Choice of drug therapy in primary (essential) hypertension

INTRODUCTION — The global prevalence of hypertension is high, and among nonpregnant adults in the United States, treatment of hypertension is the most common reason for office visits and for the use of chronic prescription medications [1,2]. Over several decades, the intensity (eg, number and doses) of antihypertensive drug therapy has been recognized as being more important for preventing cardiovascular disease than the choice of which specific drug to use initially. In addition, although selected antihypertensive drug classes are more beneficial than others in patients with certain comorbidities, the clinical benefit of antihypertensive drug therapy in the majority of patients is linked to the magnitude of blood pressure lowering, rather than the choice of drug.

The approach to antihypertensive drug selection, titration, and combination is discussed in this topic. Other content related to hypertension is presented elsewhere:

●Measurement of blood pressure to diagnose and manage hypertension (see "Blood pressure measurement in the diagnosis and management of hypertension in adults" and "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring")

●Definition of hypertension and identification of candidates for drug therapy (see "Overview of hypertension in adults")

●Evaluation of adults with hypertension (see "Initial evaluation of adults with hypertension")

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

●(Related Pathway(s): Hypertension: Initial management and Hypertension: Management of patients on monotherapy who have uncontrolled blood pressure and Hypertension: Management of patients on combination therapy (two antihypertensive drugs) who have uncontrolled blood pressure.)

INITIAL DRUG THERAPY — All hypertensive patients should be prescribed nonpharmacologic therapy (ie, lifestyle modification). Details of lifestyle interventions to lower blood pressure are presented separately. (See "Overview of hypertension in adults", section on 'Nonpharmacologic therapy' and "Diet in the treatment and prevention of hypertension" and "Salt intake and hypertension" and "Potassium and hypertension" and "Overweight, obesity, and weight reduction in hypertension" and "Exercise in the treatment and prevention of hypertension".)

In addition to nonpharmacologic therapy, some patients should be initiated on antihypertensive drug therapy. Our recommendations regarding indications for drug therapy are discussed elsewhere. (See "Overview of hypertension in adults", section on 'Who should be treated with pharmacologic therapy?'.) (Related Pathway(s): Hypertension: Initial management.)

Choosing between monotherapy and combination drug therapy — Among patients selected for antihypertensive drug treatment, therapy should be initiated with either one drug (ie, monotherapy) or two drugs (ie, combination therapy, preferably in a single pill to improve adherence) [3-5].

Although initiating therapy with more than two antihypertensive agents has been examined in some trials (ie, with a "polypill") [6-8], the experience with this approach is limited and is therefore not recommended.

When deciding between initial monotherapy versus initial combination therapy, our approach is as follows:

●When to initiate treatment with two drugs (combination therapy) – In general, patients with a systolic pressure 10 to 20 mmHg above goal and/or a diastolic pressure 10 mmHg above goal should have antihypertensive drug therapy initiated with low to moderate doses of two agents with complementary mechanisms of action. Some experts begin with two agents in patients with stage 2 hypertension (ie, systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg), whereas other experts would initiate therapy with two drugs in patients whose systolic pressure is ≥150 mmHg and/or diastolic pressure ≥90 mmHg.

Combination therapy lowers blood pressure more than monotherapy and increases the likelihood that target blood pressure will be achieved in a reasonable time period [9-13]. In addition, using two drugs may lead to attainment of goal blood pressure with lower doses of each medication, and this reduces the risk of dose-related side effects [14-16]. Our approach is consistent with guidance from the American College of Cardiology (ACC)/American Heart Association (AHA) and the European Society of Hypertension (ESH) [3,4].

When starting treatment with two agents, we suggest using a single-pill combination (ie, in which both drugs are contained in a single pill) rather than using free equivalents (ie, in which the same drugs and doses are prescribed as separate pills) (table 1). Some experts initiate therapy with a single-pill combination containing low doses of each drug, whereas other experts initiate free equivalents and then, after titrating the dose of each drug, convert to a single-pill combination. Single-pill combinations lead to greater blood pressure reduction, increased attainment of blood pressure goal, and better medication adherence as compared with free equivalents [15,17,18].

However, there are some settings in which we treat with free equivalents rather than a single-pill combination. As an example, in patients with a history of multiple drug allergies or intolerances, starting with one drug and then adding a second agent several weeks later makes it less complicated for the clinician to identify the culprit drug if a side effect occurs. Also, because they are simpler to titrate when frequent dose adjustment is needed, free equivalents are also appropriate for complex cases of hypertension (ie, patients with renovascular or other secondary forms of hypertension, and those with target organ damage such as heart failure or kidney function impairment). In each of these settings, the free equivalents can eventually be replaced by a single-pill combination once the blood pressure is controlled and the patient is tolerating therapy.

Single-pill combinations are often more expensive, may not be paid for by prescription drug insurance, and vary in availability by region.

●When to initiate treatment with one drug (monotherapy) – In patients with stage 1 hypertension (systolic pressure 130 to 139 mmHg and/or diastolic pressure 80 to 89 mmHg) who are selected for drug therapy, we initiate antihypertensive therapy with one agent. In addition, some but not all experts start with monotherapy if the systolic blood pressure is 140 to 149 mmHg and the diastolic pressure is <90 mmHg. (See "Overview of hypertension in adults", section on 'Who should be treated with pharmacologic therapy?'.)

Initial monotherapy is also appropriate for patients who are deemed to be at higher risk for adverse effects as a result of antihypertensive therapy. Such patients include those adhering to a very low salt intake, those who are underweight or frail, those with a known orthostatic decline in blood pressure, and, as noted above, those with a history of multiple drug allergies or intolerances.

Regardless of whether treatment is begun with one or two drugs, the initial drug dose should generally be low. Angiotensin receptor blockers (ARBs) are an exception as they do not cause severe dose-related side effects [19,20], and their maximal antihypertensive effect is moderate in most patients. Thus, initiation with a moderate to high dose of an ARB is reasonable because this prevents the need for unnecessary dose titration.

Whether starting with one drug or two, by far the most important strategy for ultimately achieving blood pressure control is to avoid therapeutic inertia [21,22]. Therapeutic inertia is defined as failing to initiate or adjust/intensify prescribed drug therapy despite the recognition of uncontrolled hypertension. A nationally representative survey of ambulatory primary care practices found that when blood pressure was >140/90 mmHg, treatment was intensified with prescription of a new drug at only 17 percent of office visits [23-25]. Moreover, therapeutic inertia appears to have a greater impact on inadequate hypertension control than patient nonadherence to prescribed drug therapy [22].

Dose titration and monitoring of patients initiated on antihypertensive drug therapy are discussed below. (See 'Dose titration and monitoring' below.)

Choice of initial therapy in most patients — The three primary options for antihypertensive drug therapy in most patients include an ACE inhibitor (or ARB), a calcium channel blocker, or a thiazide diuretic (preferably a thiazide-like diuretic) [3].

Patients selected for initial monotherapy — In patients selected to initiate antihypertensive therapy with one drug, we select from among the following medication classes [3]:

●Angiotensin-converting enzyme (ACE) inhibitor

●Angiotensin receptor blocker (ARB)

●Calcium channel blocker

●Thiazide diuretic

If there are no compelling reasons to select a specific drug class, we suggest treating with an ACE inhibitor (or ARB) or a dihydropyridine calcium channel blocker, rather than a thiazide diuretic (algorithm 1). (Related Pathway(s): Hypertension: Initial management.)

When used as monotherapy, the four drug classes mentioned produce similar benefits on cardiovascular endpoints [26-29]. However, the combination of an ACE inhibitor and a dihydropyridine calcium channel blocker may provide superior protection against cardiovascular events compared with a combination of a thiazide diuretic with the same ACE inhibitor [30]. Since the majority of patients who begin treatment with monotherapy will ultimately require additional drugs to control their blood pressure, starting with a medicine that is part of the optimal two-drug combination is a simpler strategy than starting with, for example, a thiazide diuretic as a single drug and then, when two drugs are warranted, stopping the thiazide then adding a calcium antagonist plus an ACE inhibitor (or ARB). The data supporting this approach come from the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which is discussed below. (See 'Adding a second drug (preferred combination therapy)' below.)

Nevertheless, a thiazide diuretic is a reasonable alternative as monotherapy, and may be preferred over an ACE inhibitor, ARB, or dihydropyridine calcium channel blocker in patients with edema, osteoporosis, or calcium nephrolithiasis with hypercalciuria. If a thiazide diuretic is used, we suggest treating with a thiazide-like diuretic (ie, chlorthalidone, indapamide) rather than hydrochlorothiazide. (See "General principles of the treatment of edema in adults", section on 'Use of diuretics' and "Drugs that affect bone metabolism", section on 'Drugs that may have beneficial effects' and "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'High urine calcium'.)

In addition, some patients have a compelling reason to use an agent from a specific class (eg, mineralocorticoid receptor antagonists in patients with heart failure with preserved ejection fraction, beta blockers in patients following a myocardial infarction). These compelling indications are discussed below (table 2). (See 'Choice of initial therapy in patients with comorbidities' below.)

In the absence of a compelling indication, we and others recommend that beta blockers not be used as first-line therapy, particularly in patients over age 60 years [3,31-35]. Compared with other antihypertensive drugs in the primary treatment of hypertension, beta blockers appear to be associated with inferior protection against stroke risk and all-cause mortality [35-39]. Such disadvantages of beta blockers are primarily seen in patients over age 60 years [38,40-42]. Beta blockers are also associated with impaired glucose tolerance and an increased risk of new-onset diabetes [32], with the exception of vasodilating beta blockers such as carvedilol and nebivolol [43,44]. (See "Treatment of hypertension in patients with diabetes mellitus".)

As noted above, when a thiazide diuretic is used, we suggest selecting a thiazide-like diuretic (chlorthalidone or indapamide) rather than hydrochlorothiazide. Chlorthalidone and indapamide are significantly more potent antihypertensive agents than hydrochlorothiazide, a thiazide-type diuretic, at similar dose levels [45-50]. In a meta-analysis of 14 trials that compared the blood pressure reduction with one of three dose levels of hydrochlorothiazide (low, intermediate, high) with a similar dose of one of the thiazide-like diuretics, systolic pressure reduction was greater with chlorthalidone and indapamide (by 3.6 and 5.1 mmHg, respectively) [45].

A possibly more important difference than potency is the longer duration of action of chlorthalidone and indapamide (24 or more hours versus 6 to 12 hours with hydrochlorothiazide) (table 3) [46-48]. This may not affect office blood pressure if the medication is taken in the morning but may result in a greater fall in nighttime blood pressure. In one small trial, for example, nighttime blood pressure decreased by 13.5 mmHg with 25 mg/day of chlorthalidone and by 6.4 mmHg with 50 mg/day of hydrochlorothiazide [47].

The effects of chlorthalidone and hydrochlorothiazide on cardiovascular outcomes were directly compared in a trial of 13,523 older male veterans (mean age 72 years) who had uncontrolled hypertension (mean systolic pressure 139 mmHg) despite taking hydrochlorothiazide 25 mg daily with (87 percent) or without (13 percent) other antihypertensive agents [51]. Patients were randomly assigned to continue hydrochlorothiazide or switch to 12.5 mg of chlorthalidone. At 2.4 years, rates of all-cause mortality, stroke, myocardial infarction, and hospitalization for heart failure were the same in each group. Blood pressure was also similar between the groups and remained uncontrolled throughout the trial. A serum potassium ≤3 mEq/L occurred in 5 percent of those taking chlorthalidone and 3.6 percent of those taking hydrochlorothiazide.

Several limitations of this trial diminish the usefulness of the findings. The primary problem is that when a patient has uncontrolled blood pressure despite taking 25 mg of hydrochlorothiazide, our approach would be to switch the patient to 25 mg of chlorthalidone (not 12.5 mg) in order to attain the benefits from its increased antihypertensive efficacy. The 25 mg dose of chlorthalidone was also the dose used in cardiovascular outcome trials such as ALLHAT [52]. In addition, more than 15 percent of patients assigned to chlorthalidone switched back to hydrochlorothiazide during the course of the trial, whereas 4 percent switched from hydrochlorothiazide to chlorthalidone, an outcome that could have biased the results of the trial toward the null. The reasons for this large difference in crossover were not discussed but could be explained at least in part by the need for patients to split their chlorthalidone tablets, which are not available in a 12.5 mg pill and which are typically not scored.

Other studies, including several network meta-analyses, concluded that cardiovascular outcomes were superior with chlorthalidone as compared with hydrochlorothiazide [53-58]. By contrast, some retrospective observational studies suggest that chlorthalidone and hydrochlorothiazide lead to similar rates of cardiovascular events but that chlorthalidone increases the risk of adverse metabolic effects (eg, hypokalemia) [59,60]. However, the metabolic derangements associated with chlorthalidone can be attenuated, at least in part, by pairing it with an ACE inhibitor or ARB.

Dose titration and monitoring of patients initiated on antihypertensive drug therapy are discussed below. (See 'Dose titration and monitoring' below.)

Patients selected for initial combination therapy — When two drugs are used, they should be from different antihypertensive drug classes [3]. In most patients, the drugs should be selected from among the three preferred classes (ie, ACE inhibitors [or ARBs], calcium channel blockers, and thiazide diuretics [ideally a thiazide-like rather than a thiazide-type diuretic]). Conversely, some patients may have an indication for a drug from a different class, as described below (table 2). (See 'Choice of initial therapy in patients with comorbidities' below.)

Among those without an indication for one of the nonpreferred agents, we suggest treating with the combination of an ACE inhibitor (or ARB) and a calcium channel blocker, preferably a dihydropyridine calcium blocker. The rationale for this approach comes from the ACCOMPLISH trial, which is presented below. (See 'Adding a second drug (preferred combination therapy)' below.) (Related Pathway(s): Hypertension: Initial management.)

In addition, we suggest prescribing these two agents as a single-pill combination, if feasible (table 1 and algorithm 1). Some experts initiate therapy with a single-pill combination, whereas other experts initiate free equivalents and then, after titrating the dose of each drug, convert to a single-pill combination. Single-pill combinations lead 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) [17,18]. In addition, observational data suggest that single-pill combination therapy reduces the risk of cardiovascular disease and mortality compared with free equivalents [61].

The combination of an ACE inhibitor (or ARB) with a thiazide diuretic is a reasonable alternative, particularly in patients who have conditions that can benefit from a thiazide diuretic (eg, edema, osteoporosis, calcium nephrolithiasis with hypercalciuria). However, thiazide-like diuretics (ie, chlorthalidone, indapamide) are preferred over thiazide-type diuretics (eg, hydrochlorothiazide), and there are only two single-pill combinations available that combine an ACE inhibitor (or ARB) with a thiazide-like diuretic (ie, perindopril-indapamide and azilsartan-chlorthalidone).

Although treating with a calcium channel blocker and a thiazide diuretic is also a reasonable option, there are no such single-pill combinations available.

Dose titration and monitoring of patients initiated on antihypertensive drug therapy are discussed below. (See 'Dose titration and monitoring' below.)

In contrast to the preferred combinations mentioned above, it is important to avoid ineffective and/or potentially hazardous two-drug combinations [62]:

●Patients should not simultaneously be prescribed both an ACE inhibitor and an ARB; combining these drugs is associated with adverse cardiovascular and kidney events. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Combination of ACE inhibitors and ARBs' and "Treatment of hypertension in patients with diabetes mellitus", section on 'Avoid combination renin-angiotensin system inhibition' and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Combination of ACE inhibitors and ARBs'.)

Similarly, a direct renin inhibitor should not be combined with an ACE inhibitor or ARB.

●A beta blocker should not be simultaneously prescribed with a nondihydropyridine calcium channel blocker (ie, diltiazem, verapamil), since both classes have negative inotropic and chronotropic effects.

●The combination of an alpha blocker (eg, prazosin) and a central adrenergic inhibitor (eg, clonidine) should be avoided, since significant orthostatic hypotension may result.

●Unlike other combinations that have near additive antihypertensive effects, a beta blocker plus a central adrenergic inhibitor is a less effective and risky combination and should be avoided.

Choice of initial therapy in patients with comorbidities

Patients with heart failure — Patients with heart failure may have reduced ejection fraction (ie, HFrEF), mildly reduced ejection fraction (ie, HFmrEF), or preserved ejection fraction (ie, HFpEF). Such patients are often prescribed multiple specific drugs to improve survival and reduce morbidity, independent of the blood pressure, including inhibitors of the renin-angiotensin system (eg, ACE inhibitors, ARBs, or ARB-neprilysin inhibitors), beta blockers, diuretics, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, and mineralocorticoid receptor antagonists. Thus, the drugs used to treat hypertension in patients with heart failure are those used to reduce morbidity and mortality from heart failure.

The approach to pharmacologic therapy in patients with heart failure is presented in detail separately:

●(See "Primary pharmacologic therapy for heart failure with reduced ejection fraction".)

●(See "Treatment and prognosis of heart failure with mildly reduced ejection fraction".)

●(See "Treatment and prognosis of heart failure with preserved ejection fraction".)

Patients with recent myocardial infarction — Beta blockers, while generally not recommended as initial monotherapy or as part of combination therapy in patients with hypertension, are indicated in patients who have had a myocardial infarction (MI) in the previous three years. However, some experts treat with a beta blocker for just six months to one year following an MI, whereas other experts continue these agents indefinitely. Patients who have had an MI are also typically prescribed an ACE inhibitor or ARB, regardless of whether they have albuminuria, since they reduce morbidity and mortality after an MI [3,63]. The treatment of hypertension after MI is discussed in more detail elsewhere. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".)

Expert panels, such as the ACC/AHA and the European Society of Cardiology (ESC), suggest treating with a beta blocker (bisoprolol, carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, propranolol, or timolol) for three years after the MI, with continuation of the drug beyond three years deemed reasonable. Indefinite treatment with an ACE inhibitor or ARB is also recommended.

However, most of the data showing benefit from the use of beta blockers post-MI accrued during the pre-reperfusion era. Data from contemporary post-MI cohort studies are inconsistent and suggest that there is no discernable survival benefit when beta blockers are prescribed in patients with preserved ejection fraction [64,65]. Thus, the appropriate duration of beta blocker use after MI is unclear, and beta blocker discontinuation can reduce polypharmacy and side effects, and may improve adherence to other beneficial medications [66].

Patients with CKD — Our approach to selecting antihypertensive therapy in patients with chronic kidney disease (CKD) is as follows:

●Severely increased albuminuria – In patients with severely increased albuminuria (ie, ≥300 mg/day on a 24-hour urine or ≥300 mg/g of creatinine [34 mg/mmol] on a spot urine albumin-to-creatinine ratio), treat with a maximally tolerated dose of an ACE inhibitor or ARB. These agents reduce the risk of progression to end-stage kidney disease (ESKD) in such patients. The evidence is discussed elsewhere. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of diabetic kidney disease".)

●Moderately increased albuminuria – In patients with moderately increased albuminuria (ie, 30 to 299 mg/day on a 24-hour urine or 30 to 299 mg/g of creatinine [3.4 to 34 mg/mmol] on a spot urine albumin-to-creatinine ratio), we and most other experts also include a maximally tolerated dose of an ACE inhibitor or ARB in the treatment regimen. However, unlike in patients with severely increased albuminuria, a preferential benefit from ACE inhibitors and ARBs on patient-important endpoints (eg, ESKD) in patients with moderately increased albuminuria is unproven. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Treatment of diabetic kidney disease".)

●CKD with normal albumin excretion – In patients with albumin excretion in the normal range, the authors and editors of this topic have somewhat different opinions on the use of ACE inhibitors and ARBs. Some contributors use one of these agents in nearly all patients with CKD, regardless of the degree of albuminuria. Other contributors, citing the lack of evidence for preferential benefit, do not favor ACE inhibitors or ARBs over other acceptable first-line drugs (eg, dihydropyridine calcium channel blockers, diuretics).

However, this disagreement is moot in most cases since hypertension is more difficult to treat in patients with CKD [67], and therefore such patients require multiple drugs to control the blood pressure (and an ACE inhibitor or ARB is typically incorporated into the regimen).

●Incorporation of diuretics – Most patients with CKD will require diuretic therapy to attain goal blood pressure. When using diuretics in patients with CKD, we typically treat with a thiazide-like diuretic (ie, chlorthalidone or indapamide). Indapamide has proven antihypertensive efficacy among those with estimated glomerular filtration rate (eGFR) as low as 30 mL/min/1.73m² [45,68]; chlorthalidone appears to be effective at eGFRs as low as 20 mL/min/1.73 m² [69]. Unlike thiazide-like diuretics, thiazide-type diuretics (eg, hydrochlorothiazide) have reduced efficacy in patients with moderate to severe CKD (eg, eGFR <45 mL/min/1.73m²). (See "Thiazides versus loop diuretics in the treatment of hypertension", section on 'Patients with chronic kidney disease'.)

Loop diuretics are an alternative to thiazide-like diuretics in patients with severely decreased eGFR and, in addition, may be required in combination with a thiazide-like diuretic (ie, dual nephron blockade) among those with refractory edema. If furosemide is prescribed, it should be dosed at least twice daily due to its short duration action (four to six hours). (See "Causes and treatment of refractory edema in adults", section on 'Combination oral diuretic therapy'.)

In the absence of heart failure, potassium-sparing diuretics (eg, spironolactone) should generally be avoided in patients with moderate to severe CKD.

Renal autoregulation is often abnormal and occurs more slowly in patients with CKD (figure 1) [70], and successful blood pressure lowering can, at least over the short term, precipitate a reduction in glomerular filtration rate (GFR) and a corresponding rise in serum creatinine. As a result, we typically monitor kidney function and electrolytes approximately one to two weeks after adding or intensifying antihypertension drug therapy (eg, one week if eGFR is <45 mL/min/1.73m² and two weeks in other patients with CKD).

However, an increase in serum creatinine should not lead to discontinuation or reduction in therapy (unless the decrease in GFR is severe and/or progressive). The impairment in GFR following the institution or intensification of antihypertensive therapy is usually moderate and at least partially reversible within several weeks. In addition, attainment of goal blood pressure leads to reductions in cardiovascular events, even among patients who experience a reduction in GFR as a result of antihypertensive therapy. (See "Effect of antihypertensive treatment on kidney function in primary (essential) hypertension", section on 'Acute effects' and "Goal blood pressure in adults with hypertension", section on 'Patients with chronic kidney disease'.)

Patients with diabetes — Nearly 80 percent of individuals with diabetes have hypertension. The approach to antihypertensive drug selection in those with diabetes has changed substantively over time. Formerly, it was believed that ACE inhibitors and ARBs provided a special clinical benefit over other agents such as calcium channel blockers and diuretics. However, this is not the case in the majority of patients. Rather, the benefit of ACE inhibitors and ARBs over other drugs is limited to patients with diabetes and albuminuria. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Choice of antihypertensive drug therapy'.)

Thus, an ACE inhibitor or an ARB is appropriate as first-line therapy in patients with diabetes who have albuminuria, particularly those with severely increased albuminuria (ie, albumin-to-creatinine ratio ≥300 mg/g [34 mg/mmol] or 24-hour urine albumin excretion ≥300 mg).

Among patients without albuminuria, the approach to antihypertensive therapy is the same as in patients without diabetes. Since hypertension is often more difficult to control among individuals with diabetes (therefore requiring combination therapy), ACE inhibitors and ARBs are nevertheless commonly prescribed to patients without albuminuria. (See 'Choice of initial therapy in most patients' above.)

In addition, patients with diabetes are at higher risk for heart failure and/or MI; certain antihypertensive agents are indicated in such patients. (See 'Patients with heart failure' above and 'Patients with recent myocardial infarction' above.)

The rationale and supporting data for our approach to antihypertensive drug therapy in patients with diabetes are presented in another topic. (See "Treatment of hypertension in patients with diabetes mellitus".)

Patients with orthostatic hypotension — Although infrequently done in clinical practice, all patients with newly diagnosed hypertension should be evaluated, typically at the time of diagnosis, for a substantial orthostatic decline in blood pressure [3,4]. The definition, evaluation, and diagnosis of orthostatic hypotension are discussed elsewhere. (See "Mechanisms, causes, and evaluation of orthostatic hypotension".)

We evaluate all patients newly diagnosed with hypertension for orthostatic changes in blood pressure, irrespective of symptoms. This is because most patients with orthostatic hypotension do not report symptoms of dizziness or lightheadedness when their blood pressure falls after two to five minutes of upright posture; conversely, most patients with postural symptoms of dizziness or lightheadedness do not have orthostatic hypotension.

Our approach to pharmacologic therapy in patients whose systolic blood pressure falls by more than 10 to 20 mmHg after changing from a seated to upright posture is as follows:

●Choice of pharmacologic therapy – The choice of therapy is generally the same as in patients without orthostatic blood pressure changes. However, we avoid, if possible, the use of diuretics since these agents may exacerbate orthostatic hypotension [71], although the data are inconsistent [72]. Thus, initial monotherapy (or combination therapy) in such patients should consist of a calcium channel blocker and/or an ACE inhibitor (or ARB). If a diuretic is necessary, a low dose should be used. Alpha blockers, central adrenergic inhibitors, and nitrates should be avoided since they worsen orthostatic hypotension. (See 'Choice of initial therapy in most patients' above.)

●Goal blood pressure – Although goal blood pressure is the same in patients with significant orthostatic changes as it is in other patients, we use standing (rather than seated) measurements to determine if the patient's blood pressure is at goal. Orthostatic measurements should be obtained at subsequent follow-up visits until the condition resolves.

Patients with atrial fibrillation — In patients with atrial fibrillation, we use either a beta blocker or nondihydropyridine calcium channel blocker. Among those treated with a rate control strategy, these agents are effective in slowing the heart rate. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".)

We also treat with one of these agents in patients who are managed with a rhythm control strategy (and who are in sinus rhythm). Such patients may have breakthrough atrial fibrillation (ie, failure of rhythm control); a beta blocker or nondihydropyridine calcium channel blocker in this setting can prevent a rapid ventricular response.

Additional antihypertensive therapy, if needed, usually consists of an ACE inhibitor (or ARB) and/or a thiazide diuretic. A dihydropyridine calcium channel blocker can be used in conjunction with a beta blocker, but the combination of a beta blocker and a nondihydropyridine calcium channel blocker is not typically used (unless needed for blood pressure control in a patient with allergies or intolerances to other antihypertensive drugs).

Earlier, small trials reported that ACE inhibitors or ARBs prevented recurrence of atrial fibrillation among those who had been converted to sinus rhythm [73-78]. However, three subsequent, large trials performed in patients with a history of atrial fibrillation found that these drugs do not prevent recurrence compared with alternative therapy [79-81]. Thus, while UpToDate does not recommend ACE inhibitors or ARBs specifically to prevent atrial fibrillation recurrence, these agents are often necessary for blood pressure control or because they are indicated for other comorbidities. This is discussed in detail elsewhere. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation".)

Other aspects of antihypertensive therapy in patients with atrial fibrillation include the following:

●It is more difficult to obtain accurate blood pressure measurements in patients with atrial fibrillation, especially among those with high beat-to-beat heart rate variability and/or tachycardia [82]. Thus, at each follow-up visit for hypertension, blood pressure should be measured in triplicate; also, ambulatory blood pressure monitoring can be useful in this patient population.

●In patients taking oral anticoagulants, patients on antihypertensive drug therapy should be assessed for orthostatic hypotension

Patients who could become pregnant — In patients who could become pregnant and who require antihypertensive drug therapy, we typically initiate a dihydropyridine calcium channel blocker (eg, nifedipine extended release or amlodipine); if additional agents are needed, we use thiazide-like diuretics (eg, chlorthalidone) and certain beta blockers (eg, labetalol, carvedilol, metoprolol) (algorithm 2).

ACE inhibitors and ARBs are avoided in this setting because of potential teratogenicity (should the patient become pregnant); mineralocorticoid receptor antagonists and direct renin inhibitors should also be avoided. By contrast, patients who have undergone surgical sterilization or who are using a long-acting contraceptive (intrauterine device [IUD] or levonorgestrel implant) have unintended pregnancy rates of <1 percent and could reasonably be prescribed a medication that would typically be contraindicated in pregnancy.

There is a theoretical concern that diuretics could adversely affect the physiologic increase in plasma volume during pregnancy and therefore lead to harm if the patient becomes pregnant. However, there is no evidence that these agents are teratogenic or adversely affect pregnancy. Nevertheless, if a patient taking a thiazide-like or thiazide-type diuretic becomes pregnant, many clinicians would discontinue the medication or reduce the dose. The management of hypertension during pregnancy is discussed in detail elsewhere. (See "Treatment of hypertension in pregnant and postpartum patients".)

Role of patient race in selection of initial monotherapy — Although some experts choose different drug classes for monotherapy in Black patients as compared with other patients, it is reasonable for clinicians to choose a consistent therapeutic approach regardless of race. There is substantial variability in the blood pressure response to drugs such as ACE inhibitors within self-identified Black or African American patients that is larger than the variability in blood pressure response between Black and White individuals [83]. Thus, although blood pressure responses to ACE inhibitor monotherapy are, on average, lesser among Black patients as compared with White patients, there is considerable overlap in the response [83]. When used as combination therapy (ie, combined with either a calcium channel blocker or a diuretic), ACE inhibitors and ARBs are the most effective two drug combinations. Accordingly, our recommendations for combination therapy do not differ according to race. (See 'Patients selected for initial combination therapy' above and 'Adding a second drug (preferred combination therapy)' below.)

The preference for a calcium channel blocker or a thiazide-like diuretic as monotherapy in self-described Black patients emanates from evidence in randomized trials showing that these drugs have superior blood pressure-lowering efficacy and superior protection against cardiovascular events (compared with ACE inhibitors or ARBs) [84-94]. However, hypertension control rates among Black patients, as well as racial disparities in control, have not improved, despite an increase in the use of calcium channel blockers in this population (and a corresponding decrease in the use of ACE inhibitors and ARBs) [95].

Thus, the focus on single-drug blood pressure responses in Black individuals should be deemphasized in favor of treating this high-risk cohort intensively enough by utilizing initial combination therapy and avoiding therapeutic inertia. In one large health system, for example, implementation of a race-agnostic therapeutic algorithm that focused on combination therapy and avoidance of therapeutic inertia resulted in hypertension control rates exceeding 80 percent for White, Black, and Hispanic patients [96]. In addition, the disparity in hypertension control comparing Black patients with White patients decreased from 6.3 to 2.8 percent.

SUBSEQUENT APPROACH IF BLOOD PRESSURE IS UNCONTROLLED

Confirm that blood pressure is uncontrolled — There are essentially four, potentially overlapping, explanations for uncontrolled blood pressure in patients who have initiated antihypertensive therapy (either with monotherapy or initial combination therapy):

●Initial therapy is inadequate, due to inadequate drug dose, inadequate number of drugs, and/or physiologic factors that render the patient unresponsive to the chosen agents.

●The patient is partially or completely nonadherent to antihypertensive therapy.

●The patient has white coat effect (ie, the blood pressure is controlled out of the office but elevated during office visits).

●The blood pressure is being measured incorrectly during office visits.

Before escalating antihypertensive drug therapy, it is generally prudent to confirm that the patient is adherent and that the blood pressure is truly above goal (either with out-of-office blood pressure measurements or a series of properly performed office-based measurements) [3]. (See 'Assess medication adherence' below and 'Assure proper blood pressure measurement' below.)

If blood pressure is only slightly above goal, it may be appropriate to reassess after two to three months rather than immediately intensifying drug therapy. However, if the mild elevation persists, therapeutic inertia should be avoided, and therapy should be intensified.

Assess medication adherence — If goal blood pressure is not attained with initial therapy, adherence should be assessed.

Nonadherence to medication is a common contributor to why an individual's blood pressure remains uncontrolled despite prescription of antihypertensive drug therapy. In one meta-analysis, for example, 45 percent of all patients with hypertension were partially or completely nonadherent to antihypertensive therapy; the prevalence of partial or complete nonadherence was 84 percent among those with uncontrolled blood pressure [97]. Another meta-analysis concluded that approximately 30 percent of patients with apparent treatment resistance were nonadherent, but there was a high degree of heterogeneity, with nonadherence rates of 3 percent to 86 percent, depending upon the individual study [98]. In general, those 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 [99], and as many as 50 percent who actually do initiate antihypertensive medications stop taking them within one year [100].

There are various methods for assessing adherence, each of which has significant limitations [101]: direct patient queries, structured questionnaires, pill counts, electronic surveillance of prescription refill data, direct observation of pill taking, electronic monitoring systems, measurement of drug effects (eg, activity of angiotensin-converting enzyme [ACE] in serum), and direct measurement of drug levels in either blood or urine. These methods are discussed elsewhere. (See "Patient adherence and the treatment of hypertension", section on 'Assessment of adherence'.)

Our strategies to prevent nonadherence may also be helpful in addressing it once identified [101]:

●Prescribe long-acting rather than short-acting medications and specifically those that are dosed once daily.

●Prescribe single-pill combinations rather than free equivalents (ie, combination therapy as separate pills).

●Synchronize prescriptions so as to minimize the need for repeated trips to the pharmacy for refills.

●Counsel patients that, as their blood pressure falls, they may have symptoms of fatigue, but that these symptoms are typically transient and that the medications should be continued.

These and other strategies are presented in detail elsewhere. (See "Patient adherence and the treatment of hypertension", section on 'Methods to improve adherence'.)

Assure proper blood pressure measurement — Accurate measurement of blood pressure is imperative for making sound therapeutic decisions regarding antihypertensive drug therapy. However, in most clinical settings, blood pressure is not measured accurately.

Before intensifying antihypertensive therapy in patients with uncontrolled blood pressure (based upon casual office readings) despite adherence to prescribed treatment, one or more of the following methods should be used to confirm poor control (see "Blood pressure measurement in the diagnosis and management of hypertension in adults"):

●Standardized (ie, properly performed) office blood pressure (table 4). (See "Blood pressure measurement in the diagnosis and management of hypertension in adults", section on 'Routine office-based blood pressure'.)

●Automated office blood pressure monitoring (AOBPM), in which an oscillometric device is programed to average multiple consecutive readings after the patient has rested in a seated position for several minutes. The device is activated by a care provider, who can continue their work and even leave the room. AOBPM requires specialized equipment but saves time and minimally interrupts clinic flow. Like with standardized office blood pressure just mentioned, talking during the measurements should be avoided. (See "Blood pressure measurement in the diagnosis and management of hypertension in adults", section on 'Automated office blood pressure measurement'.)

●Self-measured (ie, home) blood pressure measurement. Typically, multiple readings are obtained daily over several consecutive days, and then these readings are averaged to guide clinical decision making. A common scenario is to instruct patients to take two to four readings daily for five to seven days before attending the clinic. Patients must be instructed on proper measurement technique using validated/calibrated blood pressure measurement devices (table 4). (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring", section on 'Performance and interpretation of self-measured blood pressure (SMBP)'.)

●24-hour ambulatory blood pressure monitoring. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring", section on 'Performance and interpretation of ambulatory blood pressure monitoring (ABPM)'.)

In most outpatient clinical settings, blood pressure is regularly measured incorrectly (ie, casually measured blood pressure, without proper technique). The primary reason for the ubiquitous use of incorrect measurement technique is that of convenience. Specifically, casual blood pressure measurement is simple, quick, and avoids workflow disruptions and interruptions.

However, casual blood pressure measurement on average produces an overestimate of the patient's blood pressure, leading to overestimates of hypertension severity and overmedication. Clinical practices that employ proper measurement technique observe a reduction in the mean clinic blood pressure (11/5 mmHg in one study despite no therapeutic changes) [102] and an improvement in practice-wide hypertension control (from 51 to 65 percent in one author's academic medical center).

Uncontrolled on monotherapy

Sequential monotherapy versus adding a second drug — Among patients who do not attain goal blood pressure despite adherence to at least moderate-dose monotherapy, the options include:

●Adding a second drug (ie, stepped-care approach)

●Replacing the patient's antihypertensive agent with a drug from a different class (ie, sequential monotherapy)

In patients started on a single drug, our approach is to add a second drug rather than attempting sequential monotherapy. Antihypertensive efficacy is greater with adding a second drug. In addition, attainment goal blood pressure is likely to occur more rapidly with the stepped-care approach than with sequential monotherapy. This is important because most practicing clinicians intensify antihypertensive drugs at only a fraction of the visits at which they encounter an elevated blood pressure reading [21,103].

The best data come from a trial of 605 individuals with hypertension who were randomly assigned to initial combination therapy with losartan and hydrochlorothiazide or to sequential monotherapy followed, if needed, by combination therapy [11]. In the sequential monotherapy group, the dose of the first drug was doubled at four weeks; at eight weeks, the first drug was replaced by the other drug, and the dose of that drug was doubled at twelve weeks. Starting at 16 weeks, combination therapy was used.

Blood pressure reduction was greater with initial combination therapy than with sequential monotherapy, although the blood pressures in the two groups became similar once the sequential monotherapy group was switched to combination therapy [11]. In addition, attainment of goal blood pressure (defined in this study as <140/90 mmHg) occurred in approximately 75 percent of those assigned to initial combination therapy and in only approximately 40 percent of those assigned sequential monotherapy. After the sequential monotherapy group was switched to combination therapy, the control rate increased to match the initial combination therapy group.

By contrast, there is interindividual heterogeneity in the blood pressure response to specific antihypertensive medications [104], and therefore switching from one drug that has a suboptimal effect to a different drug may lead to improved control [105]. In addition, there is one trial that reported numerically similar proportions of hypertension control comparing a stepped-care approach with sequential monotherapy [10]. However, the agents and dosing strategies that were used in this trial were different in the stepped-care and sequential monotherapy groups, limiting the interpretation of this study.

Despite recommendations to add an additional antihypertensive drug when the patient has not attained goal blood pressure, clinicians frequently fail to do this in practice (therapeutic inertia). In the United States, for example, the number of antihypertensive drugs prescribed to adults with hypertension has not changed over the past decade, even though the prevalence of poor hypertension control is high and increasing [106]. Of those individuals with uncontrolled hypertension, 40 percent are treated with only one antihypertensive medication.

Adding a second drug (preferred combination therapy) — In most patients who require two antihypertensive agents, the drugs should generally be selected from among the three preferred classes (ie, ACE inhibitors [or angiotensin receptor blockers (ARBs)], dihydropyridine calcium channel blockers, and thiazide diuretics [ideally a thiazide-like rather than a thiazide-type diuretic]). Conversely, some patients may have an indication for a drug from a different class, as described previously (table 2). (See 'Choice of initial therapy in patients with comorbidities' above.)

However, among those without an indication for one of the nonpreferred agents, we suggest treating with the combination of an ACE inhibitor (or ARB) and a calcium channel blocker, preferably a dihydropyridine calcium blocker. In addition, we suggest prescribing these two agents as a single-pill combination, if feasible (algorithm 1). Single-pill combinations lead 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) [17,18].

The combination of an ACE inhibitor (or ARB) with a thiazide diuretic is a reasonable alternative, particularly in patients who have conditions that can benefit from a thiazide diuretic (eg, edema, osteoporosis, calcium nephrolithiasis with hypercalciuria). However, thiazide-like diuretics (ie, chlorthalidone, indapamide) are preferred over thiazide-type diuretics (eg, hydrochlorothiazide), and there are only two single-pill combinations available that combine an ACE inhibitor (or ARB) with a thiazide-like diuretic (ie, perindopril-indapamide and azilsartan-chlorthalidone).

Although treating with a calcium channel blocker and a thiazide diuretic is also a reasonable option, there are no such single-pill combinations available.

The best available data comparing combination therapies for hypertension come from the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, which enrolled 11,506 patients with hypertension who were at high risk for cardiovascular disease [30]. Patients were randomly assigned to treatment with benazepril (40 mg daily) plus amlodipine (5 to 10 mg daily) or benazepril plus hydrochlorothiazide (12.5 to 25 mg daily). More than 80 percent of patients in both groups attained a mean systolic pressure <130 mmHg by 24-hour ambulatory monitoring [107].

At three years, the composite cardiovascular endpoint (ie, the combination of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac death, or coronary revascularization) occurred less frequently in the benazepril plus amlodipine group (9.6 versus 11.8 percent, hazard ratio 0.80, 95% CI 0.72-0.90). Benazepril-amlodipine therapy led to a similar reduction in the composite of cardiovascular death or nonfatal myocardial infarction or stroke (5 versus 6.3 percent). All-cause mortality was slightly less common in the benazepril plus amlodipine group (4.1 versus 4.5 percent) although this was not statistically significant.

Although office-based systolic pressure was slightly higher in the group receiving hydrochlorothiazide (by 1 mmHg) [30], the 24-hour average ambulatory systolic pressure was 1.6 mmHg lower among those assigned benazepril plus hydrochlorothiazide [107]. Thus, differences in attained blood pressure likely do not account for the totality of the observed benefit from combining benazepril with amlodipine.

In addition to the cardiovascular benefits, kidney events (defined as doubling of serum creatinine or end-stage kidney disease [ESKD]) were less frequent in patients who were assigned to benazepril plus amlodipine (2 versus 3.7 percent) [108].

The ACCOMPLISH trial provides evidence that the combination of an ACE inhibitor with a dihydropyridine calcium channel blocker is superior to a combination that includes a thiazide diuretic (ie, hydrochlorothiazide). However, as noted above, thiazide-like diuretics (chlorthalidone and indapamide) are more potent and are therefore preferred over thiazide-type diuretics. Whether combining an ACE inhibitor (or ARB) with a dihydropyridine calcium channel blocker is superior to combining it with a thiazide-like diuretic is unknown. Nevertheless, because single-pill combinations that contain a thiazide-like diuretic are few and often difficult to obtain, we favor the combination of an ACE inhibitor (or ARB) plus a dihydropyridine calcium channel blocker when two agents are required.

Adding a third drug (if needed) — As noted earlier, the three primary options for antihypertensive drug therapy in most patients include an ACE inhibitor (or ARB), dihydropyridine calcium channel blocker, and thiazide diuretic (preferably a thiazide-like diuretic) [3]. (See 'Choice of initial therapy in most patients' above.)

Thus, in patients whose blood pressure is uncontrolled despite adherence to two drugs, we add a drug from the third class of agents. 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.

Some patients may have an indication for a drug from a different class, as described previously (table 2). (See 'Choice of initial therapy in patients with comorbidities' above.)

Apparent treatment-resistant hypertension — Patients who are prescribed three antihypertensive drugs at intermediate or high (or maximally tolerated) doses, inclusive of a diuretic, and who have uncontrolled blood pressure are defined as having apparent treatment-resistant hypertension; those prescribed four or more medications (whether or not their blood pressure is controlled) are also defined as having apparent treatment-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 elsewhere. (See "Definition, risk factors, and evaluation of resistant hypertension", section on 'Apparent, true, and pseudoresistant hypertension'.)

Apparent resistant hypertension is relatively common. As an example, in an analysis of National Health and Nutrition Examination Survey (NHANES) data through 2016, 22 percent of drug-treated individuals with hypertension were prescribed three or more antihypertensive drugs. Given that nonadherence and white coat effect are prevalent, the proportion of patients with true resistant hypertension is likely considerably less. (See "Definition, risk factors, and evaluation of resistant hypertension", section on 'Prevalence'.)

Refractory hypertension is defined as having uncontrolled blood pressure despite prescription of five or more antihypertensive drugs. In one study, approximately 6 percent of those with apparent resistant hypertension had refractory hypertension [109]. Compared with patients who have apparent resistant hypertension, those with refractory hypertension have higher rates of kidney failure and cardiovascular disease [110]. In addition, rates of nonadherence to therapy are higher among those with apparent refractory hypertension (60 percent in one study) [111]. (See "Definition, risk factors, and evaluation of resistant hypertension", section on 'Refractory hypertension'.)

The evaluation and treatment of patients with resistant and refractory hypertension is presented separately (algorithm 3 and figure 2). (See "Definition, risk factors, and evaluation of resistant hypertension" and "Treatment of resistant hypertension".)

DOSE TITRATION AND MONITORING — Patients treated with antihypertensive drug therapy should be evaluated (either in person or by telehealth) every two to four weeks until their blood pressure is at goal. Waiting four weeks to reevaluate after starting or intensifying therapy is typically appropriate to permit long-acting antihypertensive drugs enough time to manifest their full blood pressure-lowering effect. This approach is consistent with the American College of Cardiology (ACC)/American Heart Association (AHA) 2017 hypertension guideline [3]. Reevaluating at two weeks (or even sooner) is appropriate for patients with severely elevated blood pressure.

If blood pressure is uncontrolled, we typically escalate doses of individual antihypertensive drugs to at least half the maximum recommended dose (ie, to a moderate or high dose) before adding additional therapy.

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

To determine if a patient has attained goal blood pressure, it is important that blood pressure be measured appropriately. As discussed elsewhere, there are four methods to properly measure blood pressure (see "Blood pressure measurement in the diagnosis and management of hypertension in adults", section on 'Our approach to measuring blood pressure'):

●Automated office blood pressure (AOBP)

●Standardized office blood pressure

●Self-measured blood pressure (ie, home blood pressure)

●24-hour ambulatory blood pressure

The technology of devices available for self-measured blood pressure has advanced considerably. Now, many home monitors contain memory that automatically stores readings, and some even have the capability of making automated readings while asleep. If home monitoring is performed, the patient should be trained in proper self-measurement technique, and the accuracy of their device should be periodically evaluated (eg, annually). Self-measured blood pressure is discussed in detail elsewhere. (See "Out-of-office blood pressure measurement: Ambulatory and self-measured blood pressure monitoring".)

We monitor electrolytes and serum creatinine one to three weeks after initiation or titration of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and diuretics (table 5). In patients on stable doses of medications, electrolytes and creatinine are typically monitored annually.

OVERVIEW OF ADVERSE EFFECTS — Adverse effects of commonly used antihypertensive drugs are discussed in detail elsewhere (table 5):

●Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) (see "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers")

●Calcium channel blockers (see "Major side effects and safety of calcium channel blockers")

●Thiazide diuretics (see "Diuretic-induced hyponatremia" and "Diuretic-induced hyperuricemia and gout" and "Time course of loop and thiazide diuretic-induced electrolyte complications" and "Use of thiazide diuretics in patients with primary (essential) hypertension")

●Beta blockers (see "Major side effects of beta blockers")

BEDTIME VERSUS MORNING DOSING — The contributors to this topic take different approaches to the timing of antihypertensive therapy:

●One author and both section editors typically prescribe once-daily medications in the morning rather than the evening. This approach is supported by the European Society of Hypertension (ESH) [112].

●The other author prescribes once-daily drugs in the evening (between 6 and 8 PM [between 18:00 and 20:00]), except for diuretic medications (which are prescribed in the morning), unless the patient has glaucoma. Patients with glaucoma, particularly open-angle glaucoma, should not be prescribed antihypertensive medicines at night [113-117].

The best data come from the Treatment In the Morning or Evening (TIME) trial [118]. In this study, more than 21,000 adults with hypertension were randomly assigned to take their antihypertensive medications in the morning or the evening. At approximately five years, rates of cardiovascular events were similar between the groups. There were no important differences in safety or adverse events comparing morning with evening dosing.

Although not specifically designed to compare morning with evening dosing, the Colchicine for Prevention of Vascular Inflammation in Noncardioembolic Stroke (CONVINCE) trial compared sustained release verapamil (given at bedtime) with an active comparator (either hydrochlorothiazide or atenolol, which were dosed in the morning); there was no difference in the rates of cardiovascular events among the groups [119].

These data conflict with two other trials (the MAPEC and Hygia studies), which concluded that evening dosing leads to fewer cardiovascular events and lower mortality compared with morning dosing [117,120,121]. However, both the MAPEC and Hygia trials were published by the same research group and both trials reported very large benefits from shifting one or more antihypertensive drugs from the morning to bedtime (eg, 50 percent or greater relative reductions in stroke, myocardial infarction, and cardiovascular death). Effects of this magnitude are rarely if ever observed in rigorous cardiovascular trials; in addition, the biologic rationale (a modest reduction in nighttime blood pressure without a major difference in 24-hour blood pressure) does not support such large effects [122].

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 e-mail 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: Medicines for high blood pressure (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)")

SUMMARY AND RECOMMENDATIONS

●Initial drug therapy: Deciding whether to start with one drug or two – Among patients selected for antihypertensive drug treatment, therapy should be initiated with either one drug (ie, monotherapy) or two drugs (ie, combination therapy, preferably in a single pill to improve adherence). Our approach is as follows (see 'Choosing between monotherapy and combination drug therapy' above):

•When to initiate treatment with two drugs (combination therapy) – In general, patients with a systolic pressure 10 to 20 mmHg above goal and/or a diastolic pressure 10 mmHg above goal should have antihypertensive drug therapy initiated with low to moderate doses of two agents with complementary mechanisms of action. Some experts begin with two agents in patients with stage 2 hypertension (ie, systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg), whereas other experts would initiate therapy with two drugs in patients whose systolic pressure is ≥150 mmHg and/or diastolic pressure ≥90 mmHg.

Combination therapy lowers blood pressure more than monotherapy and increases the likelihood that target blood pressure will be achieved in a reasonable time period. In addition, using two drugs may lead to attainment of goal blood pressure with lower doses of each medication, and this reduces the risk of dose-related side effects.

•When to initiate treatment with one drug (monotherapy) – In patients with stage 1 hypertension (systolic pressure 130 to 139 mmHg and/or diastolic pressure 80 to 89 mmHg) who are selected for drug therapy, we initiate antihypertensive therapy with one agent. In addition, some but not all experts start with monotherapy if the systolic blood pressure is 140 to 149 mmHg and the diastolic pressure is <90 mmHg. (See "Overview of hypertension in adults", section on 'Who should be treated with pharmacologic therapy?'.)

Initial monotherapy is also appropriate for patients who are deemed to be at higher risk for adverse effects as a result of antihypertensive therapy. Such patients include those adhering to a very low salt intake, those who are underweight or frail, those with a known orthostatic decline in blood pressure, and those with a history of multiple drug allergies or intolerances.

Regardless of whether treatment is begun with one or two drugs, the initial drug dose should generally be low. However, by far the most important strategy for ultimately achieving blood pressure control is to avoid therapeutic inertia. Therapeutic inertia is defined as failing to initiate or adjust/intensify prescribed drug therapy despite the recognition of uncontrolled hypertension.

●Choice of initial therapy

•If combination therapy is selected – When two drugs are used, they should be from different antihypertensive drug classes. In most patients, the 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 [ideally a thiazide-like rather than a thiazide-type diuretic]).

Among patients without an indication for a specific drug class, we suggest treating with the combination of an ACE inhibitor (or ARB) and a calcium channel blocker, preferably a dihydropyridine calcium blocker, rather than other combinations (Grade 2B). The combination of an ACE inhibitor (or ARB) with a thiazide diuretic is a reasonable alternative, particularly in patients who have conditions that can benefit from a thiazide diuretic (eg, edema, osteoporosis, calcium nephrolithiasis with hypercalciuria).

In addition, we suggest prescribing these two agents as a single-pill combination, if feasible (table 1 and algorithm 1) (Grade 2B). Some experts initiate therapy with a single-pill combination, whereas other experts initiate free equivalents and then, after titrating the dose of each drug, convert to a single-pill combination.

•If monotherapy is selected – In patients selected to initiate antihypertensive therapy with one drug, we select from among the following medication classes (see 'Patients selected for initial monotherapy' above):

-Angiotensin converting enzyme (ACE) inhibitor

-Angiotensin receptor blocker (ARB)

-Calcium channel blocker

-Thiazide diuretic

If there are no compelling reasons to select a specific drug class, we suggest treating with an ACE inhibitor (or ARB) or a dihydropyridine calcium channel blocker, rather than a thiazide diuretic (algorithm 1) (Grade 2C). A thiazide diuretic is a reasonable alternative as monotherapy and may be preferred in patients with edema, osteoporosis, or calcium nephrolithiasis with hypercalciuria. If a thiazide diuretic is used, we suggest treating with a thiazide-like diuretic (ie, chlorthalidone, indapamide) rather than hydrochlorothiazide (Grade 2C). (See 'Patients selected for initial monotherapy' above.)

●Compelling indications for certain drugs – Some patients have a compelling reason to use an agent from a specific class (eg, mineralocorticoid receptor antagonists in patients with heart failure, beta blockers in patients following a myocardial infarction) (table 2). (See 'Choice of initial therapy in patients with comorbidities' above.)

●Approach in patients with uncontrolled blood pressure despite initial therapy – There are essentially four, potentially overlapping, explanations for uncontrolled blood pressure in patients who have initiated antihypertensive therapy (either with monotherapy or initial combination therapy):

•Initial therapy is inadequate, due to inadequate drug dose, inadequate number of drugs, and/or physiologic factors that render the patient unresponsive to the chosen agents.

•The patient is partially or completely nonadherent to antihypertensive therapy.

•The patient has white coat effect (ie, the blood pressure is controlled out of the office but elevated during office visits).

•The blood pressure is being measured incorrectly during office visits.

Before escalating antihypertensive drug therapy, it is generally prudent to confirm that the patient is adherent and that the blood pressure is truly above goal (either with out-of-office blood pressure measurements or a series of properly performed office-based measurements). (See 'Assess medication adherence' above and 'Assure proper blood pressure measurement' above.)

•Patients on monotherapy (one drug) with uncontrolled hypertension – Among patients who do not attain goal blood pressure despite adherence to at least moderate-dose monotherapy, we suggest adding a second drug (ie, stepped-care approach) rather than replacing the patient's antihypertensive agent with a drug from a different class (ie, sequential monotherapy) (Grade 2B). (See 'Uncontrolled on monotherapy' above.)

As noted above, among those without an indication for one of the nonpreferred agents, we suggest treating with the combination of an ACE inhibitor (or ARB) and a calcium channel blocker, preferably a dihydropyridine calcium blocker (Grade 2B). In addition, we suggest prescribing these two agents as a single-pill combination, if feasible (algorithm 1) (Grade 2B).

•Patients on combination therapy (two drugs) with uncontrolled hypertension – The three primary options for antihypertensive drug therapy in most patients include an ACE inhibitor (or ARB), dihydropyridine calcium channel blocker, and thiazide diuretic (preferably a thiazide-like diuretic). Thus, in patients whose blood pressure is uncontrolled despite adherence to two drugs, we add a drug from the third class of agents.

•Apparent treatment-resistant hypertension – Patients who are prescribed three antihypertensive drugs at intermediate or high (or maximally tolerated) doses, inclusive of a diuretic, and who have uncontrolled blood pressure are defined as having apparent treatment-resistant hypertension; those prescribed four or more medications (whether or not their blood pressure is controlled) are also defined as having apparent treatment-resistant hypertension. Resistant hypertension is presented in detail elsewhere (algorithm 3 and figure 2). (See "Definition, risk factors, and evaluation of resistant hypertension" and "Treatment of resistant hypertension".)

●Dose titration and monitoring – Patients treated with antihypertensive drug therapy should be evaluated (either in person or by telehealth) every two to four weeks until their blood pressure is at goal. Waiting four weeks to reevaluate after starting or intensifying therapy is typically appropriate to permit long-acting antihypertensive drugs enough time to manifest their full blood pressure-lowering effect. If blood pressure is uncontrolled, we typically escalate doses of individual antihypertensive drugs to at least half the maximum recommended dose (ie, to a moderate or high dose) before adding additional therapy. After goal blood pressure is attained, we usually follow patients every three to six months (either in person or by telehealth). (See 'Dose titration and monitoring' above.)

We monitor electrolytes and serum creatinine one to three weeks after initiation or titration of ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, and diuretics (table 5). In patients on stable doses of medications, electrolytes and creatinine are typically monitored annually.

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Norman M Kaplan, MD, who contributed to earlier versions of this topic review.