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. This approach is supported by the most recent guidelines, including the 2024 ESC guidelines for the management of elevated blood pressure and hypertension 1. Combination therapy with medications from different classes, such as an ACE inhibitor with a thiazide diuretic or a calcium channel blocker with an ARB, typically provides more effective blood pressure reduction with fewer side effects than high-dose monotherapy.

The benefits of combination therapy include:

• Additive or synergistic effects on blood pressure reduction
• Targeting multiple pathophysiological pathways contributing to hypertension
• Potential for fewer side effects and improved adherence due to lower doses of individual medications
• Faster achievement of blood pressure control

Some key points to consider when using combination therapy:

• Single-pill combinations are preferred for simplicity and adherence
• The major four drug classes (ACE inhibitors, ARBs, dihydropyridine CCBs, and thiazide or thiazide-like diuretics) are recommended as first-line BP-lowering medications, either alone or in combination
• Doses of BP-lowering drugs should be titrated to achieve optimal blood pressure control while minimizing side effects

It's also important to note that patient-level response to individual BP-lowering drug classes can be heterogeneous, suggesting some patients may benefit from more personalized treatment compared with routine combinations 1. Additionally, the evidence for reduced CVD outcomes with BP-lowering drugs in combination therapy is based on observational studies, and there are no outcomes data from prospective trials that prove superiority of upfront combination therapy over upfront monotherapy in the isolated treatment of hypertension.

However, given the totality of evidence for outcomes benefit in observational studies, randomized trial data for better BP control and adherence, and importantly, also given CVD outcomes benefit for polypills (a form of single-pill combination) in randomized trials, the 2024 ESC guidelines provide a Class I recommendation for upfront combination therapy in adults with confirmed hypertension 1.

In summary, combination therapy with multiple antihypertensive medications at lower doses is a recommended approach for managing hypertension, particularly for patients with stage 2 hypertension or those with blood pressure significantly above their target, as it can provide more effective blood pressure reduction with fewer side effects than high-dose monotherapy.

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.