Choice of drug therapy in primary (essential) hypertension - Up To Date PDF

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12/1/2021

Choice of drug therapy in primary (essential) hypertension - UpToDate

Author: Johannes FE Mann, MD Section Editors: George L Bakris, MD, William B White, MD Deputy Editor: John P Forman, MD, MSc Contributor Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through:Dec 2020.|This topic last updated:Sep 17, 2020.

INTRODUCTION There is general agreement as to which antihypertensive drugs are appropriate for initial therapy in most patients with hypertension. The major options are: ●

Thiazide-type diuretics

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Angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs)

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Calcium channel blockers

Recommendations concerning the use of particular agents for the initial treatment of hypertension will be presented here. The diagnosis and evaluation of hypertension, as well as a discussion of goal blood pressure in the treatment of hypertension, are presented separately: ●

(See "Overview of hypertension in adults".)

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(See "Initial evaluation of the hypertensive adult".)

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(See "Goal blood pressure in adults with hypertension".)

RELATIVE EFFICACY OF ANTIHYPERTENSIVE DRUGS Each of the antihypertensive therapy classes is roughly equally effective in lowering the blood pressure, producing a good antihypertensive response in 30 to 50 percent of patients (

figure 1A-B) [1-5]. There is, however, wide interpatient variability as many

patients will respond well to one drug but not to another. In addition, there are few clinical parameters that reliably predict individual responses to one drug or another. (See 'Initial monotherapy' below.) Importance of attained blood pressure—Meta-analyses, the 2017 American College of Cardiology/American Heart Association statement on the treatment of blood pressure [6], uptodate.searchbox.science/contents/choice-of-drug-therapy-in-primary-essential-hypertension?search=Hypertention&source=search_result&se… 1/32

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the 2020 International Society of Hypertension (ISH) Global Hypertension Practice Guidelines [7], and the 2018 European Society of Hypertension/European Society of Cardiology guidelines on the management of hypertension [8] 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 (assuming that the patient does not have an indication for a particular drug, such as diltiazem, verapamil, or a beta blocker for rate control in atrial fibrillation) [1,2,9-13]. This conclusion was based upon the finding in a number of large randomized trials that, at the same level of blood pressure control, most antihypertensive drugs provide the same degree of cardiovascular protection. As an example, the CAPPP, STOP-Hypertension-2, NORDIL, UKPDS, and INSIGHT trials found little overall difference in outcomes between older (such as diuretics and beta blockers) and newer antihypertensive drugs (such as angiotensin-converting enzyme [ACE] inhibitors and calcium channel blockers) [3,14], and the CAMELOT trial found no significant difference in outcomes with amlodipine and enalapril, two newer antihypertensive drug classes at that time [15]. Similar conclusions have been reached in patients at increased cardiovascular risk. When differences in outcomes have been noted in trials comparing different antihypertensive drugs, the treatment strategy that produced better outcomes had also produced better blood pressure control. As examples: ●

The ASCOT trial found a lower rate of cardiovascular disease and death with a calcium channel blocker (amlodipine) compared with a beta blocker (atenolol). However, patients in the amlodipine arm had a significantly lower mean blood pressure at the end of the study (3/2 mmHg) [16].

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Ramipril and perindopril produced better outcomes than placebo in the HOPE and EUROPA trials of patients at increased cardiovascular risk, but the blood pressure was significantly lower in the treated patients: 3.3/1.4 mmHg (with a greater difference overnight) in HOPE and 5/2 mmHg in EUROPA [17,18].

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In the VALUE trial of over 15,000 patients who had either prior atherosclerotic cardiovascular disease or at least one cardiovascular risk factor, amlodipine produced better outcomes than valsartan but also greater blood pressure reduction [19]. When 5000 pairs were matched exactly for systolic blood pressure and other risk factors, the two groups had nearly identical rates of cardiovascular events [20].

Possible exceptions to these general findings were thought to come from the ALLHAT and ACCOMPLISH trials.

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ALLHAT trial—The ALLHAT trial randomly assigned over 41,000 hypertensive patients (mean blood pressure 146/84 mmHg) with at least one other coronary risk factor to one of four initial regimens: chlorthalidone (12.5 to 25 mg/day), amlodipine, lisinopril, or doxazosin; the doxazosin arm was prematurely terminated due to an increased risk of heart failure [21]. At a mean follow-up of 4.9 years, the primary outcome (fatal coronary heart disease or nonfatal myocardial infarction) was the same in the three arms ( figure 2) [21]. However, the chlorthalidone arm had a significantly lower rate of heart failure than amlodipine and lisinopril (

figure 3) and a significantly lower rate of

combined cardiovascular disease outcomes than lisinopril (

figure 4).

It seems likely that the benefits seen with chlorthalidone were due at least in part to an earlier and greater degree of blood pressure reduction, similar to the findings with amlodipine in the VALUE trial described in the preceding section [20]. Chlorthalidone was associated with a small but significantly lower systolic pressure over the course of the study than amlodipine or lisinopril (133.9 versus 134.7 and 135.9 mmHg, respectively) and a higher proportion of patients who attained the blood pressure goal of less than 140/90 mmHg (68.2 versus 66.3 and 61.2 percent, respectively). The difference in mean systolic blood pressure was most pronounced in the first two years (136.4 versus 137.8 and 139.2 mmHg, respectively). Twenty-four-hour blood pressure monitoring was not obtained in ALLHAT, which may have been important since chlorthalidone is long acting, while the effect of lisinopril may diminish toward the end of the day, especially at doses of 10 mg/day. One cannot exclude the possibility that the observed benefits with chlorthalidone in ALLHAT were due at least in part to the lower attained blood pressure, which is in keeping with the findings in other trials cited in the preceding section. Looking at the data in another way, there was no difference in the primary end point among the three treated groups (

figure 2), despite the lower attained blood pressure

with chlorthalidone. This raises the possibility that thiazide diuretics may actually be associated with worse outcomes at the same attained blood pressure. Thiazide-like versus thiazide-type diuretics—Chlorthalidone and indapamide, commonly used thiazide-like diuretics, are significantly more potent antihypertensive agents than hydrochlorothiazide, a commonly used thiazide-type diuretic, at similar dose levels [22-27]. In a meta-analysis of 14 trials that compared the blood pressure reduction with one of three dose levels of hydrochlorothiazide (low, intermediate, high) to a similar dose level of one of the thiazide-like diuretics, systolic pressure reduction was greater with chlorthalidone and indapamide (by 3.6 and 5.1 mmHg, respectively) [22]. This may not be so important for efficacy, since the dose-response curve for thiazide diuretics in the treatment of primary hypertension (formerly called "essential" uptodate.searchbox.science/contents/choice-of-drug-therapy-in-primary-essential-hypertension?search=Hypertention&source=search_result&se… 3/32

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hypertension) is relatively flat (

figure 5) [2,28,29]. However, metabolic complications,

such as hypokalemia, glucose intolerance, and hyperuricemia increase with dose ( figure 6) [2,28,29]. In two major trials of low-dose chlorthalidone (12.5 to 25 mg/day), treatment for hypokalemia was required in 7 to 8 percent of patients [21,30]. (See "Use of thiazide diuretics in patients with primary (essential) hypertension" and "Causes of hypokalemia in adults", section on 'Diuretics'.) 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 1) [23-25]. 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 with chlorthalidone compared to baseline (eg, -13.5 mmHg with 12.5 mg/day [force titrated to 25 mg/day] versus -6.4 mmHg with 25 mg/day [force titrated to 50 mg/day] of hydrochlorothiazide in a small randomized, crossover trial) [24]. The lesser efficacy of hydrochlorothiazide throughout the day was also demonstrated in a study in which both 24-hour ambulatory monitoring and office blood pressure were performed in 228 hypertensive patients at baseline and after four weeks of therapy with hydrochlorothiazide (25 mg/day) [31]. The mean four-week decrease in blood pressure was significantly greater when measured with office readings than with 24-hour ambulatory monitoring (14/8 versus 10/6 mmHg). Efficacy in preventing cardiovascular events—Nearly all cardiovascular outcome trials in hypertension that examined diuretics compared chlorthalidone or indapamide with placebo or active comparators. However, there are no randomized trials that directly compare cardiovascular outcomes in hypertensive patients treated with hydrochlorothiazide (or other thiazide-type diuretics such as chlorothiazide) versus chlorthalidone (or other thiazide-like diuretics such as indapamide). In the absence of such head-to-head trials, a multiple-treatment (network) meta-analysis of 21 trials including approximately 120,000 patients was conducted in which thiazide-type diuretics (such as hydrochlorothiazide) and thiazide-like diuretics (such as chlorthalidone) were indirectly compared by evaluating their efficacy against placebo or common comparator drugs (eg, ACE inhibitors were compared with hydrochlorothiazide in ANBP2 and with chlorthalidone in ALLHAT) [32]. After controlling for achieved blood pressure, thiazide-like but not thiazidetype diuretics reduced the risk of cardiovascular events compared with placebo (relative risk 0.88, 95% CI 0.79 to 0.98) and heart failure (relative risk 0.71, 95% CI 0.57 to 0.89). Compared with thiazide-type diuretics, thiazide-like diuretics significantly lowered the relative risk of cardiovascular events by 12 percent and heart failure by 21 percent. The results of this meta-analysis are consistent with an earlier network meta-analysis [33] and with observational data from the Multiple Risk Factor Intervention Trial (MRFIT) [34]. Among hypertensive men in MRFIT, 2392 were treated with chlorthalidone and 4049 were uptodate.searchbox.science/contents/choice-of-drug-therapy-in-primary-essential-hypertension?search=Hypertention&source=search_result&se… 4/32

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treated with hydrochlorothiazide. During six years of follow-up, cardiovascular events (defined as myocardial infarction, stroke, coronary artery bypass surgery, heart failure, left ventricular hypertrophy, peripheral artery disease, or angina) were significantly less common with chlorthalidone compared with hydrochlorothiazide (hazard ratio 0.79, 95% CI 0.68 to 0.92). Through the course of the study, systolic blood pressure and LDL cholesterol levels were also lower with chlorthalidone compared with hydrochlorothiazide. By contrast, other observational studies suggest that chlorthalidone and hydrochlorothiazide lead to similar rates of cardiovascular events but that chlorthalidone increases the risk of adverse metabolic effects [35,36]. As an example, in a retrospective study of more than 700,000 hypertensive patients prescribed one of these two drugs, chlorthalidone was not associated with a reduced risk of myocardial infarction, stroke, or heart failure (hazard ratio 1.0, 95% CI 0.85-1.17) compared with hydrochlorothiazide, but was associated with an increased risk of hypokalemia (hazard ratio 2.72, 95% CI 2.38-3.12), hyponatremia (hazard ratio 1.31, 95% CI 1.16-1.47), and acute kidney injury (hazard ratio 1.37, 95% CI 1.15-1.63) [35]. Nevertheless, the trial evidence supporting the efficacy of lowdose thiazide diuretics in the management of hypertension comes primarily from those using chlorthalidone, such as ALLHAT [21]. There is little if any trial evidence that hydrochlorothiazide alone in a dose of 12.5 to 25 mg/day reduces cardiovascular events [37-39], and the blood pressure may not be as well controlled overnight [24,40]. Choice between thiazide-like and thiazide-type diuretics—Based upon the above observations, we and other experts suggest that thiazide-like diuretics (such as chlorthalidone, 12.5 to 25 mg/day) are preferred to thiazide-type diuretics [25,37-39,41,42]. However, the choice may vary with the clinical setting: ●

In most patients not previously treated with a thiazide diuretic, we suggest 12.5 to 25 mg/day of chlorthalidone (or 1.25 to 5 mg/day of indapamide), rather than hydrochlorothiazide. However, among older patients who are less than 10 mmHg above goal blood pressure, low-dose hydrochlorothiazide is a reasonable alternative.

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Among patients already treated with low-dose hydrochlorothiazide, the optimal approach has not been defined. Some experts would switch all patients to chlorthalidone or indapamide at their next visit, with the possible exception of those who monitor their blood pressure at home and have values below goal at the end of the drug's dosing period.

Monitoring for hypokalemia—Chlorthalidone produced hypokalemia requiring therapy in 7 to 8 percent of patients in large clinical trials including ALLHAT and SHEP [21,30]. It is possible that hypokalemia is more common with chlorthalidone than hydrochlorothiazide [26], given its longer duration of action. Concurrent use of a low-salt

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diet will both contribute to blood pressure lowering and reduce the risk of hypokalemia [43,44]. (See "Causes of hypokalemia in adults", section on 'Diuretics'.) Monitoring for the development of hypokalemia is warranted with all thiazide diuretics. In stable patients on a fixed dose of either chlorthalidone or hydrochlorothiazide, potassium loss, like other diuretic-induced fluid and electrolyte complications, occurs only during the first two weeks of therapy before a new steady state is established (

figure 7). Thus, a

stable patient with a normal serum potassium concentration at three weeks is not at risk of late hypokalemia unless the diuretic dose is increased, extrarenal potassium losses increase, or dietary potassium intake is reduced. (See "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'The steady state' and "Time course of loop and thiazide diureticinduced electrolyte complications".) Issues with thiazide-like diuretics—The basic principles of monitoring for hypokalemia with chlorthalidone and indapamide are identical to those with hydrochlorothiazide, as described in the preceding section. There are two other potential limitations associated with chlorthalidone: ●

There is no 12.5 mg chlorthalidone tablet. Thus, 25 mg tablets of generic chlorthalidone need to be cut in half.

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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. (See 'Combination therapy' below.)

ACCOMPLISH trial—Only one major trial, ACCOMPLISH, directly compared different combination regimens in hypertensive patients who require two drugs [45]. The ACCOMPLISH trial included 11,506 patients with hypertension who were at high risk for a cardiovascular event and, despite prior antihypertensive therapy in 97 percent (most requiring two or more drugs), had a mean baseline blood pressure of 145/80 mmHg [46]. The patients were randomly assigned to initial combination therapy with benazepril (20 mg/day) plus either amlodipine (5 mg/day) or hydrochlorothiazide (12.5 mg/day). Benazepril was increased to 40 mg/day in both groups at one month. If goal blood pressure was not attained, the amlodipine dose was increased to 10 mg/day and the hydrochlorothiazide dose to 25 mg/day. The primary end point was measured as the time to the first event, which was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, uptodate.searchbox.science/contents/choice-of-drug-therapy-in-primary-essential-hypertension?search=Hypertention&source=search_result&se… 6/32

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hospitalization for angina, resuscitation after sudden cardiac death or coronary revascularization. The trial was terminated early upon recommendation of the Data Safety Monitoring Board at a mean follow-up of 36 months when a substantial disadvantage associated with the hydrochlorothiazide arm was noted and the prespecified stopping rule was exceeded. The primary end point was achieved significantly less often in the benazepril-amlodipine group (9.6 versus 11.8 percent, hazard ratio 0.80, 95% CI 0.72-0.90). However, in a prespecified, post-hoc analysis, the superiority of amlodipine-based therapy was most pronounced in nonobese individuals; both combinations produced similar outcomes among obese patients [47]. Benazepril-amlodipine therapy led to a similar reduction in the secondary end point of cardiovascular death or nonfatal myocardial infarction or stroke (5 versus 6.3 percent, hazard ratio 0.79). These benefits increased progressively over the duration of the trial. The development of chronic kidney disease (mostly defined as doubling of the serum creatinine) was also less common with benazepril-amlodipine (2 versus 3.7 percent) [48]. The mean office blood pressure was slightly (approximately 1 mmHg) but significantly lower in the benazepril-amlodipine group (131.6/73.3 compared to 132.5/74.4 mmHg). However, in contrast to all other major randomized trials that compared the outcomes with different antihypertensive drugs, ACCOMPLISH included 24-hour blood pressure monitoring in a subset of 573 patients [49]. The 24-hour average blood pressure was higher (1.6/0.3 mmHg) in the benazepril-amlodipine group, although this was not statistically significant. Similar trends were noted with daytime and nighttime average blood pressures. Thus, the clinical benefits observ...