What is the best antihypertensive medication for a patient with a history of multiple non-melanoma skin cancers and melanomas, considering the potential risk of skin cancer associated with certain antihypertensive agents, such as thiazides, indapamide (Indapamide), and chlorthalidone (Chlorthalidone)?

Antihypertensive Selection in Patients with History of Skin Cancer

Direct Recommendation

For patients with a history of multiple non-melanoma skin cancers and melanomas, avoid thiazide diuretics (including hydrochlorothiazide) and instead use ACE inhibitors, ARBs, or calcium channel blockers as first-line antihypertensive therapy. 1

Evidence Supporting Thiazide Avoidance

The most recent and highest-quality evidence demonstrates clear skin cancer risks with thiazides:

• A 2021 population-based cohort study of 302,634 adults found that increasing thiazide exposure was associated with significantly increased rates of keratinocyte carcinoma (adjusted HR 1.08 per Defined Annual Dose, 95% CI 1.03-1.14) and melanoma (adjusted HR 1.34,95% CI 1.01-1.78). 1

• This dose-response relationship is critical: higher cumulative thiazide exposure correlates with greater skin cancer risk, making these agents particularly problematic for long-term use in high-risk patients. 1

• The photosensitizing properties of thiazides likely explain this association through DNA damage induction in predisposed individuals. 2

Status of Indapamide and Chlorthalidone

Despite suggestions that indapamide and chlorthalidone might be safer alternatives, current evidence does not support this distinction:

• The 2021 Canadian study specifically evaluated thiazides as a class and found increased skin cancer risk, without evidence that indapamide or chlorthalidone are exempt from this class effect. 1

• The 2007 ESH/ESC guidelines group chlorthalidone and indapamide together with thiazide diuretics when discussing antihypertensive options, suggesting they share similar properties. 3

• No high-quality studies have demonstrated that indapamide or chlorthalidone carry lower skin cancer risk compared to hydrochlorothiazide. The absence of evidence for safety should not be interpreted as evidence of safety in patients with established skin cancer history.

Preferred Antihypertensive Classes

ACE inhibitors and ARBs are the safest choices:

• The 2021 study found no consistent evidence of association between ACE inhibitors, ARBs, or calcium channel blockers and keratinocyte carcinoma or melanoma. 1

• A 2018 meta-analysis confirmed no association between thiazide diuretics, ACE inhibitors, or ARBs and skin cancer risk. 4

• For patients with diabetes or albuminuria, ACE inhibitors or ARBs provide additional cardiovascular and renal protection beyond blood pressure control. 5

Calcium channel blockers require caution:

• While the 2021 study found no association with skin cancer for calcium channel blockers 1, a 2018 meta-analysis reported a modest increased risk (SRR 1.14,95% CI 1.07-1.21). 4

• If calcium channel blockers are used, select long-acting dihydropyridines like amlodipine, and counsel patients about skin self-examination. 4

Beta-blockers also require caution:

• A 2018 meta-analysis found beta-blocker use associated with increased melanoma risk (SRR 1.21,95% CI 1.05-1.40). 4

• Reserve beta-blockers for compelling indications such as post-MI, heart failure with reduced ejection fraction, or angina. 5

Clinical Algorithm for This Patient Population

1. First-line therapy: ACE inhibitor (e.g., lisinopril 10 mg daily or ramipril 2.5-5 mg daily) or ARB if ACE inhibitor not tolerated 5, 1

2. If additional agent needed: Add amlodipine 5-10 mg daily, with patient counseling about skin monitoring 6, 1

3. Avoid entirely: Hydrochlorothiazide, chlorthalidone, indapamide, and other thiazide-type diuretics 1

4. Use beta-blockers only for: Post-MI (minimum 3 years), heart failure with reduced ejection fraction, or angina 5

5. Monitor: Blood pressure every 1-2 weeks until target achieved; serum creatinine and potassium 7-14 days after ACE inhibitor/ARB initiation 5

Critical Counseling Points

Patients must understand:

• Their history of multiple skin cancers places them at substantially elevated risk for recurrence. 3

• Thiazide diuretics increase this risk further through photosensitization and should be avoided regardless of dose. 1

• Regular dermatologic surveillance remains essential regardless of antihypertensive choice. 4

• Sun protection measures (sunscreen, protective clothing, avoiding peak sun hours) are mandatory. 3

Common Pitfalls to Avoid

• Do not assume indapamide or chlorthalidone are safe alternatives to hydrochlorothiazide in patients with skin cancer history—no evidence supports this distinction. 1

• Do not use combination pills containing hydrochlorothiazide (e.g., lisinopril/HCTZ, losartan/HCTZ) even at low doses, as cumulative exposure drives risk. 1

• Do not prioritize blood pressure control over cancer risk in this population—effective alternatives exist that do not increase skin cancer risk. 1

• Do not forget to document the rationale for avoiding thiazides in the medical record to prevent future prescribers from inadvertently adding them. 1