Is using multiple antihypertensive (blood pressure lowering) agents more effective than increasing the dose of a single agent for managing hypertension?

From the Guidelines

Using multiple antihypertensive medications at lower doses is generally better than maximizing the dose of a single agent for most patients with hypertension. Combination therapy with medications from different classes (such as an ACE inhibitor like lisinopril with a thiazide diuretic like hydrochlorothiazide, or a calcium channel blocker like amlodipine with an ARB like losartan) typically provides more effective blood pressure reduction with fewer side effects than high-dose monotherapy, as supported by the most recent guidelines 1. This approach works because different medication classes target different physiological pathways involved in blood pressure regulation, creating synergistic effects. For example, while an ACE inhibitor blocks the renin-angiotensin system, adding a diuretic addresses sodium and fluid retention. Most patients with stage 2 hypertension (BP ≥140/90 mmHg) will require at least two medications to reach target blood pressure goals. When initiating combination therapy, start with lower doses of each medication (such as lisinopril 10mg daily plus hydrochlorothiazide 12.5mg daily) and titrate as needed. The physiological basis for this approach is that dose-response curves for blood pressure reduction typically flatten at higher doses while side effect rates continue to increase linearly, making combination therapy more favorable from a benefit-risk perspective.

The benefits of combination therapy are further supported by the fact that it can lead to better adherence and persistence, as well as fewer side effects, compared to high-dose monotherapy 1. Additionally, combination therapy can provide a more rapid reduction in blood pressure, which is particularly important for patients with high-risk hypertension. The 2024 ESC guidelines recommend upfront combination therapy with two first-line agents of different classes, either as separate agents or in a fixed-dose combination, for adults with stage 2 hypertension and an average BP more than 20/10 mm Hg above their BP target 1.

Some key points to consider when initiating combination therapy include:

• Starting with lower doses of each medication and titrating as needed
• Using medications from different classes to target different physiological pathways
• Monitoring blood pressure and adjusting the treatment plan as needed
• Considering the use of fixed-dose combination products to improve adherence and reduce side effects
• Being cautious when initiating antihypertensive pharmacotherapy with 2 drugs in older patients, as hypotension or orthostatic hypotension may develop in some patients, as noted in the 2018 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline 1.

Overall, the use of multiple antihypertensive medications at lower doses is a effective and safe approach for managing hypertension, and is supported by the most recent guidelines and evidence 1.

From the FDA Drug Label

The antihypertensive effects of lisinopril are maintained during long-term therapy. When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive. Concomitant administration of lisinopril and hydrochlorothiazide further reduced blood pressure in Black and non-Black patients and any racial differences in blood pressure response were no longer evident. The addition of a low dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily resulted in placebo-adjusted blood pressure reductions of 15.5/9.2 mmHg.

The use of multiple antihypertensive agents, such as lisinopril and hydrochlorothiazide, or losartan and hydrochlorothiazide, can be more effective than increasing the dose of a single agent for managing hypertension. The combination of these drugs has been shown to have additive effects on blood pressure reduction, and can help to eliminate racial differences in blood pressure response 2 3.

• The combination of lisinopril and hydrochlorothiazide has been shown to further reduce blood pressure in both Black and non-Black patients.
• The addition of hydrochlorothiazide to losartan has been shown to result in significant placebo-adjusted blood pressure reductions.
• The use of multiple antihypertensive agents can be an effective strategy for managing hypertension, especially in patients who do not respond to single-agent therapy.

From the Research

Effectiveness of Multiple Antihypertensive Agents

• Using multiple antihypertensive agents can be more effective than increasing the dose of a single agent for managing hypertension, as evidenced by studies 4, 5, 6, 7.
• Combination therapy with two or more antihypertensive medications can achieve effective control of blood pressure in a larger percentage of patients 4, 6.
• Certain combinations, such as a calcium channel blocker and angiotensin converting enzyme inhibitor, have been associated with similar or fewer adverse effects and better outcomes than other combinations 6.

Comparison of Monotherapy and Combination Therapy

• Monotherapy may not be sufficient to achieve blood pressure goals in up to 75% of patients, making combination therapy a more effective option 6.
• Combination antihypertensive therapy, especially with fixed-dose formulations, may more effectively control blood pressure and improve medication persistence while decreasing adverse effects, healthcare costs, and physician therapeutic inertia 6.
• However, some studies suggest that dual-agent therapy carries an increased risk of adverse effects and drug interactions compared to monotherapy 8.

Selection of Antihypertensive Agents

• The selection of a specific combination drug regimen should be based on the perceived need for diuretic therapy as first- or second-step therapy, as well as the patient's individual characteristics and medical history 4, 8.
• Rational alternatives to traditional combination therapies exist, including an ACE inhibitor/calcium channel blocker or a dihydropyridine CCB/b blocker combination 4.
• Initial combination antihypertensive therapy may benefit patients with stage I or II hypertension, and more widespread use should be encouraged 6.