Hypertension in adults: Antihypertensive medication titration

INTRODUCTION — 

Over one billion people worldwide have high blood pressure, affecting nearly 30 percent of the adult population worldwide and 45 percent of the adult population in the United States [1]. In the United States, treatment of hypertension is the most common reason for office visits and for the use of chronic prescription medications [2,3].

This topic presents an overview of the evaluation of patients and medication titration when blood pressure is not at goal despite initial antihypertensive drug therapy. Other content related to hypertension is presented separately:

●Measurement of blood pressure to diagnose and manage hypertension (see "Hypertension in adults: Blood pressure measurement and diagnosis" and "Ambulatory blood pressure monitoring: Indications and procedure")

●Initial drug therapy in adults with hypertension (see "Hypertension in adults: Initial drug therapy")

●Goal blood pressure (see "Goal blood pressure in adults with hypertension")

GOAL BLOOD PRESSURE — 

Goal blood pressure (ie, "target blood pressure") is determined by the patient's underlying cardiovascular risk (table 1) and the method of blood pressure measurement. (See "Hypertension in adults: Blood pressure measurement and diagnosis", section on 'Methods for measuring blood pressure'.)

●Higher-risk population – Patients with one or more of the following conditions warrant more intensive blood pressure lowering (table 1). In such patients, we use a goal blood pressure range of 120 to 125 mmHg systolic and <80 mmHg diastolic using standard blood pressure measurement methods. (See "Goal blood pressure in adults with hypertension", section on 'Intensive goal blood pressure targets for higher-risk patients' and "Hypertension in adults: Blood pressure measurement and diagnosis", section on 'Methods for measuring blood pressure'.)

•Known atherosclerotic cardiovascular disease (ASCVD)

•Heart failure

•Diabetes mellitus

•Chronic kidney disease

•Age 65 years or older

•An estimated 10-year risk of an ASCVD event of at least 10 percent, using the American Heart Association Predicting Risk of Cardiovascular Disease Events calculator or another ASCVD risk assessment tool (see "Cardiovascular disease risk assessment for primary prevention: Risk calculators")

●Average-risk population – Patients without any of the above risk factors are considered average risk and warrant a less intensive blood pressure target. In such patients, we use a goal blood pressure range of 125 to 135 mmHg systolic and less than 90 mmHg diastolic using standard blood pressure measurement methods. (See "Goal blood pressure in adults with hypertension", section on 'Less intensive goal blood pressure in lower-risk patients' and "Hypertension in adults: Blood pressure measurement and diagnosis", section on 'Methods for measuring blood pressure'.)

Although we discourage their use, if nonstandardized, or "casual," blood pressure measurement methods are used, a higher blood pressure target is applied (table 1) because of the substantial variability these inferior methods introduce. (See "Hypertension in adults: Blood pressure measurement and diagnosis", section on 'Methods for measuring blood pressure'.)

Less aggressive goals may be appropriate for individual patients, including those with orthostatic hypotension or a history of medication intolerance and in patients who are underweight or frail.

These targets vary slightly from national and international society guidelines (table 2). Goal blood pressure and the evidence supporting blood pressure targets in higher-risk individuals are discussed in further detail separately. (See "Goal blood pressure in adults with hypertension".)

UNCONTROLLED BLOOD PRESSURE: INITIAL ASSESSMENT

Confirm accurate blood pressure measurement — When blood pressure is not at goal, despite antihypertensive drug therapy, we first confirm the blood pressure is truly above goal with out-of-office blood pressure measurements or a series of office-based measurements using standardized blood pressure measurement technique (table 3 and table 4). We discourage nonstandardized, "casual" blood pressure measurement methods because they produce inaccurate and highly variable blood pressure readings. (See "Hypertension in adults: Blood pressure measurement and diagnosis", section on 'Blood pressure measurement methods'.)

If the white coat effect is a diagnostic concern, we prioritize out-of-office blood pressure measurement with either self-measured blood pressure (SMBP) or ambulatory blood pressure monitoring (ABPM). If SMBP and/or ABPM are not feasible due to access or cost, automated office blood pressure (AOBP) measurement is a reasonable alternative method for diagnosing white coat hypertension, although, as an in-office measurement, AOBP does not fully ameliorate the possibility of white coat effect. (See "Hypertension in adults: Blood pressure measurement and diagnosis", section on 'White coat hypertension'.)

Address medication nonadherence — Patients with elevated blood pressure despite antihypertensive therapy should have a comprehensive assessment of adherence, including a discussion of medication side effects, socioeconomic factors, and other potential barriers to adherence (table 5 and table 6). Methods to identify nonadherence and strategies to address nonadherence are discussed in further detail separately. (See "Medication adherence in patients with hypertension".)

Nonadherence to medication is a common contributor to uncontrolled blood pressure. In one meta-analysis, 45 percent of all patients with hypertension were partially or completely nonadherent to antihypertensive therapy [4]. In another meta-analysis, approximately 30 percent of patients with apparent treatment resistance were nonadherent, but there was a high degree of heterogeneity, with nonadherence rates of 3 to 86 percent, depending on the individual study [5]. In general, studies that relied upon self-report found lower rates of nonadherence, whereas analyses that used more objective measures reported higher rates. Reports from other surveys indicate that at least 20 percent of patients never initiate newly prescribed antihypertensive drug therapy [6] and as many as 50 percent who actually do initiate antihypertensive medications stop taking them within one year [7].

Avoid therapeutic inertia — Therapeutic inertia is the failure to intensify antihypertensive medication when blood pressure is above goal. Although therapeutic inertia is widely regarded as a major contributor to uncontrolled hypertension, most clinicians intensify antihypertensive drugs at only a fraction of the visits at which they encounter an elevated blood pressure reading [8-13]. As an example, in one large, nationally representative study of 7404 outpatient clinic visits in the United States from 2008 to 2018, patients with hypertension who presented to their primary care clinicians with an uncontrolled blood pressure (defined in that study as ≥140 mmHg systolic and/or ≥90 mmHg diastolic) had their antihypertensive regimen intensified just 14 percent of the time [8]. In addition, while the prevalence of uncontrolled hypertension is high and increasing in the United States, the number of antihypertensive drugs prescribed to adults with hypertension has not changed over the past decade, and only one in four drug-treated adults with hypertension is prescribed more than two antihypertensive drugs [14].

Clinician uncertainty regarding patient medication adherence is frequently cited as a leading reason for therapeutic inertia; however, its contribution to poor blood pressure control is likely overestimated [15]. In one study, for example, an inadequate antihypertensive regimen was the most probable reason for uncontrolled hypertension (72 percent) compared with patient nonadherence (13 percent) [10].

The gap between guidelines and actual care reflects a complex interplay among patient, clinician, and organizational factors [15,16]. At each visit, the clinician must translate clinical complexity, competing priorities, potentially unreliable blood pressure data, and health system barriers into either "appropriate inaction" or "inappropriate inertia." In addition to clinician education, additional studies are needed to identify individual and system-wide strategies to address therapeutic inertia in hypertension.

UNCONTROLLED ON A SINGLE MEDICATION — 

Patients with uncontrolled blood pressure despite antihypertensive drug therapy should have confirmation of inadequate control using proper (ideally out-of-office) blood pressure measurements and an assessment of adherence before their regimen is intensified. (See 'Confirm accurate blood pressure measurement' above and 'Address medication nonadherence' above.)

Escalate the single medication to a moderate dose — If blood pressure is uncontrolled on low-dose monotherapy, we escalate the medication dose to at least half the maximum recommended dose (ie, to a moderate or high dose) before adding additional therapy. Adding a second drug is a reasonable alternative to maximizing the dose of a single agent as two-drug combinations facilitate the achievement of the goal blood pressure with lower doses of each medication, thereby reducing the risk of dose-related side effects [17-19]. (See 'Add a second medication' below.)

Add a second medication — If the patient does not attain goal blood pressure, despite adherence to at least moderate-dose monotherapy, we add a second drug, rather than attempting sequential monotherapy.

The two drugs should be selected from among the three preferred classes (ie, angiotensin-converting enzyme [ACE] inhibitors [or angiotensin receptor blockers (ARBs)], calcium channel blockers, and thiazide diuretics [preferably a thiazide-like rather than a thiazide-type diuretic]) [20]. We suggest prescribing these two agents as a single-pill combination if feasible. If the initial single agent has been well tolerated without adverse effects, we select a single-pill combination that includes the initial agent when possible (table 7). Our approach to drug selection otherwise mirrors the approach for patients warranting initial combination therapy (algorithm 1), including consideration of conditions with additional indications for a specific antihypertensive class (table 8); specifically, we prefer two-drug combination therapy with an ACE inhibitor or ARB plus a dihydropyridine calcium channel blocker, rather than other combinations. The rationale for our approach is presented separately. (See "Hypertension in adults: Initial drug therapy", section on 'Drug selection'.)

Compared with sequential monotherapy, adding a second drug increases antihypertensive efficacy through complementary mechanisms of action and facilitates more rapid attainment of the goal blood pressure. Two-drug treatment also reduces the potential for adverse effects from maximum doses of individual drugs. In one study of 605 individuals with hypertension, initial combination therapy produced greater blood pressure reduction and greater attainment of goal blood pressure (defined in this study as <140/90 mmHg) compared with sequential monotherapy [21]. The blood pressures in both groups became similar once the sequential monotherapy group was switched to combination therapy at 16 weeks. (See "Hypertension in adults: Initial drug therapy", section on 'Combination therapy for most patients'.)

Using single-pill combinations, in which both drugs are contained in a single pill, leads to greater blood pressure reduction, increased attainment of blood pressure goal, and better medication adherence as compared with free equivalents (ie, in which the two drugs are prescribed as separate pills) [22,23]. This is discussed in further detail separately. (See "Hypertension in adults: Initial drug therapy", section on 'Single-pill combinations versus free equivalents'.)

UNCONTROLLED ON TWO MEDICATIONS — 

Patients with uncontrolled blood pressure despite antihypertensive drug therapy should have confirmation of inadequate control using proper (ideally out-of-office) blood pressure measurements and an assessment of adherence before their regimen is intensified. (See 'Confirm accurate blood pressure measurement' above and 'Address medication nonadherence' above.)

Escalate the doses of existing medications

●For patients on single-pill combination therapy, we escalate to a moderate or high dose of the single-pill combination (table 7) before adding additional therapy.

●For patients on free equivalents of two separate agents, we titrate the dose of each free equivalent to at least moderate or high doses before adding additional therapy. At low and moderate doses, the doses of both agents can be escalated together in a single visit. At higher doses, it is reasonable to make only one medication change per visit as the risk of dose-related side effects is increased.

Add a third medication — In patients whose blood pressure is uncontrolled despite adherence to two drugs at moderate or high doses, we add a drug from the third class of preferred agents (ie, angiotensin-converting enzyme [ACE] inhibitors [or angiotensin receptor blockers (ARBs)], calcium channel blockers, and thiazide diuretics [preferably a thiazide-like rather than a thiazide-type diuretic]) [20]. As an example, in a patient who has not attained goal blood pressure, despite taking an ACE inhibitor and calcium channel blocker, we add a thiazide-like diuretic (ie, chlorthalidone or indapamide). Some patients may have an indication for a drug from a different class, as described previously (table 8). (See "Hypertension in adults: Initial drug therapy", section on 'Comorbidities that influence drug choice'.)

We prefer adding a thiazide-like diuretic (ie, chlorthalidone or indapamide) in patients taking an ACE inhibitor (or ARB) and a dihydropyridine calcium channel blocker, instead of hydrochlorothiazide, since the thiazide-like diuretics have greater blood pressure-lowering efficacy and were preferentially used in hypertension clinical trials. However, hydrochlorothiazide is a reasonable alternative if there are substantial concerns about medication adherence. There are several three-drug, single-pill combinations available that incorporate hydrochlorothiazide with an ARB and amlodipine (table 7), and adherence may be improved if all three medications can be given in a single pill.

A three-drug, single-pill combination that included a thiazide-like diuretic (ie, indapamide) with telmisartan and amlodipine was examined in a trial of 1385 patients with uncontrolled blood pressure, most of whom were taking one or two antihypertensive medications at baseline [24]. Compared with two-drug, single-pill combinations (telmisartan-amlodipine, amlodipine-indapamide, or telmisartan-indapamide), the three-drug, single-pill combination had significantly greater effects on systolic blood pressure reduction (by 5.4, 4.4, and 2.5 mmHg, respectively). While promising, this agent is not yet available in the United States. Studies of three-drug, single-pill combinations that are available in the United States (table 7) are an area of future study. (See "Hypertension in adults: Initial drug therapy", section on 'Drug selection'.)

RESISTANT AND REFRACTORY HYPERTENSION — 

Apparent resistant hypertension is defined as a blood pressure that remains above goal despite concurrent prescription of three or more antihypertensive drugs taken at intermediate or high doses, or at maximally tolerated doses, inclusive of a diuretic. Those prescribed four or more medications, if controlled, also have apparent resistant hypertension. The word "apparent" is used because many such patients have pseudoresistant hypertension (eg, due to nonadherence to prescribed therapy or white coat effect). This issue is presented in detail separately. (See "Definition, risk factors, and evaluation of resistant hypertension", section on 'Apparent, true, and pseudoresistant hypertension'.)

Refractory hypertension is defined as uncontrolled blood pressure despite concurrent prescription of five or more antihypertensive drugs, inclusive of a diuretic. Historically, refractory hypertension has not been distinguished from resistant hypertension. In one study, approximately 6 percent of those with apparent resistant hypertension had refractory hypertension [25]. Compared with patients who have apparent resistant hypertension, those with refractory hypertension have higher rates of kidney failure and cardiovascular disease [26]. In addition, rates of nonadherence to therapy are higher among those with apparent refractory hypertension (60 percent in one study) [27]. (See "Definition, risk factors, and evaluation of resistant hypertension", section on 'Refractory hypertension'.)

The evaluation and treatment of patients with resistant and refractory hypertension are presented separately (algorithm 2 and figure 1). (See "Definition, risk factors, and evaluation of resistant hypertension" and "Treatment of resistant hypertension".)

FOLLOW-UP — 

We evaluate patients every two to four weeks (either in person or by telehealth) after intensifying antihypertensive drug therapy until blood pressure is at goal (table 1). In most patients, we wait four weeks after starting or intensifying therapy to permit long-acting antihypertensive drugs enough time to manifest their full blood pressure-lowering effect. Patients with severely elevated blood pressure should be re-evaluated sooner, typically within several days to a week. This approach is consistent with the American College of Cardiology/American Heart Association 2017 hypertension guideline [20].

We monitor electrolytes and serum creatinine one to three weeks after initiation or titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and diuretics (table 9). In patients on stable doses of medications, electrolytes and creatinine are monitored annually. More frequent monitoring is indicated for patients with comorbidities associated with fluid or electrolyte imbalances.

After the goal blood pressure is attained, we usually follow patients every three to six months (either in person or by telehealth).

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: High blood pressure in adults (The Basics)" and "Patient education: Medicines for high blood pressure (The Basics)" and "Patient education: Blood pressure measurement (The Basics)")

●Beyond the Basics topics (see "Patient education: High blood pressure in adults (Beyond the Basics)" and "Patient education: High blood pressure treatment in adults (Beyond the Basics)" and "Patient education: High blood pressure, diet, and weight (Beyond the Basics)" and "Patient education: Coping with high prescription drug prices in the United States (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goal blood pressure – Goal blood pressure (ie, "target blood pressure") is determined by the patient's underlying cardiovascular risk and the method of blood pressure measurement (table 1). Less aggressive goals may be appropriate for individual patients, including those with orthostatic hypotension or a history of medication intolerance and in patients who are underweight or frail. (See 'Goal blood pressure' above and "Goal blood pressure in adults with hypertension".)

●Initial assessment when blood pressure is not at goal – When blood pressure is not at goal, despite antihypertensive drug therapy, we repeat blood pressure measurement using a standardized method to confirm blood pressure is truly above goal and white coat effect is not present (table 3 and table 4). (See 'Uncontrolled blood pressure: Initial assessment' above.)

We also assess medication adherence, including a discussion of medication side effects, socioeconomic factors, and other potential barriers to adherence (table 5 and table 6). Both patient treatment nonadherence and clinician therapeutic inertia, or a failure to intensify antihypertensive medication when indicated, are major contributors to uncontrolled hypertension. (See 'Address medication nonadherence' above and 'Avoid therapeutic inertia' above.)

●Antihypertensive medication titration

•Uncontrolled on a single medication – If blood pressure is uncontrolled on low-dose monotherapy, we escalate the medication dose to at least half the maximum recommended dose (ie, to a moderate or high dose) before adding additional therapy. If the patient does not attain goal blood pressure, despite adherence to at least moderate-dose monotherapy, we add a second drug, preferably a single-pill combination that includes the initial agent (table 7 and algorithm 1). (See 'Uncontrolled on a single medication' above.)

•Uncontrolled on two medications – For patients on single-pill combination therapy, we escalate to a moderate or high dose of the single-pill combination (table 7). For patients on free equivalents of two separate agents, we titrate the dose of each free equivalent to a moderate or high dose.

In patients whose blood pressure is uncontrolled despite adherence to two drugs at moderate or high doses, we add a drug from the third class of preferred agents (ie, angiotensin-converting enzyme inhibitors [or angiotensin receptor blockers], calcium channel blockers, and thiazide diuretics [preferably a thiazide-like rather than a thiazide-type diuretic]). Some patients may have an indication for a drug from a different class (table 8). (See 'Uncontrolled on two medications' above.)

●Follow-up – We evaluate patients every two to four weeks (either in person or by telehealth) after intensifying antihypertensive drug therapy until blood pressure is at goal (table 1). (See 'Follow-up' above.)

●Resistant hypertension – Apparent resistant hypertension is defined as blood pressure that remains above goal despite concurrent use of three or more antihypertensive agents of different classes, including a diuretic. Those prescribed four or more medications, if controlled, also have apparent resistant hypertension. The evaluation and treatment of patients with resistant hypertension are presented separately (algorithm 2 and figure 1). (See "Definition, risk factors, and evaluation of resistant hypertension" and "Treatment of resistant hypertension".)