Is it okay to use Angiotensin-Converting Enzyme (ACE) inhibitors, Angiotensin Receptor Blockers (ARBs), or Calcium Channel Blockers (CCBs) as first-line agents for hypertension management?

ACE Inhibitors, ARBs, and CCBs as First-Line Antihypertensive Agents

Yes, ACE inhibitors, ARBs, and calcium channel blockers are all appropriate first-line agents for hypertension management, along with thiazide diuretics, as they consistently reduce cardiovascular disease risk and mortality. 1

General Population Recommendations

For most patients without specific comorbidities, initiate therapy with any of the following first-line agents: thiazide diuretics, ACE inhibitors, ARBs, or CCBs, as all four classes demonstrate equivalent efficacy in reducing cardiovascular events and mortality. 1, 2

• The 2017 ACC/AHA guidelines explicitly designate these four drug classes as first-line options with Class I, Level A evidence. 1
• The 2022 harmonized ACC/AHA and ESC/ESH guidelines reaffirm this recommendation, noting that selection should be based on patient-specific factors rather than inherent superiority of one class over another. 1
• β-blockers are not recommended as first-line agents because they are significantly less effective for cardiovascular disease prevention and stroke protection compared to the four preferred classes, unless specific cardiac indications exist (ischemic heart disease, heart failure). 1

Population-Specific Modifications

Black Patients

For Black patients, initiate therapy with either a thiazide diuretic or CCB, as these are more effective than ACE inhibitors or ARBs in this population. 1, 2

• ACE inhibitors and ARBs demonstrate reduced antihypertensive efficacy in Black patients when used as monotherapy. 2
• If combination therapy is needed in Black patients, use ARB + CCB or CCB + thiazide diuretic as the preferred initial combination. 1

Patients with Chronic Kidney Disease and Albuminuria

For patients with CKD stages 1-3 and severely increased urine albumin excretion, use ACE inhibitors or ARBs as first-line agents unless contraindicated. 1, 2

• ACE inhibitors and ARBs reduce kidney disease progression endpoints including rate of eGFR decline, 50% decline in eGFR, and incident kidney failure in patients with significant albuminuria. 1
• This recommendation applies specifically to patients with albuminuria; for CKD patients without albuminuria, any of the four first-line classes is appropriate. 2

Patients with Diabetes

For diabetic patients, ACE inhibitors or ARBs are preferred first-line agents, particularly when albuminuria is present (microalbuminuria or clinical nephropathy). 1, 2

• ACE inhibitors reduce both macrovascular and microvascular complications in diabetic patients. 1
• For type 1 diabetic patients with nephropathy, ACE inhibitors are first-line; for type 2 diabetic patients with nephropathy, both ACE inhibitors and ARBs are considered first-line therapy. 1
• All four first-line classes are effective for blood pressure reduction in diabetes, but ACE inhibitors/ARBs provide additional renoprotective benefits. 2

Patients with Coronary Artery Disease

For patients with established coronary artery disease, ACE inhibitors or ARBs are suggested as first-line agents. 2

Critical Safety Considerations

Combination Therapy Restrictions

Never combine ACE inhibitors with ARBs (or with renin inhibitors), as this increases risks of hyperkalemia, acute kidney injury, and hypotension without providing additional cardiovascular benefit. 1, 3, 4

• The VA NEPHRON-D trial demonstrated that combining losartan with lisinopril in diabetic patients with nephropathy resulted in increased hyperkalemia and acute kidney injury without additional benefit for renal or cardiovascular outcomes. 4
• This combination is designated as Class III: Harm with Level A evidence by ACC/AHA guidelines. 1
• Although ACE inhibitor + ARB combinations may reduce proteinuria, this benefit does not justify the increased risk when used solely for hypertension management. 1

Monitoring Requirements

When initiating ACE inhibitors or ARBs, monitor serum creatinine, eGFR, and potassium within 7-14 days and at least annually thereafter. 2, 3, 4

• Potassium-sparing diuretics (spironolactone, amiloride, triamterene) increase hyperkalemia risk when combined with ACE inhibitors or ARBs; monitor potassium frequently with these combinations. 3
• NSAIDs can attenuate the antihypertensive effect and worsen renal function when combined with ACE inhibitors or ARBs, particularly in elderly or volume-depleted patients. 3, 4

Practical Implementation Algorithm

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

• Start with a single first-line agent (thiazide diuretic, ACE inhibitor, ARB, or CCB) based on patient characteristics above. 1, 2
• In high-risk patients (CVD, CKD, diabetes, or organ damage), start drug therapy immediately. 1
• In low-moderate risk patients, attempt lifestyle interventions for 3-6 months before initiating pharmacotherapy. 1

For Stage 2 Hypertension or BP >20/10 mmHg above target:

• Initiate combination therapy with two first-line agents from different classes. 1, 2
• Preferred combinations: ACE inhibitor or ARB + CCB, ACE inhibitor or ARB + thiazide diuretic, or CCB + thiazide diuretic. 2
• Single-pill combinations improve adherence and should be strongly favored. 1

If BP remains uncontrolled on two agents:

• Add a third agent from a different class, preferably as a single-pill combination. 2
• Achieve target BP within 3 months of treatment initiation. 1

If BP remains uncontrolled on three agents:

• Add spironolactone (mineralocorticoid receptor antagonist) as fourth-line therapy. 1, 2
• If spironolactone is not tolerated or contraindicated, consider amiloride, doxazosin, eplerenone, clonidine, or β-blocker. 1

Common Pitfalls to Avoid

• Do not use ACE inhibitors as monotherapy in Black patients—they are less effective; use thiazide diuretics or CCBs instead. 2
• Do not underdose medications before adding additional agents—titrate to full dose before adding a second drug. 2
• Do not combine ACE inhibitors with ARBs—this increases harm without benefit. 1, 3, 4
• Do not overlook the need for aggressive initial therapy—patients with BP >20/10 mmHg above target require two-drug initial therapy. 1, 2
• Do not fail to monitor renal function and potassium—check within 7-14 days of starting ACE inhibitors or ARBs. 2, 3, 4