If drugs for erectile dysfunction cause cancer, would you want to know?

If this is one of those "ignorance is bliss" situations, read no further...

With that in mind, I present to you a study linking erectile dysfunction drugs to malignant melanoma.

For the video version of this post, click here.

The background here is that ED drugs work by inhibiting phosphodiesterase-5, and the down-regulation of that enzyme also occurs in some biochemical pathways that lead to melanoma, so we can put a check mark next to biologic plausibility. Human evidence of the link, prior to this week, involves a cohort study in the US which suggested that men taking sildenafil had a nearly two-fold increase in melanoma risk (but of the melanoma cases, only 14 had been taking sildenafil).

This week, appearing in the Journal of the American Medical Association we get the results of a Swedish study that examined over 5000 cases of melanoma in an effort to put this issue to bed.

The researchers used a preexisting cohort of around 600,000 Swedish men.  In that group, there were roughly 4000 cases of melanoma, which they matched (based on year of birth) to 20,000 controls.

In unadjusted analyses, the PDE-5 inhibitors were associated with about a 30% increase in melanoma. This persisted after adjusting for a smattering of confounders such as income and comorbidity scores, but the authors state that they believed their adjustments were incomplete. If the association were causal, it would mean an additional 7 cases of melanoma out of every 100,000 men taking ED drugs.

But despite the association, two major findings make the link hard to believe. First, the relationship between ED drugs and melanoma was only seen in those who had a one-time prescription for the drug. If the drugs were causal, we’d expect an increase in risk among those who got more prescriptions.  In addition, the researchers found a link between ED drug use and basal-cell carcinoma, a malignancy that doesn’t have a known PDE5 link.  This all suggests that men who take ED drugs might also engage in other behaviors that increase the risk of melanoma - like taking vacations in sunny places.

Just to make it clear that we’re not totally out of the woods here, I should note that this PDE5 pathway only appears to be relevant in the roughly 50% of melanoma cases that have a BRAF mutation - it’s conceivable that if the researchers could stratify by BRAF status, they may have found a link. For now, though, we can rest easy - data linking ED drugs and melanoma is simply not that firm.

The Risk of Venous Clots Differ Depending on Which Oral Contraceptive You Take

 

For the video version of this post, click here.

At any given time, there are around 11 million women in the US who are actively taking combined oral contraceptive pills. The first case-report describing a blood-clot in a woman taking the pill was published in 1961, and large epidemiologic studies have since confirmed that the pill increases clot risk, particularly in those who smoke or are above age 35.

But different formulations of oral contraceptives may affect clot risk differently. And here’s where the data gets more interesting. Progrestin-only pills don’t seem to increase clot risk very much, but combined estrogen / progestin pills do. So estrogen seems to be the culprit. Strangely, though, the clot risk seems to differ depending on which progesterone analogue is mixed with the estrogen.

Trying to quantify these risks is really hard.  Many women will use many formulations  over their lifetime, and may go on and off the pill sporadically.

So to study this, you need a really good database. Ideally, an electronic system that is tracking every prescription women get, and all the relevant outcomes. A study appearing in the British Medical Journal uses just that - two large, primary care databases to track the link between various pill formulations and venous thromboembolism.

This was a case-control study.  Identify the cases of VTE, match to controls who didn’t have VTE, and examine how the risk factors differ.

But the devil is in the details. The best way to mess up a case control study is to choose the wrong controls.  The strangest quirk of the BMJ study is that the controls had some different inclusion criteria than the cases.  Potential cases, identified at the time of VTE, were excluded if they had received anticoagulant therapy in the past 42 days.  The controls were excluded if they had EVER received anticoagulant therapy.  This choice would lead to higher-risk people being in the case group, and that could bias the final results.

What the final results showed is that more modern formulations of the pill, so-called 3rd and 4th generation OCPs, had higher risk of VTE than older formulations. Being on one of the older pills increased the risk of VTE by about 2.5 times.  Being on a newer pill upped that risk to around 4 - 5 fold.

Is this effect real? Maybe. It is possible that docs who prescribe newer generation OCPs are more vigilant about VTE symptoms, leading to increased diagnosis.  But regardless, it bears noting that the absolute risk here remains very small. Out of 10,000 women on an older generation pill, 7 will be diagnosed with a VTE compared to 14 on a newer generation pill.

A reasonable strategy may be to prescribe 2nd generation OCPs to women who are concerned about these risks.  Of course, for women who smoke or have significant VTE risk factors, another method of contraception may be easier to swallow.