently state that the treatment of hypertension should be based not only on blood pressure values but also on patients' cardiovascular risk factors.502,1200,1219 For secondary prevention of recurrent cardiovascular disease events in adults with clinical cardiovascular disease or for primary prevention in adults with an estimated 10-year ASCVD risk of 10% or higher, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an average systolic blood pressure of 130 mm Hg or an average diastolic blood pressure of 80 mm Hg or higher.1200 For primary prevention of cardiovascular disease events in adults with a low (less than 10%) estimated 10-year risk of ASCVD, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.1200 After initiation of antihypertensive drug therapy, regardless of the ASCVD risk, the 2017 ACC/AHA hypertension guideline generally recommends a blood pressure goal of less than 130/80 mm Hg in all patients.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg also is recommended for noninstitutionalized ambulatory patients 65 years of age or older.1200 While these blood pressure goals are lower than those recommended for most patients in previous guidelines, they are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210
Most data indicate that patients with a higher cardiovascular risk will benefit the most from tighter blood pressure control; however, some experts state this treatment goal also may be beneficial in those at lower cardiovascular risk.1200 Other clinicians believe that the benefits of such blood pressure lowering do not outweigh the risks in those patients considered to be at lower risk of cardiovascular disease and that reclassifying individuals formerly considered to have prehypertension as having hypertension may potentially lead to use of drug therapy in such patients without consideration of cardiovascular risk.1201,1222,1223,1229 Previous hypertension guidelines, such as those from the JNC 8 expert panel, generally recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients.501 Some clinicians continue to support the target blood pressures recommended by the JNC 8 expert panel because of concerns that such recommendations in the 2017 ACC/AHA hypertension guideline are based on extrapolation of data from the high-risk population in the SPRINT study to a lower-risk population.1223,1224 Also, because more than 90% of patients in SPRINT were already receiving antihypertensive drugs at baseline, data are lacking on the effects of initiating drug therapy at a lower blood pressure threshold (130/80 mm Hg) in patients at high risk of cardiovascular disease.1223 The potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs should be considered when deciding a patient's blood pressure treatment goal.1200,1220,1229
The 2017 ACC/AHA hypertension guideline recommends an ASCVD risk assessment for all adults with hypertension; however, experts state that it can be assumed that patients with hypertension and diabetes mellitus or chronic kidney disease (CKD) are at high risk for cardiovascular disease and that antihypertensive drug therapy should be initiated in these patients at a blood pressure of 130/80 mm Hg or higher.1200 The 2017 ACC/AHA hypertension guideline also recommends a blood pressure goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus or CKD.1200 These recommendations are based on a systematic review of high-quality evidence from randomized controlled trials, meta-analyses, and post-hoc analyses that have demonstrated substantial reductions in the risk of important clinical outcomes (e.g., cardiovascular events) regardless of comorbid conditions or age when systolic blood pressure is lowered to less than 130 mm Hg.1200,1213 However, some clinicians have questioned the generalizability of findings from some of the trials (e.g., SPRINT) used to support the 2017 ACC/AHA hypertension guideline.1224 For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease.1209,1210 While benefits of intensive blood pressure control were observed in this patient population, some clinicians have questioned whether these findings apply to younger patients who have a low risk of cardiovascular disease.1223 In patients with CKD in the SPRINT trial, intensive blood pressure management (achieving a mean systolic blood pressure of approximately 122 mm Hg compared with 136 mm Hg with standard treatment) provided a similar beneficial reduction in the composite cardiovascular disease primary outcome and all-cause mortality as in the full patient cohort.1200,1210 Because most patients with CKD die from cardiovascular complications, the findings of this study further support a lower blood pressure target of less than 130/80 mm Hg.1200
Data are lacking to determine the ideal blood pressure goal in adult patients with hypertension and diabetes mellitus; also, studies evaluating the benefits of intensive blood pressure control in patients with diabetes mellitus have provided conflicting results.521,1200,1213 Clinical studies reviewed for the 2017 ACC/AHA hypertension guideline have shown similar quantitative benefits from blood pressure lowering in hypertensive patients with or without diabetes mellitus.1213 In a randomized, controlled study (ACCORD-BP) that compared a higher (systolic blood pressure less than 140 mm Hg) versus lower (systolic blood pressure less than 120 mm Hg) blood pressure goal in patients with diabetes mellitus, there was no difference in the incidence of cardiovascular outcomes (e.g., composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke).521,1214 However, some experts state that this study was underpowered to detect a difference between the 2 treatment groups and that the factorial design of the study complicated interpretation of the results.1200,1216 Although SPRINT did not include patients with diabetes mellitus, patients in this study with prediabetes demonstrated a similar cardiovascular benefit from intensive treatment of blood pressure as normoglycemic patients.1200 A meta-analysis of data from the ACCORD and SPRINT studies suggests that the findings of both studies are consistent and that patients with diabetes mellitus benefit from more intensive blood pressure control.1202,1217 These data support the 2017 ACC/AHA hypertension guideline recommendation of a blood pressure treatment goal of less than 130/80 mm Hg in adult patients with hypertension and diabetes mellitus.1200 Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus.1214 The ADA states that a lower blood pressure goal (e.g., less than 130/80 mm Hg) may be appropriate for patients with a high risk of cardiovascular disease and diabetes mellitus if it can be achieved without undue treatment burden.1214
Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension, particularly in high-risk groups (e.g., patients with diabetes mellitus, cardiovascular disease, or cerebrovascular disease; black patients); when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.503,507,515,526,530,1200
Choice of Initial Drug Therapy
In current hypertension management guidelines, angiotensin II receptor antagonists are recommended as one of several preferred drugs for the initial treatment of hypertension; other preferred options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501,502,503,504,1200 The 2017 ACC/AHA adult hypertension guideline states that an ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, or thiazide or thiazide-like diuretic (preferably chlorthalidone) are all acceptable choices for initial antihypertensive drug therapy in the general population of nonblack patients, including those with diabetes mellitus;1200 drugs from any of these classes generally produce similar benefits in terms of overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,504,1200,1213 Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as diabetes mellitus or CKD; angiotensin II receptor antagonists also may be preferred, generally as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or following MI.501,502,504,523,524,527,534,535,536,543,1200,1214,1215 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension.)
In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.1200,1218 (See Chronic Kidney Disease under Hypertension: Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, in Uses.) However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).1200,1218 Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.1218 Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.1218
Experts state that in patients with stage 1 hypertension (especially the elderly, those with a history of hypotension, or those who have experienced adverse drug effects), 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 blood pressure.1200 Although some patients can begin treatment with a single antihypertensive agent, starting with 2 first-line drugs in different pharmacologic classes (either as separate agents or in a fixed-dose combination) is recommended in patients with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target blood pressure.1200 Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly).71,109,1200 Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred.1200 Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided.1200 Many patients who begin therapy with a single antihypertensive agent will subsequently require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal.1200 Experts state that other patient-specific factors, such as age, concurrent medications, drug adherence, drug interactions, the overall treatment regimen, cost, and comorbidities, also should be considered when deciding on an antihypertensive drug regimen.1200 For any stage of hypertension, antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved. (See Follow-up and Maintenance Drug Therapy under Hypertension: General Considerations for Initial and Maintenance Antihypertensive Therapy, in Uses.)
Follow-up and Maintenance Drug Therapy
Several strategies are used for the titration and combination of antihypertensive drugs; these strategies, which are generally based on those used in randomized controlled studies, include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination).1200 Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects.1200 After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved.1200 Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs.107,1200 In addition to measuring blood pressure, clinicians should evaluate patients for orthostatic hypotension, adverse drug effects, adherence to drug therapy and lifestyle modifications, and the need for drug dosage adjustments.1200 Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.1200
Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors
Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.71,502,1200 (See Table 2 on Compelling Indications for Drug Classes based on Comorbid Conditions, in Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.)
The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics but may include ACE inhibitors and/or β-blockers, with the addition of other drugs such as thiazide diuretics or calcium-channel blockers as necessary to achieve blood pressure goals.523,525 Many experts recommend the use of an ACE inhibitor (or an angiotensin II receptor antagonist if ACE inhibitors are not tolerated) and/or a β-blocker in hypertensive patients with stable ischemic heart disease because of the cardioprotective benefits of these drugs; all patients who have survived an MI should be treated with a β-blocker because of the demonstrated mortality benefit of these agents.523,525,527,1200
While available evidence suggests that angiotensin II receptor antagonists as single therapies are not superior to other antihypertensive agents in the reduction of cardiovascular outcomes,501,1200 angiotensin II receptor antagonists, usually in conjunction with other agents such as cardiac glycosides, diuretics, and β-blockers, have been shown to reduce morbidity and mortality in patients with existing heart failure.524 Because of the established benefits of ACE inhibitors in patients with heart failure, the American College of Cardiology Foundation (ACCF), AHA, and Heart Failure Society of America (HFSA) recommend the use of these drugs in all patients with symptomatic or asymptomatic (i.e., structural heart disease but no signs or symptoms) heart failure with reduced left ventricular ejection fraction (LVEF).52,99,100,101,524,528 Experts recommend an angiotensin II receptor antagonist as an alternative to therapy with an ACE inhibitor in patients with symptomatic or asymptomatic (i.e., structural heart disease but no signs or symptoms) heart failure with reduced LVEF.524,700 (See Uses: Heart Failure.)
Experts state that initial treatment of hypertension in adults with diabetes mellitus and hypertension should include any of the usual first-line agents (ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics).1200,1214,1215 In adults with diabetes mellitus, hypertension, and albuminuria, treatment with an ACE inhibitor or angiotensin II receptor antagonist may be considered to reduce the progression of kidney disease.1200,1215 While there is evidence demonstrating the benefits of angiotensin II receptor antagonists in reducing the development or progression of microvascular or macrovascular complications in hypertensive patients with type 1 or type 2 diabetes mellitus, 56,57,58 in the absence of albuminuria, the risk of progressive kidney disease is low, and ACE inhibitors and angiotensin II receptor antagonists have not demonstrated superior cardioprotection when compared with other first-line agents.1214,1215 Results of several studies indicate that adequate control of blood pressure in patients with type 2 diabetes mellitus reduces the development or progression of complications of diabetes (e.g., death related to diabetes, stroke, heart failure, microvascular disease).79,80,81,82,83,84,85,86,501,1214,1215 Most patients with diabetes mellitus will require 2 or more antihypertensive agents to achieve blood pressure control.1200,1215
Hypertensive patients with CKD (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m2 or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure.102,218,501,536,537,543 Use of angiotensin II receptor antagonists or ACE inhibitors may be reasonable in patients with diabetic or nondiabetic CKD (Stage 1 or 2 with albuminuria or Stage 3 or higher);1200 these drugs have been shown to slow the progression of kidney disease.43,56,58,59,102,106,501,502,534,535,536,542 Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria.535,543 Increases in serum creatinine (up to 30%) may be observed as a result of a decrease in intraglomerular pressure and concurrent reduction in GFR.1200 The 2017 ACC/AHA hypertension guideline states that in patients with less severe kidney disease (i.e., stage 1 or 2 CKD without albuminuria), any of the first-line antihypertensive agents (e.g., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics) can be used for the initial treatment of hypertension.1200 Diuretics also may be useful in the management of CKD, and may potentiate the effects of angiotensin II receptor antagonists, ACE inhibitors, and other antihypertensive agents when used in combination.
Some experts recommend a blood pressure goal of less than 140/90 mm Hg in patients with ischemic stroke or transient ischemic attack (TIA),526 while others state that a blood pressure goal of less than 130/80 mm Hg may be reasonable.1200 The 2017 ACC/AHA hypertension guideline states that adults not previously treated for hypertension who experience a stroke or TIA and who have an established blood pressure of 140/90 mm Hg or higher should receive antihypertensive therapy a few days after the event to reduce the risk of recurrent stroke or other vascular events.1200 In patients with a recent lacunar stroke, experts suggest that a systolic blood pressure goal of 130 mm Hg may be reasonable based on results of a randomized open-label study (the Secondary Prevention of Small Subcortical Strokes [SPS3] trial).518,526,1200 Although experts state that the optimal choice of drug for the management of hypertension in patients with a previous TIA or ischemic stroke is uncertain, available data indicate that an ACE inhibitor, angiotensin II receptor antagonist, thiazide diuretic, or the combination of a thiazide diuretic and an ACE inhibitor may be effective.526,1200 Administration of an ACE inhibitor in combination with a thiazide diuretic has been shown to lower rates of recurrent stroke.394,526
Other Special Considerations for Antihypertensive Drug Therapy
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 Like ACE inhibitors,66,67 angiotensin II receptor antagonists may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients.1,3 In general, black patients tend to respond better to thiazide diuretics or calcium-channel blocking agents than to angiotensin II receptor antagonists.66,67,69,501,1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 In addition, some experts state that when use of angiotensin II receptor antagonists is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.69
For further information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Both angiotensin II receptor antagonists (e.g., valsartan) and ACE inhibitors have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria,59,60,61,62,63,1232 and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion.535,536,1232 The ADA states that the use of an ACE inhibitor or angiotensin II receptor antagonist is not recommended for the primary prevention of diabetic nephropathy in patients with diabetes mellitus who are normotensive, have normal levels of urinary protein excretion, and have a normal GFR.1232 The usual precautions of angiotensin II receptor antagonist or ACE inhibitor therapy in patients with substantial renal impairment should be observed.1 (See Renal Effects under Warnings/Precautions: Other Warnings/Precautions, in Cautions.) For additional information on the use of angiotensin II receptor antagonists in the treatment of diabetic nephropathy, see Uses: Diabetic Nephropathy, in Losartan 24:32.08 and in Irbesartan 24:32.08.
Valsartan is used in the management of heart failure.1,38,52,132,133
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524,700,701,703 Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations.524,700 Experts recommend that all asymptomatic patients with reduced LVEF (ACCF/AHA stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality.524 In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and HFSA recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.700 While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction,524 some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients.700,702 ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [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.700 However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised.700 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.700 For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.
While angiotensin II receptor antagonists are considered reasonable alternatives in patients who are unable to tolerate ACE inhibitors (e.g., because of cough or angioedema),524,528 angioedema has been reported rarely with the use of valsartan during postmarketing experience.1,37,38,50 (See Sensitivity Reactions under Cautions: Warnings/Precautions.)
Several clinical trials have evaluated the use of angiotensin II receptor antagonists in patients with heart failure as add-on therapy to conventional regimens compared with an ACE inhibitor, as add-on therapy to conventional regimens including an ACE inhibitor, as combination therapy with an ACE inhibitor compared with therapy with either type of agent alone, or as an alternative therapy in patients intolerant of ACE inhibitors.38,52,132,133 In a large, double-blind, placebo-controlled study (Valsartan Heart Failure Trial [Val-HeFT]) in patients with mild to severe (NYHA class II-IV) heart failure and LVEF less than 40%, addition of valsartan 40 mg twice daily (initial dosage, with dosage doubled every 2 weeks to a target dosage of 160 mg twice daily) to standard therapy (principally ACE inhibitors, diuretics, digoxin, and β-blockers) was associated with a reduction in the composite end point of heart failure-related morbidity and mortality (defined as cardiac arrest with resuscitation, hospitalization for worsening heart failure, or administration of IV inotropic or vasodilator drugs for 4 or more hours without hospitalization) after an average of approximately 23 months.1,52 Valsartan therapy also improved secondary cardiovascular outcomes such as NYHA class, ejection fraction, and symptoms of heart failure (dyspnea, fatigue, edema, rales), and prevented deterioration of the patients' well-being (as determined by quality of life measurements).52 However, improvement in heart failure morbidity occurred principally in patients not receiving adjunctive therapy with an ACE inhibitor, and overall mortality was not affected by valsartan therapy.1,52 For additional details of studies on the use of angiotensin II receptor antagonists in the management of heart failure, see Uses: Heart Failure, in Losartan 24:32.08 and and Candesartan 24:32.08.
Data from other long-term placebo-controlled clinical trials indicate that angiotensin II receptor antagonists produce hemodynamic and neurohormonal effects associated with their suppression of the renin-angiotensin system; reduced hospitalizations and mortality also have been demonstrated.524,528 However, these drugs did not show consistent effects on cardiac symptoms or exercise tolerance in some studies.38 In one comparative (Evaluation of Losartan in the Elderly [ELITE]) study in geriatric patients 65 years of age and older who received losartan (up to 50 mg daily) or captopril (up to 150 mg daily) in addition to conventional therapy for 48 weeks, patients receiving losartan had a 46% lower risk of death and also experienced a lower incidence of adverse effects than those receiving captopril.38,45 However, after interim analysis of data, the difference in survival was no longer statistically significant and no difference in morbidity and mortality or frequency in hospitalizations for heart failure was found between the 2 therapies.38 Results of a follow-up study (ELITE II) failed to confirm a survival benefit for losartan therapy compared with captopril.133 In this study, losartan did not provide a statistically significant difference in reduction of overall death, sudden cardiac death, and/or resuscitated cardiac arrest compared with captopril, although ELITE II was not designed to demonstrate equivalence between the 2 therapies.133 In addition, results of another study (Randomized Evaluation of Strategies for Left Ventricular Dysfunction [RESOLVD]) in patients with ischemic or nonischemic dilated cardiomyopathy and mild to moderate heart failure showed no differences in exercise capacity or risk of cardiac events in patients receiving candesartan (up to 16 mg daily), enalapril (up to 20 mg daily), or a combination of candesartan and enalapril, in addition to conventional therapy.38
Heart Failure or Left Ventricular Dysfunction After Acute Myocardial Infarction
Valsartan is used to reduce the risk of cardiovascular mortality following acute MI in clinically stable patients with demonstrated clinical evidence of heart failure (signs, symptoms, radiologic evidence) or left ventricular systolic dysfunction (i.e., LVEF 40% or less).1,110,111 While ACE inhibitors generally are the preferred agents for this use because of their established benefits, angiotensin II receptor antagonists may be substituted in patients who are intolerant to ACE inhibitor therapy.527,1100
Efficacy of valsartan for reducing risk of mortality from any cause has been evaluated in a large, double-blind, randomized, long-term (median follow-up: 24.7 months) study (VALsartan In Acute myocardial iNfarcTion trial [VALIANT]) involving 14,703 patients with acute MI complicated by heart failure or left ventricular systolic dysfunction.1,110,111 The primary end point of this study was death from any cause, while secondary end points included time to cardiovascular mortality and time to the first occurrence of cardiovascular reinfarction or hospitalization for heart failure.1,110,111 A prespecified analysis was designed to demonstrate the noninferiority or equivalence of valsartan to captopril in the event that valsartan would not clearly be shown to be superior to the ACE inhibitor.110 Such analysis also was based on results from previous placebo-controlled studies, in which administration of ACE inhibitors has been associated with reduction in mortality.110
Results of VALIANT indicate that when compared with those receiving captopril (titrated to 50 mg 3 times daily) or the combination of valsartan (titrated to 80 mg twice daily) and captopril (titrated to 50 mg 3 times daily), valsartan therapy (titrated to 160 mg twice daily) initiated 0.5-10 days after an acute MI was associated with a reduction of all-cause mortality similar to the reduction observed among those receiving captopril or the combination of valsartan and captopril.1,110 Nine hundred and seventy-nine (19.9%) patients receiving valsartan died (hazard ratio of 1; 97.5% confidence interval: 0.9-1.11) compared with 958 (19.5%) of those receiving captopril.1,110,111 In addition, 941 (19.3%) patients receiving valsartan in combination with captopril died (compared with 19.5% of those receiving captopril) (hazard ratio of 0.98; 97.5% confidence interval: 0.89-1.09).1,110,111 Valsartan therapy also was comparable to ACE inhibitor therapy in terms of the composite end point of fatal and nonfatal cardiovascular events (hospitalization for heart failure and recurrent nonfatal MI).1,110,111 Benefits associated with valsartan were not affected by age, gender, race, or baseline therapies.1 In this study, combined therapy with valsartan and captopril increased the rate of adverse effects without providing further benefit on survival.1,110,111 Although findings of this study provide evidence of comparable benefit, at least in high-risk patients, most experts continue to recommend that angiotensin II receptor antagonists be reserved for patients who do not tolerate ACE inhibitors since experience with ACE inhibitors is more extensive.110,111,527
Valsartan is administered orally.1 Although food may decrease the rate and extent (e.g., by about 40%) of valsartan absorption, the manufacturers state that the drug can be administered without regard to meals.1,9
Valsartan may be administered as an extemporaneously prepared oral suspension in pediatric patients who are unable to swallow tablets or in those for whom the calculated daily dosage does not correspond to the available tablet strengths.1 An extemporaneous suspension containing valsartan 4 mg/mL can be prepared in the following manner.1 First, 80 mL of suspending vehicle (e.g., Ora-Plus®) is added to an amber glass bottle containing eight 80-mg tablets of valsartan, and the contents are shaken for at least 2 minutes.1 The concentrated suspension should be allowed to stand for at least 1 hour following reconstitution and then should be shaken for at least an additional minute.1 The concentrated suspension of valsartan should be diluted with 80 mL of sweetening vehicle (e.g., Ora-Sweet SE®), and the container then shaken for at least 10 seconds to disperse the contents.1 The suspension should be shaken for at least 10 seconds before each dose is dispensed.1 When stored in an amber glass bottle with child-resistant screw-cap closure at a temperature of less than 30°C or at 2-8°C, the extemporaneous suspension is stable for up to 30 or up to 75 days, respectively.1
Dosage of valsartan must be individualized and adjusted according to blood pressure response.1,37,116
The manufacturers state the usual initial dosage of valsartan as monotherapy in adults is 80 or 160 mg once daily in patients without depletion of intravascular volume; patients requiring greater reductions in blood pressure initially may be started at the higher dosage.1,37 If blood pressure response is inadequate with the initial dosage, dosage may be increased as tolerated up to a maximum of 320 mg daily or a diuretic may be added.1,37 The usual maintenance dosage of valsartan is 80-320 mg given once daily.1,1200 However, addition of a diuretic generally has a greater effect on blood pressure reduction than dosage increases of valsartan as dosage exceeds 80 mg daily.1 Valsartan also can be used concomitantly with other antihypertensive agents.1
The usual initial dosage of valsartan in children and adolescents 6-16 years of age with hypertension is 1.3 mg/kg (up to 40 mg) once daily.1,1150 Dosage should be adjusted according to blood pressure response.1 Some experts state that the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur.1150 Dosages exceeding 2.7 mg/kg (up to 160 mg) once daily have not been evaluated in pediatric patients.1,1150 Because systemic exposure to valsartan is 1.6 times greater when the drug is administered as an extemporaneously prepared suspension compared with administration as the commercially available tablets, children being switched from the suspension to the oral tablets may require an increase in dosage of the drug.1 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Valsartan/Hydrochlorothiazide Fixed-combination Therapy
Commercially available preparations containing valsartan in fixed combination with hydrochlorothiazide can be used as a substitute for the individually titrated drugs.37 Alternatively, in patients who do not respond adequately to monotherapy with valsartan (or another angiotensin II receptor antagonist) or, alternatively, with hydrochlorothiazide, combined therapy with the drugs can be used.37 The manufacturers state that patients who do not respond adequately to monotherapy with valsartan (or another angiotensin II receptor antagonist) or hydrochlorothiazide may be switched to therapy with the fixed-combination preparation at an initial dosage of valsartan 160 mg and hydrochlorothiazide 12.5 mg once daily.37 In addition, patients who experience dose-limiting adverse effects during monotherapy with valsartan or hydrochlorothiazide can be switched to a lower dosage of that drug, given as a fixed-combination preparation containing valsartan and hydrochlorothiazide, to achieve similar blood pressure control.37 If needed, dosage of the fixed combination may be increased up to a maximum of 320 mg of valsartan and 25 mg of hydrochlorothiazide (given once daily) after 3-4 weeks.37 The maximum antihypertensive effect is attained within 2-4 weeks after initiation of therapy or a change in dosage.37
Commercially available preparations containing valsartan in fixed combination with hydrochlorothiazide may be used for initial treatment of hypertension in patients likely to require combined therapy with multiple antihypertensive drugs to achieve blood pressure control.37 In such patients, therapy with the fixed-combination preparation should be initiated at a dosage of 160 mg of valsartan and 12.5 mg of hydrochlorothiazide once daily.37 Dosage should be adjusted according to the patient's response after 1-2 weeks of therapy.37 The decision to use the fixed combination of valsartan and hydrochlorothiazide for initial treatment of hypertension should be based on assessment of potential benefits and risks of such therapy.37 The fixed combination of valsartan and hydrochlorothiazide is not recommended as initial therapy in patients with depletion of intravascular volume.37 In patients whose baseline blood pressure is 160/100 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 41, 50, or 84% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 60, 57, or 80% with valsartan (320 mg daily) alone, hydrochlorothiazide (25 mg daily) alone, or valsartan combined with hydrochlorothiazide (at the same dosages), respectively.37
Valsartan/Amlodipine Fixed-combination Therapy
Patients whose hypertension is adequately controlled with valsartan and amlodipine administered separately may be switched to the fixed-combination preparation containing the corresponding individual doses.116 Alternatively, the manufacturers state that patients who do not respond adequately to monotherapy with valsartan (or another angiotensin II receptor antagonist) or, alternatively, with amlodipine (or another dihydropyridine-derivative calcium-channel blocker) may be switched to therapy with the fixed-combination preparation containing valsartan and amlodipine.116 In addition, patients who experience dose-limiting adverse effects during monotherapy with valsartan or amlodipine can be switched to a lower dosage of that drug, given as a fixed-combination preparation containing valsartan and amlodipine, to achieve similar blood pressure control; dosage should be adjusted according to the patient's response after 3-4 weeks of therapy.116 If needed, dosage of the fixed-combination preparation may be increased up to a maximum of 320 mg of valsartan and 10 mg of amlodipine given once daily; because most of the antihypertensive effect of a given dosage is achieved within 2 weeks, dosage may be adjusted after 1-2 weeks, if needed, to attain blood pressure control.116
Commercially available preparations containing valsartan in fixed combination with amlodipine may be used for initial treatment of hypertension in patients likely to require combined therapy with multiple antihypertensive drugs to achieve blood pressure control.116 In such patients, therapy with the fixed-combination preparation should be initiated at a dosage of 160 mg of valsartan and 5 mg of amlodipine once daily in individuals without depletion of intravascular volume.116 The decision to use the fixed combination of valsartan and amlodipine for initial management of hypertension should be based on assessment of potential benefits and risks of such therapy, including consideration of whether the patient is likely to tolerate the lowest available dosage of the combined drugs.116 In patients whose baseline blood pressure is 160/100 mm Hg, the estimated probability of achieving control of systolic blood pressure (defined as systolic blood pressure of less than 140 mm Hg) is 47, 67, or 80% and of achieving control of diastolic blood pressure (defined as diastolic blood pressure of less than 90 mm Hg) is 62, 80, or 85% with valsartan (320 mg daily) alone, amlodipine (10 mg daily) alone, or valsartan combined with amlodipine (at the same dosages), respectively.116
Valsartan/Amlodipine/Hydrochlorothiazide Fixed-combination Therapy
The fixed-combination preparation containing valsartan, amlodipine, and hydrochlorothiazide may be used to provide additional blood pressure control in patients who do not respond adequately to combination therapy with any 2 of the following classes of antihypertensive agents: angiotensin II receptor antagonists, calcium-channel blockers, or diuretics.134 Patients who experience dose-limiting adverse effects of valsartan, amlodipine, or hydrochlorothiazide while receiving any dual combination of these drugs may be switched to a lower dosage of that drug, given as a fixed-combination preparation containing all 3 of these drugs, to achieve similar blood pressure reductions.134 The fixed-combination preparation containing valsartan, amlodipine, and hydrochlorothiazide also can be used as a substitute for the individually titrated drugs.134 If necessary, dosage of the fixed-combination preparation may be increased after 2 weeks for additional blood pressure control (but should not exceed a maximum dosage of 320 mg of valsartan, 10 mg of amlodipine, and 25 mg of hydrochlorothiazide once daily).134 The commercially available preparation containing valsartan in fixed combination with amlodipine and hydrochlorothiazide should not be used for the initial management of hypertension.134
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with angiotensin II receptor antagonist monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with valsartan, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220 (See General Considerations for Initial and Maintenance Antihypertensive Therapy under Uses: Hypertension.)
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
For the management of heart failure (New York Heart Association [NYHA] class II-IV) in patients unable to tolerate therapy with angiotensin-converting enzyme (ACE) inhibitors, the manufacturers recommend an initial valsartan dosage of 40 mg twice daily;1 some experts recommend an initial dosage of 20-40 mg twice daily in patients with chronic heart failure and reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage C heart failure).524 Dosage of valsartan should be increased until a dosage of 160 mg twice daily (the maximum dosage used in clinical trials) or the highest tolerated dosage is reached.1,524 While patients with heart failure generally have some reduction in blood pressure with valsartan therapy, discontinuance of therapy usually is not necessary when dosage recommendations are followed.1 Consideration should be given to reducing the dosage of concurrent diuretic therapy.1
Heart Failure or Left Ventricular Dysfunction after Acute Myocardial Infarction
When used after myocardial infarction (MI) in adults with clinical signs of heart failure or left ventricular systolic dysfunction, valsartan therapy may be initiated as early as 12 hours after the MI.1 An initial dosage of 20 mg twice daily is recommended.1 Dosage may be increased within 7 days to 40 mg twice daily with subsequent titrations to a target maintenance dosage of 160 mg twice daily, as tolerated.1 If hypotension or renal dysfunction occurs, dosage reduction should be considered.1 While post-MI patients generally have some reduction in blood pressure with valsartan therapy, discontinuance of therapy usually is not necessary when dosage recommendations are followed.1 Valsartan may be given with other standard post-MI therapy (e.g., thrombolytics, aspirin, β-adrenergic blocking agents [β-blockers], hydroxymethylglutaryl-CoA [HMG-CoA] reductase inhibitors [statins]).1
The manufacturers state that modification of valsartan dosage is not necessary for patients with mild to moderate renal impairment;1,37,116 however, valsartan has not been studied in patients with creatinine clearances of less than 10 mL/minute1,37,116 and should be used with caution in adults with severe renal impairment.1,18,116 Valsartan is not removed by hemodialysis.1 Use of valsartan in pediatric patients with glomerular filtration rates of less than 30 mL/minute per 1.73 m2 has not been studied.1 Safety and efficacy of commercially available preparations containing valsartan in fixed combination with hydrochlorothiazide have not been established in patients with severe renal impairment.37,134
The manufacturers state that valsartan should be used with caution in patients with hepatic impairment.1,37,116 Although systemic exposure to valsartan (as measured by area under the serum concentration-time curve [AUC]) is increased approximately twofold in patients with mild to moderate chronic liver disease, the manufacturers state that modification of valsartan dosage is not necessary for these patients.1,37,116 The amount of amlodipine in fixed-combination preparations containing valsartan and amlodipine exceeds the recommended initial dosage of amlodipine (2.5 mg daily) for patients with hepatic impairment.116,134,135
The manufacturers state that modification of valsartan dosage is not necessary for geriatric patients.1,37,116 However, the amount of amlodipine in fixed-combination preparations containing valsartan and amlodipine exceeds the recommended initial dosage of amlodipine (2.5 mg daily) for geriatric patients.116,134,135
Known hypersensitivity to valsartan or any ingredient in the formulation.1,37,116,134
Concomitant use of valsartan and aliskiren in patients with diabetes mellitus.1,37,116,134,550 (See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)
Fetal/Neonatal Morbidity and Mortality
Drugs that act directly on the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists) can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters.1,16,17,20,21,22,23,24,25,26,27,28,29,31,32,33,34,35,36,37,116 Valsartan should be discontinued as soon as possible when pregnancy is detected,1,37,116 unless continued use is considered life-saving.1,16,115 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.17,25 For additional information on the risk of such drugs (i.e., angiotensin II antagonists and ACE inhibitors) during pregnancy, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.
Sensitivity reactions, including various anaphylactoid reactions and/or angioedema, have been reported in patients receiving angiotensin II receptor antagonists, including valsartan.1,37,116,118 These drugs should be used with extreme caution in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.117,119 The manufacturer states that valsartan should not be readministered to patients with a history of angioedema.1
Valsartan rarely is associated with severe hypotension in patients with uncomplicated hypertension.1,37,116 Symptomatic hypotension may occur in patients with an activated renin-angiotensin system (e.g., patients with volume or salt depletion secondary to salt restriction or high-dose diuretic therapy).1,37,116 Volume and/or salt depletion should be corrected before starting valsartan therapy, or therapy should be initiated under close medical supervision.1,37,116
Patients with heart failure and those with clinical signs of left ventricular systolic dysfunction following acute myocardial infarction (MI) generally have some reduction in blood pressure with valsartan therapy, but drug discontinuance generally is not necessary when recommended dosages are used.1,116 Caution should be observed when initiating valsartan therapy in these patients.1,116
If symptomatic hypotension occurs, the patient should be placed in the supine position;1,37,116 if hypotension is severe, IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered.1,37,116 Transient hypotension is not a contraindication to additional doses of valsartan, and therapy with the drug can be reinstated cautiously after blood pressure has been stabilized (e.g., with volume expansion).1,37,116
In July 2010, the US Food and Drug Administration (FDA) initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis suggested a possible association between the use of these agents and an increased risk of cancer.120,121,123,126 The meta-analysis, which combined cancer-related findings from 5 randomized, controlled trials in over 60,000 patients, found a modest but significant increase in the risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist (mostly telmisartan) compared with those in control groups (7.2 versus 6%, respectively; risk ratio 1.08).120,121,123 However, because of several limitations of the study (e.g., trials included in the meta-analysis were not specifically designed to evaluate cancer outcomes, lack of individual patient data), the validity of these findings has been questioned.129,130,131
Subsequent studies, including a larger, more comprehensive meta-analysis conducted by FDA, have not shown an increased risk of cancer in patients receiving angiotensin II receptor antagonists.126,127,128,129 FDA's meta-analysis, which included trial-level data from 31 randomized studies (total of approximately 156,000 patients), found no evidence of an increased risk of cancer in patients who received an angiotensin II receptor antagonist compared with those who received other treatments (placebo or active control).126 The overall rate of new cancer occurrence was essentially the same in both groups of patients (1.82 and 1.84 cases per 100 patient-years, respectively).126 In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups.126 Based on these results and a review of all currently available data related to this potential safety concern, FDA has concluded that use of angiotensin II receptor antagonists is not associated with an increased risk of cancer.126
Because the renin-angiotensin-aldosterone (RAA) system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly (e.g., renal failure) in these patients during therapy with an ACE inhibitor or an angiotensin II receptor antagonist (e.g., valsartan).1,37,116 Dosage reduction or discontinuance of valsartan or diuretic therapy may be required.1,116 Renal artery stenosis, preexisting renal impairment, and concomitant diuretic therapy also are risk factors for renal impairment during therapy with drugs that inhibit the RAA system.1,37,116 Although reports received to date have involved patients treated with ACE inhibitors, this adverse effect also would be expected to occur when drugs with similar pharmacologic activity (e.g., angiotensin II receptor antagonists) are used in a similar manner.1,37,116 (See Cautions: Renal Effects, in Enalapril 24:32.04.)
Hyperkalemia may occur in patients receiving valsartan, especially in those with heart failure and preexisting renal impairment.1,116 Dosage reduction or discontinuance of valsartan therapy may be required.1
Fixed-combination Preparations
When valsartan is used as a fixed combination that includes amlodipine and/or hydrochlorothiazide, the cautions, precautions, and contraindications associated with the concomitant agent(s) must be considered in addition to those associated with valsartan.37,116,134
Category D.1,37,116 (See Users Guide.)
Valsartan can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman.1,37,116 Valsartan should be discontinued as soon as possible when pregnancy is detected.1,37,116 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Valsartan is distributed into milk in rats.1,37,116 It is not known whether valsartan is distributed into human milk.1,37,116 A decision should be made whether to discontinue nursing or the drug because of the potential risk in nursing infants.1,37,116
Safety and efficacy of valsartan have been established in a randomized, double-blind clinical trial in pediatric patients 6-16 years of age with hypertension; adverse effects of the drug in this age group were similar to those observed in adults.1 Although there was some evidence of efficacy in randomized, double-blind clinical trials in pediatric patients 6 months to 5 years of age with hypertension,1,551,553 2 deaths and 3 cases of transaminase elevations were observed in a one-year open-label extension study in patients 1-5 years of age.1 A causal relationship to the drug has not been established; however, use of valsartan in pediatric patients younger than 6 years of age is not recommended.1 In pediatric patients with hypertension in whom underlying renal abnormalities may be more common, renal function and serum potassium should be carefully monitored.1 Pharmacokinetics of the drug have been studied in pediatric patients 1-16 years of age.1
Safety and efficacy of valsartan in fixed combination with hydrochlorothiazide and/or amlodipine in pediatric patients have not been established.37,116,134
Safety and efficacy of valsartan in pediatric patients with glomerular filtration rates of less than 30 mL/minute per 1.73 m2 have not been established.1
For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
No substantial differences in safety and efficacy of valsartan in geriatric patients relative to younger adults have been observed, but increased sensitivity cannot be ruled out.1,37,116,134
Valsartan should be used with caution in patients with obstructive biliary disease552 or hepatic impairment since the drug is eliminated primarily by biliary excretion and clearance of the drug may be reduced.1,37,116,552
Valsartan should be used with caution in patients with severe renal impairment.1,18,37,116 (See Renal Effects and also see Hyperkalemia under Warning/Precautions: Other Warnings/Precautions, in Cautions.)
Adverse effects occurring in 1% or more of adults with hypertension receiving valsartan and more frequently than with placebo include viral infection,1 fatigue,1 and abdominal pain;1 adverse effects in pediatric patients 6-16 years of age generally are similar to those in adults.1
Adverse effects occurring in 2% or more of patients with heart failure receiving valsartan and more frequently than with placebo include dizziness,1 hypotension,1 diarrhea,1 arthralgia,1 fatigue,1 back pain,1 postural dizziness,1 hyperkalemia,1 and postural hypotension.1 In patients receiving valsartan following acute MI, the most common adverse effects resulting in discontinuance of the drug included hypotension,1 cough,1 and increased serum creatinine concentration.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
In vitro studies suggest valsartan is minimally metabolized by cytochrome P-450 (CYP) microsomal isoenzyme 2C9 and does not inhibit CYP enzymes at therapeutic concentrations.1,37,116,134 Therefore, drug interactions mediated by CYP enzymes are considered unlikely with valsartan.1,37,116,134
Drugs That Inhibit Hepatic Transport Systems
In vitro data suggest that valsartan is a substrate of organic anion transporter protein (OATP) 1B1 (hepatic uptake transporter) and multidrug resistance protein MRP2 (hepatic efflux transporter).1 Use of valsartan concomitantly with inhibitors of OATP 1B1 (e.g., cyclosporine, rifampin) or MRP2 (e.g., ritonavir) may result in increased systemic exposure to valsartan.1
Drugs that Block the Renin-Angiotensin System
Concomitant use of valsartan with other drugs that block the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, aliskiren) may increase the risk of renal impairment, hyperkalemia, and hypotension; when valsartan is used concomitantly with such drugs, blood pressure, renal function, and serum concentrations of electrolytes should be monitored closely.1,37,116,134 Concomitant use of valsartan with aliskiren is contraindicated in patients with diabetes mellitus; in addition, such concomitant use should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m2).1,37,116,134,550 (See Cautions in Aliskiren Hemifumarate 24:32.40.)
Drugs or Foods That Increase Serum Potassium Concentration
Concomitant use of potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium concentrations (e.g., heparin) with valsartan may result in increased hyperkalemic effects1,37,116,134 and, in patients with heart failure, increases in serum creatinine concentration.1,116 Monitoring of serum potassium concentrations is recommended during concomitant use.1,37,116,134
Antihypertensive effect of combined atenolol and valsartan therapy exceeds that of either drug alone, but the reduction in heart rate with the drugs in combination does not exceed that observed with atenolol alone.1,37,116 Pharmacokinetic interaction is unlikely.1,37,116
Hypotensive effects of valsartan and hydrochlorothiazide are additive;1,37 pharmacokinetic interaction is unlikely.1,37,116
Increased lithium concentrations and clinical toxicity have been reported in patients receiving valsartan concomitantly with lithium.1,37,116,134 Monitoring of serum lithium concentrations is recommended during concomitant use.1,37,116,134
Nonsteroidal Anti-inflammatory Agents
Hypotensive effects of angiotensin II receptor antagonists may be attenuated when these agents are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors.1
Deterioration of renal function may occur when angiotensin II receptor antagonists are used concomitantly with NSAIAs, including selective COX-2 inhibitors, in geriatric patients, patients with volume depletion (including those receiving concomitant diuretic therapy), or patients with renal impairment; renal function should be monitored periodically in patients receiving concomitant therapy with valsartan and an NSAIA.1
Concurrent use of valsartan and warfarin did not affect the pharmacokinetics of valsartan or the anticoagulant effect of warfarin.1,37,116
Pharmacokinetic interactions with amlodipine, cimetidine, digoxin, furosemide, glyburide, and indomethacin are unlikely.1,37,116
Valsartan, a nonpeptide tetrazole derivative, is an angiotensin II type 1 (AT1) receptor antagonist.1,2,3,4,5,6,7,8,9,10 Valsartan has pharmacologic actions similar to those of losartan; however, unlike losartan, valsartan is not a prodrug and its pharmacologic activity does not depend on hydrolysis in the liver.4,9
Valsartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects, by selectively inhibiting access of angiotensin II to AT1 receptors within many tissues, including vascular smooth muscle and the adrenal gland.1,6,9 By comparison, angiotensin-converting enzyme (ACE, kininase II) inhibitors block the conversion of angiotensin I to angiotensin II; however, the blockade of angiotensin II production by ACE inhibitors is not complete since the vasopressor hormone can be formed via other enzymes that are not blocked by ACE inhibitors.6,10 Because valsartan, unlike ACE inhibitors, does not inhibit ACE, the drug does not interfere with response to bradykinins and substance P; a beneficial consequence is the absence of certain ACE inhibitor-induced adverse effects (e.g., cough), but possible renal and/or cardioprotective effects may be sacrificed.1,4,6,10 Valsartan also does not interfere with angiotensin II synthesis.1
Valsartan is eliminated mainly by biliary excretion; following oral administration, about 83% of the administered dose is recovered in feces and 13% in urine.1,552 The drug is eliminated mainly as unchanged drug, with only about 20% of a dose recovered as metabolites.1 In vitro studies indicate that valsartan is minimally metabolized by cytochrome P-450 (CYP) microsomal isoenzyme 2C9.1
When valsartan is used in fixed combination with hydrochlorothiazide and/or amlodipine, importance of advising patients of important precautionary information about the concomitant agent(s).37,116,134
Importance of informing women of childbearing potential about the risks of use during pregnancy.1,37,114,115,116,134
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,37,116 All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.1,37,116 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)
Importance of contacting clinician if dizziness or faintness develops or if unexplained weight gain or swelling of the feet, ankles, or hands occurs.1,37,116
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1,37,116
Importance of informing patients of other important precautionary information.1,37,116 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets | 40 mg* | Diovan® (scored) | |
Valsartan Tablets | ||||
80 mg* | Diovan® | Novartis | ||
Valsartan Tablets | ||||
160 mg* | Diovan® | Novartis | ||
Valsartan Tablets | ||||
320 mg* | Diovan® | Novartis | ||
Valsartan Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets, film-coated | 80 mg with Hydrochlorothiazide 12.5 mg* | Diovan® HCT | Novartis |
Valsartan and Hydrochlorothiazide Tablets | ||||
160 mg with Amlodipine Besylate 5 mg (of amlodipine)* | Amlodipine Besylate and Valsartan Tablets | |||
Novartis | ||||
160 mg with Amlodipine Besylate 5 mg (of amlodipine) and Hydrochlorothiazide 12.5 mg* | Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets | |||
Novartis | ||||
160 mg with Amlodipine Besylate 5 mg (of amlodipine) and Hydrochlorothiazide 25 mg* | Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets | |||
Exforge HCT® | Novartis | |||
160 mg with Amlodipine Besylate 10 mg (of amlodipine)* | Amlodipine Besylate and Valsartan Tablets | |||
Exforge® | Novartis | |||
160 mg with Amlodipine Besylate 10 mg (of amlodipine) and Hydrochlorothiazide 12.5 mg* | Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets | |||
Exforge HCT® | Novartis | |||
160 mg with Amlodipine Besylate 10 mg (of amlodipine) and Hydrochlorothiazide 25 mg* | Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets | |||
Exforge HCT® | Novartis | |||
160 mg with Hydrochlorothiazide 12.5 mg* | Diovan® HCT | Novartis | ||
Valsartan and Hydrochlorothiazide Tablets | ||||
160 mg with Hydrochlorothiazide 25 mg* | Diovan® HCT | Novartis | ||
Valsartan and Hydrochlorothiazide Tablets | ||||
320 mg with Amlodipine Besylate 5 mg (of amlodipine)* | Amlodipine Besylate and Valsartan Tablets | |||
Exforge® | Novartis | |||
320 mg with Amlodipine Besylate 10 mg (of amlodipine)* | Amlodipine Besylate and Valsartan Tablets | |||
Exforge® | Novartis | |||
320 mg with Amlodipine Besylate 10 mg (of amlodipine) and Hydrochlorothiazide 25 mg* | Amlodipine Besylate, Valsartan, and Hydrochlorothiazide Tablets | |||
Exforge HCT® | Novartis | |||
320 mg with Hydrochlorothiazide 12.5 mg* | Diovan® HCT | Novartis | ||
Valsartan and Hydrochlorothiazide Tablets | ||||
320 mg with Hydrochlorothiazide 25 mg* | Diovan® HCT | Novartis | ||
Valsartan and Hydrochlorothiazide Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Novartis. Diovan® (valsartan) tablets prescribing information. East Hanover, NJ; 2015 Jul.
2. Corea L, Cardoni O, Fogari F et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: a comparative study of the efficacy and safety against amlodipine. Clin Pharmacol Ther . 1996; 60:341-6. [PubMed 8841157]
3. Oparil S, Dyke S, Harris F et al. The efficacy and safety of valsartan compared with placebo in the treatment of patients with essential hypertension. Clin Ther . 1996; 18:797-810. [PubMed 8930424]
4. Holwerda NJ, Fogari R, Angeli P et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety compared with placebo and enalapril. J Hypertens . 1996; 14:1147-51. [PubMed 8986917]
5. Criscione L, de Gasparo M, Buhlmayer P et al. Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol . 1993; 110:761-771. [PubMed 8242249][PubMedCentral]
6. Bauer JH, Reams GP. The angiotensin II type 1 receptor antagonists: a new class of antihypertensive drugs. Arch Intern Med . 1995; 155:1361-68. [PubMed 7794084]
7. Ellis ML, Patterson JH. A new class of antihypertensive therapy: angiotensin II receptor antagonists. Pharmacotherapy . 1996; 16:849-60. [PubMed 8888079]
8. Müller P, Cohen T, de Gasparo M et al. Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects. Eur J Clin Pharmacol . 1994; 47: 231-45. [PubMed 7867676]
9. Criscione L, Bradley WA, Buhlmayer P et al. Valsartan: preclinical and clinical profile of an antihypertensive angiotensin-II antagonist. Cardiovasc Drug Rev . 1995; 13:230-50.
10. Anon. Valsartan for hypertension. Med Lett Drugs Ther . 1997; 39:43-4. [PubMed 9137296]
11. 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. [PubMed 9074572]
13. Anon. Drugs for hypertension. Med Lett Drugs Ther . 1995; 37:45-50. [PubMed 7760767]
16. Novartis. Lotensin® (benazepril hydrochloride) tablets prescribing information. Summit, NJ; 1995 Oct.
17. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull . 1992; 22:2.
18. Novartis, East Hanover, NJ: Personal communication.
20. Rey E, LeLorier J, Burgess E et al. Report of the Canadian Hypertension Society consensus conference: 3. pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ . 1997; 157:1245-54. [PubMed 9361646][PubMedCentral]
21. American College of Obstetricians and Gynecologists. ACOG technical bulletin No. 219: hypertension in pregnancy. 1996 Jan.
22. Hanssens M, Keirse MJ, Van Assche FA. Fetal and neonatal effects of treatment with angiotensin-converting enzyme inhibitors in pregnancy. Obstet Gynecol . 1991; 78:128-35. [PubMed 2047053]
23. Brent RL, Beckman D. Angiotensin-converting enzyme inhibitors, an embryopathic class of drugs with unique properties: information for clinical teratology counselors. Teratology . 1991; 43:543-6. [PubMed 1882342]
24. Piper JM, Ray WA, Rosa FW. Pregnancy outcome following exposure to angiotensin-converting enzyme inhibitors. Obstet Gynecol . 1992; 80:429-32. [PubMed 1495700]
25. Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med . 1996; 335:257-65. [PubMed 8657243]
26. Barr M, Cohen MM. ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection. Teratology . 1991; 44:485-95. [PubMed 1771591]
27. ER Squibb & Sons, Inc. Capozide® (captopril/hydrochlorothiazide) prescribing information. In: Physicians' desk reference. 47th ed. Montvale, NJ: Medical Economics Company Inc; 1993:2359-62.
28. Bristol-Myers Squibb Company. Capoten® (captopril) tablets prescribing information (J4-458F). In: Physicians' desk reference. 51st ed. Montvale, NJ: Medical Economics Company Inc; 1997:740-4.
29. Joint letter of Bristol-Myers Squibb Company; Ciba-Geigy Corporation, Pharmaceutical Division; Hoechst-Roussel Pharmaceuticals Inc; ICI Pharmaceutical Group, ICI Americas Inc; Merck Human Health Division; Parke-Davis, Division of Warner-Lambert Company. Important warning information regarding use of ACE inhibitors in pregnancy. 1992 Mar 16.
30. Bristol-Myers Squibb. Princeton, NJ: Personal communication.
31. Merck. Vasotec® (enalapril maleate) tablets prescribing information. West Point, PA; 1995 Jul.
32. Merck. Vaseretic® (enalapril maleate-hydrochlorothiazide) prescribing information. West Point, PA; 1995 Jul.
33. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med . 1988; 108:215-6. [PubMed 2829674]
34. Anon. ACE-inhibitors: contraindicated in pregnancy. WHO Drug Information . 1990; 4:23.
35. Merck. Vasotec® (enalaprilat) IV prescribing information. West Point, PA; 1994 Apr.
36. Scott AA, Puronit DM. Neonatal renal failure: a complication of maternal antihypertensive therapy. Am J Obstet Gynecol . 1989; 160:1223-4. [PubMed 2543224]
37. Novartis Pharmaceuticals. Diovan HCT® (valsartan and hydrochlorothiazide) tablets prescribing information. East Hanover, NJ. 2015 Jul.
38. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membreship 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.
39. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]
40. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]
42. Food and Drug Administration. Avapro (irbesartan) Tablets [May 9, 2000: Bristol-Myers Squibb]. MedWatch drug labeling changes. Rockville, MD; May 2000. From FDA website. [Web]
43. 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. [PubMed 10977801]
45. 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. [PubMed 9074572]
46. 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. [PubMed 9635947]
50. Hunt SA, Abraham WT, Chin MH et al. ACC/AHA 2005 guideline update for the diagnosis 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 (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation . 2005; 112:e154-235. Epub 2005 Sep 13. Available from AHA website. Accessed October 24, 2006. [PubMed 16160202][Web]
52. 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. [PubMed 11759645]
53. 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. [PubMed 2196359]
54. 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. [PubMed 11940556]
55. 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. [PubMed 12093785]
56. 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. [PubMed 11565518]
57. Parving H-H, 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. [PubMed 11565519]
58. 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. [PubMed 11565517]
59. 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. [PubMed 8413456]
60. Remuzzi G. Slowing the progression of diabetic nephropathy. N Engl J Med . 1993; 329:1496-7. [PubMed 8413463]
61. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]
62. 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. [PubMed 8295285]
63. Fournier A. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med . 1994; 330:937. [PubMed 8114873]
64. 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. [PubMed 8416309]
65. Björck S, Mulec H, Johnsen SA et al. Renal protective effect of enalapril in diabetic nephropathy. BMJ . 1992; 304:339-43. [PubMed 1540729][PubMedCentral]
66. Appel LJ. The verdict from ALLHATthiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-42. [PubMed 12479770]
67. 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. [PubMed 12479763]
69. Douglas JG, Bakris GL, Epstein M et al. Management of high blood pressure in African Americans: Consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003; 163:525-41.
71. The Guidelines Subcommitee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.
72. Watson RDS, Littler WA. Onset and duration of β-adrenergic receptor blockade following single oral dose acebutolol hydrochloride (Sectral). Br J Clin Pharmacol . 1979; 7:557-61. [PubMed 37868][PubMedCentral]
73. Gradman AH, Winkle RA, Fitzgerald JW et al. Suppression of premature ventricular contractions by acebutolol. Circulation . 1977; 55:785-91. [PubMed 66105]
74. Fournier A, Hardin JM, Alexandre JM et al. Anti-hypertensive effect of acebutolol: its relation to sympathetic nervous system responsiveness and to plasma renin and dopamine-β-hydroxylase activities. Clin Sci Mol Med . 1976; 51:477-80s.
75. Alhenc-Gelas F, Plouin PF, Ducrocq MB et al. Comparison of the antihypertensive and hormonal effects of a cardioselective beta-blocker, acebutolol, and diuretics in essential hypertension. Am J Med . 1978; 64:1005-12. [PubMed 655186]
76. Riley LJ Jr, Vlasses PH, Ferguson RK. Clinical pharmacology and therapeutic applications of the new oral converting enzyme inhibitor, enalapril. Am Heart J . 1985; 109:1085-9. [PubMed 2986440]
77. Kaplan NM. Initial treatment of adult patients with essential hypertension. Part 2: alternating monotherapy is the preferred treatment. Pharmacotherapy . 1985; 5:195-200. [PubMed 4034407]
79. Genuth S. United Kingdom prospective diabetes study results are in. J Fam Pract . 1998; 47:(Suppl 5):S27.
80. Watkins PJ. UKPDS: a message of hope and a need for change. Diabet Med . 1998; 15:895-6. [PubMed 9827842]
81. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ . 1998; 317:703-13. [PubMed 9732337][PubMedCentral]
82. Bretzel RG, Voit K, Schatz H et al. The United Kingdom Prospective Diabetes Study (UKPDS): implications for the pharmacotherapy of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes . 1998; 106:369-72. [PubMed 9831300]
83. Tatti P, Pahor M, Byington RP et al. Outcome results of the fosinopril versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care . 1998; 21:597-603. [PubMed 9571349]
84. American Diabetes Association. The United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes: what you need to know about the results of a long-term study. Washington, DC; 1998 Sep 15 from American Diabetes Association web site. [Web]
85. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ . 1998; 317:713-20. [PubMed 9732338][PubMedCentral]
86. Davis TM. United Kingdom Prospective Diabetes Study: the end of the beginning? Med J Aust . 1998; 169:511-2.
88. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet . 2000; 355: 253-9.
89. Niskanen L, Hender T, Hansson L et al. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/β-blocker-based treatment regimen. Diabetes Care . 2001; 24:2091-6. [PubMed 11723089]
90. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs. Lancet . 2000;356:1955-64. [PubMed 11130523]
91. Black HR, Elliott WJ, Grandits G, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA . 2003;289:2073-2082. [PubMed 12709465]
92. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE). Lancet . 2002;359:995-1003. [PubMed 11937178]
93. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med . 2000;342:145-153. [PubMed 10639539]
94. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet . 2001;358:1033-41. [PubMed 11589932]
95. Wing LMH, Reid CM, Ryan P, et al, for Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med . 2003;348:583-92. [PubMed 12584366]
96. Psaty BM, Smith NL, Siscovick DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]
97. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med . 2001;344:1651-58. [PubMed 11386263]
98. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation . 1994;90:1765-1773. [PubMed 7923660]
99. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med . 1991;325:293-302. [PubMed 2057034]
100. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet . 1993; 342:821-8. [PubMed 8104270]
101. Kober L, Torp-Pedersen C, Carlsen JE, et al, for Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med . 1995;333:1670-6. [PubMed 7477219]
102. Wright JT Jr, Agodoa L, Contreras G, et al. Successful blood pressure control in the African American Study of Kidney Disease and Hypertension. Arch Intern Med . 2002;162:1636-43. [PubMed 12123409]
104. Tepper D. Frontiers in congestive heart failure: effect of metoprolol CR/XL in chronic heart failure: MetoprololCR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Congest Heart Fail . 1999;5:184-5. [PubMed 12189311]
105. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med . 1999; 341:709-17. [PubMed 10471456]
106. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia) Lancet . 1997; 349:1857-63.
107. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) . 2002;4:393-404. [PubMed 12461301]
108. Black HR, Elliott WJ, Neaton JD et al. Baseline characteristics and elderly blood pressure control in the CONVINCE trial. Hypertension . 2001; 37:12-18. [PubMed 11208750]
109. Reviewers' comments (personal observations) on the Thiazides General Statement 40:28.
110. Pfeffer MA, McMurray JJV, Velasquez EJ et al for the Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med . 2003; 349:1893-906. [PubMed 14610160]
111. Mann DL, Deswal A. Angiotensin-receptor blockade in acute myocardial infarctiona matter of dose. N Engl J Med . 2003; 349:1963-5. Editorial. [PubMed 14610159]
114. 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. [PubMed 16760444]
115. Food and Drug Administration. FDA public health advisory: angiotensin-converting enzyme inhibitor (ACE inhibitor) drugs and pregnancy. From FDA website. [Web]
116. Novartis Pharmaceuticals Corp. Exforge® (amlodipine and valsartan) tablets prescribing information. East Hanover, NJ; 2015 Aug.
117. 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.
118. Merck & Co., Inc. Cozaar® (losartan potassium) tablets prescribing information. Whitehouse Station, NJ; 2008 Sep.
119. Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother . 2000; 34:526-8. [PubMed 10772441]
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 ([Web]).
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. [PubMed 20542468][PubMedCentral]
122. Nissen SE. Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Lancet Oncol . 2010; 11:605-6. [PubMed 20542469]
123. Sica DA. Angiotensin receptor blockers and the risk of malignancy: a note of caution. Drug Saf . 2010; 33:709-12. [PubMed 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. [Web]
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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 21633727][PubMedCentral]
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. [PubMed 13678870]
133. 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; 355:1582-7. [PubMed 10821361]
134. Novartis Pharmaceuticals Corporation. Exforge HCT® (amlodipine, valsartan, hydrochlorothiazide) tablets prescribing information. East Hanover, NJ; 2015 Jul.
135. Pfizer Laboratories. Norvasc® (amlodipine besylate) tablets prescribing information. New York; 2015 Mar.
218. National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis . 2002; 39(Suppl 2):S1-246.
394. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet . 2001;358:1033-41. [PubMed 11589932]
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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 24424788]
506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]
507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 24591473]
518. SPS3 Study Group, Benavente OR, Coffey CS et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet . 2013; 382:507-15. [PubMed 23726159][PubMedCentral]
521. ACCORD Study Group, Cushman WC, Evans GW et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med . 2010; 362:1575-85. [PubMed 20228401][PubMedCentral]
522. Patel A, ADVANCE Collaborative Group, MacMahon S et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet . 2007; 370:829-40. [PubMed 17765963]
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. [PubMed 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; :. [PubMed 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. [PubMedCentral]
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. [PubMed 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. [PubMed 24641124]
531. . Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet . 2000; 355:253-9. [PubMed 10675071]
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. [PubMed 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. [PubMed 23684145][PubMedCentral]
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(suppl): 337-414.
537. Levey AS, de Jong PE, Coresh J et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int . 2011; 80:17-28. [PubMed 21150873]
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. [PubMed 22555213]
542. National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis . 2002; 39(Suppl 2):S1-246.
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. [Web]
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. [Web]
551. Schaefer F, Coppo R, Bagga A et al. Efficacy and safety of valsartan in hypertensive children 6 months to 5 years of age. J Hypertens . 2013; 31:993-1000. [PubMed 23511339]
552. Thomas MC, Johnston CI. Valsartan. J Drug Eval . 2004; 3:67-101.
553. Flynn JT, Meyers KE, Neto JP et al. Efficacy and safety of the angiotensin receptor blocker valsartan in children with hypertension aged 1 to 5 years. Hypertension . 2008; 52:222-8. [PubMed 18591457]
700. 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.
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. [PubMed 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. [PubMed 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. [PubMed 26992459]
1100. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014; 130:e344-426. [PubMedCentral]
1150. Flynn JT, Kaelber DC, Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics . 2017; 140 [PubMed 28827377]
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. [PubMed 29133356]
1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 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. [PubMed 29357392]
1205. Aronow WS, Frishman WH. Implications of the New National Guidelines for Hypertension. Cardiol Rev . 2018 Mar/Apr; 26:55-61. [PubMed 29419560]
1206. Benjamin EJ, Virani SS, Callaway CW et al. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation . 2018; 137:e67-e492. [PubMed 29386200]
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. [PubMed 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. [PubMed 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. [PubMed 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. [PubMed 29146534]
1214. American Diabetes Association. 9. Cardiovascular disease and risk management: standards of medical care in diabetes 2018. Diabetes Care . 2018; 41:S86-S104. [PubMed 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. [PubMed 28830958]
1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]
1217. Perkovic V, Rodgers A. Redefining Blood-Pressure Targets--SPRINT Starts the Marathon. N Engl J Med . 2015; 373:2175-8. [PubMed 26551394]
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. [PubMed 29598869]
1219. Karmali KN, Lloyd-Jones DM. Global risk assessment to guide blood pressure management in cardiovascular disease prevention. Hypertension . 2017; 69:e2-e9. [PubMed 28115516]
1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 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. [PubMed 29710197]
1223. LeFevre M. ACC/AHA hypertension guideline: What is new? What do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]
1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]
1225. Einstadter D, Bolen SD, Misak JE et al. Association of repeated measurements with blood pressure control in primary care. JAMA Intern Med . 2018; 178(6):858-60. [PubMed 29710186]
1226. Baron RB. Treating blood pressure correctly by measuring it correctly. JAMA Intern Med . 2018; 178(6):860-1. [PubMed 29710072]
1227. Muntner P, Carey RM, Gidding S et al. Potential US population impact of the 2017 ACC/AHA high blood pressure guideline. Circulation . 2018; 137(2):109-18. [PubMed 29133599]
1228. Bundy JD, Mills KT, Chen J et al. Estimating the association of the 2017 and 2014 hypertension guidelines with cardiovascular events and deaths in US adults. An analysis of national data. JAMA Cardiol . 2018; 3(7):572-581. [PubMed 29800138]
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. [PubMed 29242891]
1230. Vasan RS, Larson MG, Leip EP et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med . 2001; 345(18):1291-7. [PubMed 11794147]
1232. American Diabetes Association. 10. Microvascular complications and foot care: standards of medical care in diabetes 2018. Diabetes Care . 2018; 41:S105-S118. [PubMed 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(4 Suppl 2):S90-7. [PubMed 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. [PubMed 21388309]
1235. Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension . 2000;35:539-543. [PubMed 10679494]
1236. Leenen FHH, Nwachuku CE, Black HR et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium-channel blocker versus angiotensin-converting enzyme inhibitor in the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Hypertension . 2006; 48:374-84. [PubMed 16864749]
1237. Messerli FH, Staessen JA. Amlodipine better than lisinopril: how one randomized clinical trial ended fallacies from observational studies. Hypertension . 2006; 48:359-61. [PubMed 16894055]
1238. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality. Lancet . 2002;360:1903-13. [PubMed 12493255]
1239. 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. [PubMed 15811979]
1240. Neaton JD, Kuller LH. Diuretics are color blind. JAMA . 2005; 293:1663-6. [PubMed 15811986]