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Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants
JOURNAL OF VASCULAR SURGERY Volume 62, Number 4
Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants Han H, Hutter CM, Lin Y, et al. JAMA 2015;313:1133-42. Conclusions: Regular aspirin and/or NSAID use is associated with a lower risk of colorectal cancer and is tied to specific genetic variants. Summary: There is data that suggests that the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of colorectal neoplasms. (Chan AT, JAMA 2005; 294:914-923 and Friis S et al, Cancer Causes Control 2009; 20:731-740 and Rothwell PM et al, Lancet 2010; 376:1741-1750) Since virtually all vascular surgical patients are treated with aspirin or other antiplatelet agents with potential anti-inflammatory actions, the association of decreased colorectal cancer risks in such patients is of potential interest to those treating vascular surgical patients. The mechanisms, however, behind the association are not well understood. Chemo prevention of cancer is not currently recommended because of the uncertainty of risk benefit profile. The authors sought to identify genetic markers that characterize individuals who may obtain differential benefit from aspirin and NSAIDs. They conducted a discover-based, genome-wide analysis of gene X environment interactions between use of aspirin, NSAIDs or both and single nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. This was a case controlled study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia and Germany including colorectal cancer cases (N ¼ 8634) and matched controls (N ¼ 8553), ascertained between 1976 and 2011. All participants were of European descent. Overall regular use of aspirin and/or NSAIDs was associated with a lower risk of colorectal cancer (prevalence, 28% vs 38%; odd ratio [OR], 0.69 [95% CI, 0.64-0.74]; P ¼ 6.2 x 1028) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P ¼ 4.6 x 109 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with re2965667-TT genotype (prevalence, 28% vs 38% OR, 0.66 [95% CI, 0.61-0.70]; P ¼ 7.7 x 1033) but with a higher rate risk among those with rare TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P ¼ .002). In case-only interaction analysis, the SNP re 16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P ¼ 8.2 x 109 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P¼1.9 x 1030) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P ¼ .76). Comment: The study is intriguing for a couple of reasons. First of all, most vascular surgical patients are treated with aspirin, by doing so we may lower the risk colorectal cancer in many of our patients. In addition, the offtarget effect of aspirin in terms of beneficial effects on colorectal cancer can be attributed to genetic variation at two highly correlated SNPs at specific chromosomes. Perhaps off target and even on target effects of other drugs such as statins will eventually be able to be correlated with specific genetic makers. Ultimately everything tends to boil down to biochemistry and genes. Identification of specific and active approaches to utilization of
Abstracts 1091
medications may eventually result in a more efficient use of current medications and development of more targeted and specific future medications. In the meantime our patients have another reason to take their aspirin every day. Pharmacotherapy for Neuropathic Pain in Adults: A Systematic Review and Meta-Analysis Finnerup NB, Attal N, Haroutounian S, et al. Lancet Neurol 2015;14: 162-73. Conclusions: Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Summary: There are guidelines for pharmacotherapy for neuropathic pain. The Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain guidelines are based on results of a systemic review and meta-analysis. However, given new drug treatments and clinical trials and standards of quality for assessment of evidence, the authors’ of this paper felt that an update of evidence based recommendations for pharmacologic treatment of neuropathic pain was needed. Between April 2013 and January 2014, NeuPSIG did a systemic review and meta-analysis of randomized, double blind studies of oral and topical pharmacal therapy for neuropathic pain. This included studies published in peer reviewed journals since January 1966 and unpublished trials retrieved from clinicaltrials.gov and web sites of pharmaceutical companies. They used a number needed to treat (NNT) analysis for 50% pain relief as the primary measure of the efficacy and also assessed publication bias. NNT was calculated with the fixed-effects Mantel-Haenszel method. There were 229 studies included in the meta-analysis. Analysis of publication bias suggests a 10% over statement of treatment effects. Studies published in peerreviewed journals reported greater effects than the unpublished studies (r2 .93%, P ¼ .009). Combined NNTs were 6.4 (95% CI 5.2-8.4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (914 studies): 7.7 (6.5-9.4), for pre-gabalin: 7.2 (5.9-9.21), for gabapentin, including gabapentin extended release and enacarbil 10.6 (7.8-9.19.0). NNTs were lower for tricyclic antidepressants, strong opioids, Tramadol, and Botulinum toxin and undetermined for Lidocaine patches. Based on the GRADE final assessment of evidence was moderate or high for all treatments, apart from Lidocaine patches; tolerability and safety were higher for topical drugs; and cost was lower for tricyclic antidepressants and Tramadol. Comment: The findings suggest strong recommendations for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, Pregabalin, and Gabapentin as first line treatments for neuropathic pain. Weak recommendations are for use of lidocaine patches, Capsaicin high concentration patches and Tramadol. Second line treatments would be strong opioids and Botulinum toxin A. Botulinum toxin A and topical agents should only be recommended for peripheral neuropathic pain. Overall, the results of the meta-analysis suggest a revision of the NeuPSIG recommendations for the pharmacol therapy of neuropathic pain with downgrading of strong opioids to a third line treatment whereas previously they had been considered first or second line treatment. The article provides an excellent overview of the issues involved with the treatment of neuropathic pain; a common and complicated condition in patients with peripheral vascular disease.
Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants Han H, Hutter CM, Lin Y, et al. JAMA 2015;313:1133-42. Conclusions: Regular aspirin and/or NSAID use is associated with a lower risk of colorectal cancer and is tied to specific genetic variants. Summary: There is data that suggests that the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a lower risk of colorectal neoplasms. (Chan AT, JAMA 2005; 294:914-923 and Friis S et al, Cancer Causes Control 2009; 20:731-740 and Rothwell PM et al, Lancet 2010; 376:1741-1750) Since virtually all vascular surgical patients are treated with aspirin or other antiplatelet agents with potential anti-inflammatory actions, the association of decreased colorectal cancer risks in such patients is of potential interest to those treating vascular surgical patients. The mechanisms, however, behind the association are not well understood. Chemo prevention of cancer is not currently recommended because of the uncertainty of risk benefit profile. The authors sought to identify genetic markers that characterize individuals who may obtain differential benefit from aspirin and NSAIDs. They conducted a discover-based, genome-wide analysis of gene X environment interactions between use of aspirin, NSAIDs or both and single nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. This was a case controlled study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia and Germany including colorectal cancer cases (N ¼ 8634) and matched controls (N ¼ 8553), ascertained between 1976 and 2011. All participants were of European descent. Overall regular use of aspirin and/or NSAIDs was associated with a lower risk of colorectal cancer (prevalence, 28% vs 38%; odd ratio [OR], 0.69 [95% CI, 0.64-0.74]; P ¼ 6.2 x 1028) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P ¼ 4.6 x 109 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with re2965667-TT genotype (prevalence, 28% vs 38% OR, 0.66 [95% CI, 0.61-0.70]; P ¼ 7.7 x 1033) but with a higher rate risk among those with rare TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P ¼ .002). In case-only interaction analysis, the SNP re 16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P ¼ 8.2 x 109 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P¼1.9 x 1030) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P ¼ .76). Comment: The study is intriguing for a couple of reasons. First of all, most vascular surgical patients are treated with aspirin, by doing so we may lower the risk colorectal cancer in many of our patients. In addition, the offtarget effect of aspirin in terms of beneficial effects on colorectal cancer can be attributed to genetic variation at two highly correlated SNPs at specific chromosomes. Perhaps off target and even on target effects of other drugs such as statins will eventually be able to be correlated with specific genetic makers. Ultimately everything tends to boil down to biochemistry and genes. Identification of specific and active approaches to utilization of
Abstracts 1091
medications may eventually result in a more efficient use of current medications and development of more targeted and specific future medications. In the meantime our patients have another reason to take their aspirin every day. Pharmacotherapy for Neuropathic Pain in Adults: A Systematic Review and Meta-Analysis Finnerup NB, Attal N, Haroutounian S, et al. Lancet Neurol 2015;14: 162-73. Conclusions: Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Summary: There are guidelines for pharmacotherapy for neuropathic pain. The Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain guidelines are based on results of a systemic review and meta-analysis. However, given new drug treatments and clinical trials and standards of quality for assessment of evidence, the authors’ of this paper felt that an update of evidence based recommendations for pharmacologic treatment of neuropathic pain was needed. Between April 2013 and January 2014, NeuPSIG did a systemic review and meta-analysis of randomized, double blind studies of oral and topical pharmacal therapy for neuropathic pain. This included studies published in peer reviewed journals since January 1966 and unpublished trials retrieved from clinicaltrials.gov and web sites of pharmaceutical companies. They used a number needed to treat (NNT) analysis for 50% pain relief as the primary measure of the efficacy and also assessed publication bias. NNT was calculated with the fixed-effects Mantel-Haenszel method. There were 229 studies included in the meta-analysis. Analysis of publication bias suggests a 10% over statement of treatment effects. Studies published in peerreviewed journals reported greater effects than the unpublished studies (r2 .93%, P ¼ .009). Combined NNTs were 6.4 (95% CI 5.2-8.4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (914 studies): 7.7 (6.5-9.4), for pre-gabalin: 7.2 (5.9-9.21), for gabapentin, including gabapentin extended release and enacarbil 10.6 (7.8-9.19.0). NNTs were lower for tricyclic antidepressants, strong opioids, Tramadol, and Botulinum toxin and undetermined for Lidocaine patches. Based on the GRADE final assessment of evidence was moderate or high for all treatments, apart from Lidocaine patches; tolerability and safety were higher for topical drugs; and cost was lower for tricyclic antidepressants and Tramadol. Comment: The findings suggest strong recommendations for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, Pregabalin, and Gabapentin as first line treatments for neuropathic pain. Weak recommendations are for use of lidocaine patches, Capsaicin high concentration patches and Tramadol. Second line treatments would be strong opioids and Botulinum toxin A. Botulinum toxin A and topical agents should only be recommended for peripheral neuropathic pain. Overall, the results of the meta-analysis suggest a revision of the NeuPSIG recommendations for the pharmacol therapy of neuropathic pain with downgrading of strong opioids to a third line treatment whereas previously they had been considered first or second line treatment. The article provides an excellent overview of the issues involved with the treatment of neuropathic pain; a common and complicated condition in patients with peripheral vascular disease.