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Uses

Hypertension

Valsartan is used alone or in combination with other classes of antihypertensive agents (e.g., thiazide diuretics) in the management of hypertension. 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. 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. 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.

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. However, recommendations for initial drug selection and use in specific patient populations may vary across these expert guidelines. 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. 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). 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.

Disease Overview

Worldwide, hypertension is the most common modifiable risk factor for cardiovascular events and mortality. 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. 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 organizations (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, which results in an increase of approximately 14% in the prevalence of hypertension in the US. 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. Among US adults receiving antihypertensive drugs, approximately 53% have inadequately controlled blood pressure according to current ACC/AHA treatment goals.

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. The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors. It is important that very high blood pressure be managed promptly to reduce the risk of target organ damage. The higher the blood pressure, the more likely the development of myocardial infarction (MI), heart failure, stroke, and renal disease. 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. 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. 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.

Blood Pressure Classification

Accurate blood pressure measurement is essential for the proper diagnosis and management of hypertension. Error in measuring blood pressure is a major cause of inadequate blood pressure control and may lead to overtreatment. Because a patient's blood pressure may vary in an unpredictable fashion, a single blood pressure measurement is not sufficient for clinical decision-making. 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. Out-of-office blood pressure measurements may be useful for confirming and managing hypertension. 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.

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.(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. 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. Individuals with systolic blood pressure and diastolic blood pressure in 2 different categories should be designated as being in the higher blood pressure category.

Table 1. ACC/AHA Blood Pressure Classification in Adults [1200 ]
Category SBP (mm Hg) DBP (mm Hg)
Normal <120 and <80
Elevated 120-129 and <80
Hypertension, Stage 1 130-139 or 80-89
Hypertension, Stage 2 >=140 or >=90

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

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

Systolic blood pressure

Diastolic blood pressure

The blood pressure thresholds used to define hypertension, when to initiate drug therapy, and the ideal target blood pressure values remain controversial. 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. 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. 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. A linear relationship has been demonstrated between cardiovascular risk and blood pressure even at low systolic blood pressures (e.g., 120-124 mm Hg). The 2017 ACC/AHA hypertension guideline recommends estimating a patient's ASCVD risk using the ACC/AHA Pooled Cohort equations (available online at http://tools.acc.org/ASCVD-Risk-Estimator), 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. 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. 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.

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. 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. 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, 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.

Treatment Benefits

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%. 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. 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. 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. 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.

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. Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed. 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. 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.

General Considerations for Initial and Maintenance Antihypertensive Therapy

Nonpharmacologic 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. 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. 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.

Initiation of Drug Therapy

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. 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. 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.

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. 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. 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. 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. 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. 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.

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. 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. 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. 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. 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. 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.

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. 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. 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. 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. For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease. 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. 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. 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.

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. 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. 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). 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. 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. 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. 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. Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus. 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.

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.

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. 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; drugs from any of these classes generally produce similar benefits in terms of overall mortality and cardiovascular, cerebrovascular, and renal outcomes. 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.(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.(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). Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy. 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.

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. 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. 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). 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. 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. 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. 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. 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). Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects. After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved. Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs. 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. Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.

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.

Ischemic Heart Disease

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. 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.

Heart Failure

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, 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. 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). 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.(See Uses: Heart Failure.)

Diabetes Mellitus

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). 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. 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, 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. 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). Most patients with diabetes mellitus will require 2 or more antihypertensive agents to achieve blood pressure control.

Chronic Kidney Disease

Hypertensive patients with CKD (glomerular filtration rate [GFR] less than 60 mL/minute per 1.73 m or kidney damage for 3 or more months) usually will require more than one antihypertensive agent to reach target blood pressure. 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); these drugs have been shown to slow the progression of kidney disease. Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria. Increases in serum creatinine (up to 30%) may be observed as a result of a decrease in intraglomerular pressure and concurrent reduction in GFR. 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. 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.

Cerebrovascular Disease

Some experts recommend a blood pressure goal of less than 140/90 mm Hg in patients with ischemic stroke or transient ischemic attack (TIA), while others state that a blood pressure goal of less than 130/80 mm Hg may be reasonable. 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. 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). 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. Administration of an ACE inhibitor in combination with a thiazide diuretic has been shown to lower rates of recurrent stroke.

Other Special Considerations for Antihypertensive Drug Therapy

Race

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control. Like ACE inhibitors, angiotensin II receptor antagonists may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients. In general, black patients tend to respond better to thiazide diuretics or calcium-channel blocking agents than to angiotensin II receptor antagonists. 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. 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.

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.

Diabetic Nephropathy

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, 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. 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. The usual precautions of angiotensin II receptor antagonist or ACE inhibitor therapy in patients with substantial renal impairment should be observed.(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, and in

Heart Failure

Valsartan is used in the management of heart failure.

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. 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. 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. 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. 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, 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. 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. 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. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.

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), angioedema has been reported rarely with the use of valsartan during postmarketing experience.(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. 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. 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). 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. For additional details of studies on the use of angiotensin II receptor antagonists in the management of heart failure, and .

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. However, these drugs did not show consistent effects on cardiac symptoms or exercise tolerance in some studies. 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. 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. Results of a follow-up study (ELITE II) failed to confirm a survival benefit for losartan therapy compared with captopril. 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. 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.

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). 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.

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. 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. 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. 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.

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. 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. 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). 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). Benefits associated with valsartan were not affected by age, gender, race, or baseline therapies. In this study, combined therapy with valsartan and captopril increased the rate of adverse effects without providing further benefit on survival. 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.

Dosage and Administration

Administration

Valsartan is administered orally. 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.

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. An extemporaneous suspension containing valsartan 4 mg/mL can be prepared in the following manner. 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. 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. 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. The suspension should be shaken for at least 10 seconds before each dose is dispensed. 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.

Dosage

Hypertension

Dosage of valsartan must be individualized and adjusted according to blood pressure response.

Valsartan Therapy

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. 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. The usual maintenance dosage of valsartan is 80-320 mg given once daily. 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. Valsartan also can be used concomitantly with other antihypertensive agents.

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. Dosage should be adjusted according to blood pressure response. 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. Dosages exceeding 2.7 mg/kg (up to 160 mg) once daily have not been evaluated in pediatric patients. 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. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

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. 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. 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. 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. 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. The maximum antihypertensive effect is attained within 2-4 weeks after initiation of therapy or a change in dosage.

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. 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. Dosage should be adjusted according to the patient's response after 1-2 weeks of therapy. 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. The fixed combination of valsartan and hydrochlorothiazide is not recommended as initial therapy in patients with depletion of intravascular volume. 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.

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. 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. 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. 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.

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. 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. 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. 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.

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. 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. The fixed-combination preparation containing valsartan, amlodipine, and hydrochlorothiazide also can be used as a substitute for the individually titrated drugs. 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). The commercially available preparation containing valsartan in fixed combination with amlodipine and hydrochlorothiazide should not be used for the initial management of hypertension.

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. 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.(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.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure. However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial. While previous hypertension guidelines have based target blood pressure goals on age and comorbidities, 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. 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.(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,

Heart Failure

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; 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). 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. 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. Consideration should be given to reducing the dosage of concurrent diuretic therapy.

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. An initial dosage of 20 mg twice daily is recommended. 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. If hypotension or renal dysfunction occurs, dosage reduction should be considered. 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. 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]).

Special Populations

The manufacturers state that modification of valsartan dosage is not necessary for patients with mild to moderate renal impairment; however, valsartan has not been studied in patients with creatinine clearances of less than 10 mL/minute and should be used with caution in adults with severe renal impairment. Valsartan is not removed by hemodialysis. Use of valsartan in pediatric patients with glomerular filtration rates of less than 30 mL/minute per 1.73 m has not been studied. Safety and efficacy of commercially available preparations containing valsartan in fixed combination with hydrochlorothiazide have not been established in patients with severe renal impairment.

The manufacturers state that valsartan should be used with caution in patients with hepatic impairment. 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. 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.

The manufacturers state that modification of valsartan dosage is not necessary for geriatric patients. 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.

Cautions

Contraindications

Known hypersensitivity to valsartan or any ingredient in the formulation.

Concomitant use of valsartan and aliskiren in patients with diabetes mellitus.(See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)

Warnings/Precautions

Warnings

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. Valsartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy. For additional information on the risk of such drugs (i.e., angiotensin II antagonists and ACE inhibitors) during pregnancy, and in .

Sensitivity Reactions

Sensitivity reactions, including various anaphylactoid reactions and/or angioedema, have been reported in patients receiving angiotensin II receptor antagonists, including valsartan. 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. The manufacturer states that valsartan should not be readministered to patients with a history of angioedema.

Other Warnings/Precautions

Cardiovascular Effects

Valsartan rarely is associated with severe hypotension in patients with uncomplicated hypertension. 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). Volume and/or salt depletion should be corrected before starting valsartan therapy, or therapy should be initiated under close medical supervision.

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. Caution should be observed when initiating valsartan therapy in these patients.

If symptomatic hypotension occurs, the patient should be placed in the supine position; if hypotension is severe, IV infusion of 0.9% sodium chloride injection to expand fluid volume should be considered. 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).

Malignancies

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. 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). 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.

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. 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). 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). In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups. 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.

Renal Effects

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). Dosage reduction or discontinuance of valsartan or diuretic therapy may be required. 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. 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.

Hyperkalemia

Hyperkalemia may occur in patients receiving valsartan, especially in those with heart failure and preexisting renal impairment. Dosage reduction or discontinuance of valsartan therapy may be required.

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.

Specific Populations

Pregnancy

Category D.

Valsartan can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Valsartan should be discontinued as soon as possible when pregnancy is detected.(See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Valsartan is distributed into milk in rats. It is not known whether valsartan is distributed into human milk. A decision should be made whether to discontinue nursing or the drug because of the potential risk in nursing infants.

Pediatric Use

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. 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, 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. 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. In pediatric patients with hypertension in whom underlying renal abnormalities may be more common, renal function and serum potassium should be carefully monitored. Pharmacokinetics of the drug have been studied in pediatric patients 1-16 years of age.

Safety and efficacy of valsartan in fixed combination with hydrochlorothiazide and/or amlodipine in pediatric patients have not been established.

Safety and efficacy of valsartan in pediatric patients with glomerular filtration rates of less than 30 mL/minute per 1.73 m have not been established.

For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Geriatric Use

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.

Hepatic Impairment

Valsartan should be used with caution in patients with obstructive biliary disease or hepatic impairment since the drug is eliminated primarily by biliary excretion and clearance of the drug may be reduced.

Renal Impairment

Valsartan should be used with caution in patients with severe renal impairment. (See Renal Effects and also see Hyperkalemia under Warning/Precautions: Other Warnings/Precautions, in Cautions.)

Common Adverse Effects

Adverse effects occurring in 1% or more of adults with hypertension receiving valsartan and more frequently than with placebo include viral infection, fatigue, and abdominal pain; adverse effects in pediatric patients 6-16 years of age generally are similar to those in adults.

Adverse effects occurring in 2% or more of patients with heart failure receiving valsartan and more frequently than with placebo include dizziness, hypotension, diarrhea, arthralgia, fatigue, back pain, postural dizziness, hyperkalemia, and postural hypotension. In patients receiving valsartan following acute MI, the most common adverse effects resulting in discontinuance of the drug included hypotension, cough, and increased serum creatinine concentration.

Drug Interactions

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. Therefore, drug interactions mediated by CYP enzymes are considered unlikely with valsartan.

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). 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.

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. 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 m).

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 effects and, in patients with heart failure, increases in serum creatinine concentration. Monitoring of serum potassium concentrations is recommended during concomitant use.

Atenolol

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. Pharmacokinetic interaction is unlikely.

Hydrochlorothiazide

Hypotensive effects of valsartan and hydrochlorothiazide are additive; pharmacokinetic interaction is unlikely.

Lithium

Increased lithium concentrations and clinical toxicity have been reported in patients receiving valsartan concomitantly with lithium. Monitoring of serum lithium concentrations is recommended during concomitant use.

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.

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.

Warfarin

Concurrent use of valsartan and warfarin did not affect the pharmacokinetics of valsartan or the anticoagulant effect of warfarin.

Other Drugs

Pharmacokinetic interactions with amlodipine, cimetidine, digoxin, furosemide, glyburide, and indomethacin are unlikely.

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