SUMMARY AND RECOMMENDATIONSThe American Heart Association and the European Society of Hypertension/European Society of Cardiology (ESH/ESC), as well as various meta-analyses, all concluded that the amount of blood pressure reduction is the major determinant of reduction in cardiovascular risk in both younger and older patients with hypertension, not the choice of antihypertensive drug. This conclusion also applies to patients at increased cardiovascular risk as shown in the ALLHAT, VALUE, and CAMELOT trials. (See 'Importance of attained blood pressure' above and 'ALLHAT trial' above.)
However, there may be exceptions when using combination therapy. In the ACCOMPLISH trial, amlodipine plus benazepril was associated with a 20 percent lower rate of cardiovascular events compared to hydrochlorothiazide plus benazepril, despite slightly higher 24-hour blood pressures in the amlodipine arm. (See 'ACCOMPLISH trial' above.)
Some hypertensive patients have underlying conditions for which specific antihypertensive drugs might offer particular benefit independent of blood pressure control, such as diltiazem, verapamil, or a beta blocker for rate control in atrial fibrillation. The following recommendations do not apply to such patients. (See 'Clinical reasons for specific drugs' above.)
Monotherapy — Patients with hypertension who are less than 20/10 mmHg above goal can initially be treated with monotherapy. Among such patients who do not have an indication for a specific drug, the major classes of drugs that have been used for monotherapy are a low-dose thiazide diuretic, long-acting angiotensin-converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARB), or a long-acting dihydropyridine calcium channel blocker.
●Given the preference for an ACE inhibitor/ARB plus a dihydropyridine calcium channel blocker in patients requiring combination therapy, we suggest use of one of these drug classes as initial therapy so that the other can be added, if necessary (Grade 2C). If this approach is chosen, an ACE inhibitor/ARB may be more effective in younger patients, and a dihydropyridine calcium channel blocker may be more effective in older adult and black patients. (See 'Initial monotherapy' above and 'Monotherapy based upon age and race' above.)
●If a diuretic is chosen, we suggest chlorthalidone or indapamide rather than hydrochlorothiazide (Grade 2B). The basic principles of monitoring for hypokalemia with these drugs are identical to those with hydrochlorothiazide. (See 'Choice between thiazide-like and thiazide-type diuretics' above and 'Issues with thiazide-like diuretics' above and 'Monitoring for hypokalemia' above.)
●We recommend that patients who have a minimal or no response to the initial antihypertensive drug be treated with sequential monotherapy (Grade 1B). (See 'Sequential monotherapy' above.)
Combination therapy
●Among patients who have an untreated office (or clinic) blood pressure more than 20/10 mmHg above goal, we recommend therapy with the combination of a long-acting ACE inhibitor/ARB plus a long-acting dihydropyridine calcium channel blocker (Grade 1B). (See 'ACCOMPLISH trial'above and 'First-line combination therapy' above.)
●Among nonobese patients who are already being treated with an ACE inhibitor/ARB plus a thiazide diuretic and have attained goal blood pressure, we suggest stopping the thiazide and switching to a long-acting dihydropyridine calcium channel blocker (Grade 2B). Among obese patients, the combination of an ACE inhibitor/ARB plus a thiazide diuretic can be continued. We suggest continuing therapy in patients who are well controlled on combinations other than an ACE inhibitor/ARB plus a thiazide (Grade 2C).
●Among patients being treated with a thiazide diuretic as monotherapy who have responded but have not attained goal blood pressure, we suggest stopping the thiazide and switching to a long-acting ACE inhibitor/ARB plus a long-acting dihydropyridine calcium channel blocker (Grade 2B).
ACKNOWLEDGMENT
ACE inhibitors — Angiotensin-converting enzyme (ACE) inhibitors are first-line therapy in all patients who have HF or asymptomatic LV dysfunction, in all patients who have had an ST elevation MI, in patients with a non-ST elevation MI who have had an anterior infarction, diabetes, or systolic dysfunction, and in patients with proteinuric chronic kidney disease. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'ACE inhibitor'.)
It has been suggested that ACE inhibitors and ARBs have a cardioprotective effect independent of blood pressure lowering in patients at high risk for a cardiovascular event. However, as mentioned above and described in detail elsewhere, the available evidence suggests that the attained blood pressure, not the drug used, is of primary importance in such patients. (See 'Importance of attained blood pressure' above.)
Angiotensin II receptor blockers — The specific indications for and efficacy of angiotensin II receptor blockers (ARBs) are similar to those with ACE inhibitors. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
There is at least one setting in which ARBs have specific benefit and which a similar trial has not been performed with ACE inhibitors: severe hypertension with ECG evidence of left ventricular hypertrophy in the LIFE trial [58]. An ARB can be used instead of an ACE inhibitor in such patients, although it is highly likely that an ACE inhibitor is equally effective. We would not switch such a patient who is already receiving and tolerating an ACE inhibitor to an ARB.
An ARB is particularly indicated in patients who do not tolerate ACE inhibitors (primarily because of cough). (See "Differences between angiotensin-converting enzyme inhibitors and receptor blockers".)
Thiazide diuretics — The preferred thiazide diuretic in patients with primary hypertension is chlorthalidone since major trials such as ALLHAT have shown benefit with this regimen. Indapamide, another thiazide-like diuretic, may be used in place of chlorthalidone. There is little, if any, evidence that hydrochlorothiazide improves cardiovascular outcomes. Hydrochlorothiazide is both less potent and shorter acting than chlorthalidone and indapamide. (See 'Thiazide-like versus thiazide-type diuretics' above and 'Initial monotherapy' above.)
One problem with low-dose chlorthalidone is that there is no 12.5 mg tablet. Thus, 25 mg tablets of generic chlorthalidone need to be cut in half; however, these tablets are not scored, and attempts to halve them may result in uneven dosing. In addition, in patients who require combination therapy, fixed-dose combination pills of chlorthalidone with ACE inhibitors and long-acting calcium channel blockers are not available (in contrast to hydrochlorothiazide). However, chlorthalidone (at a dose of either 12.5 or 25 mg) is available in combination with azilsartan medoxomil, an ARB. Indapamide, an alternative to chlorthalidone, has both a low-dose option available (1.25 mg) and a fixed-dose combination with an ACE inhibitor (perindopril).
If monotherapy is appropriate in a patient with hypertension and osteoporosis, thiazide-like diuretics may have advantages over ACE inhibitors, ARBs, and calcium channel blockers. These drugs stimulate distal tubular reabsorption of calcium, leading to a decrease in urinary calcium excretion. As a result, thiazide diuretics may have a beneficial effect on bone mineral density. (See "Drugs that affect bone metabolism", section on 'Thiazide diuretics'.)
The rates of hip or pelvic fractures among patients treated with thiazide-like diuretics, ACE inhibitors, and calcium channel blockers were compared in a post-hoc analysis of the ALLHAT trial (discussed above) [70]. At approximately five years, those randomly assigned chlorthalidone had significantly fewer hip or pelvic fractures as compared with those assigned either lisinopril or amlodipine (1.3 versus 1.7 percent). (See 'ALLHAT trial' above.)
Diuretics should also be given for volume control in patients with heart failure or chronic kidney disease, with or without nephrotic syndrome; these settings usually require loop diuretics. In addition, a mineralocorticoid receptor antagonist (spironolactone or eplerenone) is indicated in patients with HF who have relatively preserved renal function and for the prevention or treatment of hypokalemia. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Mineralocorticoid receptor antagonist'.)
Calcium channel blockers — There are no absolute indications for calcium channel blockers in patients with hypertension. Long-acting dihydropyridines are most commonly used. Like beta blockers, the nondihydropyridine calcium channel blockers (verapamil, diltiazem) can be given for rate control in patients with atrial fibrillation or for control of angina in patients with coronary disease and normal left ventricular systolic function [71]. Calcium channel blockers also may be preferred in patients with obstructive airways disease. (See "Treatment of hypertension in asthma and COPD".)
Beta blockers — A beta blocker without intrinsic sympathomimetic activity should be given after an acute myocardial infarction and to stable patients with heart failure or asymptomatic left ventricular dysfunction (beginning with very low doses to minimize the risk and degree of initial worsening of myocardial function). The use of beta blockers in these settings is in addition to the recommendations for ACE inhibitors in these disorders. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults", section on 'Beta blocker'.)
Beta blockers are also given for rate control in patients with atrial fibrillation, for control of angina, and for symptom control in a number of other disorders (table 2).
In the absence of such indications, we and others (including the 2014 statement from the American Society of Hypertension and the International Society of Hypertension) recommend that beta blockers not be used as first-line therapy, particularly in patients over age 60 years [47,50,72-74]. Compared with other antihypertensive drugs in the primary treatment of hypertension, beta blockers (not all trials used atenolol) may be associated with inferior protection against stroke risk (particularly among smokers) [74-76], and perhaps, with atenolol, a small increase in mortality [77]. These effects are primarily seen in patients over age 60 years [76,78-80]. Beta blockers are also associated with impaired glucose tolerance and an increased risk of new onset diabetes [50], with the exception of vasodilating beta blockers such as carvedilol and nebivolol [81,82]. (See "Treatment of hypertension in patients with diabetes mellitus", section on 'Beta blockers'.)
Alpha blockers — The ALLHAT trial cited above included a doxazosin arm that was terminated prematurely because of a significantly increased risk of heart failure compared to chlorthalidone (relative risk 2 after adjusting for a 3 mmHg higher in-trial systolic pressure with doxazosin) noted during an interim analysis [83] and a higher rate of cardiovascular events [84]. Thus, an alpha blocker is not recommended for initial monotherapy, with the possible exception of older men with symptoms of prostatism and if they are not at high cardiovascular risk. (See "Medical treatment of benign prostatic hyperplasia".)
COMBINATION THERAPYTwo major issues related to combination therapy include the use of combination therapy as first-line therapy and addition of a second drug when the goal blood pressure is not achieved with monotherapy. The following discussion assumes that the patient does not have a clinical reason to use a particular drug. (See 'Clinical reasons for specific drugs' above.)
Recommendations for combination therapy were made by the 2018 European Society of Hypertension/European Society of Cardiology (ESH/ESC) and by the 2017 American College of Cardiology/American Heart Association (ACC/AHA) Guideline for High Blood Pressure in Adults; each clearly supports initial combination therapy for those 20/10 mmHg above the goal [6,69].
First-line combination therapy — Administering two drugs as initial therapy should be considered when the blood pressure is more than 20/10 mmHg above goal, as recommended by the ESH/ESC and ACC/AHA panels [6,69]. This strategy may increase the likelihood that target blood pressures are achieved in a reasonable time period. Fixed-dose combination preparations are available that may improve patient compliance, blood pressure control, and, if both drugs are given at lower doses, reduce side effects [2,56,85-90].
Supine and standing pressures should be measured prior to the initiation of combination therapy in patients at increased risk for orthostatic (postural) hypotension, such as older adult patients and those with diabetes. Orthostatic hypotension is diagnosed when, within two minutes of quiet standing, one or more of the following is present (see "Mechanisms, causes, and evaluation of orthostatic hypotension"):
●At least a 20 mmHg fall in systolic pressure
●At least a 10 mmHg fall in diastolic pressure
●Symptoms of cerebral hypoperfusion, such as dizziness
Based upon the results of the ACCOMPLISH trial [42], we recommend the use of a long-acting dihydropyridine calcium channel blocker plus a long-acting angiotensin-converting enzyme (ACE) inhibitor/ARB (such as amlodipine plus benazepril as used in ACCOMPLISH). In addition, in nonobese patients already being treated with and doing well on the combination of a thiazide diuretic and a long-acting angiotensin inhibitor, we suggest replacing the thiazide diuretic with a long-acting dihydropyridine calcium channel blocker. In obese patients, the combination of a thiazide diuretic and a long-acting angiotensin inhibitor can be continued [44]. (See 'ACCOMPLISH trial' above.)
Combination therapy with more than two agents — Some studies have compared triple combination therapy with dual combination therapy or usual care in hypertensive adults [91-94]. Most have compared standard doses of an ACE inhibitor (or ARB), amlodipine, plus a thiazide diuretic with dual combination therapy selected from these three options. In general, patients treated with triple combination therapy attained lower blood pressures and were more likely to achieve their blood pressure goal at 12 to 24 weeks; by contrast, those treated with triple therapy were more likely to have treatment-related adverse events. One small trial examined the effects of single-pill quadruple (rather than triple) therapy, with each agent given at one quarter the normal starting dose in an attempt to limit side effects (ie, irbesartan at 37.5 mg, amlodipine at 1.25 mg, hydrochlorothiazide at 6.25 mg, and atenolol at 12.5 mg) [95]. Compared with placebo, quadruple therapy reduced 24-hour systolic pressure by 19 mmHg and increased the proportion attaining goal blood pressure (100 versus 33 percent). The small sample size and lack of an active comparator limits the relevance of this study [96].
Addition of a second drug — As noted above, each of the recommended first-line agents will normalize the blood pressure in up to 30 to 50 percent of patients with mild hypertension [5]. In the patient who is relatively unresponsive to one drug, sequentially trying different agents may allow 60 to 80 percent of patients with mild hypertension to be initially controlled with a single agent [51,55]. These issues are discussed in detail above. (See 'Initial monotherapy' above.)
We generally limit dose titration to one step with a given drug (eg, 12.5 to 25 mg of chlorthalidone or 5 to 10 mg of amlodipine). Using higher doses generally produces a lesser blood pressure response and more toxicity than switching to an initial dose of a second drug (figure 8) [5,56,97].
Over time, more than one drug will be needed in many patients who are initially controlled. In ALLHAT, for example, the proportion of patients treated with more than one drug increased from 26 to 33 percent at one year to 40 to 43 percent at five years [19].
As noted above, we suggest that combination therapy consist of a long-acting dihydropyridine calcium channel blocker plus a long-acting ACE inhibitor/ARB (such as amlodipine plus benazepril). Thus, if the patient is being treated with one of the drugs, add the other. In patients being treated with a thiazide diuretic, we suggest discontinuing the thiazide and starting combination therapy. Approximately 75 percent of patients in ACCOMPLISH had previously been treated with two or more antihypertensive drugs. (See 'ACCOMPLISH trial' above.)
Beta blockers are now used rarely as initial therapy except for patients with another indication for their use. The preferred second drugs in patients who are treated with a beta blocker are a thiazide diuretic or a dihydropyridine calcium channel blocker [68]. An alpha blocker would be chosen only if there is another reason for its use, such as symptomatic benign prostatic hyperplasia.
An ACE inhibitor or ARB is likely to be less effective in patients treated with a beta blocker since beta blockers reduce renin secretion and therefore angiotensin II formation [98], and a beta blocker should be used with caution in combination with verapamil and to a lesser degree diltiazem. These drugs can potentiate the cardiac depressant effect of the beta blocker, possibly leading to or exacerbating bradycardia or heart block, particularly if one of the drugs is given intravenously.
BEDTIME VERSUS MORNING DOSINGThe average nocturnal blood pressure is approximately 15 percent lower than daytime values. Failure of the blood pressure to fall by at least 10 percent during sleep is called "nondipping," and is a stronger predictor of adverse cardiovascular outcomes than daytime blood pressure. (See "Ambulatory and home blood pressure monitoring and white coat hypertension in adults", section on 'Nocturnal blood pressure and nondippers'.)
In some studies, shifting at least one antihypertensive medication from the morning to the evening can both restore the normal nocturnal blood pressure dip [99-102] and reduce 24-hour mean blood pressure [103,104]. However, several blinded and unblinded trials found no difference in 24-hour mean or nocturnal blood pressure with evening versus morning dosing of antihypertensive therapy and no effect on the proportion of dipping [102,105-108].
Other trials also employed nocturnal therapy, although they were not specifically designed to compare bedtime versus morning dosing of antihypertensive therapy:
●In the HOPE and EUROPA trials, angiotensin-converting enzyme (ACE) inhibitor therapy given at bedtime reduced the incidence of cardiovascular events as compared with placebo.
●In the CONVINCE trial, sustained release verapamil (given at bedtime) did not reduce cardiovascular events compared with either hydrochlorothiazide or atenolol (given in the morning) [109].
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