Should treatment of hypertension always start with monotherapy?

Treatment of Hypertension: Monotherapy vs. Combination Therapy

Treatment of hypertension should NOT always start as monotherapy, particularly for patients with stage 2 hypertension (≥160/100 mmHg) or with BP more than 20/10 mmHg above target. 1

Initial Treatment Strategy Based on Hypertension Severity

Stage 1 Hypertension (130-139/80-89 mmHg)

• Monotherapy is reasonable as initial treatment 1
• Begin with a single antihypertensive drug with dosage titration and sequential addition of other agents as needed to achieve BP target 1
• Appropriate first-line options include:
  • ACE inhibitors (e.g., lisinopril)
  • ARBs (e.g., losartan)
  • Calcium channel blockers (e.g., amlodipine)
  • Thiazide or thiazide-like diuretics 1, 2

Stage 2 Hypertension (≥140/90 mmHg)

• Combination therapy is recommended when BP is ≥160/100 mmHg or >20/10 mmHg above target 1
• Use 2 first-line agents of different classes, either as separate agents or in a fixed-dose combination 1
• Preferred combinations:
  • ACE inhibitor or ARB + calcium channel blocker
  • ACE inhibitor or ARB + thiazide-like diuretic 1

Special Population Considerations

Black Patients

• Initial therapy should include a thiazide diuretic or calcium channel blocker 1, 2
• If using ARBs, they may be preferred over ACE inhibitors due to lower risk of angioedema 2

Patients with Diabetes or CKD

• Include an ACE inhibitor or ARB in the regimen 2
• Target BP <130/80 mmHg 2

Evidence Supporting This Approach

The 2017 ACC/AHA guidelines explicitly recommend initiation with combination therapy for stage 2 hypertension, stating: "Initiation of antihypertensive drug therapy with 2 first-line agents of different classes, either as separate agents or in a fixed-dose combination, is recommended in adults with stage 2 hypertension and an average BP more than 20/10 mm Hg above their BP target." 1

The 2024 ESC guidelines support upfront low-dose combination therapy for hypertension, citing benefits of targeting multiple pathophysiological pathways, potentially reducing side effects, and achieving swifter BP control 1.

Rationale for Combination Therapy

• Most patients with hypertension require multiple agents for BP control 3, 4, 5
• Combination therapy provides:
  • More rapid BP control in higher-risk patients 1
  • Greater BP lowering when drugs have complementary mechanisms 6
  • Potentially better adherence with fixed-dose combinations 1

Caveats and Pitfalls

1. Avoid inappropriate combinations:

   • Two RAS blockers (e.g., ACE inhibitor + ARB) should not be used together 1
   • Some combinations (e.g., calcium antagonists + diuretics) may have no additive BP-lowering effects 6

2. Monitor for adverse effects:

   • When initiating combination therapy in older adults, monitor carefully for hypotension or orthostatic hypotension 1
   • Check renal function and electrolytes within 2-4 weeks of starting RAS blockers 2

3. Evidence limitations:

   • The Cochrane review notes limited evidence from large clinical trials directly comparing monotherapy versus combination therapy as initial treatment for clinical outcomes (mortality, cardiovascular events) 7
   • Most recommendations are based on BP-lowering efficacy rather than hard clinical endpoints

Treatment Algorithm

1. Assess hypertension severity and cardiovascular risk

   • Measure BP accurately using validated device with appropriate cuff size 1
   • Calculate 10-year ASCVD risk

2. Select initial therapy based on:

   • BP level (stage 1 vs. stage 2)
   • Distance from BP target
   • Patient characteristics (age, race, comorbidities)

3. For stage 1 hypertension (130-139/80-89 mmHg):

   • Start with monotherapy
   • Titrate dose if needed
   • Add second agent if BP target not achieved

4. For stage 2 hypertension (≥140/90 mmHg) or BP >20/10 mmHg above target:

   • Start with combination therapy
   • Preferably use fixed-dose combinations for better adherence

5. Follow up within 2-4 weeks to assess response and adjust therapy as needed 2

While monotherapy may be appropriate for some patients with mild hypertension, the evidence clearly indicates that combination therapy is superior for patients with more severe hypertension or those significantly above their BP target.