On 2017 Aug 22, Anton Pottegård commented:

On the misleading conclusion reached by Wang et al. regarding use of phosphodiesterase 5 inhibitors and risk of melanoma

Recently, Wang et al. published their findings from a meta-analysis on the putative association between use of phosphodiesterase 5 inhibitors (PDE5i) and risk of melanoma (Wang J, 2017). With this letter, we, the authors of four of the main studies on which their meta-analysis was founded, would like to express our serious concerns as to the conclusions reached by Wang et al.

The initial report on the potential for an association between use of the PDE5i sildenafil and an increased risk of melanoma was published by Li et al. in JAMA Internal Medicine in 2014 (Li WQ, 2014). A large proportion of melanomas contain mutations that lead to suppression of phosphodiesterase enzyme 5A (Gray-Schopfer V, 2007), which again leads to melanoma cell invasion (Arozarena I, 2011). As PDE5is infer a direct pharmacological inhibition of the same enzyme, the hypothesis that use of PDE5i would infer an increased risk of melanoma is biologically plausible.

Four different teams subsequently tried to replicate these findings. In a case-control study using nationwide Swedish health registries, Loeb et al. reported a modest increased risk among PDE5i users (adjusted odds ratio (OR) 1.21, 95% confidence interval (CI) 1.08-1.36) (Loeb S, 2015). However, they clearly pointed out that the association was unlikely to be causal, because there was a lack of dose-response in the observed association (i.e. no increase in risk with greater exposure). Further, the strongest association was observed with early stage melanoma, which lacks biological gradient. Lastly, the authors also observed PDE5i users to have an increased risk of basal cell carcinoma, which was a negative control outcome with no hypothesized association with PDE5i use. This last observation suggested possible confounding by UV exposure, which is the key risk factor for both BCC and melanoma.

The next three studies were published in close succession. Two cohort studies based on data from the UK Clinical Practice Research Datalink (CPRD) found weak evidence of a small increased risk of melanoma among those prescribed a PDE5i (Lian et al (Lian Y, 2016): hazard ratio (HR) 1.18, 95%CI 0.95-1.47); Matthews et al. (Matthews A, 2016): HR 1.14, 95%CI 1.01-1.29). In the study by Lian et al. (Lian Y, 2016), associations were also observed with basal cell and squamous cell carcinoma with respect to certain prescription and pill categories, thereby arguing against a causal association due to lack of specificity. Matthews et al. (Matthews A, 2016) again found no gradient in the association, and observed an association with UV-related negative control outcomes including basal cell carcinoma. They also reported an association between previous solar keratosis and later use of phosphodiesterase inhibitors, strongly suggesting confounding due to PDE5i users having more sun exposure. Lastly, in July 2016, Pottegård et al. (Pottegård A, 2016) published the results of two case-control studies, finding weak evidence of a small positive association in Denmark (OR 1.22, 95%CI 0.99-1.49), and no evidence of an association in the US (OR 0.95, 95%CI 0.78-1.14). Again, no dose-response pattern was found, and as in the analysis by Loeb et al., the highest estimates were obtained for early stage disease.

In summary, all four papers reported a slightly increased risk of malignant melanoma among PDE5i users. Critically, however, all the studies included analyses that probed Hill's criteria for causality (Hill AB, 2015), and the findings of all four studies suggested the association was unlikely to be causal. In summarizing the evidence from these papers, the systematic review by Wang et al. focuses heavily on the single point estimate obtained in their meta-analysis, disregarding the supplementary analyses and the conclusions regarding causality within the individual papers. For this reason, we believe that the conclusions reached by Wang et al. are misleading.

Importantly, Loeb et al. have recently performed a similar meta-analysis to that of Wang et al., arriving at an almost identical point estimate, but with a considerably more informed interpretation (https://doi.org/10.1093/jnci/djx086). While acknowledging the weak positive association between PDE5i use and malignant melanoma, they conclude that the association is unlikely to be causal. Having authored the individual papers, we collectively support this conclusion.

Anton Pottegård (1); Krishnan Bhaskaran (2); Anthony Matthews (2); Laurent Azoulay (3); Pär Stattin (4); Laurel A Habel (5); and Stacy Loeb (6)

(1) Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark (2) Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (3) Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada (4) Department of Surgical Sciences, Uppsala University, Uppsala, Sweden (5) Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA (6) Department of Urology and Population Health, New York University, NY, NY, USA

On 2017 Aug 22, Anton Pottegård commented:

On the misleading conclusion reached by Wang et al. regarding use of phosphodiesterase 5 inhibitors and risk of melanoma

Recently, Wang et al. published their findings from a meta-analysis on the putative association between use of phosphodiesterase 5 inhibitors (PDE5i) and risk of melanoma (Wang J, 2017). With this letter, we, the authors of four of the main studies on which their meta-analysis was founded, would like to express our serious concerns as to the conclusions reached by Wang et al.

The initial report on the potential for an association between use of the PDE5i sildenafil and an increased risk of melanoma was published by Li et al. in JAMA Internal Medicine in 2014 (Li WQ, 2014). A large proportion of melanomas contain mutations that lead to suppression of phosphodiesterase enzyme 5A (Gray-Schopfer V, 2007), which again leads to melanoma cell invasion (Arozarena I, 2011). As PDE5is infer a direct pharmacological inhibition of the same enzyme, the hypothesis that use of PDE5i would infer an increased risk of melanoma is biologically plausible.

Four different teams subsequently tried to replicate these findings. In a case-control study using nationwide Swedish health registries, Loeb et al. reported a modest increased risk among PDE5i users (adjusted odds ratio (OR) 1.21, 95% confidence interval (CI) 1.08-1.36) (Loeb S, 2015). However, they clearly pointed out that the association was unlikely to be causal, because there was a lack of dose-response in the observed association (i.e. no increase in risk with greater exposure). Further, the strongest association was observed with early stage melanoma, which lacks biological gradient. Lastly, the authors also observed PDE5i users to have an increased risk of basal cell carcinoma, which was a negative control outcome with no hypothesized association with PDE5i use. This last observation suggested possible confounding by UV exposure, which is the key risk factor for both BCC and melanoma.

The next three studies were published in close succession. Two cohort studies based on data from the UK Clinical Practice Research Datalink (CPRD) found weak evidence of a small increased risk of melanoma among those prescribed a PDE5i (Lian et al (Lian Y, 2016): hazard ratio (HR) 1.18, 95%CI 0.95-1.47); Matthews et al. (Matthews A, 2016): HR 1.14, 95%CI 1.01-1.29). In the study by Lian et al. (Lian Y, 2016), associations were also observed with basal cell and squamous cell carcinoma with respect to certain prescription and pill categories, thereby arguing against a causal association due to lack of specificity. Matthews et al. (Matthews A, 2016) again found no gradient in the association, and observed an association with UV-related negative control outcomes including basal cell carcinoma. They also reported an association between previous solar keratosis and later use of phosphodiesterase inhibitors, strongly suggesting confounding due to PDE5i users having more sun exposure. Lastly, in July 2016, Pottegård et al. (Pottegård A, 2016) published the results of two case-control studies, finding weak evidence of a small positive association in Denmark (OR 1.22, 95%CI 0.99-1.49), and no evidence of an association in the US (OR 0.95, 95%CI 0.78-1.14). Again, no dose-response pattern was found, and as in the analysis by Loeb et al., the highest estimates were obtained for early stage disease.

In summary, all four papers reported a slightly increased risk of malignant melanoma among PDE5i users. Critically, however, all the studies included analyses that probed Hill's criteria for causality (Hill AB, 2015), and the findings of all four studies suggested the association was unlikely to be causal. In summarizing the evidence from these papers, the systematic review by Wang et al. focuses heavily on the single point estimate obtained in their meta-analysis, disregarding the supplementary analyses and the conclusions regarding causality within the individual papers. For this reason, we believe that the conclusions reached by Wang et al. are misleading.

Importantly, Loeb et al. have recently performed a similar meta-analysis to that of Wang et al., arriving at an almost identical point estimate, but with a considerably more informed interpretation (https://doi.org/10.1093/jnci/djx086). While acknowledging the weak positive association between PDE5i use and malignant melanoma, they conclude that the association is unlikely to be causal. Having authored the individual papers, we collectively support this conclusion.

Anton Pottegård (1); Krishnan Bhaskaran (2); Anthony Matthews (2); Laurent Azoulay (3); Pär Stattin (4); Laurel A Habel (5); and Stacy Loeb (6)

(1) Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark (2) Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (3) Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada (4) Department of Surgical Sciences, Uppsala University, Uppsala, Sweden (5) Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA (6) Department of Urology and Population Health, New York University, NY, NY, USA