What are the preferred pharmacological agents, such as Angiotensin-Converting Enzyme (ACE) inhibitors or calcium channel blockers, for the management of periodically elevated blood pressures, also known as Hypertension?

Preferred Pharmacological Agents for Periodically Elevated Blood Pressures

For most patients with confirmed hypertension, initiate combination therapy with an ACE inhibitor or ARB plus a dihydropyridine calcium channel blocker (such as amlodipine) or a thiazide-like diuretic as first-line treatment. 1

First-Line Medication Classes

The following four drug classes have demonstrated the most effective reduction in blood pressure and cardiovascular events and are recommended as first-line treatments 1:

• ACE inhibitors (e.g., lisinopril, enalapril, ramipril)
• Angiotensin receptor blockers (ARBs) (e.g., losartan, valsartan)
• Dihydropyridine calcium channel blockers (e.g., amlodipine, felodipine)
• Thiazide and thiazide-like diuretics (e.g., chlorthalidone, indapamide, hydrochlorothiazide)

Initial Treatment Strategy Based on Blood Pressure Level

For Stage 1 Hypertension (BP 140-159/90-99 mmHg)

Start with combination therapy using two agents from different classes for most patients, as this provides more effective blood pressure control than monotherapy 1. The preferred combinations are 1, 2:

• ACE inhibitor or ARB + dihydropyridine calcium channel blocker
• ACE inhibitor or ARB + thiazide-like diuretic

Exceptions where monotherapy may be considered 1:

• Patients aged ≥85 years
• Those with symptomatic orthostatic hypotension
• Patients with moderate-to-severe frailty
• Elevated BP (systolic 120-139 mmHg) with concomitant indication for treatment

For Stage 2 Hypertension (BP ≥160/100 mmHg)

Initiate combination therapy immediately with two antihypertensive agents from different classes, as blood pressure is more than 20/10 mmHg above target 1, 2. Prompt management within 1 week is essential to reduce risk of target organ damage 1.

Preferred Combination Regimens

Primary Recommendation: ACE Inhibitor/ARB + Dihydropyridine Calcium Channel Blocker

This combination is preferred based on superior cardiovascular outcomes 2. The ACCOMPLISH trial demonstrated that ACE inhibitor plus calcium channel blocker reduced cardiovascular events by 21% compared to ACE inhibitor plus diuretic, despite only a 1 mmHg difference in blood pressure control 2.

Specific evidence-based combinations 2, 3, 4:

• Lisinopril 10-20 mg + amlodipine 5-10 mg daily
• Other ACE inhibitors (enalapril, ramipril) + dihydropyridine calcium channel blockers

Alternative Preferred Combination: ACE Inhibitor/ARB + Thiazide-Like Diuretic

This combination remains highly effective and cost-effective, with proven reduction in cardiovascular events 2, 1. Thiazide-like diuretics (chlorthalidone, indapamide) are preferred over hydrochlorothiazide due to stronger evidence for cardiovascular event reduction 2.

Choosing Between ACE Inhibitors and ARBs

Either ACE inhibitors or ARBs can be used interchangeably as first-line agents 1, 2. Key considerations:

• ARBs offer similar efficacy with fewer side effects, particularly avoiding the cough associated with ACE inhibitors (occurs in 5-20% of patients) 2
• ACE inhibitors have slightly more robust mortality data from older trials 1
• Both classes provide equivalent cardiovascular and renal protection 2

Single-Agent Therapy Considerations

If monotherapy is chosen (for exceptions noted above), the hierarchy based on evidence quality is 2, 5:

1. Thiazide-like diuretics (chlorthalidone preferred): Strongest evidence for mortality reduction, with prevention of 2-3 deaths and 2 strokes per 100 patients treated for 4-5 years 5
2. ACE inhibitors: Demonstrated all-cause mortality reduction in multiple trials 5
3. Dihydropyridine calcium channel blockers: Effective for blood pressure reduction, particularly in older and Black patients 2

Special Population Considerations

Black Patients

Calcium channel blockers and thiazide diuretics are more effective than ACE inhibitors or ARBs as monotherapy 2, 3. However, combination therapy with ACE inhibitor/ARB plus calcium channel blocker or diuretic remains appropriate 1.

Patients ≥60 Years

Calcium channel blockers or thiazide diuretics are often preferred 2, though combination therapy remains the standard approach for most patients 1.

Patients with Diabetes and Albuminuria

ACE inhibitor or ARB is mandatory as part of the regimen to reduce progressive kidney disease 2. Combine with calcium channel blocker or thiazide diuretic for blood pressure control 2.

Patients with Coronary Artery Disease

ACE inhibitors or ARBs are recommended as first-line therapy 2, 6. For post-myocardial infarction patients, add beta-blocker to ACE inhibitor 6.

Patients with Heart Failure with Reduced Ejection Fraction

ACE inhibitors are the preferred initial therapy, with beta-blockers added for additional mortality benefit 6. Avoid non-dihydropyridine calcium channel blockers (diltiazem, verapamil) in systolic heart failure 6.

Escalation to Three-Drug Therapy

If blood pressure is not controlled with two drugs, escalate to a three-drug combination 1:

• ACE inhibitor or ARB + dihydropyridine calcium channel blocker + thiazide-like diuretic
• Preferably use single-pill combination formulations to improve adherence 1

Critical Combinations to Avoid

Never combine ACE inhibitor + ARB 1, 2. This dual RAS blockade increases risk of:

• Hyperkalemia
• Hypotension
• Renal dysfunction
• No additional cardiovascular benefit 1, 2

Blood Pressure Targets

Target systolic blood pressure of 120-129 mmHg for most adults, provided treatment is well tolerated 1. If this target cannot be achieved due to poor tolerance, use the "as low as reasonably achievable" (ALARA) principle 1.

Target blood pressure <130/80 mmHg is recommended by American guidelines for all hypertensive patients 1.

Monitoring Requirements

After initiating ACE inhibitor or ARB therapy 2:

• Check serum creatinine and potassium within 7-14 days
• Recheck at least annually thereafter
• Monitor for hyperkalemia, especially when combined with other potassium-retaining agents

For Stage 2 hypertension, evaluate monthly and adjust promptly until blood pressure control is achieved 2.

Fixed-Dose Single-Pill Combinations

Single-pill combination formulations are strongly recommended over separate pills to improve adherence 1. Multiple fixed-dose combinations are available for the preferred regimens listed above.

Common Pitfalls to Avoid

• Underdosing medications before adding additional agents: Titrate to effective doses before declaring treatment failure 2
• Using beta-blockers as first-line monotherapy: Beta-blockers lack evidence for initial hypertension treatment unless specific compelling indications exist (post-MI, heart failure, angina) 1
• Prescribing non-dihydropyridine calcium channel blockers (diltiazem, verapamil) in patients with systolic heart failure: These agents can worsen heart failure 6
• Failing to initiate combination therapy in Stage 2 hypertension: Monotherapy is inadequate for blood pressure ≥160/100 mmHg 1, 2
• Using alpha-blockers as first-line therapy: These increase cardiovascular events, especially heart failure, compared to diuretics 1