Sildenafil, tadalafil and vardenafil belong to one drug class, the PDE5 inhibitors. People search for them with the same three questions: which one works best, whether a daily dose makes sense, and whether they are safe with heart medicine. The published trials answer some of these clearly and others only in part.
Sildenafil: the trial record
The best-known trial of oral sildenafil enrolled men with erectile dysfunction in a 12-week study in which the dose was raised up to 100 mg. In the last four weeks, 69% of sexual attempts succeeded with sildenafil, against 22% with placebo (P less than 0.001). Men averaged 5.9 successful attempts a month, against 1.5 on placebo. Headache, flushing and indigestion were the most common side effects, in 6% to 18% of men.
Tadalafil: as needed or every day
Tadalafil is used either as needed (10 or 20 mg in the trials) or as a daily low dose (2.5 or 5 mg). One open-label crossover trial compared them directly. Men who already responded to as-needed PDE5 treatment took tadalafil 5 mg once daily, or sildenafil as needed, for eight weeks. Daily tadalafil scored higher on the sexual self-confidence measure than as-needed sildenafil (difference 0.12, 95% CI 0.04 to 0.19, P = .001), and relationship scores did not differ. Against as-needed tadalafil there was no difference.
Vardenafil
Vardenafil works through the same pathway and is covered by the same rules on nitrates and riociguat. We have not placed its trial figures next to the others here, because the summaries we could check were pooled or sponsor-reported rather than full trial reports. Ask your physician which of the three fits your medicines and your history.
Nitrates and riociguat
Do not combine a PDE5 inhibitor with a nitrate in any form, including nitroglycerin spray, patches and tablets. The U.S. sildenafil label lists organic nitrates as a contraindication, because the combination potentiates the blood pressure drop, and it is unknown when nitrates can be given safely after a dose. Riociguat, used for pulmonary hypertension, is also contraindicated. UK guidance says not to use nitroglycerin spray within 24 hours of sildenafil or vardenafil, or within 48 hours of tadalafil.
Blood pressure and alpha-blockers
The U.S. sildenafil label does not contraindicate alpha-blockers. It asks that the man be stable on alpha-blocker therapy before starting, and that sildenafil begin at 25 mg. The label also describes men with left ventricular outflow obstruction, such as aortic stenosis, as more sensitive to the blood pressure drop.
Heart and mortality data
Kloner and colleagues used US claims data on 23,816 men with erectile dysfunction and cardiovascular risk factors who had at least one PDE5 inhibitor prescription, matched to 48,682 men who did not. Over a mean follow-up of 29 to 37 months, major adverse cardiovascular events were 13% lower (hazard ratio 0.87, 95% CI 0.79 to 0.95), all-cause mortality 25% lower (0.75, 0.65 to 0.87), and cardiovascular death 39% lower (0.61, 0.41 to 0.90).
This is a retrospective study. Exposure meant at least one pharmacy claim, not confirmed use. Men who fill these prescriptions may be healthier to begin with, and the study was funded by a grant from Sanofi. It supports overall cardiovascular safety in these men. It does not show that the medicines extend life.
What this does not say
- The trials used brand-name products. Our products are compounded or generic versions, and the trials did not test them.
- The trials cited here ran from 8 to 12 weeks. A randomized trial has not established long-term effects on heart outcomes.
- Men with heart disease still need the cardiac assessment set out in the Princeton consensus before sexual activity or treatment.
- Results are averages. They do not predict what one man will experience, and side effects vary.
How our physicians use these medicines
Before we prescribe, we check blood pressure, heart history and every medicine you take, including any nitrate. We ask about alpha-blockers and about recent chest symptoms. We choose between as-needed and daily use with you, and we tell you what each one can and cannot do.
The nitrate question comes first, every time.
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- 1.Sildenafil Study Group (Goldstein I et al.). Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338:1397-1404. The New England Journal of Medicine
- 2.Rubio-Aurioles E et al. A randomized open label trial with a crossover comparison of sexual self-confidence and other treatment outcomes following tadalafil once a day vs tadalafil or sildenafil on demand in men with erectile dysfunction. J Sex Med. 2012;9:1418-1429. The Journal of Sexual Medicine
- 3.Kloner RA et al. Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors. J Sex Med. 2023;20(1):38-48. The Journal of Sexual Medicine
- 4.VIAGRA (sildenafil citrate) prescribing information. Pfizer. Pfizer Labeling
- 5.Nitrates and phosphodiesterase inhibitors: UK drug interaction guidance. GPnotebook
- 6.Nehra A et al. The Princeton III consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012;87(8):766-778. Mayo Clinic Proceedings