In a hypertensive man with new‑onset erectile dysfunction (blood pressure <180/110 mm Hg, not taking nitrates), how do sildenafil, tadalafil, vardenafil, and avanafil compare regarding safety, efficacy, onset of action, duration, dosing options, side‑effect profile, and cost?

Comparison of PDE5 Inhibitors for Erectile Dysfunction in Hypertensive Men

Direct Recommendation

For a hypertensive man with new-onset ED (BP <180/110, not on nitrates), sildenafil 50mg should be the first-line treatment due to its superior efficacy profile, while tadalafil 10mg represents the best alternative for men prioritizing tolerability and longer duration of action. 1, 2

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Efficacy Comparison

Sildenafil demonstrates the highest overall efficacy among PDE5 inhibitors:

• Sildenafil 50mg has a 98% probability of being the most effective treatment based on network meta-analysis of 179 randomized trials involving 50,620 patients, with sildenafil 25mg showing statistically superior IIEF improvements over all other interventions 1
• Tadalafil 10mg and 20mg show good efficacy profiles with 73% and 76% probability of effectiveness, respectively 1
• Vardenafil 10mg demonstrates intermediate efficacy but markedly lower global efficacy compared to sildenafil 50mg 2
• Avanafil shows the least impressive efficacy among the four agents, with its use "hardly justified given the lack of expressive efficacy" 1

In hypertensive patients specifically, vardenafil increases IIEF-EF scores by 8.9 points over placebo (95% CI: 7.4-10.5), with equal efficacy in those with and without hypertension 3

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Onset and Duration of Action

Critical timing differences exist that impact clinical use:

• Sildenafil and vardenafil: onset 30-120 minutes, duration approximately 4 hours 4
• Tadalafil: onset 30-120 minutes, duration up to 36 hours 4, 5
• Avanafil: similar onset profile to other agents (specific data limited in provided evidence)

The longer duration of tadalafil (36 hours vs 4 hours) makes it preferred by many men in comparison studies, likely due to greater spontaneity in sexual activity 5

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Safety Profile and Cardiovascular Considerations

All PDE5 inhibitors are safe in hypertensive patients with controlled BP, but critical contraindications exist:

Absolute Contraindications with Nitrates:

• Sildenafil and vardenafil: wait at least 24 hours after last dose before ANY nitrate administration 6, 7
• Tadalafil: wait at least 48 hours after last dose before ANY nitrate administration due to its 17.5-hour half-life 7, 8
• This combination causes life-threatening hypotension, myocardial infarction, and death—classified as ACC/AHA Class III (Harm), meaning it should NEVER be performed 7, 6

General Safety:

• Overall safety is good even in patients with cardiovascular disease history, with postmarketing surveillance showing no new cardiovascular concerns 9
• PDE5 inhibitors may actually benefit hypertension and endothelial dysfunction in at-risk patients 9

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Side Effect Profile

Distinct adverse event patterns differentiate the agents:

• Mirodenafil 150mg causes the most adverse events overall, especially flushing and headaches 1
• Sildenafil 100mg: highest rate of visual disorders (due to PDE6 inhibition causing color perception changes) 5, 1
• Vardenafil: most prone to nasal congestion, longest QTc interval prolongation 4, 1
• Tadalafil: shortest QTc prolongation, lowest overall adverse event rate 4, 2
• Common side effects across all agents: headache, facial flushing, nasal congestion, dyspepsia 4

In the trade-off analysis, sildenafil 50mg has the highest overall adverse event rate despite superior efficacy, while tadalafil 10mg has the lowest overall adverse event rate with intermediate efficacy 2

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Dosing Options and Food Interactions

Practical dosing considerations:

• Sildenafil: 25mg, 50mg, 100mg; shows interaction with food intake 4, 1
• Tadalafil: 10mg, 20mg; minimal food interaction 4
• Vardenafil: 10mg standard dose; shows interaction with food intake 4, 3
• Avanafil: 100mg standard dose 2

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Drug Interactions

Important metabolic considerations:

• All PDE5 inhibitors may interact with medications metabolized similarly, including erythromycin and HIV protease inhibitors 4
• No mandatory waiting period required when switching between different PDE5 inhibitors 7

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Clinical Algorithm for Selection

Follow this decision pathway:

1. First-line: Sildenafil 50mg for maximum efficacy in most patients 1, 2

2. Switch to tadalafil 10mg if:

   • Patient prioritizes tolerability over maximum efficacy 2
   • Patient desires longer duration for spontaneity (36 hours vs 4 hours) 5
   • Patient experiences visual disturbances with sildenafil 5, 1

3. Consider vardenafil 10mg if:

   • Both sildenafil and tadalafil have failed or are not tolerated 3
   • Patient has no concerns about nasal congestion 1

4. Avoid avanafil as first-line due to lack of compelling efficacy advantage 1

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Critical Pitfalls to Avoid

Never assume topical nitrates are safer—nitroglycerin patches and ointments carry the same absolute contraindication as all other nitrate formulations 7, 6

Always ask about PDE5 inhibitor use before administering nitroglycerin to any patient presenting with chest pain 6

Document which specific PDE5 inhibitor was prescribed and educate patients about the 24-hour (sildenafil/vardenafil) or 48-hour (tadalafil) nitrate-free window 7, 6

If nitrates are contraindicated due to recent PDE5 inhibitor use, use beta-blockers as first-line anti-ischemic therapy, with non-dihydropyridine calcium channel blockers for recurrent ischemia 7, 6

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Cost Considerations

While specific cost data is not provided in the evidence, sildenafil is available as a generic medication and typically represents the most cost-effective option, which supports its position as first-line therapy (general medical knowledge)