What is the evidence for or against the use of single pill, triple therapy (ACEi (Angiotensin-Converting Enzyme inhibitor) or ARB (Angiotensin Receptor Blocker), CCB (Calcium Channel Blocker), and diuretic) in the treatment of hypertension in general and special populations?

Evidence for Single-Pill Triple Therapy in Hypertension Management

Single-pill triple therapy combining an ACEi/ARB, CCB, and diuretic is strongly recommended for patients with uncontrolled hypertension on dual therapy, offering improved blood pressure control, adherence, and clinical outcomes compared to multiple separate pills.

Rationale for Triple Therapy

Triple therapy is often necessary for optimal blood pressure control:

• Approximately 25-33% of hypertensive patients require three or more medications to achieve blood pressure control 1
• Triple combinations with complementary mechanisms of action (RAS blocker, CCB, and diuretic) are recognized as rational and effective 2
• The 2022 ACC/AHA and ESC/ESH guidelines acknowledge that most patients will require multiple drugs to achieve BP control 3

Evidence Supporting Single-Pill Triple Therapy

Efficacy

• Triple-combination regimens result in greater proportions of patients achieving BP control compared with dual-combination regimens 2
• Significant additional BP reductions of 37-40 mmHg systolic and 21-25 mmHg diastolic can be achieved in patients with stage II hypertension 4
• Maximum doses of triple therapy components produce superior results to any two components alone 4

Adherence Benefits

• Single-pill combinations significantly improve medication adherence compared to separate pills 5
• Fixed-dose combinations improve long-term BP control through better adherence 1
• The 2024 ESC guidelines specifically recommend single-pill combinations to improve adherence 3

Recommended Combinations

• The preferred triple therapy combination is a RAS blocker (ACEi or ARB) + CCB + thiazide/thiazide-like diuretic 3
• Multiple guidelines (French, NICE, JNC 8, Taiwan, ASH/ISH) recommend combining ACEi/ARB with a CCB and a diuretic when three drugs are required 3
• The 2024 ESC guidelines recommend a single-pill combination containing these three classes at low doses initially 3

Special Populations

Elderly Patients (≥65 years)

• Triple therapy is effective in elderly patients 4
• Target systolic BP for older adults is <130 mmHg if tolerated 5

Black Patients

• For Black patients, ARB-based combinations are preferred over ACEi-based regimens 5
• Triple therapy is effective across different racial groups, including Black patients 4

Patients with Comorbidities

• Triple therapy is effective in patients with diabetes, metabolic syndrome, and other comorbidities 4
• For patients with known cardiovascular disease, target systolic BP is <130 mmHg 5

Implementation Algorithm

1. Initial Assessment:

   • For patients with BP ≥140/90 mmHg, start with dual therapy (preferably single-pill combination)
   • For patients with BP ≥20/10 mmHg above target, consider triple therapy from the outset 3

2. Progression to Triple Therapy:

   • If BP remains uncontrolled on maximally tolerated dual therapy, advance to triple therapy
   • Use a single-pill combination of RAS blocker + CCB + thiazide diuretic 3

3. Monitoring:

   • Follow up monthly after initiation until target BP is reached 5
   • Review and modify treatment every 2-4 weeks until appropriate regimen is established 3

4. Resistant Hypertension:

   • If BP remains uncontrolled on triple therapy, consider adding spironolactone as fourth agent 3, 5
   • Refer to specialist center for appropriate work-up 3

Important Cautions

• Avoid combining two RAS blockers (ACEi + ARB) as this increases adverse effects without additional benefit 3, 5
• The most common adverse effect of triple therapy is peripheral edema related to amlodipine 4
• Triple therapy is generally well-tolerated with adverse event profiles similar to dual regimens 1

By implementing single-pill triple therapy in appropriate patients, clinicians can improve blood pressure control rates, enhance medication adherence, and potentially reduce cardiovascular morbidity and mortality in patients with hypertension.