What are the current guidelines for evaluating and treating erectile dysfunction, including first‑line PDE5 inhibitor therapy, contraindications, and second‑line options?

Erectile Dysfunction Treatment Guidelines

First-Line Therapy: PDE5 Inhibitors

Oral PDE5 inhibitors (sildenafil, tadalafil, vardenafil, or avanafil) should be offered as first-line therapy for erectile dysfunction unless contraindicated. 1

All FDA-approved PDE5 inhibitors demonstrate similar efficacy, with 73-88% of patients reporting improved erections compared to 26-32% with placebo, and approximately 69% achieving successful intercourse attempts versus 33% with placebo. 2, 3 No single agent has been proven superior to others in head-to-head trials. 1, 2

Choosing Between PDE5 Inhibitors

Select tadalafil when:

• The patient values sexual spontaneity and prefers not to time medication with sexual activity (36-hour duration of action) 3, 4
• Coexisting benign prostatic hyperplasia is present (tadalafil 5 mg daily treats both conditions simultaneously) 3
• The patient prefers once-daily dosing to eliminate timing concerns entirely (2.5-5 mg daily) 3

Select sildenafil when:

• The patient prefers scheduled sexual activity with a more predictable window of action 4
• There is concern about potential need for emergency nitrates (shorter 24-hour waiting period versus 48 hours for tadalafil) 1

Select avanafil when:

• Rapid onset is prioritized (efficacy within 15 minutes in 64-71% of patients) 5
• Minimizing dyspepsia is important (lowest rates among PDE5 inhibitors) 5

Select vardenafil when:

• Intermediate duration of action is desired with dose-dependent efficacy 3

Critical Safety Screening Before Prescribing

Absolute Contraindications

PDE5 inhibitors are absolutely contraindicated with any form of nitrate use due to risk of potentially fatal hypotension. 1, 3 Explicitly ask about:

• Sublingual nitroglycerin
• Long-acting nitrates
• Recreational "poppers" (amyl nitrite)
• Riociguat (soluble guanylate cyclase stimulator) 3

Cardiovascular Risk Stratification

Assign patients to risk categories based on the Princeton Consensus Panel criteria: 1

High-risk patients (defer ED treatment until cardiac condition stabilized):

• Unstable or refractory angina
• Uncontrolled hypertension
• Left ventricular dysfunction/CHF (NYHA class ≥II)
• MI or stroke within previous 2 weeks
• High-risk arrhythmias
• Hypertrophic obstructive cardiomyopathy
• Moderate-to-severe valvular disease 1

Low-risk patients (safe for PDE5 inhibitors):

• Asymptomatic coronary artery disease with <3 risk factors
• Controlled hypertension
• Mild, stable angina
• Successful coronary revascularization
• Uncomplicated past MI
• Mild valvular disease
• CHF (NYHA class I) 1

Assess functional capacity: Ask if the patient can walk 1 mile in 20 minutes or climb 2 flights of stairs in 20 seconds without symptoms. 5, 3 If unable, refer to cardiology before prescribing. 5, 3

Indeterminate-risk patients: Refer to cardiology for evaluation before initiating ED therapy. 1

Defining an Adequate Trial

Before declaring treatment failure, patients must complete at least 5 separate attempts at the maximum tolerated dose with proper technique. 3 This converts up to 30% of apparent non-responders into successful responders. 3

Requirements for an adequate trial:

• Minimum 5 attempts at current dose 3
• Adequate sexual stimulation (PDE5 inhibitors require arousal to work) 5, 3
• Proper timing (avoid large or fatty meals that reduce efficacy) 3
• Limited alcohol consumption (heavy use impairs erectile function independently) 3
• Realistic expectations (medication enhances but does not replace natural arousal) 3

Addressing Modifiable Factors Before Dose Escalation

Systematically evaluate these factors before increasing dose or switching agents: 3

1. Hormonal abnormalities: Check total testosterone, free testosterone, and SHBG. Men with testosterone deficiency respond less robustly to PDE5 inhibitors alone. 5, 3 Combining testosterone therapy with PDE5 inhibitors is more effective than either alone in hypogonadal men. 5, 3

2. Concomitant medications: Identify drugs that worsen ED (antihypertensives, antidepressants, opioids, hormone therapy) and CYP3A inhibitors that interact with PDE5 inhibitors. 3

3. Psychological factors: Screen for depression, anxiety, and relationship conflict—these significantly impact treatment response. 3

4. Lifestyle factors: Address heavy alcohol use, smoking, obesity, and sedentary lifestyle. 1, 3

5. Proper technique: Verify adequate sexual stimulation, correct timing relative to meals, and appropriate expectations. 3

Dose Titration Strategy

For patients tolerating medication well but with suboptimal erectile function, increase to maximum dose after completing an adequate trial at the current dose. 3

Dose-response considerations:

• Sildenafil and vardenafil: Show dose-dependent efficacy improvement 3
• Tadalafil: Does NOT show dose-dependent improvement between 5 mg, 10 mg, and 20 mg; choose based on tolerability rather than expecting dramatically better efficacy at higher doses 3

Higher doses increase adverse events (headache, dyspepsia, back pain, myalgia, flushing) in a dose-dependent manner. 3

Special Population Considerations

Patients with diabetes or post-prostatectomy have more severe ED at baseline and respond less robustly to PDE5 inhibitors. 5, 3 Dose escalation to maximum is particularly appropriate in these groups when initial doses are well-tolerated. 3

Patients with mild-to-moderate hepatic or renal impairment: Use caution with lower initial doses. 5

Patients with severe hepatic impairment: PDE5 inhibitors are generally not recommended. 3

Switching to Another PDE5 Inhibitor

Switch to a different PDE5 inhibitor only after:

• Completing maximum-dose regimen for at least 5 attempts 3
• All modifiable factors have been addressed 3
• Testosterone supplementation evaluated when levels are low 3

Individual response variability justifies switching agents, as some men who fail one PDE5 inhibitor achieve success with another. 3

Second-Line Therapies

Proceed to second-line therapies only after failure of at least two different PDE5 inhibitors at maximum dose with proper technique and after addressing all modifiable factors. 3

Second-line options (in order of invasiveness):

1. Vacuum erection devices: Mechanical solution with no systemic side effects 1, 3

2. Intraurethral alprostadil suppositories: Less effective than injections but less invasive; first administration should be supervised due to ~3% risk of syncope 3

3. Intracavernosal injection therapy (alprostadil, papaverine, phentolamine): Most effective non-surgical option but highest risk of priapism 1, 3

4. Penile prosthesis implantation: Definitive surgical solution for refractory cases 1, 3

Emergency Nitrate Protocol

If a patient on PDE5 inhibitors requires emergency nitrate administration:

• Wait 24 hours after sildenafil or vardenafil 1
• Wait 48 hours after tadalafil 1
• Administer only under close medical supervision with continuous patient monitoring 1

Ongoing Management

Periodic follow-up should assess: 3

• Efficacy and side effects
• Cardiovascular health changes
• New medications (especially nitrates)
• Treatment effectiveness
• Relationship issues

Common pitfalls to avoid:

• Declaring treatment failure without completing an adequate trial (at least 5 attempts at maximum dose) 3
• Failing to verify adequate sexual stimulation is occurring 3
• Not addressing heavy alcohol use before dose escalation 3
• Missing hormonal abnormalities (particularly testosterone deficiency) 3
• Ignoring psychological or relationship factors 3
• Taking medication with large or fatty meals 3