Optimizing hypertension treatment: Evidence-based approaches and new drugs

Evidence for starting with combination therapy

No randomized controlled trials have directly compared monotherapy at escalating doses vs dual combined therapy. However, multiple studies suggest that starting with a combination of medications helps to achieve target blood pressures faster, is more useful in controlling blood pressure in the long term, and reduces blood pressure more than monotherapy.^5,6

Which combination is best? The ACCOMPLISH trial⁴ randomized 11,506 “high-risk” patients with a history of coronary events, stroke, left ventricular hypertrophy, or peripheral arterial disease to receive either benazepril plus amlodipine (n = 5,744) or benazepril plus hydrochlorothiazide (n = 5,762). The primary composite end point consisted of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after cardiac arrest, and coronary revascularization.

At a mean of 36 months, both groups showed similar blood pressure control, with mean blood pressures of 132/73 mm Hg in the benazepril-amlodipine group vs 133/74 mm Hg in the benazepril-hydrochlorothiazide group. However, the incidence of the primary end point was 20% lower in the benazepril-amlodipine group than in the benazepril-hydrochlorothiazide group (hazard ratio 0.80, 95% confidence interval 0.72–0.90).⁴ The absolute risk reduction was 2.2%, and calculating the number needed to treat (NNT) as 1 divided by the absolute risk reduction, 45 patients therefore needed to be treated with benazepril-amlodipine rather than benazepril-hydrochlorothiazide to prevent 1 end-point event.

Recommendations for starting with combination therapy

Both the European Society of Cardiology and the American Heart Association and American College of Cardiology recommend starting therapy for hypertension with the combination of low or moderate doses of an ACE inhibitor or ARB and a calcium channel blocker or thiazide diuretic, preferably in the form of a single pill.^7,8 While the American guidelines recommend this strategy for patients with stage 2 hypertension (ie, systolic blood pressure ≥ 140 mm Hg, diastolic pressure ≥ 90 mm Hg, or both), Black patients, and patients with blood pressure more than 20/10 mm Hg above target,⁸ the European guidelines recommend it for most patients with hypertension.⁷

Both guidelines note that many Black patients have low-renin, salt-sensitive hypertension and tend to respond better to a thiazide or a thiazide-like diuretic, a calcium channel blocker, or both. The American guidelines specifically recommend a thiazide diuretic or calcium channel blocker as initial therapy in Black adults without heart failure or kidney disease, whereas the European guidelines similarly caution that ACE inhibitor or ARB monotherapy is generally less effective in this group. Both guidelines agree that many Black patients need combination therapy (eg, a calcium channel blocker plus thiazide diuretic) to improve their blood pressure control.

Definitions and targets differ somewhat. In the European guidelines, elevated office blood pressure is 120/70 to less than 140/90 mm Hg, while hypertension is 140/90 and higher. In the American guidelines, elevated blood pressure means 120 to 129 mm Hg systolic and less than 80 mm Hg diastolic, while hypertension begins at 130 mm Hg or 80 mm Hg diastolic. As for goals of treatment, in Europe the target is 120 to 129 over 70 to 79 mm Hg, but only if treatment is tolerated. In the United States, less than 130/80 “is recommended” for those at risk of a cardiovascular event, but “may be reasonable” for those with the same blood pressure but no additional markers of risk.

Evidence supporting continuing hydrochlorothiazide

The Diuretic Comparison Project,⁹ performed in the US Department of Veterans Affairs health system, randomized 13,523 patients (97% men, mean age 72 years, baseline systolic blood pressure 139 mm Hg) who at baseline were receiving hydrochlorothiazide at 25 or 50 mg daily to either remain on hydrochlorothiazide or to switch to an equivalent dose of chlorthalidone.

The trial’s primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non–cancer-related death. At a median of 2.4 years, there was no significant difference in the incidence of this outcome between the 2 groups (hazard ratio in the chlorthalidone group 1.04, 95% confidence interval 0.94–1.16).

Limitations of this trial were that it was open label, used lower doses of chlorthalidone and hydrochlorothiazide than in many other cardiovascular outcome studies, and relied on claims data to ascertain outcomes. Concomitant medications and adherence could also have influenced results.

Evidence favoring chlorthalidone

Why not add hydrochlorothiazide 12.5 mg, the second of the choices above? Didn’t the Diuretic Comparison Project⁹ find that hydrochlorothiazide and chlorthalidone were equivalent in terms of that trial’s primary outcome, and therefore both drugs are acceptable choices of a thiazide diuretic? Yes, this is a proper interpretation—if goal blood pressure has already been achieved. However, at the same dose, chlorthalidone lowers blood pressure more and should be chosen if significant additional blood pressure lowering is needed. Hydrochlorothiazide 12.5 mg would have less of an effect than chlorthalidone 25 mg.

Both chlorthalidone and hydrochlorothiazide have been used for many years. Chlorthalidone, the older of the 2 drugs, was used more frequently from the 1960s to the 1980s.¹⁰ Hydrochlorothiazide, approved by the US Food and Drug Administration in 1977, subsequently replaced chlorthalidone as the thiazide diuretic drug of choice.¹¹

The 2 drugs differ significantly pharmacologically. Hydrochlorothiazide has a shorter half-life—6 to 9 hours, vs 40 to 60 hours for chlorthalidone. Also, although data vary, chlorthalidone appears to be roughly 1.5 to 2 times more potent than hydrochlorothiazide.¹²

Multiple trials addressed which of the thiazide diuretics is superior in controlling blood pressure and preventing cardiovascular events. Pareek et al¹³ conducted a small, double-blind, randomized controlled trial (n = 54) comparing the effect of hydrochlorothiazide 12.5 mg, continuous-release hydrochlorothiazide 12.5 mg, and chlorthalidone 6.25 mg on 24-hour ambulatory blood pressures in patients with stage 1 hypertension. While all 3 medications lowered office blood pressure readings, only chlorthalidone reduced ambulatory and nighttime blood pressures, underscoring its greater potency. Similarly, 2 meta-analyses found that chlorthalidone lowers blood pressure more than hydrochlorothiazide.^14,15

Chlorthalidone is usually started at a dose of 12.5 mg once daily, whereas hydrochlorothiazide can be started at 12.5 or 25 mg once daily.

Recommendations for chlorthalidone vs hydrochlorothiazide

Neither the American nor the European guidelines formally recommends chlorthalidone over hydrochlorothiazide; both agents are considered appropriate first-line thiazide or thiazide-like diuretics. However, the 2018 American Heart Association Scientific Statement on resistant hypertension¹⁶ recommends switching to indapamide or chlorthalidone for patients with confirmed resistant hypertension if blood pressure remains uncontrolled on a less-potent thiazide diuretic such as hydrochlorothiazide.

Both chlorthalidone and hydrochlorothiazide can cause electrolyte disturbances, most commonly hypokalemia, and necessitate periodic assessment of serum potassium and renal function. While chlorthalidone may lower blood pressure more than hydrochlorothiazide, it is associated with higher rates of hypokalemia, warranting close electrolyte monitoring. If there are concerns about the potential side effects of chlorthalidone, one can consider indapamide, starting at 1.25 or 2.5 mg daily, which is intermediate in efficacy between chlorthalidone and hydrochlorothiazide.¹⁷

Evidence that nonadherence is common

Nonadherence to antihypertensive therapy contributes to inadequate blood pressure control and is common in patients with apparent treatment-resistant hypertension. For instance, a systematic review of 42 studies that included 71,353 patients found that 46% of the patients were not adherent to their regimen if assessed by direct observed therapy or urine assays.¹⁸

A systematic review of 9 studies that included 747 patients from 5 countries found that 13% to 46% of patients with apparent treatment-resistant hypertension were partially nonadherent to their antihypertensive regimens, and 2% to 35% were completely nonadherent. The investigators mainly used objective assessments such as urine or blood testing.¹⁹

Patients who experience real or perceived side effects from multiple antihypertensive medications present significant treatment challenges. To enhance treatment adherence, blood pressure regimens should be simplified by using long-acting combination agents whenever feasible, thereby minimizing the number of prescribed pills and allowing for once-daily dosing. Adherence to treatment declines with pill burden, dosing complexity, and out-of-pocket costs. Also, it is essential to discuss and manage medication-related adverse effects, adjusting or substituting the offending agent as necessary.

Evidence favoring spironolactone as the fourth drug

Around 9.2% cases of hypertension are resistant, which includes truly refractory cases and those due to nonadherence to treatment.²⁰ Studies in the 2000s attempted to define the best next option for patients with resistant hypertension but were limited by open-label methods, lack of an active comparator, inability to confirm resistant hypertension, and limited numbers of patients.^21,22 However, several randomized controlled trials since then found that spironolactone is more effective than placebo and other drugs in controlling blood pressure in patients with resistant hypertension.^23–26

Our best data come from the PATHWAY-2 (Prevention and Treatment of Hypertension With Algorithm-Based Therapy) trial,²⁷ in which 335 patients already taking an ACE inhibitor or ARB, calcium channel blocker, and thiazide-type diuretic were randomized to additionally receive doxazosin, bisoprolol, spironolactone, or placebo in a double-blind, crossover protocol. Spironolactone was superior to the other drugs in terms of efficacy of blood pressure control and percentage of patients reaching targets.

Additionally, the ReHOT (Resistant Hypertension Optimal Treatment) trial²⁸ compared spironolactone vs clonidine in 187 patients with true resistant hypertension. The rate of the primary end point, which included office blood pressure control (< 140/90 mm Hg) and 24-hour ambulatory blood pressure control (< 130/80 mm Hg), was similar in both groups (relative risk in the clonidine group 1.01, 95% confidence interval 0.55–1.88). However, spironolactone resulted in a greater decrease in 24-hour systolic and diastolic blood pressure, as well as in diastolic daytime ambulatory blood pressure compared with clonidine.²⁸

Evidence for testing for primary aldosteronism

Primary aldosteronism was once considered rare but is now recognized as the most common endocrine cause of secondary hypertension. A 2006 study reported the prevalence of primary aldosteronism in patients with newly diagnosed hypertension at 11.2%, and most patients who had it actually had normal potassium levels.²⁹ In patients with resistant hypertension, the prevalence of primary aldosteronism is higher, ranging from 11.3% to 29.1% in various studies.³⁰

However, few patients are tested for primary aldosteronism even though clinical tools are readily available. In a cohort of 18,908 patients with treatment-resistant hypertension, only 4.2% (795 patients) were screened for primary aldosteronism. Among the screened patients, 16.9% tested positive for primary aldosteronism.³¹

Aprocitentan, an endothelin receptor antagonist

PRECISION (Parallel-Group, Phase 3 Study With Aprocitentan in Subjects With Resistant Hypertension)³² was a multicenter trial of aprocitentan, an endothelin receptor antagonist. It included 730 patients with resistant hypertension on at least 3 antihypertensive medications, who were assigned to receive aprocitentan 12.5 mg, aprocitentan 25 mg, or placebo during the initial 4-week double-blind period. Both doses of aprocitentan significantly reduced systolic blood pressure, which was 3.8 mm Hg lower in the 12.5-mg group and 3.7 mm Hg lower in the 25-mg group than in the placebo group.

In the subsequent 32-week single-blind phase, all participants received aprocitentan 25 mg, followed by a 12-week double-blind withdrawal phase in which they were randomized again to either aprocitentan 25 mg or placebo. During the withdrawal phase, systolic blood pressure in the placebo group increased and was 5.8 mm Hg higher in this group than in the group that continued on aprocitentan (P < .0001).

Aldosterone synthase inhibitors: Lorundrostat, baxdrostat

Lorundrostat, an aldosterone synthase inhibitor, underwent a phase 2 trial in 200 patients with uncontrolled hypertension who were taking 2 or more antihypertensive drugs; the patients were divided into 2 cohorts according to their plasma renin activity and plasma aldosterone level.³³ The cohort with suppressed plasma renin activity and elevated aldosterone (n = 163) was randomized to receive placebo or lorundrostat in 5 different dosages; at 8 weeks, the systolic blood pressure was 9.6 mm Hg lower in those receiving lorundrostat 50 mg than in those receiving placebo, and 7.8 mm Hg lower in those receiving lorundrostat 100 mg than in those receiving placebo.

The remaining 37 patients, who did not have suppressed plasma renin activity, received either placebo or lorundrostat 100 mg once daily; in those on the active drug, the reduction in systolic blood pressure was 11.4 mm Hg, which was similar to the reduction in the cohort with suppressed plasma renin activity receiving the same dosage.

Baxdrostat is another aldosterone synthase inhibitor. In a multicenter, placebo-controlled trial, 275 patients with treatment-resistant hypertension who were receiving stable doses of at least 3 antihypertensive agents were randomized to receive either baxdrostat 0.5 mg, 1 mg, or 2 mg or placebo once daily for 12 weeks. A total of 248 patients completed the trial. Baxdrostat led to significant, dose-related reductions in blood pressure without serious adverse events or occurrences of adrenocortical insufficiency. At week 12, compared with baseline, systolic blood pressure was 20.3 mm Hg lower in the 2-mg group, 17.5 mm Hg lower in the 1-mg group, 12.1 mm Hg lower in the 0.5-mg group, and 9.4 mm Hg lower in the placebo group.³⁴

RNA interference therapy with zilebesiran: An injection every few months?

Treatment with small interfering RNAs (siRNAs) has expanded from being used in rare genetic conditions to being used in more common diseases such as hypercholesterolemia (eg, inclisiran).³⁵

Zilebesiran, a novel siRNA therapy currently in clinical trials, is being developed for hypertension treatment. Given subcutaneously, it targets angiotensinogen synthesis in the liver, reducing angiotensin I and II levels and lowering blood pressure. Unlike standard renin-angiotensin system inhibitors, which can lead to renin-angiotensin system escape as a result of compensatory renin increases, zilebesiran’s effect on angiotensinogen depletion may offer more sustained blood pressure control.³⁶

In a phase 1 study, 107 patients with hypertension were randomized in a 2:1 ratio to receive a single subcutaneous dose of zilebesiran (range 10–800 mg) or placebo. Those who received zilebesiran had dose-dependent reductions in systolic and diastolic blood pressure, which were maintained for up to 24 weeks at doses of 200 mg or higher. At week 6, compared with baseline, the mean systolic blood pressure was 21.8 mm Hg lower in those receiving zilebesiran 800 mg.³⁷

Further, the KARDIA-2 (Zilebesiran as Add-On Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication) trial³⁸ demonstrated that adding zilebesiran to standard antihypertensive therapies is a promising strategy for blood pressure control in patients with uncontrolled hypertension. KARDIA-2 was a double-blinded, placebo-controlled trial that included 663 participants randomized to receive indapamide, amlodipine, or olmesartan and then further randomized to receive an injection of zilebesiran or placebo, while continuing to receive the 3 standard drugs.

At 3 months, the mean 24-hour ambulatory systolic blood pressure had dropped 12.1 mm Hg more in the indapamide-plus-zilebesiran group than in the indapamide-plus-placebo group, 9.7 mm Hg more in the amlodipine-plus-zilebesiran group than in the amlodipine-plus-placebo group, and 4.0 mm Hg more in the olmesartan-plus-zilebesiran group than in the olmesartan-plus-placebo group. All of these differences were statistically significant. These reductions were sustained up to 6 months in the indapamide and amlodipine groups.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptor agonist

A post hoc analysis³⁹ of SURMOUNT-1 (A Study of Tirzepatide [LY3298176] in Participants With Obesity or Overweight)⁴⁰ suggests that tirzepatide reduces ambulatory blood pressures. SURMOUNT-1⁴⁰ compared tirzepatide in weekly injections of 5, 10, or 15 mg vs placebo in 2,539 nondiabetic patients with relatively controlled blood pressure and a body mass index greater than 27 kg/m² and found that the drug “provided substantial and sustained reductions in body weight.” Investigators then looked at a subgroup of 600 patients who underwent 24-hour ambulatory blood pressure monitoring. At 36 weeks, in the tirzepatide 5-mg group, the mean placebo-adjusted change in systolic blood pressure was −7.4 mm Hg (95% confidence interval −10 to −4.7); in the tirzepatide 15-mg group it was −8 mm Hg (95% confidence interval −10.6 to −5.4).³⁹ Further analysis noted that 70% of systolic blood pressure reductions were mediated by weight reduction. Results from the analysis were similar with both daytime and nighttime systolic blood pressure.