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 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. 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.
Considerations in Initiating Antihypertensive Therapy
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 requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.
While the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended antihypertensive drug therapy in all patients with systolic/diastolic blood pressure of 140/90 mm Hg or higher who fail to respond to lifestyle/behavioral modifications, other experts, including the panel members appointed to the Eighth Joint National Committee (JNC 8 expert panel) recommend a higher systolic blood pressure threshold for older individuals (e.g., the JNC 8 expert panel recommends a threshold of 150 mm Hg for patients 60 years of age or older).
In addition, there is some variation in the blood pressure thresholds and treatment goals recommended for patients with diabetes mellitus or chronic kidney disease. In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had blood pressures of 130/80 mm Hg or higher; however, current hypertension management guidelines generally recommend the same blood pressure threshold of 140/90 mm Hg for initiating antihypertensive drug therapy in these individuals as for the general population of patients without these conditions, although a lower goal (e.g., less than 130/80 mm Hg) may still be considered.
Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension; when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies. For additional details,
Antihypertensive drug therapy generally should be initiated gradually and titrated at intervals of approximately 2-4 weeks to achieve the target blood pressure. The goal is to reduce blood pressure to levels below the threshold used for initiating drug therapy. Addition of a second drug should be initiated when use of monotherapy in adequate dosages fails to achieve goal blood pressure. Some experts state that initial antihypertensive therapy with a combination of drugs may be considered in patients with systolic/diastolic blood pressure greater than 20/10 mm Hg above goal 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). Initial combined therapy may be particularly useful in patients with markedly high baseline blood pressures and those with additional risk factors.
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 options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. 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 chronic kidney disease; 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 postmyocardial infarction.
(See Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors under Uses: Hypertension.)
Follow-up and Maintenance Therapy
Several strategies are recommended for the titration and combination of antihypertensive drugs; these strategies 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). In patients who fail to respond adequately to initial monotherapy with an angiotensin II receptor antagonist, the JNC 8 expert panel states that a thiazide diuretic or a calcium-channel blocker may be added. If goal blood pressure is not achieved with optimal dosages of these 2 drugs, a third antihypertensive agent from one of the recommended drug classes may be added; if more than 3 drugs are required, other antihypertensive agents (e.g., β-adrenergic blocking agents (β-blockers), aldosterone antagonists, centrally acting agents) may be considered. Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects. If the blood pressure goal cannot be achieved using the above recommended strategies, consultation with a hypertension specialist should be considered.
Antihypertensive Therapy for Patients with Underlying Cardiovascular or 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. 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 a myocardial infarction (MI) should be treated with a β-blocker because of the demonstrated mortality benefit of these agents. Other antihypertensive drugs such as calcium-channel blockers or thiazide diuretics may be added to the regimen as necessary to achieve blood pressure goals.
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), American Heart Association (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.)
Angiotensin II receptor antagonists, ACE inhibitors, calcium-channel blockers, and thiazide diuretics have all been recommended for initial antihypertensive therapy in patients with diabetes mellitus, although certain agents may be preferred. 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). Angiotensin II receptor antagonists have been shown to retard the progression of albuminuria and the development and progression of nephropathy in patients with diabetes mellitus; in addition, there is some evidence suggesting that the drugs may also provide cardioprotective benefits. According to the American Diabetes Association (ADA), drugs that inhibit the renin-angiotensin system (i.e., angiotensin II receptor antagonists, ACE inhibitors) may have advantages with respect to cardiovascular outcomes when used for initial or early treatment of hypertension in diabetic patients, and should therefore be included in the antihypertensive regimen of such patients; the renoprotective effect of these drugs provides another compelling reason for their use in diabetic patients who may have albuminuria or renal insufficiency.
(See Uses: Diabetic Nephropathy.)If additional blood pressure control is required, a calcium-channel blocker or thiazide diuretic may be added. Because angiotensin II receptor antagonists and ACE inhibitors tend not to be as effective in black patients, some experts recommend a thiazide diuretic or a calcium-channel blocker as the initial antihypertensive drug of choice in black patients with diabetes. (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses.)
Chronic Kidney Disease
Hypertensive patients with chronic kidney disease (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 is recommended in patients with diabetic or nondiabetic chronic kidney disease; these drugs have been shown to slow the progression of kidney disease, but evidence of a cardiovascular benefit is not as clear. Evidence of a renoprotective benefit is strongest in those with higher levels of albuminuria. Although angiotensin II receptor antagonists and ACE inhibitors generally are not recommended as the drugs of first choice for initial antihypertensive therapy in black patients, some experts suggest that these drugs be used for their renoprotective effects in black patients with chronic kidney disease and proteinuria because of the high likelihood that these patients will progress to end-stage renal disease. Diuretics also may be useful in the management of chronic kidney disease, and may potentiate the effects of angiotensin II receptor antagonists, ACE inhibitors, and other antihypertensive agents when used in combination.
Other Special Considerations for Antihypertensive Therapy
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, such diminished response to an angiotensin II receptor antagonist is largely eliminated when the drug is administered concomitantly with a thiazide diuretic or a calcium-channel blocker. 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, 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, 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 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
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,
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.