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Update on resveratrol
• Found abundantly in nature, this polyphenolic phytoalexin is believed to exhibit a wide range of biologic activity.
• Potent antioxidant, anti-inflammatory, and antiproliferative properties.
• Highly studied polyphenolic substance also considered a chemopreventive agent against skin cancer.
• In small studies, has contributed to antiaging, antiacne, antierythema, and skin-lightening results.
Resveratrol (trans-3,5,4’-trihydroxystilbene), a polyphenolic phytoalexin synthesized in nearly 70 plant species, is found to be particularly abundant in Vitis vinifera (grape vine) and its derivatives (e.g., red wine, purple grape juice), various berries, peanuts, jackfruit, pomegranate, eucalyptus, the roots of Polygonum cuspidatum (Japanese knotweed, which is used in traditional Chinese and Japanese medicine to treat dermatitis, among other conditions)1, Scots pine, spruce, corn lily, gnetum, and butterfly orchid.2-6 Several studies have demonstrated that resveratrol possesses potent antioxidant, anticarcinogenic, anti-inflammatory, as well as antimicrobial characteristics.7-11 Specifically, in vitro and in vivo studies have shown that resveratrol exerts chemopreventive and antiproliferative activity against various cancers, including skin cancer, by suppressing cellular events associated with tumor initiation, promotion, and progression, and triggering apoptosis in such tumor cells.12-14 It also is reputed to impart antiaging benefits.15 This column will focus on recent research findings pertaining to effects on the skin as well as topical uses of this botanical agent, the main source of which, V. vinifera, has been used since antiquity.
Resveratrol was first identified from the roots of Veratrum grandiflorum (white hellebore) in 1940,16-19 but research on the compound did not take root until after a 1997 report in Science suggested chemopreventive properties. In that study, purified resveratrol was found to exhibit major inhibitory activity against cancer initiation, promotion, and progression.20 Since then, copious research on this botanical compound has yielded a reputation as a strong antioxidant, anti-inflammatory, and antiproliferative agent.7,21,22 Most importantly, resveratrol is considered to act as a chemopreventive agent against skin cancer and antiproliferative influence on oral squamous, breast, colon, and prostate cancer cells.12,14 It is also one of the most studied polyphenolic compounds.
Skin cancer and photoprotection
In 2012, Osmond et al. conducted in vitro and in vivo experiments to assess the potential of resveratrol as a chemotherapy adjunct for melanoma treatment. Resveratrol significantly reduced melanoma cell viability in both melanoma cell lines tested, and selectively spared cells in the nonmalignant fibroblast lines, compared with its cytotoxic impact on melanoma cells. Further, cytotoxicity to malignant cells was greatly enhanced by 72 hours of treatment with resveratrol and temozolomide, compared with temozolomide treatment alone. No significant differences were seen in vivo. The researchers concluded that the in vitro antitumor activity of resveratrol suggested its potential as a therapeutic agent in melanoma management.23
Resveratrol has been shown to protect against UVB-mediated cutaneous damage in SKH-1 hairless mice. Afaq et al. demonstrated that UVB-induced skin edema was significantly suppressed by the topical application of resveratrol to SKH-1 hairless mice.7
In a different study by the same team, topically applied resveratrol significantly inhibited UVB-mediated increases in bifold skin thickness and edema and greatly diminished UVB-induced lipid peroxidation, cyclo-oxygenase and ornithine decarboxylase (ODC) activities, as well as protein expression of the ODC enzyme in SKH-1 hairless mice.24 In an experiment by some of the same researchers, resveratrol was topically applied to SKH-1 hairless mice 30 minutes before exposure to UVB; 24 hours later, significant decreases were observed in bifold skin thickness, hyperplasia, and leukocyte infiltration. Critical cell cycle regulatory proteins, the target of the investigation, were substantially down-regulated because of the resveratrol. The investigators concluded that resveratrol might have the potential to play a significant role in preventing UVB-mediated photodamage and carcinogenesis.25
More recently, in 2015, Sirerol et al. found that the topical treatment with pterostilbene, a natural dimethoxy analog of resveratrol, effectively shielded SKH-1 hairless mice from UVB-induced photodamage and carcinogenesis.26
Interestingly, recent in vitro studies by Sticozzi and colleagues have shown that topical resveratrol dose-dependently protected human keratinocytes from cigarette smoke–induced reduction of scavenger receptor B1 protein expression27 and can lower cigarette smoke–induced reactive oxygen species and carbonyl formation in human keratinocytes.28
Antiaging activity
In 2010, Giardina et al. performed an in vitro study to evaluate the tonic-trophic characteristics of resveratrol alone and resveratrol plus N-acetyl-cysteine on cultured skin fibroblasts. Both formulations dose-dependently increased cell proliferation and inhibition of collagenase activity.29
In 2012, Wu et al. investigated the protective effects of resveratrate, a stable derivative of resveratrol, against damage to human skin caused by repetitive solar simulator UV radiation (ssUVR) in 15 healthy human volunteers. Six sites on nonexposed dorsal skin of each participant were assessed, with four sites exposed to ssUVR and the remaining sites serving as positive control (ssUVR only) and baseline control (no treatment or exposure). The researchers noted minimal erythema on areas treated with resveratrate and the resveratrol derivative significantly inhibited sunburn cell formation. They concluded that resveratrate protects the skin against sunburn and suntan caused by repetitive ssUVR.4
Also that year, Buonocore et al. conducted a placebo-controlled, double-blind study in 50 subjects that revealed the antiaging efficacy of a dietary nutraceutical blend of resveratrol and procyanidin. Specifically, skin moisturization and elasticity improved while wrinkle depth and skin roughness lessened after 60 days of treatment.30
In a 2013 in vitro study of the skin permeation kinetics of polyphenols using diffusion cells via ex vivo pig skin and a cellulose membrane, Zillich et al. showed that several polyphenols, including resveratrol, epigallocatechin gallate, quercetin, rutin, and protocatechuic acid formulated in oil-in-water emulsions could permeate the stratum corneum and were identified in the epidermis and dermis. The team concluded that their findings validate the use of polyphenols as active ingredients in antiaging products.31
In 2014, Farris et al. found that the topical application of resveratrol in a proprietary blend (1% resveratrol, 0.5% baicalin, 1% vitamin E) yielded a statistically significant amelioration of fine lines and wrinkles, hyperpigmentation, radiance, as well as skin roughness, firmness, elasticity, and laxity in a small study over 12 weeks.32
Skin lightening
Resveratrol has also been used as a promising topical treatment for hyperpigmentation disorders.33 The compound has been shown to work synergistically with 4-n-butylresorcinol (a derivative of resorcinol, one of the main phenols found in argan oil) to reduce tyrosinase levels and significantly diminish melanin synthesis, more effectively than either compound alone.34 In 2012, Franco et al. observed that resveratrol can inhibit tyrosinase but it does not sufficiently suppress melanin production to justify its use as a lone skin-whitening agent in pharmaceutical formulations, but warrants attention as a coadjuvant for treating hyperpigmentation.35 The skin-lightening capacity of resveratrol supported by a 2013 study in which 52 medicinal plants grown in Korea were tested for human tyrosinase activity and the dried stems of the grape tree V. vinifera were found to potently suppress human tyrosinase, and more effectively than arbutin.36 It is worth noting that resveratrol, through its antioxidant activity and possible inhibitory effect on cytochrome P450 2E1 expression, has been shown to protect mouse primary hepatocytes from hydroquinone-induced cytotoxicity.37 Also, J.M. Galgut and S.A. Ali, noted the gathering of pigment cells and resultant skin lightening from the effects of topical ethanolic extract of Arachis hypogaea (peanuts, which contain half the resveratrol of red wine) on the tail melanophores of tadpole Bufo melanostictus, concluding that resveratrol merits attention for potential clinical use as a nontoxic melanolytic agent to treat hyperpigmentation.38,34
Acne
Resveratrol is considered an emerging agent in the topical armamentarium for treating acne.39 In a single-blind pilot study in 2011, Fabbrocini et al. investigated the potential therapeutic impact of resveratrol on 20 patients with acne. A resveratrol-containing hydrogel was applied daily on the right side of the face for 60 days, with the left side receiving the hydrogel vehicle as control. No adverse effects were reported and all patients were satisfied with the treatment. Researchers reported a 53.75 % mean reduction in the Global Acne Grading System score on the resveratrol-treated sides and a 6.10 % decrease on the control sides. Histologic analysis revealed a statistically significant reduction of lesions in areas treated with resveratrol (66.7 % mean reduction in the average area of microcomedones on the resveratrol-treated sides vs. 9.7% reduction on the control sides).40
A 2015 comprehensive literature review of randomized clinical trials and controlled trials by Dall’oglio et al. found that cosmetics with antimicrobial and anti-inflammatory ingredients, including resveratrol, may accelerate acne resolution.41
Significantly, resveratrol is one of the novel acne treatments considered to have little potential for susceptibility to antibiotic resistance to Propionibacterium acnes.42
Erythema
In a small 2013 study by Ferzli et al., 16 subjects with erythema applied a formulation containing resveratrol, green tea polyphenols, and caffeine twice daily to the whole face. Clinical photographs and spectrally enhanced images taken before treatment and every 2 weeks through 3 months were assessed. The investigators reported that improvement was seen in 16 of 16 clinical images and 13 of 16 spectrally enhanced images. Erythema reduction was observable by 6 weeks of treatment, and no adverse effects were observed.43
Conclusion
Resveratrol is emerging as a compound with the potential to deliver significant health benefits, particularly in terms of photoprotective, cancer preventive, and cardioprotective activity. While there are 2 strong decades of research, more is necessary to elucidate the full potential of resveratrol as a first-line dermatologic therapy. Preclinical data do support the use of resveratrol in various product types (e.g., emollients, patches, sunscreens, and additional skin care products) intended to prevent skin cancer or to prevent or treat other conditions caused or exacerbated by solar exposure, such as photoaging. I look forward to seeing clinical evidence of the efficacy of topically applied resveratrol.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. She also developed and owns the Baumann Skin Type Solution skin-typing systems and related products.
References
1. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):28-37.
2. Science. 1997 Jan 10;275(5297):218-20.
3. Cancer Res. 2001 Feb 15;61(4):1604-10.
4. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):345-50.
5. Photochem Photobiol. 2008 Mar-Apr;84(2):415-21.
6. Dose Response. 2010 Mar 18;8(4):478-500.
7. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):28-37.
8. Neoplasia. 2003 Jan-Feb;5(1):74-82.
9. An Illustrated Guide to 101 Medicinal Herbs: Their History, Use, Recommended Dosages, and Cautions (Loveland, Colo.: Interweave Press, 1998, pp. 108-9.)
11. Eur J Pharm Sci. 2015 Oct 12;78:204-13.
12. Pancreas. 2002 Nov;25(4):e71-6.
13. Toxicol Appl Pharmacol. 2007 Nov 1;224(3):274-83.
14. J Biol Chem. 2003 Oct 17;278(42):41482-90.
15. J Drugs Dermatol. 2014 Dec;13(12):1467-72.
16. Fitoterapia. 2013 Apr;86:84-91.
17. Ann N Y Acad Sci. 2011 Jan;1215:60-71.
18. Recent Pat Cardiovasc Drug Discov. 2007 Jun;2(2):133-8.
19. Anticancer Res. 2004 Sep-Oct;24(5A):2783-840.
20. Science. 1997 Jan 10;275(5297):218-20.
21. Biochem Pharmacol. 2002 Jan 15:63(2):99-104.
22. Biomed Pap Med Fac univ Palacky Olomouc Czech Repub. 2003 Dec;147(2):137-45.
23. J Surg Res. 2012 Jan;172(1):109-15.
24. Front Biosci. 2002 Apr 1;7:d784-92.
25. Oncogene. 2004 Jul 1;23(30):5151-60.
26. Free Radic Biol Med. 2015 Aug;85:1-11.
27. Free Radic Biol Med. 2014 Apr;69:50-7.
28. Food Funct. 2014 Sep;5(9):2348-56.
29. Minerva Ginecol. 2010 Jun;62(3):195-201.
30. Clin Cosmet Investig Dermatol. 2012;5:159-65.
31. Int J Cosmet Sci. 2013 Oct;35(5):491-501.
32. J Drugs Dermatol. 2014 Dec;13(12):1467-72.
33. Semin Cutan Med Surg. 2012 Jun;31(2):133-9.
34. Pharmazie. 2012 Jun;67(6):542-6.
35. Molecules. 2012 Oct 9;17(10):11816-25.
36. Evid Based Complement Alternat Med. 2013;2013:645257.
37. Int J Environ Res Public Health. 2012 Sep 19;9(9):3354-64.
38. J Recept Signal Transduct Res. 2011 Oct;31(5):374-80.
39. Am J Clin Dermatol. 2012 Dec 1;13(6):357-64.
40. Am J Clin Dermatol. 2011 Apr 1;12(2):133-41.
41. G Ital Dermatol Venereol. 2015 Feb;150(1):1-11.
• Found abundantly in nature, this polyphenolic phytoalexin is believed to exhibit a wide range of biologic activity.
• Potent antioxidant, anti-inflammatory, and antiproliferative properties.
• Highly studied polyphenolic substance also considered a chemopreventive agent against skin cancer.
• In small studies, has contributed to antiaging, antiacne, antierythema, and skin-lightening results.
Resveratrol (trans-3,5,4’-trihydroxystilbene), a polyphenolic phytoalexin synthesized in nearly 70 plant species, is found to be particularly abundant in Vitis vinifera (grape vine) and its derivatives (e.g., red wine, purple grape juice), various berries, peanuts, jackfruit, pomegranate, eucalyptus, the roots of Polygonum cuspidatum (Japanese knotweed, which is used in traditional Chinese and Japanese medicine to treat dermatitis, among other conditions)1, Scots pine, spruce, corn lily, gnetum, and butterfly orchid.2-6 Several studies have demonstrated that resveratrol possesses potent antioxidant, anticarcinogenic, anti-inflammatory, as well as antimicrobial characteristics.7-11 Specifically, in vitro and in vivo studies have shown that resveratrol exerts chemopreventive and antiproliferative activity against various cancers, including skin cancer, by suppressing cellular events associated with tumor initiation, promotion, and progression, and triggering apoptosis in such tumor cells.12-14 It also is reputed to impart antiaging benefits.15 This column will focus on recent research findings pertaining to effects on the skin as well as topical uses of this botanical agent, the main source of which, V. vinifera, has been used since antiquity.
Resveratrol was first identified from the roots of Veratrum grandiflorum (white hellebore) in 1940,16-19 but research on the compound did not take root until after a 1997 report in Science suggested chemopreventive properties. In that study, purified resveratrol was found to exhibit major inhibitory activity against cancer initiation, promotion, and progression.20 Since then, copious research on this botanical compound has yielded a reputation as a strong antioxidant, anti-inflammatory, and antiproliferative agent.7,21,22 Most importantly, resveratrol is considered to act as a chemopreventive agent against skin cancer and antiproliferative influence on oral squamous, breast, colon, and prostate cancer cells.12,14 It is also one of the most studied polyphenolic compounds.
Skin cancer and photoprotection
In 2012, Osmond et al. conducted in vitro and in vivo experiments to assess the potential of resveratrol as a chemotherapy adjunct for melanoma treatment. Resveratrol significantly reduced melanoma cell viability in both melanoma cell lines tested, and selectively spared cells in the nonmalignant fibroblast lines, compared with its cytotoxic impact on melanoma cells. Further, cytotoxicity to malignant cells was greatly enhanced by 72 hours of treatment with resveratrol and temozolomide, compared with temozolomide treatment alone. No significant differences were seen in vivo. The researchers concluded that the in vitro antitumor activity of resveratrol suggested its potential as a therapeutic agent in melanoma management.23
Resveratrol has been shown to protect against UVB-mediated cutaneous damage in SKH-1 hairless mice. Afaq et al. demonstrated that UVB-induced skin edema was significantly suppressed by the topical application of resveratrol to SKH-1 hairless mice.7
In a different study by the same team, topically applied resveratrol significantly inhibited UVB-mediated increases in bifold skin thickness and edema and greatly diminished UVB-induced lipid peroxidation, cyclo-oxygenase and ornithine decarboxylase (ODC) activities, as well as protein expression of the ODC enzyme in SKH-1 hairless mice.24 In an experiment by some of the same researchers, resveratrol was topically applied to SKH-1 hairless mice 30 minutes before exposure to UVB; 24 hours later, significant decreases were observed in bifold skin thickness, hyperplasia, and leukocyte infiltration. Critical cell cycle regulatory proteins, the target of the investigation, were substantially down-regulated because of the resveratrol. The investigators concluded that resveratrol might have the potential to play a significant role in preventing UVB-mediated photodamage and carcinogenesis.25
More recently, in 2015, Sirerol et al. found that the topical treatment with pterostilbene, a natural dimethoxy analog of resveratrol, effectively shielded SKH-1 hairless mice from UVB-induced photodamage and carcinogenesis.26
Interestingly, recent in vitro studies by Sticozzi and colleagues have shown that topical resveratrol dose-dependently protected human keratinocytes from cigarette smoke–induced reduction of scavenger receptor B1 protein expression27 and can lower cigarette smoke–induced reactive oxygen species and carbonyl formation in human keratinocytes.28
Antiaging activity
In 2010, Giardina et al. performed an in vitro study to evaluate the tonic-trophic characteristics of resveratrol alone and resveratrol plus N-acetyl-cysteine on cultured skin fibroblasts. Both formulations dose-dependently increased cell proliferation and inhibition of collagenase activity.29
In 2012, Wu et al. investigated the protective effects of resveratrate, a stable derivative of resveratrol, against damage to human skin caused by repetitive solar simulator UV radiation (ssUVR) in 15 healthy human volunteers. Six sites on nonexposed dorsal skin of each participant were assessed, with four sites exposed to ssUVR and the remaining sites serving as positive control (ssUVR only) and baseline control (no treatment or exposure). The researchers noted minimal erythema on areas treated with resveratrate and the resveratrol derivative significantly inhibited sunburn cell formation. They concluded that resveratrate protects the skin against sunburn and suntan caused by repetitive ssUVR.4
Also that year, Buonocore et al. conducted a placebo-controlled, double-blind study in 50 subjects that revealed the antiaging efficacy of a dietary nutraceutical blend of resveratrol and procyanidin. Specifically, skin moisturization and elasticity improved while wrinkle depth and skin roughness lessened after 60 days of treatment.30
In a 2013 in vitro study of the skin permeation kinetics of polyphenols using diffusion cells via ex vivo pig skin and a cellulose membrane, Zillich et al. showed that several polyphenols, including resveratrol, epigallocatechin gallate, quercetin, rutin, and protocatechuic acid formulated in oil-in-water emulsions could permeate the stratum corneum and were identified in the epidermis and dermis. The team concluded that their findings validate the use of polyphenols as active ingredients in antiaging products.31
In 2014, Farris et al. found that the topical application of resveratrol in a proprietary blend (1% resveratrol, 0.5% baicalin, 1% vitamin E) yielded a statistically significant amelioration of fine lines and wrinkles, hyperpigmentation, radiance, as well as skin roughness, firmness, elasticity, and laxity in a small study over 12 weeks.32
Skin lightening
Resveratrol has also been used as a promising topical treatment for hyperpigmentation disorders.33 The compound has been shown to work synergistically with 4-n-butylresorcinol (a derivative of resorcinol, one of the main phenols found in argan oil) to reduce tyrosinase levels and significantly diminish melanin synthesis, more effectively than either compound alone.34 In 2012, Franco et al. observed that resveratrol can inhibit tyrosinase but it does not sufficiently suppress melanin production to justify its use as a lone skin-whitening agent in pharmaceutical formulations, but warrants attention as a coadjuvant for treating hyperpigmentation.35 The skin-lightening capacity of resveratrol supported by a 2013 study in which 52 medicinal plants grown in Korea were tested for human tyrosinase activity and the dried stems of the grape tree V. vinifera were found to potently suppress human tyrosinase, and more effectively than arbutin.36 It is worth noting that resveratrol, through its antioxidant activity and possible inhibitory effect on cytochrome P450 2E1 expression, has been shown to protect mouse primary hepatocytes from hydroquinone-induced cytotoxicity.37 Also, J.M. Galgut and S.A. Ali, noted the gathering of pigment cells and resultant skin lightening from the effects of topical ethanolic extract of Arachis hypogaea (peanuts, which contain half the resveratrol of red wine) on the tail melanophores of tadpole Bufo melanostictus, concluding that resveratrol merits attention for potential clinical use as a nontoxic melanolytic agent to treat hyperpigmentation.38,34
Acne
Resveratrol is considered an emerging agent in the topical armamentarium for treating acne.39 In a single-blind pilot study in 2011, Fabbrocini et al. investigated the potential therapeutic impact of resveratrol on 20 patients with acne. A resveratrol-containing hydrogel was applied daily on the right side of the face for 60 days, with the left side receiving the hydrogel vehicle as control. No adverse effects were reported and all patients were satisfied with the treatment. Researchers reported a 53.75 % mean reduction in the Global Acne Grading System score on the resveratrol-treated sides and a 6.10 % decrease on the control sides. Histologic analysis revealed a statistically significant reduction of lesions in areas treated with resveratrol (66.7 % mean reduction in the average area of microcomedones on the resveratrol-treated sides vs. 9.7% reduction on the control sides).40
A 2015 comprehensive literature review of randomized clinical trials and controlled trials by Dall’oglio et al. found that cosmetics with antimicrobial and anti-inflammatory ingredients, including resveratrol, may accelerate acne resolution.41
Significantly, resveratrol is one of the novel acne treatments considered to have little potential for susceptibility to antibiotic resistance to Propionibacterium acnes.42
Erythema
In a small 2013 study by Ferzli et al., 16 subjects with erythema applied a formulation containing resveratrol, green tea polyphenols, and caffeine twice daily to the whole face. Clinical photographs and spectrally enhanced images taken before treatment and every 2 weeks through 3 months were assessed. The investigators reported that improvement was seen in 16 of 16 clinical images and 13 of 16 spectrally enhanced images. Erythema reduction was observable by 6 weeks of treatment, and no adverse effects were observed.43
Conclusion
Resveratrol is emerging as a compound with the potential to deliver significant health benefits, particularly in terms of photoprotective, cancer preventive, and cardioprotective activity. While there are 2 strong decades of research, more is necessary to elucidate the full potential of resveratrol as a first-line dermatologic therapy. Preclinical data do support the use of resveratrol in various product types (e.g., emollients, patches, sunscreens, and additional skin care products) intended to prevent skin cancer or to prevent or treat other conditions caused or exacerbated by solar exposure, such as photoaging. I look forward to seeing clinical evidence of the efficacy of topically applied resveratrol.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. She also developed and owns the Baumann Skin Type Solution skin-typing systems and related products.
References
1. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):28-37.
2. Science. 1997 Jan 10;275(5297):218-20.
3. Cancer Res. 2001 Feb 15;61(4):1604-10.
4. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):345-50.
5. Photochem Photobiol. 2008 Mar-Apr;84(2):415-21.
6. Dose Response. 2010 Mar 18;8(4):478-500.
7. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):28-37.
8. Neoplasia. 2003 Jan-Feb;5(1):74-82.
9. An Illustrated Guide to 101 Medicinal Herbs: Their History, Use, Recommended Dosages, and Cautions (Loveland, Colo.: Interweave Press, 1998, pp. 108-9.)
11. Eur J Pharm Sci. 2015 Oct 12;78:204-13.
12. Pancreas. 2002 Nov;25(4):e71-6.
13. Toxicol Appl Pharmacol. 2007 Nov 1;224(3):274-83.
14. J Biol Chem. 2003 Oct 17;278(42):41482-90.
15. J Drugs Dermatol. 2014 Dec;13(12):1467-72.
16. Fitoterapia. 2013 Apr;86:84-91.
17. Ann N Y Acad Sci. 2011 Jan;1215:60-71.
18. Recent Pat Cardiovasc Drug Discov. 2007 Jun;2(2):133-8.
19. Anticancer Res. 2004 Sep-Oct;24(5A):2783-840.
20. Science. 1997 Jan 10;275(5297):218-20.
21. Biochem Pharmacol. 2002 Jan 15:63(2):99-104.
22. Biomed Pap Med Fac univ Palacky Olomouc Czech Repub. 2003 Dec;147(2):137-45.
23. J Surg Res. 2012 Jan;172(1):109-15.
24. Front Biosci. 2002 Apr 1;7:d784-92.
25. Oncogene. 2004 Jul 1;23(30):5151-60.
26. Free Radic Biol Med. 2015 Aug;85:1-11.
27. Free Radic Biol Med. 2014 Apr;69:50-7.
28. Food Funct. 2014 Sep;5(9):2348-56.
29. Minerva Ginecol. 2010 Jun;62(3):195-201.
30. Clin Cosmet Investig Dermatol. 2012;5:159-65.
31. Int J Cosmet Sci. 2013 Oct;35(5):491-501.
32. J Drugs Dermatol. 2014 Dec;13(12):1467-72.
33. Semin Cutan Med Surg. 2012 Jun;31(2):133-9.
34. Pharmazie. 2012 Jun;67(6):542-6.
35. Molecules. 2012 Oct 9;17(10):11816-25.
36. Evid Based Complement Alternat Med. 2013;2013:645257.
37. Int J Environ Res Public Health. 2012 Sep 19;9(9):3354-64.
38. J Recept Signal Transduct Res. 2011 Oct;31(5):374-80.
39. Am J Clin Dermatol. 2012 Dec 1;13(6):357-64.
40. Am J Clin Dermatol. 2011 Apr 1;12(2):133-41.
41. G Ital Dermatol Venereol. 2015 Feb;150(1):1-11.
• Found abundantly in nature, this polyphenolic phytoalexin is believed to exhibit a wide range of biologic activity.
• Potent antioxidant, anti-inflammatory, and antiproliferative properties.
• Highly studied polyphenolic substance also considered a chemopreventive agent against skin cancer.
• In small studies, has contributed to antiaging, antiacne, antierythema, and skin-lightening results.
Resveratrol (trans-3,5,4’-trihydroxystilbene), a polyphenolic phytoalexin synthesized in nearly 70 plant species, is found to be particularly abundant in Vitis vinifera (grape vine) and its derivatives (e.g., red wine, purple grape juice), various berries, peanuts, jackfruit, pomegranate, eucalyptus, the roots of Polygonum cuspidatum (Japanese knotweed, which is used in traditional Chinese and Japanese medicine to treat dermatitis, among other conditions)1, Scots pine, spruce, corn lily, gnetum, and butterfly orchid.2-6 Several studies have demonstrated that resveratrol possesses potent antioxidant, anticarcinogenic, anti-inflammatory, as well as antimicrobial characteristics.7-11 Specifically, in vitro and in vivo studies have shown that resveratrol exerts chemopreventive and antiproliferative activity against various cancers, including skin cancer, by suppressing cellular events associated with tumor initiation, promotion, and progression, and triggering apoptosis in such tumor cells.12-14 It also is reputed to impart antiaging benefits.15 This column will focus on recent research findings pertaining to effects on the skin as well as topical uses of this botanical agent, the main source of which, V. vinifera, has been used since antiquity.
Resveratrol was first identified from the roots of Veratrum grandiflorum (white hellebore) in 1940,16-19 but research on the compound did not take root until after a 1997 report in Science suggested chemopreventive properties. In that study, purified resveratrol was found to exhibit major inhibitory activity against cancer initiation, promotion, and progression.20 Since then, copious research on this botanical compound has yielded a reputation as a strong antioxidant, anti-inflammatory, and antiproliferative agent.7,21,22 Most importantly, resveratrol is considered to act as a chemopreventive agent against skin cancer and antiproliferative influence on oral squamous, breast, colon, and prostate cancer cells.12,14 It is also one of the most studied polyphenolic compounds.
Skin cancer and photoprotection
In 2012, Osmond et al. conducted in vitro and in vivo experiments to assess the potential of resveratrol as a chemotherapy adjunct for melanoma treatment. Resveratrol significantly reduced melanoma cell viability in both melanoma cell lines tested, and selectively spared cells in the nonmalignant fibroblast lines, compared with its cytotoxic impact on melanoma cells. Further, cytotoxicity to malignant cells was greatly enhanced by 72 hours of treatment with resveratrol and temozolomide, compared with temozolomide treatment alone. No significant differences were seen in vivo. The researchers concluded that the in vitro antitumor activity of resveratrol suggested its potential as a therapeutic agent in melanoma management.23
Resveratrol has been shown to protect against UVB-mediated cutaneous damage in SKH-1 hairless mice. Afaq et al. demonstrated that UVB-induced skin edema was significantly suppressed by the topical application of resveratrol to SKH-1 hairless mice.7
In a different study by the same team, topically applied resveratrol significantly inhibited UVB-mediated increases in bifold skin thickness and edema and greatly diminished UVB-induced lipid peroxidation, cyclo-oxygenase and ornithine decarboxylase (ODC) activities, as well as protein expression of the ODC enzyme in SKH-1 hairless mice.24 In an experiment by some of the same researchers, resveratrol was topically applied to SKH-1 hairless mice 30 minutes before exposure to UVB; 24 hours later, significant decreases were observed in bifold skin thickness, hyperplasia, and leukocyte infiltration. Critical cell cycle regulatory proteins, the target of the investigation, were substantially down-regulated because of the resveratrol. The investigators concluded that resveratrol might have the potential to play a significant role in preventing UVB-mediated photodamage and carcinogenesis.25
More recently, in 2015, Sirerol et al. found that the topical treatment with pterostilbene, a natural dimethoxy analog of resveratrol, effectively shielded SKH-1 hairless mice from UVB-induced photodamage and carcinogenesis.26
Interestingly, recent in vitro studies by Sticozzi and colleagues have shown that topical resveratrol dose-dependently protected human keratinocytes from cigarette smoke–induced reduction of scavenger receptor B1 protein expression27 and can lower cigarette smoke–induced reactive oxygen species and carbonyl formation in human keratinocytes.28
Antiaging activity
In 2010, Giardina et al. performed an in vitro study to evaluate the tonic-trophic characteristics of resveratrol alone and resveratrol plus N-acetyl-cysteine on cultured skin fibroblasts. Both formulations dose-dependently increased cell proliferation and inhibition of collagenase activity.29
In 2012, Wu et al. investigated the protective effects of resveratrate, a stable derivative of resveratrol, against damage to human skin caused by repetitive solar simulator UV radiation (ssUVR) in 15 healthy human volunteers. Six sites on nonexposed dorsal skin of each participant were assessed, with four sites exposed to ssUVR and the remaining sites serving as positive control (ssUVR only) and baseline control (no treatment or exposure). The researchers noted minimal erythema on areas treated with resveratrate and the resveratrol derivative significantly inhibited sunburn cell formation. They concluded that resveratrate protects the skin against sunburn and suntan caused by repetitive ssUVR.4
Also that year, Buonocore et al. conducted a placebo-controlled, double-blind study in 50 subjects that revealed the antiaging efficacy of a dietary nutraceutical blend of resveratrol and procyanidin. Specifically, skin moisturization and elasticity improved while wrinkle depth and skin roughness lessened after 60 days of treatment.30
In a 2013 in vitro study of the skin permeation kinetics of polyphenols using diffusion cells via ex vivo pig skin and a cellulose membrane, Zillich et al. showed that several polyphenols, including resveratrol, epigallocatechin gallate, quercetin, rutin, and protocatechuic acid formulated in oil-in-water emulsions could permeate the stratum corneum and were identified in the epidermis and dermis. The team concluded that their findings validate the use of polyphenols as active ingredients in antiaging products.31
In 2014, Farris et al. found that the topical application of resveratrol in a proprietary blend (1% resveratrol, 0.5% baicalin, 1% vitamin E) yielded a statistically significant amelioration of fine lines and wrinkles, hyperpigmentation, radiance, as well as skin roughness, firmness, elasticity, and laxity in a small study over 12 weeks.32
Skin lightening
Resveratrol has also been used as a promising topical treatment for hyperpigmentation disorders.33 The compound has been shown to work synergistically with 4-n-butylresorcinol (a derivative of resorcinol, one of the main phenols found in argan oil) to reduce tyrosinase levels and significantly diminish melanin synthesis, more effectively than either compound alone.34 In 2012, Franco et al. observed that resveratrol can inhibit tyrosinase but it does not sufficiently suppress melanin production to justify its use as a lone skin-whitening agent in pharmaceutical formulations, but warrants attention as a coadjuvant for treating hyperpigmentation.35 The skin-lightening capacity of resveratrol supported by a 2013 study in which 52 medicinal plants grown in Korea were tested for human tyrosinase activity and the dried stems of the grape tree V. vinifera were found to potently suppress human tyrosinase, and more effectively than arbutin.36 It is worth noting that resveratrol, through its antioxidant activity and possible inhibitory effect on cytochrome P450 2E1 expression, has been shown to protect mouse primary hepatocytes from hydroquinone-induced cytotoxicity.37 Also, J.M. Galgut and S.A. Ali, noted the gathering of pigment cells and resultant skin lightening from the effects of topical ethanolic extract of Arachis hypogaea (peanuts, which contain half the resveratrol of red wine) on the tail melanophores of tadpole Bufo melanostictus, concluding that resveratrol merits attention for potential clinical use as a nontoxic melanolytic agent to treat hyperpigmentation.38,34
Acne
Resveratrol is considered an emerging agent in the topical armamentarium for treating acne.39 In a single-blind pilot study in 2011, Fabbrocini et al. investigated the potential therapeutic impact of resveratrol on 20 patients with acne. A resveratrol-containing hydrogel was applied daily on the right side of the face for 60 days, with the left side receiving the hydrogel vehicle as control. No adverse effects were reported and all patients were satisfied with the treatment. Researchers reported a 53.75 % mean reduction in the Global Acne Grading System score on the resveratrol-treated sides and a 6.10 % decrease on the control sides. Histologic analysis revealed a statistically significant reduction of lesions in areas treated with resveratrol (66.7 % mean reduction in the average area of microcomedones on the resveratrol-treated sides vs. 9.7% reduction on the control sides).40
A 2015 comprehensive literature review of randomized clinical trials and controlled trials by Dall’oglio et al. found that cosmetics with antimicrobial and anti-inflammatory ingredients, including resveratrol, may accelerate acne resolution.41
Significantly, resveratrol is one of the novel acne treatments considered to have little potential for susceptibility to antibiotic resistance to Propionibacterium acnes.42
Erythema
In a small 2013 study by Ferzli et al., 16 subjects with erythema applied a formulation containing resveratrol, green tea polyphenols, and caffeine twice daily to the whole face. Clinical photographs and spectrally enhanced images taken before treatment and every 2 weeks through 3 months were assessed. The investigators reported that improvement was seen in 16 of 16 clinical images and 13 of 16 spectrally enhanced images. Erythema reduction was observable by 6 weeks of treatment, and no adverse effects were observed.43
Conclusion
Resveratrol is emerging as a compound with the potential to deliver significant health benefits, particularly in terms of photoprotective, cancer preventive, and cardioprotective activity. While there are 2 strong decades of research, more is necessary to elucidate the full potential of resveratrol as a first-line dermatologic therapy. Preclinical data do support the use of resveratrol in various product types (e.g., emollients, patches, sunscreens, and additional skin care products) intended to prevent skin cancer or to prevent or treat other conditions caused or exacerbated by solar exposure, such as photoaging. I look forward to seeing clinical evidence of the efficacy of topically applied resveratrol.
Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in the Design District in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote the textbook “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and a book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Her latest book, “Cosmeceuticals and Cosmetic Ingredients,” was published in November 2014. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Evolus, Galderma, GlaxoSmithKline, Kythera Biopharmaceuticals, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Topix Pharmaceuticals, and Unilever. She also developed and owns the Baumann Skin Type Solution skin-typing systems and related products.
References
1. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):28-37.
2. Science. 1997 Jan 10;275(5297):218-20.
3. Cancer Res. 2001 Feb 15;61(4):1604-10.
4. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):345-50.
5. Photochem Photobiol. 2008 Mar-Apr;84(2):415-21.
6. Dose Response. 2010 Mar 18;8(4):478-500.
7. Toxicol Appl Pharmacol. 2003 Jan 1;186(1):28-37.
8. Neoplasia. 2003 Jan-Feb;5(1):74-82.
9. An Illustrated Guide to 101 Medicinal Herbs: Their History, Use, Recommended Dosages, and Cautions (Loveland, Colo.: Interweave Press, 1998, pp. 108-9.)
11. Eur J Pharm Sci. 2015 Oct 12;78:204-13.
12. Pancreas. 2002 Nov;25(4):e71-6.
13. Toxicol Appl Pharmacol. 2007 Nov 1;224(3):274-83.
14. J Biol Chem. 2003 Oct 17;278(42):41482-90.
15. J Drugs Dermatol. 2014 Dec;13(12):1467-72.
16. Fitoterapia. 2013 Apr;86:84-91.
17. Ann N Y Acad Sci. 2011 Jan;1215:60-71.
18. Recent Pat Cardiovasc Drug Discov. 2007 Jun;2(2):133-8.
19. Anticancer Res. 2004 Sep-Oct;24(5A):2783-840.
20. Science. 1997 Jan 10;275(5297):218-20.
21. Biochem Pharmacol. 2002 Jan 15:63(2):99-104.
22. Biomed Pap Med Fac univ Palacky Olomouc Czech Repub. 2003 Dec;147(2):137-45.
23. J Surg Res. 2012 Jan;172(1):109-15.
24. Front Biosci. 2002 Apr 1;7:d784-92.
25. Oncogene. 2004 Jul 1;23(30):5151-60.
26. Free Radic Biol Med. 2015 Aug;85:1-11.
27. Free Radic Biol Med. 2014 Apr;69:50-7.
28. Food Funct. 2014 Sep;5(9):2348-56.
29. Minerva Ginecol. 2010 Jun;62(3):195-201.
30. Clin Cosmet Investig Dermatol. 2012;5:159-65.
31. Int J Cosmet Sci. 2013 Oct;35(5):491-501.
32. J Drugs Dermatol. 2014 Dec;13(12):1467-72.
33. Semin Cutan Med Surg. 2012 Jun;31(2):133-9.
34. Pharmazie. 2012 Jun;67(6):542-6.
35. Molecules. 2012 Oct 9;17(10):11816-25.
36. Evid Based Complement Alternat Med. 2013;2013:645257.
37. Int J Environ Res Public Health. 2012 Sep 19;9(9):3354-64.
38. J Recept Signal Transduct Res. 2011 Oct;31(5):374-80.
39. Am J Clin Dermatol. 2012 Dec 1;13(6):357-64.
40. Am J Clin Dermatol. 2011 Apr 1;12(2):133-41.
41. G Ital Dermatol Venereol. 2015 Feb;150(1):1-11.
Aesthetic dermatology: What do we know so far about Volbella?
On May 31, 2016, the Food and Drug Administration approved Juvéderm Volbella XC for use in the lips for lip augmentation and for correction of perioral rhytids, in adults over the age of 21. In the U.S. pivotal clinical trial of 168 patients, Juvederm Volbella XC was found to increase lip fullness and soften the appearance of perioral rhytids in two-thirds through 1 year.
Like its previously approved predecessor Juvéderm Voluma XC, approved for the mid-face/cheek area, Juvéderm Volbella XC is composed of hyaluronic acid (HA) using Vycross technology. Vycross technology blends different molecular weights of hyaluronic acid together, allowing for longer duration of the product. Unlike Juvéderm Voluma XC (20 mg/mL), Juvéderm Volbella XC is a lower-concentration HA (15 mg/mL) and has a lower G prime and cohesivity, allowing more horizontal spread as opposed to a lift, which makes it more appropriate for injection into the lips and superficial perioral lines.1
Juvéderm Volbella XC will not be available for use in the United States until October 2016. However, the product was first approved in Europe in 2011, and subsequently in Latin America, the Middle East, Asia Pacific, and Canada. What has been the experience of our neighboring colleagues?
In a randomized, prospective, 12-month controlled European study of 280 patients comparing Volbella to a nonanimal stabilized hyaluronic acid (NASHA), Volbella was found to be noninferior to NASHA at 3 months.2 Improvements in lip fullness, perioral lines, and oral commissures for Volbella were statistically significant at 6 and 12 months. Acute swelling was also noted to be less.
In a German 62-patient study with primary endpoints of satisfaction with improvement and look and feel of the lips, a high degree of subject satisfaction with aesthetic improvement in the lips, as well as with their natural look and feel, was noted among 83.6% and 75%-93%, respectively.3
In a retrospective chart review of 400 patients in Israel, where Volbella was injected into tear troughs (disclaimer: not approved for tear troughs in the United States) and/or lips, 17 patients (4.25%) developed prolonged inflammatory cutaneous reactions, lasting up to 11 months, which recurred (with an average number of 3.17 episodes) and occurred late (with an average onset of 8.41 weeks after the injection).4 The reactions were treated with antibiotics and hyaluronidase injections. The finding in this published report is higher than the 0.02% of delayed-onset inflammatory reaction previously reported with HA fillers.
With a full armamentarium of HA and non-HA fillers on the market, we are lucky to have many options to select from to treat aesthetic concerns of patients. For lip and perioral enhancement in the United States, Restylane, Juvéderm, Belotero, and now Volbella are all excellent options. As the dermal filler portfolio available internationally is larger than that in the United States, much can be learned from the experience of our international colleagues.
References
1. Plast Reconstr Surg. 2015 Nov;136(5 Suppl):139S-48S.
2. J Drugs Dermatol. 2015 Dec;14(12):1444-52.
3. J Cosmet Dermatol. 2014 Jun;13(2):125-34.
4. Dermatol Surg. 2016 Jan;42(1):31-7.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. Dr. Wesley has no disclosures with regard to Volbella; she participated in clinical trials for Juvéderm Voluma. Dr. Talakoub is a national trainer for Juvéderm manufacturer Allergan for all its injectables.
On May 31, 2016, the Food and Drug Administration approved Juvéderm Volbella XC for use in the lips for lip augmentation and for correction of perioral rhytids, in adults over the age of 21. In the U.S. pivotal clinical trial of 168 patients, Juvederm Volbella XC was found to increase lip fullness and soften the appearance of perioral rhytids in two-thirds through 1 year.
Like its previously approved predecessor Juvéderm Voluma XC, approved for the mid-face/cheek area, Juvéderm Volbella XC is composed of hyaluronic acid (HA) using Vycross technology. Vycross technology blends different molecular weights of hyaluronic acid together, allowing for longer duration of the product. Unlike Juvéderm Voluma XC (20 mg/mL), Juvéderm Volbella XC is a lower-concentration HA (15 mg/mL) and has a lower G prime and cohesivity, allowing more horizontal spread as opposed to a lift, which makes it more appropriate for injection into the lips and superficial perioral lines.1
Juvéderm Volbella XC will not be available for use in the United States until October 2016. However, the product was first approved in Europe in 2011, and subsequently in Latin America, the Middle East, Asia Pacific, and Canada. What has been the experience of our neighboring colleagues?
In a randomized, prospective, 12-month controlled European study of 280 patients comparing Volbella to a nonanimal stabilized hyaluronic acid (NASHA), Volbella was found to be noninferior to NASHA at 3 months.2 Improvements in lip fullness, perioral lines, and oral commissures for Volbella were statistically significant at 6 and 12 months. Acute swelling was also noted to be less.
In a German 62-patient study with primary endpoints of satisfaction with improvement and look and feel of the lips, a high degree of subject satisfaction with aesthetic improvement in the lips, as well as with their natural look and feel, was noted among 83.6% and 75%-93%, respectively.3
In a retrospective chart review of 400 patients in Israel, where Volbella was injected into tear troughs (disclaimer: not approved for tear troughs in the United States) and/or lips, 17 patients (4.25%) developed prolonged inflammatory cutaneous reactions, lasting up to 11 months, which recurred (with an average number of 3.17 episodes) and occurred late (with an average onset of 8.41 weeks after the injection).4 The reactions were treated with antibiotics and hyaluronidase injections. The finding in this published report is higher than the 0.02% of delayed-onset inflammatory reaction previously reported with HA fillers.
With a full armamentarium of HA and non-HA fillers on the market, we are lucky to have many options to select from to treat aesthetic concerns of patients. For lip and perioral enhancement in the United States, Restylane, Juvéderm, Belotero, and now Volbella are all excellent options. As the dermal filler portfolio available internationally is larger than that in the United States, much can be learned from the experience of our international colleagues.
References
1. Plast Reconstr Surg. 2015 Nov;136(5 Suppl):139S-48S.
2. J Drugs Dermatol. 2015 Dec;14(12):1444-52.
3. J Cosmet Dermatol. 2014 Jun;13(2):125-34.
4. Dermatol Surg. 2016 Jan;42(1):31-7.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. Dr. Wesley has no disclosures with regard to Volbella; she participated in clinical trials for Juvéderm Voluma. Dr. Talakoub is a national trainer for Juvéderm manufacturer Allergan for all its injectables.
On May 31, 2016, the Food and Drug Administration approved Juvéderm Volbella XC for use in the lips for lip augmentation and for correction of perioral rhytids, in adults over the age of 21. In the U.S. pivotal clinical trial of 168 patients, Juvederm Volbella XC was found to increase lip fullness and soften the appearance of perioral rhytids in two-thirds through 1 year.
Like its previously approved predecessor Juvéderm Voluma XC, approved for the mid-face/cheek area, Juvéderm Volbella XC is composed of hyaluronic acid (HA) using Vycross technology. Vycross technology blends different molecular weights of hyaluronic acid together, allowing for longer duration of the product. Unlike Juvéderm Voluma XC (20 mg/mL), Juvéderm Volbella XC is a lower-concentration HA (15 mg/mL) and has a lower G prime and cohesivity, allowing more horizontal spread as opposed to a lift, which makes it more appropriate for injection into the lips and superficial perioral lines.1
Juvéderm Volbella XC will not be available for use in the United States until October 2016. However, the product was first approved in Europe in 2011, and subsequently in Latin America, the Middle East, Asia Pacific, and Canada. What has been the experience of our neighboring colleagues?
In a randomized, prospective, 12-month controlled European study of 280 patients comparing Volbella to a nonanimal stabilized hyaluronic acid (NASHA), Volbella was found to be noninferior to NASHA at 3 months.2 Improvements in lip fullness, perioral lines, and oral commissures for Volbella were statistically significant at 6 and 12 months. Acute swelling was also noted to be less.
In a German 62-patient study with primary endpoints of satisfaction with improvement and look and feel of the lips, a high degree of subject satisfaction with aesthetic improvement in the lips, as well as with their natural look and feel, was noted among 83.6% and 75%-93%, respectively.3
In a retrospective chart review of 400 patients in Israel, where Volbella was injected into tear troughs (disclaimer: not approved for tear troughs in the United States) and/or lips, 17 patients (4.25%) developed prolonged inflammatory cutaneous reactions, lasting up to 11 months, which recurred (with an average number of 3.17 episodes) and occurred late (with an average onset of 8.41 weeks after the injection).4 The reactions were treated with antibiotics and hyaluronidase injections. The finding in this published report is higher than the 0.02% of delayed-onset inflammatory reaction previously reported with HA fillers.
With a full armamentarium of HA and non-HA fillers on the market, we are lucky to have many options to select from to treat aesthetic concerns of patients. For lip and perioral enhancement in the United States, Restylane, Juvéderm, Belotero, and now Volbella are all excellent options. As the dermal filler portfolio available internationally is larger than that in the United States, much can be learned from the experience of our international colleagues.
References
1. Plast Reconstr Surg. 2015 Nov;136(5 Suppl):139S-48S.
2. J Drugs Dermatol. 2015 Dec;14(12):1444-52.
3. J Cosmet Dermatol. 2014 Jun;13(2):125-34.
4. Dermatol Surg. 2016 Jan;42(1):31-7.
Dr. Wesley and Dr. Talakoub are cocontributors to this column. Dr. Wesley practices dermatology in Beverly Hills, Calif. Dr. Talakoub is in private practice in McLean, Va. This month’s column is by Dr. Wesley. Write to them at [email protected]. Dr. Wesley has no disclosures with regard to Volbella; she participated in clinical trials for Juvéderm Voluma. Dr. Talakoub is a national trainer for Juvéderm manufacturer Allergan for all its injectables.
It does get better ... with your help: Preventing suicide
Suicide continues to be a major public health problem in the United States. It is the second leading cause of death in young people aged 10-24 years, according to 2010 injury data from the Centers from Disease Control and Prevention.1 This problem disproportionately affects lesbian, gay, bisexual, and transgender (LGBT) youth. Compared to their heterosexual peers, LGBT youth are four times as likely to attempt suicide.2 In addition, almost 50% of transgender youth have attempted suicide.3
Why are LGBT youth at high risk for suicide? Antigay and antitrans stigma and discrimination against LGBT youth create a very stressful environment. For example, LGBT youth are two times more likely than are heterosexual youth to experience bullying4 because of their sexual orientation, and half of transgender youth have reported bullying because of their gender identity.3 LGBT youth tend to perceive lower levels of parental support than do heterosexual youth.5-8 A combination of harassment from peers and decreased perceived support from families increases the risk for suicide in LGBT youth.
However, there are factors that can reduce this risk. LGBT youth whose parents reject their sexual orientation or gender identity are eight times as likely to be suicidal,3,9 while in contrast, LGBT youth whose parents are more accepting are less likely to be suicidal.10 These studies underscore the importance of social support in reducing the stress from antigay and antitrans discrimination, and therefore, play a role in preventing suicide.
Health care providers are another source of support for LGBT youth. They can play a role in providing education and preventing suicide in this population because many victims of suicide have visited a health care provider before attempting to kill themselves.11 It is important for providers to screen for suicide in their patients. Although there is no lab test for suicidal ideation, suicidal adolescents tend to have certain risk factors. In addition to being LGBT, being bullied, and having a lack of social support, other risk factors are psychiatric illness, a history of being impulsive, alcohol and substance abuse, and most important of all, a previous suicide attempt.12
When screening for suicide risk, always remember that at the beginning of any visit with an adolescent, remind them about confidentiality and its limits (e.g., breaking confidentiality if the patient is suicidal). Although this appears counterintuitive, it actually builds rapport between you and the patient. If you don’t discuss the limits of confidentiality beforehand and have to break it because the patient is suicidal, the patient is less likely to tell you again in the future. Once you suspect suicidal ideation based on the above risk factors, you can ask:
• Have you thought about ending your own life or would you rather be dead?
• Have you done something to harm yourself or to end your life?
• Have you considered ways to end your own life?12
Some clinicians have expressed concern over asking about suicide in their adolescent patients, but doing so does not induce suicidal thoughts.13 If a patient does express any of the above, the clinician must then inquire about other risk factors that increase the individual’s chances of completing suicide. The American Association of Suicidology has listed several warning signs of imminent suicide, which can be remembered with the acronym IS PATH WARM. This stands for Ideation, Substance use, Purposelessness, heightened Anxiety, feeling Trapped, feeling Hopeless, Withdrawal from friends and family, uncontrollable Anger, engaging in Reckless behavior, and dramatic Mood changes.14
If a patient threatens to kill him/herself, has a specific plan to do so, or speaks about death and suicide, then the clinician must act immediately. Although sending a patient to the emergency department is the safest option, it is not the only option. If a good support system is present, and the patient lives in an environment where he or she does not have the means to carry out a suicide (e.g., there are no guns in the home), then the clinician can create a safety plan for the patient. A safety plan is different from a “no suicide contract.” A no suicide contract is a written commitment that the patient does not engage in suicidal behavior. Many experts caution against a no suicide contract because it can create a false sense of security for the clinician and does not address the strategies needed to combat feelings of suicidality.15,16
Usually with a safety plan, the clinician and the patient identify several people the patient can contact if the patient feels suicidal. In addition, the clinician and the patient can discuss ways the patient can cope with his/her feelings or distract himself/herself from suicidal thoughts (e.g., going out for a walk, watching a movie, etc.). Finally, if these methods fail, patients are provided with emergency hotlines or directed to the emergency department. The Suicide Prevention Resource Center has a template of a patient safety plan.
Finally, clinicians should be proactive in preventing suicide, especially for LGBT youth. Because bullying is a risk factor for suicide, and because LGBT youth are disproportionately affected by bullying, clinicians should advocate for antibullying school policies and advocate for schools to be more LGBT friendly. Clinicians also should speak to the community about suicide, its warning signs, and how to address it. Just like with any disease, prevention is the most effective form of treatment.
As clinicians, we should always be on the lookout for suicide in our young patients, especially LGBT youth. For many LGBT youth, we may be the only source of support. If patients are suicidal, we should work with them to determine how to keep the them safe. We have a powerful voice in the community. We can advocate for making schools safe for LGBT youth and educate the community in suicide prevention. Such a powerful voice proclaiming that it gets better can save a life.
Resources
• The Trevor Project: A non-profit organization dedicated to prevent suicide in LGBT Youth (www.thetrevorproject.org)
• It Gets Better Project: Another website dedicated to preventing suicide in LGBT youth by promoting the message that life will improve for LGBT teens (www.itgetsbetter.org)
• Patient Safety Plan Template from the Suicide Prevention Resource Center (www.sprc.org)
References
1. CDC. NCIPC. Web-based Injury Statistics Query and Reporting System (WISQARS). 2010.
2. MMWR Surveill Summ. 2011 Jun 10;60(7):1-133.
3. Injustice at Every Turn: A Report of the National Transgender Discrimination Survey. (Washington: National Center for Transgender Equality and National Gay and Lesbian Task Force, 2011).
4. J Adolesc Health. 2014 Sep;55(3):432-8.
5. J Youth Adolesc. 2013 Mar;42(3):376-93.
6. J Youth Adolesc. 2010 Oct;39(10):1189-98.
7. School Psychology Review. 2008;37(2):202-16.
8. J Homosex. 2010;57(2):287-309.
9. Pediatrics. 2009 Jan;123(1):346-52.
10. J Child Adolesc Psychiatr Nurs. 2010 Nov;23(4):205-13.
11. Mayo Clin Proc. 2011 Aug;86(8):792-800.
12. Ital J Pediatr. 2015 Jul 7;41:49.
13. Ment Health Fam Med. 2008 Dec;5(4):229-35.
14. Know the Warning Signs of Suicide. American Association of Suicidology.
15. J Psychiatr Ment Health Nurs. 2008 Aug;15(6):512-22.
16. J Amer Acad Psych Law. 1999;27(3):445-50.
Dr. Montano is a physician at Children’s Hospital of Pittsburgh of UPMC and a clinical instructor of pediatrics at the University of Pittsburgh School of Medicine.
Suicide continues to be a major public health problem in the United States. It is the second leading cause of death in young people aged 10-24 years, according to 2010 injury data from the Centers from Disease Control and Prevention.1 This problem disproportionately affects lesbian, gay, bisexual, and transgender (LGBT) youth. Compared to their heterosexual peers, LGBT youth are four times as likely to attempt suicide.2 In addition, almost 50% of transgender youth have attempted suicide.3
Why are LGBT youth at high risk for suicide? Antigay and antitrans stigma and discrimination against LGBT youth create a very stressful environment. For example, LGBT youth are two times more likely than are heterosexual youth to experience bullying4 because of their sexual orientation, and half of transgender youth have reported bullying because of their gender identity.3 LGBT youth tend to perceive lower levels of parental support than do heterosexual youth.5-8 A combination of harassment from peers and decreased perceived support from families increases the risk for suicide in LGBT youth.
However, there are factors that can reduce this risk. LGBT youth whose parents reject their sexual orientation or gender identity are eight times as likely to be suicidal,3,9 while in contrast, LGBT youth whose parents are more accepting are less likely to be suicidal.10 These studies underscore the importance of social support in reducing the stress from antigay and antitrans discrimination, and therefore, play a role in preventing suicide.
Health care providers are another source of support for LGBT youth. They can play a role in providing education and preventing suicide in this population because many victims of suicide have visited a health care provider before attempting to kill themselves.11 It is important for providers to screen for suicide in their patients. Although there is no lab test for suicidal ideation, suicidal adolescents tend to have certain risk factors. In addition to being LGBT, being bullied, and having a lack of social support, other risk factors are psychiatric illness, a history of being impulsive, alcohol and substance abuse, and most important of all, a previous suicide attempt.12
When screening for suicide risk, always remember that at the beginning of any visit with an adolescent, remind them about confidentiality and its limits (e.g., breaking confidentiality if the patient is suicidal). Although this appears counterintuitive, it actually builds rapport between you and the patient. If you don’t discuss the limits of confidentiality beforehand and have to break it because the patient is suicidal, the patient is less likely to tell you again in the future. Once you suspect suicidal ideation based on the above risk factors, you can ask:
• Have you thought about ending your own life or would you rather be dead?
• Have you done something to harm yourself or to end your life?
• Have you considered ways to end your own life?12
Some clinicians have expressed concern over asking about suicide in their adolescent patients, but doing so does not induce suicidal thoughts.13 If a patient does express any of the above, the clinician must then inquire about other risk factors that increase the individual’s chances of completing suicide. The American Association of Suicidology has listed several warning signs of imminent suicide, which can be remembered with the acronym IS PATH WARM. This stands for Ideation, Substance use, Purposelessness, heightened Anxiety, feeling Trapped, feeling Hopeless, Withdrawal from friends and family, uncontrollable Anger, engaging in Reckless behavior, and dramatic Mood changes.14
If a patient threatens to kill him/herself, has a specific plan to do so, or speaks about death and suicide, then the clinician must act immediately. Although sending a patient to the emergency department is the safest option, it is not the only option. If a good support system is present, and the patient lives in an environment where he or she does not have the means to carry out a suicide (e.g., there are no guns in the home), then the clinician can create a safety plan for the patient. A safety plan is different from a “no suicide contract.” A no suicide contract is a written commitment that the patient does not engage in suicidal behavior. Many experts caution against a no suicide contract because it can create a false sense of security for the clinician and does not address the strategies needed to combat feelings of suicidality.15,16
Usually with a safety plan, the clinician and the patient identify several people the patient can contact if the patient feels suicidal. In addition, the clinician and the patient can discuss ways the patient can cope with his/her feelings or distract himself/herself from suicidal thoughts (e.g., going out for a walk, watching a movie, etc.). Finally, if these methods fail, patients are provided with emergency hotlines or directed to the emergency department. The Suicide Prevention Resource Center has a template of a patient safety plan.
Finally, clinicians should be proactive in preventing suicide, especially for LGBT youth. Because bullying is a risk factor for suicide, and because LGBT youth are disproportionately affected by bullying, clinicians should advocate for antibullying school policies and advocate for schools to be more LGBT friendly. Clinicians also should speak to the community about suicide, its warning signs, and how to address it. Just like with any disease, prevention is the most effective form of treatment.
As clinicians, we should always be on the lookout for suicide in our young patients, especially LGBT youth. For many LGBT youth, we may be the only source of support. If patients are suicidal, we should work with them to determine how to keep the them safe. We have a powerful voice in the community. We can advocate for making schools safe for LGBT youth and educate the community in suicide prevention. Such a powerful voice proclaiming that it gets better can save a life.
Resources
• The Trevor Project: A non-profit organization dedicated to prevent suicide in LGBT Youth (www.thetrevorproject.org)
• It Gets Better Project: Another website dedicated to preventing suicide in LGBT youth by promoting the message that life will improve for LGBT teens (www.itgetsbetter.org)
• Patient Safety Plan Template from the Suicide Prevention Resource Center (www.sprc.org)
References
1. CDC. NCIPC. Web-based Injury Statistics Query and Reporting System (WISQARS). 2010.
2. MMWR Surveill Summ. 2011 Jun 10;60(7):1-133.
3. Injustice at Every Turn: A Report of the National Transgender Discrimination Survey. (Washington: National Center for Transgender Equality and National Gay and Lesbian Task Force, 2011).
4. J Adolesc Health. 2014 Sep;55(3):432-8.
5. J Youth Adolesc. 2013 Mar;42(3):376-93.
6. J Youth Adolesc. 2010 Oct;39(10):1189-98.
7. School Psychology Review. 2008;37(2):202-16.
8. J Homosex. 2010;57(2):287-309.
9. Pediatrics. 2009 Jan;123(1):346-52.
10. J Child Adolesc Psychiatr Nurs. 2010 Nov;23(4):205-13.
11. Mayo Clin Proc. 2011 Aug;86(8):792-800.
12. Ital J Pediatr. 2015 Jul 7;41:49.
13. Ment Health Fam Med. 2008 Dec;5(4):229-35.
14. Know the Warning Signs of Suicide. American Association of Suicidology.
15. J Psychiatr Ment Health Nurs. 2008 Aug;15(6):512-22.
16. J Amer Acad Psych Law. 1999;27(3):445-50.
Dr. Montano is a physician at Children’s Hospital of Pittsburgh of UPMC and a clinical instructor of pediatrics at the University of Pittsburgh School of Medicine.
Suicide continues to be a major public health problem in the United States. It is the second leading cause of death in young people aged 10-24 years, according to 2010 injury data from the Centers from Disease Control and Prevention.1 This problem disproportionately affects lesbian, gay, bisexual, and transgender (LGBT) youth. Compared to their heterosexual peers, LGBT youth are four times as likely to attempt suicide.2 In addition, almost 50% of transgender youth have attempted suicide.3
Why are LGBT youth at high risk for suicide? Antigay and antitrans stigma and discrimination against LGBT youth create a very stressful environment. For example, LGBT youth are two times more likely than are heterosexual youth to experience bullying4 because of their sexual orientation, and half of transgender youth have reported bullying because of their gender identity.3 LGBT youth tend to perceive lower levels of parental support than do heterosexual youth.5-8 A combination of harassment from peers and decreased perceived support from families increases the risk for suicide in LGBT youth.
However, there are factors that can reduce this risk. LGBT youth whose parents reject their sexual orientation or gender identity are eight times as likely to be suicidal,3,9 while in contrast, LGBT youth whose parents are more accepting are less likely to be suicidal.10 These studies underscore the importance of social support in reducing the stress from antigay and antitrans discrimination, and therefore, play a role in preventing suicide.
Health care providers are another source of support for LGBT youth. They can play a role in providing education and preventing suicide in this population because many victims of suicide have visited a health care provider before attempting to kill themselves.11 It is important for providers to screen for suicide in their patients. Although there is no lab test for suicidal ideation, suicidal adolescents tend to have certain risk factors. In addition to being LGBT, being bullied, and having a lack of social support, other risk factors are psychiatric illness, a history of being impulsive, alcohol and substance abuse, and most important of all, a previous suicide attempt.12
When screening for suicide risk, always remember that at the beginning of any visit with an adolescent, remind them about confidentiality and its limits (e.g., breaking confidentiality if the patient is suicidal). Although this appears counterintuitive, it actually builds rapport between you and the patient. If you don’t discuss the limits of confidentiality beforehand and have to break it because the patient is suicidal, the patient is less likely to tell you again in the future. Once you suspect suicidal ideation based on the above risk factors, you can ask:
• Have you thought about ending your own life or would you rather be dead?
• Have you done something to harm yourself or to end your life?
• Have you considered ways to end your own life?12
Some clinicians have expressed concern over asking about suicide in their adolescent patients, but doing so does not induce suicidal thoughts.13 If a patient does express any of the above, the clinician must then inquire about other risk factors that increase the individual’s chances of completing suicide. The American Association of Suicidology has listed several warning signs of imminent suicide, which can be remembered with the acronym IS PATH WARM. This stands for Ideation, Substance use, Purposelessness, heightened Anxiety, feeling Trapped, feeling Hopeless, Withdrawal from friends and family, uncontrollable Anger, engaging in Reckless behavior, and dramatic Mood changes.14
If a patient threatens to kill him/herself, has a specific plan to do so, or speaks about death and suicide, then the clinician must act immediately. Although sending a patient to the emergency department is the safest option, it is not the only option. If a good support system is present, and the patient lives in an environment where he or she does not have the means to carry out a suicide (e.g., there are no guns in the home), then the clinician can create a safety plan for the patient. A safety plan is different from a “no suicide contract.” A no suicide contract is a written commitment that the patient does not engage in suicidal behavior. Many experts caution against a no suicide contract because it can create a false sense of security for the clinician and does not address the strategies needed to combat feelings of suicidality.15,16
Usually with a safety plan, the clinician and the patient identify several people the patient can contact if the patient feels suicidal. In addition, the clinician and the patient can discuss ways the patient can cope with his/her feelings or distract himself/herself from suicidal thoughts (e.g., going out for a walk, watching a movie, etc.). Finally, if these methods fail, patients are provided with emergency hotlines or directed to the emergency department. The Suicide Prevention Resource Center has a template of a patient safety plan.
Finally, clinicians should be proactive in preventing suicide, especially for LGBT youth. Because bullying is a risk factor for suicide, and because LGBT youth are disproportionately affected by bullying, clinicians should advocate for antibullying school policies and advocate for schools to be more LGBT friendly. Clinicians also should speak to the community about suicide, its warning signs, and how to address it. Just like with any disease, prevention is the most effective form of treatment.
As clinicians, we should always be on the lookout for suicide in our young patients, especially LGBT youth. For many LGBT youth, we may be the only source of support. If patients are suicidal, we should work with them to determine how to keep the them safe. We have a powerful voice in the community. We can advocate for making schools safe for LGBT youth and educate the community in suicide prevention. Such a powerful voice proclaiming that it gets better can save a life.
Resources
• The Trevor Project: A non-profit organization dedicated to prevent suicide in LGBT Youth (www.thetrevorproject.org)
• It Gets Better Project: Another website dedicated to preventing suicide in LGBT youth by promoting the message that life will improve for LGBT teens (www.itgetsbetter.org)
• Patient Safety Plan Template from the Suicide Prevention Resource Center (www.sprc.org)
References
1. CDC. NCIPC. Web-based Injury Statistics Query and Reporting System (WISQARS). 2010.
2. MMWR Surveill Summ. 2011 Jun 10;60(7):1-133.
3. Injustice at Every Turn: A Report of the National Transgender Discrimination Survey. (Washington: National Center for Transgender Equality and National Gay and Lesbian Task Force, 2011).
4. J Adolesc Health. 2014 Sep;55(3):432-8.
5. J Youth Adolesc. 2013 Mar;42(3):376-93.
6. J Youth Adolesc. 2010 Oct;39(10):1189-98.
7. School Psychology Review. 2008;37(2):202-16.
8. J Homosex. 2010;57(2):287-309.
9. Pediatrics. 2009 Jan;123(1):346-52.
10. J Child Adolesc Psychiatr Nurs. 2010 Nov;23(4):205-13.
11. Mayo Clin Proc. 2011 Aug;86(8):792-800.
12. Ital J Pediatr. 2015 Jul 7;41:49.
13. Ment Health Fam Med. 2008 Dec;5(4):229-35.
14. Know the Warning Signs of Suicide. American Association of Suicidology.
15. J Psychiatr Ment Health Nurs. 2008 Aug;15(6):512-22.
16. J Amer Acad Psych Law. 1999;27(3):445-50.
Dr. Montano is a physician at Children’s Hospital of Pittsburgh of UPMC and a clinical instructor of pediatrics at the University of Pittsburgh School of Medicine.
Medical boards investigating negligence
(This column is the second in a three-part series.)
Question: A penicillin-allergic patient died from massive hemolysis after receiving the antibiotic ceftriaxone (Rocephin). The plaintiff alleged that the defendant was grossly negligent in administering the drug and subsequently refusing to treat or to readmit the decedent.
If this case is referred to the state’s medical board, which of the following statements is best?
A. The outcome depends on the jurisdiction.
B. Substandard medical care is not part of professional misconduct, which is what a medical board is supposed to look at.
C. Disciplinary action requires a simple showing of ordinary negligence.
D. Disciplinary action requires more than one act of ordinary negligence.
E. Disciplinary action requires proof of gross negligence.
Answer: A. Under the Medical Practice Act, each state authorizes its medical board to issue licenses and regulate physician practice. Professional misconduct is about unprofessional behavior, and covers both ethical breach and substandard care.
Medical boards do not typically adjudicate single acts of ordinary negligence, leaving them instead to the tort system and civil lawsuits. However, grossly culpable misconduct – even in a single instance – or a recurring pattern of ordinary negligence can come under medical board review. And it is common practice for boards to use malpractice data as a tool to trigger further investigations, such as a certain number of malpractice settlements over a given span of time.
States vary somewhat over when to investigate a complaint of alleged substandard practice. In California, the term “unprofessional conduct” is codified under section 2234 of the California Business and Professions Code, and the errant doctor is subject to disciplinary sanction if there is gross negligence, repeated negligent acts (defined as two or more negligent acts or omissions), or incompetence.
In Hawaii, the disciplinary law is set up under Hawaii Revised Statutes section 453-8, which lists 15 situations of wrongdoing. In the malpractice category, Hawaii’s law uses the terms hazardous misconduct, hazardous negligence, incompetence, or multiple instances of negligence.
The state of New York defines professional misconduct by reference to a comprehensive list of 49 categories under section 6530, which include gross incompetence or gross negligence on a single occasion, or negligence or incompetence on more than one occasion.
However, Maryland is an example of a jurisdiction that does not require gross or repeated negligence; the state considers any failure to meet the appropriate medical standards as professional misconduct.1
But what constitutes gross negligence?
The vast majority of medical malpractice lawsuits allege ordinary, not gross negligence. Ordinary negligence is a well-defined legal term, as illustrated in Prosser’s Textbook on Torts: “The formula under which this usually is put to the jury is that the doctor must have and use the knowledge, skill, and care ordinarily possessed and employed by members of the profession in good standing.”2
In contrast, there is no universal definition for the term gross negligence. Everyone recognizes it denotes a greater degree of culpability than ordinary negligence, but how much greater?
According to the California Supreme Court, gross negligence may be said to be “the want of even scant care or an extreme departure from the ordinary standard of conduct.”3 The law in Texas stipulates: “Gross negligence means more than momentary thoughtlessness, inadvertence, or error of judgment. It means an entire want of care as to establish that the act or omission was the result of actual, conscious indifference to the rights, safety, and welfare of the person affected.”4
Examples in case law of gross negligence (or where punitive damages were awarded, which usually signify egregious conduct) include a doctor’s wanton failure to provide follow-up care for a child who developed fever and gangrenous toes following foot surgery,5 the prescription of an excessive number of birth control pills (more than 1,000 pills within a time period when less than 200 were sufficient) with resulting liver complications,6 and leaving behind a 6.5-inch clamp in a surgical incision.7
On the other hand, a Connecticut court (which decided the case in the hypothetical above) ruled that, under the facts, the defendant’s conduct did not meet the high threshold of egregiousness that defines gross negligence.8
As in any malpractice lawsuit, a medical board investigation involves determining whether the accused physician has met the standard of care in his or her specialty, and boards usually look to expert community physicians to articulate that requisite standard.
Compared with a civil lawsuit, a disciplinary hearing has the physician at a disadvantage. Medical board complaints are easier to file; the complaining party does not need an attorney; impartial expert witnesses are the responsibility of the board, not the complainant; and no patient injury needs to be shown.
Furthermore, a settlement is rarely reached or negotiated, and penalties are potentially far more serious, such as public posting of an adverse decision and restriction or actual loss of licensure.
Reputational loss also is arguably more devastating with board censure, because an adverse action taken by a medical board indicates a violation of the Medical Practice Act. In contrast, malpractice settlements or verdicts are regularly viewed as unreliable measures of a physician’s competence.
Still, two features work in favor of the doctor facing a board hearing. First, the misconduct typically has to be recurrent or grossly negligent, rather than an isolated case of carelessness. And second, some boards (only a small minority) require evidentiary proof of fault to be “clear and convincing,” instead of the familiar “more probable than not” standard that is used in a civil negligence suit. This makes it theoretically harder to reach a finding of culpability against the doctor.
References
1. Md. Code Ann. Health Occ. section 14-404.
2. Prosser and Keeton on Torts, 5th ed., 1984.
3. Van Meter v. Bent Construction Co., 297 P.2d 644 (Cal. 1956).
4. Texas Civil Practice & Remedies Code section 41.001(7).
5. Dempsey v. Phelps, 700 So.2d 1340 (Ala. 1997).
6. Jackson v. Taylor, 912 F.2d 795 (5th Cir. 1990).
7. Fox v. Oklahoma Memorial Hospital, 774 P.2d 459 (Ok. 1989).
8. Boone v. William W. Backus Hospital, 864 A.2d 1 (Conn. 2005).
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
(This column is the second in a three-part series.)
Question: A penicillin-allergic patient died from massive hemolysis after receiving the antibiotic ceftriaxone (Rocephin). The plaintiff alleged that the defendant was grossly negligent in administering the drug and subsequently refusing to treat or to readmit the decedent.
If this case is referred to the state’s medical board, which of the following statements is best?
A. The outcome depends on the jurisdiction.
B. Substandard medical care is not part of professional misconduct, which is what a medical board is supposed to look at.
C. Disciplinary action requires a simple showing of ordinary negligence.
D. Disciplinary action requires more than one act of ordinary negligence.
E. Disciplinary action requires proof of gross negligence.
Answer: A. Under the Medical Practice Act, each state authorizes its medical board to issue licenses and regulate physician practice. Professional misconduct is about unprofessional behavior, and covers both ethical breach and substandard care.
Medical boards do not typically adjudicate single acts of ordinary negligence, leaving them instead to the tort system and civil lawsuits. However, grossly culpable misconduct – even in a single instance – or a recurring pattern of ordinary negligence can come under medical board review. And it is common practice for boards to use malpractice data as a tool to trigger further investigations, such as a certain number of malpractice settlements over a given span of time.
States vary somewhat over when to investigate a complaint of alleged substandard practice. In California, the term “unprofessional conduct” is codified under section 2234 of the California Business and Professions Code, and the errant doctor is subject to disciplinary sanction if there is gross negligence, repeated negligent acts (defined as two or more negligent acts or omissions), or incompetence.
In Hawaii, the disciplinary law is set up under Hawaii Revised Statutes section 453-8, which lists 15 situations of wrongdoing. In the malpractice category, Hawaii’s law uses the terms hazardous misconduct, hazardous negligence, incompetence, or multiple instances of negligence.
The state of New York defines professional misconduct by reference to a comprehensive list of 49 categories under section 6530, which include gross incompetence or gross negligence on a single occasion, or negligence or incompetence on more than one occasion.
However, Maryland is an example of a jurisdiction that does not require gross or repeated negligence; the state considers any failure to meet the appropriate medical standards as professional misconduct.1
But what constitutes gross negligence?
The vast majority of medical malpractice lawsuits allege ordinary, not gross negligence. Ordinary negligence is a well-defined legal term, as illustrated in Prosser’s Textbook on Torts: “The formula under which this usually is put to the jury is that the doctor must have and use the knowledge, skill, and care ordinarily possessed and employed by members of the profession in good standing.”2
In contrast, there is no universal definition for the term gross negligence. Everyone recognizes it denotes a greater degree of culpability than ordinary negligence, but how much greater?
According to the California Supreme Court, gross negligence may be said to be “the want of even scant care or an extreme departure from the ordinary standard of conduct.”3 The law in Texas stipulates: “Gross negligence means more than momentary thoughtlessness, inadvertence, or error of judgment. It means an entire want of care as to establish that the act or omission was the result of actual, conscious indifference to the rights, safety, and welfare of the person affected.”4
Examples in case law of gross negligence (or where punitive damages were awarded, which usually signify egregious conduct) include a doctor’s wanton failure to provide follow-up care for a child who developed fever and gangrenous toes following foot surgery,5 the prescription of an excessive number of birth control pills (more than 1,000 pills within a time period when less than 200 were sufficient) with resulting liver complications,6 and leaving behind a 6.5-inch clamp in a surgical incision.7
On the other hand, a Connecticut court (which decided the case in the hypothetical above) ruled that, under the facts, the defendant’s conduct did not meet the high threshold of egregiousness that defines gross negligence.8
As in any malpractice lawsuit, a medical board investigation involves determining whether the accused physician has met the standard of care in his or her specialty, and boards usually look to expert community physicians to articulate that requisite standard.
Compared with a civil lawsuit, a disciplinary hearing has the physician at a disadvantage. Medical board complaints are easier to file; the complaining party does not need an attorney; impartial expert witnesses are the responsibility of the board, not the complainant; and no patient injury needs to be shown.
Furthermore, a settlement is rarely reached or negotiated, and penalties are potentially far more serious, such as public posting of an adverse decision and restriction or actual loss of licensure.
Reputational loss also is arguably more devastating with board censure, because an adverse action taken by a medical board indicates a violation of the Medical Practice Act. In contrast, malpractice settlements or verdicts are regularly viewed as unreliable measures of a physician’s competence.
Still, two features work in favor of the doctor facing a board hearing. First, the misconduct typically has to be recurrent or grossly negligent, rather than an isolated case of carelessness. And second, some boards (only a small minority) require evidentiary proof of fault to be “clear and convincing,” instead of the familiar “more probable than not” standard that is used in a civil negligence suit. This makes it theoretically harder to reach a finding of culpability against the doctor.
References
1. Md. Code Ann. Health Occ. section 14-404.
2. Prosser and Keeton on Torts, 5th ed., 1984.
3. Van Meter v. Bent Construction Co., 297 P.2d 644 (Cal. 1956).
4. Texas Civil Practice & Remedies Code section 41.001(7).
5. Dempsey v. Phelps, 700 So.2d 1340 (Ala. 1997).
6. Jackson v. Taylor, 912 F.2d 795 (5th Cir. 1990).
7. Fox v. Oklahoma Memorial Hospital, 774 P.2d 459 (Ok. 1989).
8. Boone v. William W. Backus Hospital, 864 A.2d 1 (Conn. 2005).
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
(This column is the second in a three-part series.)
Question: A penicillin-allergic patient died from massive hemolysis after receiving the antibiotic ceftriaxone (Rocephin). The plaintiff alleged that the defendant was grossly negligent in administering the drug and subsequently refusing to treat or to readmit the decedent.
If this case is referred to the state’s medical board, which of the following statements is best?
A. The outcome depends on the jurisdiction.
B. Substandard medical care is not part of professional misconduct, which is what a medical board is supposed to look at.
C. Disciplinary action requires a simple showing of ordinary negligence.
D. Disciplinary action requires more than one act of ordinary negligence.
E. Disciplinary action requires proof of gross negligence.
Answer: A. Under the Medical Practice Act, each state authorizes its medical board to issue licenses and regulate physician practice. Professional misconduct is about unprofessional behavior, and covers both ethical breach and substandard care.
Medical boards do not typically adjudicate single acts of ordinary negligence, leaving them instead to the tort system and civil lawsuits. However, grossly culpable misconduct – even in a single instance – or a recurring pattern of ordinary negligence can come under medical board review. And it is common practice for boards to use malpractice data as a tool to trigger further investigations, such as a certain number of malpractice settlements over a given span of time.
States vary somewhat over when to investigate a complaint of alleged substandard practice. In California, the term “unprofessional conduct” is codified under section 2234 of the California Business and Professions Code, and the errant doctor is subject to disciplinary sanction if there is gross negligence, repeated negligent acts (defined as two or more negligent acts or omissions), or incompetence.
In Hawaii, the disciplinary law is set up under Hawaii Revised Statutes section 453-8, which lists 15 situations of wrongdoing. In the malpractice category, Hawaii’s law uses the terms hazardous misconduct, hazardous negligence, incompetence, or multiple instances of negligence.
The state of New York defines professional misconduct by reference to a comprehensive list of 49 categories under section 6530, which include gross incompetence or gross negligence on a single occasion, or negligence or incompetence on more than one occasion.
However, Maryland is an example of a jurisdiction that does not require gross or repeated negligence; the state considers any failure to meet the appropriate medical standards as professional misconduct.1
But what constitutes gross negligence?
The vast majority of medical malpractice lawsuits allege ordinary, not gross negligence. Ordinary negligence is a well-defined legal term, as illustrated in Prosser’s Textbook on Torts: “The formula under which this usually is put to the jury is that the doctor must have and use the knowledge, skill, and care ordinarily possessed and employed by members of the profession in good standing.”2
In contrast, there is no universal definition for the term gross negligence. Everyone recognizes it denotes a greater degree of culpability than ordinary negligence, but how much greater?
According to the California Supreme Court, gross negligence may be said to be “the want of even scant care or an extreme departure from the ordinary standard of conduct.”3 The law in Texas stipulates: “Gross negligence means more than momentary thoughtlessness, inadvertence, or error of judgment. It means an entire want of care as to establish that the act or omission was the result of actual, conscious indifference to the rights, safety, and welfare of the person affected.”4
Examples in case law of gross negligence (or where punitive damages were awarded, which usually signify egregious conduct) include a doctor’s wanton failure to provide follow-up care for a child who developed fever and gangrenous toes following foot surgery,5 the prescription of an excessive number of birth control pills (more than 1,000 pills within a time period when less than 200 were sufficient) with resulting liver complications,6 and leaving behind a 6.5-inch clamp in a surgical incision.7
On the other hand, a Connecticut court (which decided the case in the hypothetical above) ruled that, under the facts, the defendant’s conduct did not meet the high threshold of egregiousness that defines gross negligence.8
As in any malpractice lawsuit, a medical board investigation involves determining whether the accused physician has met the standard of care in his or her specialty, and boards usually look to expert community physicians to articulate that requisite standard.
Compared with a civil lawsuit, a disciplinary hearing has the physician at a disadvantage. Medical board complaints are easier to file; the complaining party does not need an attorney; impartial expert witnesses are the responsibility of the board, not the complainant; and no patient injury needs to be shown.
Furthermore, a settlement is rarely reached or negotiated, and penalties are potentially far more serious, such as public posting of an adverse decision and restriction or actual loss of licensure.
Reputational loss also is arguably more devastating with board censure, because an adverse action taken by a medical board indicates a violation of the Medical Practice Act. In contrast, malpractice settlements or verdicts are regularly viewed as unreliable measures of a physician’s competence.
Still, two features work in favor of the doctor facing a board hearing. First, the misconduct typically has to be recurrent or grossly negligent, rather than an isolated case of carelessness. And second, some boards (only a small minority) require evidentiary proof of fault to be “clear and convincing,” instead of the familiar “more probable than not” standard that is used in a civil negligence suit. This makes it theoretically harder to reach a finding of culpability against the doctor.
References
1. Md. Code Ann. Health Occ. section 14-404.
2. Prosser and Keeton on Torts, 5th ed., 1984.
3. Van Meter v. Bent Construction Co., 297 P.2d 644 (Cal. 1956).
4. Texas Civil Practice & Remedies Code section 41.001(7).
5. Dempsey v. Phelps, 700 So.2d 1340 (Ala. 1997).
6. Jackson v. Taylor, 912 F.2d 795 (5th Cir. 1990).
7. Fox v. Oklahoma Memorial Hospital, 774 P.2d 459 (Ok. 1989).
8. Boone v. William W. Backus Hospital, 864 A.2d 1 (Conn. 2005).
Dr. Tan is emeritus professor of medicine and former adjunct professor of law at the University of Hawaii, and currently directs the St. Francis International Center for Healthcare Ethics in Honolulu. This article is meant to be educational and does not constitute medical, ethical, or legal advice. Some of the articles in this series are adapted from the author’s 2006 book, “Medical Malpractice: Understanding the Law, Managing the Risk,” and his 2012 Halsbury treatise, “Medical Negligence and Professional Misconduct.” For additional information, readers may contact the author at [email protected].
Quality or convenience: Pick one
A 35-year-old male with a 5-year-history of a changing mole on his back sends a picture of the lesion to a telemedicine website for advice. The photo reveals a black nodule. The clinician replies, advising the patient that the lesion is benign.
To most dermatologists, the above scenario would occur only in a bizarre nightmare, never in real life. In real life, if the words “black” and “nodule” are used to describe a lesion, they are followed by the verb “biopsy.” Most dermatologists would recognize this as a high-risk growth and recommend additional investigation.
Unfortunately, a recent study of direct-to-consumer (DTC) telemedicine in JAMA Dermatology showed that 21% of the time, the patient was wrongfully reassured that a lesion was benign (JAMA Dermatol. 2016;152[7]:768-75). The study examined how 16 DTC telemedicine websites and apps handled six standardized dermatology cases designed to test the quality of the services. While some provided good care, others missed important diagnoses such as syphilis, eczema herpeticum, and melanoma. If these cases had been actual patients, the consequences for such mistakes could have been dire.
“The services failed to ask simple, relevant questions of patients about their symptoms, leading them to repeatedly miss important diagnoses,” Jack Resneck Jr., MD, a dermatologist at the University of California, San Francisco, and lead author of the study, told the Wall Street Journal.
The study is timely, as telemedicine is accelerating explosively. The low cost of connectivity, viable business models, and changing consumer behaviors are fueling its rocket growth. Startups in digital health and telemedicine have raised over $700 million already this year, indicating that there is more fuel to be burned and more money to be made.
DTC telemedicine describes the model when a patient sends photos directly to a clinician without a prior history with that provider. A teleconsultation, in contrast, is an interaction between two doctors. In DTC, the episode of care is usually isolated from the patient’s record, and the information is not transferred to the primary care physician. Patients pay a fee, which can range from $1.59 to $250.
Advocates of DTC cite its low cost and extraordinary convenience as arguments for its adoption. However, these disconnected visits are notable exceptions to the current trend toward better care coordination and information sharing among providers.
Quality is also a concern. Although consumers were often promised answers from board-certified physicians, the JAMA Dermatology study was unable to verify this in many cases. The researchers also found that nondermatologists, physician extenders, and physicians practicing in India were often the providers, facts that were not obvious to users.
Worse, the study found both the quality of the diagnoses and the recommendations were poor. All the providers missed the cases of syphilis and most missed eczema herpeticum. Risks of prescription medications were not disclosed two-thirds of the time. Worse yet, three services mistakenly advised that a nodular melanoma did not need further treatment. Had these been real patients, such wrongful recommendations could have resulted in deaths.
In an effort to ensure safety and reliability for consumers, the American Telemedicine Association has begun credentialing telemedicine providers. Such credentials are not required, however, and consumers are likely to be unaware of which providers have or have not met this standard. The American Academy of Dermatology addresses DTC teledermatology in its position statement, updated in 2016: “Dermatologists providing direct-to-patient teledermatology must make every effort to collect accurate, complete, and quality clinical information. When appropriate, the dermatologist may wish to contact the primary care providers or other specialists to obtain additional corroborating information.”
Currently, patients remain on their own in choosing telemedicine and other digital health services: caveat emptor. Do they want quality and convenient care? For now, it seems, they must pick only one.
Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego. He is @Dermdoc on Twitter. Write to him at [email protected].
A 35-year-old male with a 5-year-history of a changing mole on his back sends a picture of the lesion to a telemedicine website for advice. The photo reveals a black nodule. The clinician replies, advising the patient that the lesion is benign.
To most dermatologists, the above scenario would occur only in a bizarre nightmare, never in real life. In real life, if the words “black” and “nodule” are used to describe a lesion, they are followed by the verb “biopsy.” Most dermatologists would recognize this as a high-risk growth and recommend additional investigation.
Unfortunately, a recent study of direct-to-consumer (DTC) telemedicine in JAMA Dermatology showed that 21% of the time, the patient was wrongfully reassured that a lesion was benign (JAMA Dermatol. 2016;152[7]:768-75). The study examined how 16 DTC telemedicine websites and apps handled six standardized dermatology cases designed to test the quality of the services. While some provided good care, others missed important diagnoses such as syphilis, eczema herpeticum, and melanoma. If these cases had been actual patients, the consequences for such mistakes could have been dire.
“The services failed to ask simple, relevant questions of patients about their symptoms, leading them to repeatedly miss important diagnoses,” Jack Resneck Jr., MD, a dermatologist at the University of California, San Francisco, and lead author of the study, told the Wall Street Journal.
The study is timely, as telemedicine is accelerating explosively. The low cost of connectivity, viable business models, and changing consumer behaviors are fueling its rocket growth. Startups in digital health and telemedicine have raised over $700 million already this year, indicating that there is more fuel to be burned and more money to be made.
DTC telemedicine describes the model when a patient sends photos directly to a clinician without a prior history with that provider. A teleconsultation, in contrast, is an interaction between two doctors. In DTC, the episode of care is usually isolated from the patient’s record, and the information is not transferred to the primary care physician. Patients pay a fee, which can range from $1.59 to $250.
Advocates of DTC cite its low cost and extraordinary convenience as arguments for its adoption. However, these disconnected visits are notable exceptions to the current trend toward better care coordination and information sharing among providers.
Quality is also a concern. Although consumers were often promised answers from board-certified physicians, the JAMA Dermatology study was unable to verify this in many cases. The researchers also found that nondermatologists, physician extenders, and physicians practicing in India were often the providers, facts that were not obvious to users.
Worse, the study found both the quality of the diagnoses and the recommendations were poor. All the providers missed the cases of syphilis and most missed eczema herpeticum. Risks of prescription medications were not disclosed two-thirds of the time. Worse yet, three services mistakenly advised that a nodular melanoma did not need further treatment. Had these been real patients, such wrongful recommendations could have resulted in deaths.
In an effort to ensure safety and reliability for consumers, the American Telemedicine Association has begun credentialing telemedicine providers. Such credentials are not required, however, and consumers are likely to be unaware of which providers have or have not met this standard. The American Academy of Dermatology addresses DTC teledermatology in its position statement, updated in 2016: “Dermatologists providing direct-to-patient teledermatology must make every effort to collect accurate, complete, and quality clinical information. When appropriate, the dermatologist may wish to contact the primary care providers or other specialists to obtain additional corroborating information.”
Currently, patients remain on their own in choosing telemedicine and other digital health services: caveat emptor. Do they want quality and convenient care? For now, it seems, they must pick only one.
Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego. He is @Dermdoc on Twitter. Write to him at [email protected].
A 35-year-old male with a 5-year-history of a changing mole on his back sends a picture of the lesion to a telemedicine website for advice. The photo reveals a black nodule. The clinician replies, advising the patient that the lesion is benign.
To most dermatologists, the above scenario would occur only in a bizarre nightmare, never in real life. In real life, if the words “black” and “nodule” are used to describe a lesion, they are followed by the verb “biopsy.” Most dermatologists would recognize this as a high-risk growth and recommend additional investigation.
Unfortunately, a recent study of direct-to-consumer (DTC) telemedicine in JAMA Dermatology showed that 21% of the time, the patient was wrongfully reassured that a lesion was benign (JAMA Dermatol. 2016;152[7]:768-75). The study examined how 16 DTC telemedicine websites and apps handled six standardized dermatology cases designed to test the quality of the services. While some provided good care, others missed important diagnoses such as syphilis, eczema herpeticum, and melanoma. If these cases had been actual patients, the consequences for such mistakes could have been dire.
“The services failed to ask simple, relevant questions of patients about their symptoms, leading them to repeatedly miss important diagnoses,” Jack Resneck Jr., MD, a dermatologist at the University of California, San Francisco, and lead author of the study, told the Wall Street Journal.
The study is timely, as telemedicine is accelerating explosively. The low cost of connectivity, viable business models, and changing consumer behaviors are fueling its rocket growth. Startups in digital health and telemedicine have raised over $700 million already this year, indicating that there is more fuel to be burned and more money to be made.
DTC telemedicine describes the model when a patient sends photos directly to a clinician without a prior history with that provider. A teleconsultation, in contrast, is an interaction between two doctors. In DTC, the episode of care is usually isolated from the patient’s record, and the information is not transferred to the primary care physician. Patients pay a fee, which can range from $1.59 to $250.
Advocates of DTC cite its low cost and extraordinary convenience as arguments for its adoption. However, these disconnected visits are notable exceptions to the current trend toward better care coordination and information sharing among providers.
Quality is also a concern. Although consumers were often promised answers from board-certified physicians, the JAMA Dermatology study was unable to verify this in many cases. The researchers also found that nondermatologists, physician extenders, and physicians practicing in India were often the providers, facts that were not obvious to users.
Worse, the study found both the quality of the diagnoses and the recommendations were poor. All the providers missed the cases of syphilis and most missed eczema herpeticum. Risks of prescription medications were not disclosed two-thirds of the time. Worse yet, three services mistakenly advised that a nodular melanoma did not need further treatment. Had these been real patients, such wrongful recommendations could have resulted in deaths.
In an effort to ensure safety and reliability for consumers, the American Telemedicine Association has begun credentialing telemedicine providers. Such credentials are not required, however, and consumers are likely to be unaware of which providers have or have not met this standard. The American Academy of Dermatology addresses DTC teledermatology in its position statement, updated in 2016: “Dermatologists providing direct-to-patient teledermatology must make every effort to collect accurate, complete, and quality clinical information. When appropriate, the dermatologist may wish to contact the primary care providers or other specialists to obtain additional corroborating information.”
Currently, patients remain on their own in choosing telemedicine and other digital health services: caveat emptor. Do they want quality and convenient care? For now, it seems, they must pick only one.
Dr. Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego. He is @Dermdoc on Twitter. Write to him at [email protected].
Leveraging what is available
Illicit drug use in the United States continues to rise. In 2014, 27 million people reported using an illicit drug in the previous 30 days. This corresponds to nearly 1 in every 10 Americans.
Use of marijuana has the highest prevalence, followed distantly by pain relievers, tranquilizers, stimulants, and cocaine. Resources for drug users who want to quit are difficult to access – and even if those resources are available, they may be constrained.
For patients struggling with alcohol dependence who want to quit, Alcoholics Anonymous (AA) is the most well-known and ubiquitous 12-step mutual help organization (MHO). Other MHOs, such as Narcotics Anonymous (NA), exist for illicit substances such as opiates (e.g., heroin), stimulants, or cannabis. Shared experiences are hypothesized to maximize therapeutic benefit.
But what, then, should we do if somebody struggling with illicit substance dependence wants to remain abstinent from drugs and there are only AA groups around?
Harvard investigators suggest that support from AA for patients with illicit substance addiction is not associated with early discontinuation or compromised recovery. To evaluate this, researchers examined treatment outcomes among young adults participating in residential treatment in Minnesota (Alcohol Alcohol. 2014 Nov;49[6]:645-3).
Four groups of patients with drug use disorder were evaluated: alcohol, cannabis, opiates, or stimulants. The goal was to compare the relative success of individuals with fellowship “mismatch” (e.g., attending AA but was a primary user of cannabis), compared with those who had a fellowship match. Success during aftercare was defined as percentage of days abstinent and attendance at the MHO.
Investigators observed that in the first 3 months after discharge from the residential treatment program, a significant proportion (79%) of the meetings attended by the cannabis, opiates, or stimulant users were AA meetings. This mismatch was unrelated to 12-step attendance at 6 and 12 months, or to percentage of days abstinent.
Available literature suggests that 12-step MHO participation is a predictor of better treatment outcomes. The findings from this study suggest that AA attendance among patients recovering from cannabis, opiates, or stimulant use disorder is beneficial. Patients with illicit drug use disorder should be encouraged to attend AA if other MHOs are not accessible.
Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no financial disclosures relevant to this article.
Illicit drug use in the United States continues to rise. In 2014, 27 million people reported using an illicit drug in the previous 30 days. This corresponds to nearly 1 in every 10 Americans.
Use of marijuana has the highest prevalence, followed distantly by pain relievers, tranquilizers, stimulants, and cocaine. Resources for drug users who want to quit are difficult to access – and even if those resources are available, they may be constrained.
For patients struggling with alcohol dependence who want to quit, Alcoholics Anonymous (AA) is the most well-known and ubiquitous 12-step mutual help organization (MHO). Other MHOs, such as Narcotics Anonymous (NA), exist for illicit substances such as opiates (e.g., heroin), stimulants, or cannabis. Shared experiences are hypothesized to maximize therapeutic benefit.
But what, then, should we do if somebody struggling with illicit substance dependence wants to remain abstinent from drugs and there are only AA groups around?
Harvard investigators suggest that support from AA for patients with illicit substance addiction is not associated with early discontinuation or compromised recovery. To evaluate this, researchers examined treatment outcomes among young adults participating in residential treatment in Minnesota (Alcohol Alcohol. 2014 Nov;49[6]:645-3).
Four groups of patients with drug use disorder were evaluated: alcohol, cannabis, opiates, or stimulants. The goal was to compare the relative success of individuals with fellowship “mismatch” (e.g., attending AA but was a primary user of cannabis), compared with those who had a fellowship match. Success during aftercare was defined as percentage of days abstinent and attendance at the MHO.
Investigators observed that in the first 3 months after discharge from the residential treatment program, a significant proportion (79%) of the meetings attended by the cannabis, opiates, or stimulant users were AA meetings. This mismatch was unrelated to 12-step attendance at 6 and 12 months, or to percentage of days abstinent.
Available literature suggests that 12-step MHO participation is a predictor of better treatment outcomes. The findings from this study suggest that AA attendance among patients recovering from cannabis, opiates, or stimulant use disorder is beneficial. Patients with illicit drug use disorder should be encouraged to attend AA if other MHOs are not accessible.
Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no financial disclosures relevant to this article.
Illicit drug use in the United States continues to rise. In 2014, 27 million people reported using an illicit drug in the previous 30 days. This corresponds to nearly 1 in every 10 Americans.
Use of marijuana has the highest prevalence, followed distantly by pain relievers, tranquilizers, stimulants, and cocaine. Resources for drug users who want to quit are difficult to access – and even if those resources are available, they may be constrained.
For patients struggling with alcohol dependence who want to quit, Alcoholics Anonymous (AA) is the most well-known and ubiquitous 12-step mutual help organization (MHO). Other MHOs, such as Narcotics Anonymous (NA), exist for illicit substances such as opiates (e.g., heroin), stimulants, or cannabis. Shared experiences are hypothesized to maximize therapeutic benefit.
But what, then, should we do if somebody struggling with illicit substance dependence wants to remain abstinent from drugs and there are only AA groups around?
Harvard investigators suggest that support from AA for patients with illicit substance addiction is not associated with early discontinuation or compromised recovery. To evaluate this, researchers examined treatment outcomes among young adults participating in residential treatment in Minnesota (Alcohol Alcohol. 2014 Nov;49[6]:645-3).
Four groups of patients with drug use disorder were evaluated: alcohol, cannabis, opiates, or stimulants. The goal was to compare the relative success of individuals with fellowship “mismatch” (e.g., attending AA but was a primary user of cannabis), compared with those who had a fellowship match. Success during aftercare was defined as percentage of days abstinent and attendance at the MHO.
Investigators observed that in the first 3 months after discharge from the residential treatment program, a significant proportion (79%) of the meetings attended by the cannabis, opiates, or stimulant users were AA meetings. This mismatch was unrelated to 12-step attendance at 6 and 12 months, or to percentage of days abstinent.
Available literature suggests that 12-step MHO participation is a predictor of better treatment outcomes. The findings from this study suggest that AA attendance among patients recovering from cannabis, opiates, or stimulant use disorder is beneficial. Patients with illicit drug use disorder should be encouraged to attend AA if other MHOs are not accessible.
Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author and do not necessarily represent the views and opinions of the Mayo Clinic. The opinions expressed in this article should not be used to diagnose or treat any medical condition, nor should they be used as a substitute for medical advice from a qualified, board-certified practicing clinician. Dr. Ebbert has no financial disclosures relevant to this article.
The frequency of influenza and bacterial coinfection
Treatment of patients admitted to the hospital with an upper respiratory infection is often complicated by the lack of diagnostics. Even in cases where a patient has a confirmed case of influenza, there is still the possibility that they may have, or become infected by, a secondary bacterial infection. This leads clinicians to treat patients empirically with antibiotics, which can result in unnecessary antibiotic use among patients without a bacterial infection.
Though antibiotics can be a lifesaving drug, their use is not without risks. Estimates suggest that 20% of patients taking common antibiotics experience some side effect. While most side effects are not life-threatening gastrointestinal effects, other nonnegligible side effects include anaphylactic shock, drug‐induced liver injury, increases in the risk of retinal detachment, serious arrhythmias, and superinfection with resistant bacteria. Antibiotics can also lead to secondary infections, such as Clostridium difficile.
Yet, despite these risks, there has been limited research on the percentage of patients with influenza who actually have a bacterial coinfection. A recent systematic review and meta-analysis conducted by my colleagues at Johns Hopkins University and the Center for Disease Dynamics, Economics & Policy examined the frequency of bacterial coinfection among hospitalized patients with influenza and identified the most common infecting bacterial species.
The findings, published in the journal Influenza and Other Respiratory Viruses, found that in the majority of studies, between 11% and 35% of patients with confirmed influenza had a bacterial coinfection. The most common coinfecting bacteria were found to be Streptococcus pneumoniae and Staphylococcus aureus. Combined, S. pneumoniae and S. aureus accounted for more than 60% of the identified coinfecting bacteria; however, many other bacterial species were found to cause infections as well.
The results suggest that while bacterial infection is common in influenza patients, only about a quarter of patients are likely to be infected. However, the studies were widely heterogeneous, both in patient makeup and results. Analyses of age, setting, enrollment year, study type, study size, and bacterial collection methods did not reveal a source for the heterogeneity in results. Thus, additional factors, such as patient comorbidities or prior antibiotic use, which could not be systematically assessed, may affect the likelihood of coinfection.
Given that the symptoms of influenza and bacterial infection often overlap, correctly diagnosing bacterial coinfection without a laboratory culture can present a challenge. This diagnostic uncertainty leads to significant overuse of antibiotics in patients with influenza alone. Most influenza cases will never result in serious bacterial infections (particularly in nonhospitalized patients), and thus a lot of antibiotic use is unnecessary. As mentioned earlier, unnecessary antibiotic use poses a nonnegligible risk to patients, but it also contributes significantly to rising rates of antibiotic resistance, a major public health issue.
The results from this study highlight that the majority of patients hospitalized with influenza are unlikely to be coinfected with a bacterial pathogen. Thus, it is important for clinicians to appropriately treat patients with antiviral drugs, and ensure that bacterial testing is done when presumptively starting patients on antibiotics. Based on the microbiology results, antibiotics can be stopped if no pathogen is identified or altered to be more appropriate depending on the pathogen found.
Although the findings of this study suggest we need a more thorough analysis of the issue, the results should still aid clinicians by improving their understanding of the likelihood of bacterial coinfection in hospitalized patients with influenza, and thus help them balance the need to minimize patient risks as well as the individual and societal risks of nonessential antibiotic use.
Eili Klein, PhD, is assistant professor in the department of emergency medicine at Johns Hopkins Medicine, Baltimore.
Treatment of patients admitted to the hospital with an upper respiratory infection is often complicated by the lack of diagnostics. Even in cases where a patient has a confirmed case of influenza, there is still the possibility that they may have, or become infected by, a secondary bacterial infection. This leads clinicians to treat patients empirically with antibiotics, which can result in unnecessary antibiotic use among patients without a bacterial infection.
Though antibiotics can be a lifesaving drug, their use is not without risks. Estimates suggest that 20% of patients taking common antibiotics experience some side effect. While most side effects are not life-threatening gastrointestinal effects, other nonnegligible side effects include anaphylactic shock, drug‐induced liver injury, increases in the risk of retinal detachment, serious arrhythmias, and superinfection with resistant bacteria. Antibiotics can also lead to secondary infections, such as Clostridium difficile.
Yet, despite these risks, there has been limited research on the percentage of patients with influenza who actually have a bacterial coinfection. A recent systematic review and meta-analysis conducted by my colleagues at Johns Hopkins University and the Center for Disease Dynamics, Economics & Policy examined the frequency of bacterial coinfection among hospitalized patients with influenza and identified the most common infecting bacterial species.
The findings, published in the journal Influenza and Other Respiratory Viruses, found that in the majority of studies, between 11% and 35% of patients with confirmed influenza had a bacterial coinfection. The most common coinfecting bacteria were found to be Streptococcus pneumoniae and Staphylococcus aureus. Combined, S. pneumoniae and S. aureus accounted for more than 60% of the identified coinfecting bacteria; however, many other bacterial species were found to cause infections as well.
The results suggest that while bacterial infection is common in influenza patients, only about a quarter of patients are likely to be infected. However, the studies were widely heterogeneous, both in patient makeup and results. Analyses of age, setting, enrollment year, study type, study size, and bacterial collection methods did not reveal a source for the heterogeneity in results. Thus, additional factors, such as patient comorbidities or prior antibiotic use, which could not be systematically assessed, may affect the likelihood of coinfection.
Given that the symptoms of influenza and bacterial infection often overlap, correctly diagnosing bacterial coinfection without a laboratory culture can present a challenge. This diagnostic uncertainty leads to significant overuse of antibiotics in patients with influenza alone. Most influenza cases will never result in serious bacterial infections (particularly in nonhospitalized patients), and thus a lot of antibiotic use is unnecessary. As mentioned earlier, unnecessary antibiotic use poses a nonnegligible risk to patients, but it also contributes significantly to rising rates of antibiotic resistance, a major public health issue.
The results from this study highlight that the majority of patients hospitalized with influenza are unlikely to be coinfected with a bacterial pathogen. Thus, it is important for clinicians to appropriately treat patients with antiviral drugs, and ensure that bacterial testing is done when presumptively starting patients on antibiotics. Based on the microbiology results, antibiotics can be stopped if no pathogen is identified or altered to be more appropriate depending on the pathogen found.
Although the findings of this study suggest we need a more thorough analysis of the issue, the results should still aid clinicians by improving their understanding of the likelihood of bacterial coinfection in hospitalized patients with influenza, and thus help them balance the need to minimize patient risks as well as the individual and societal risks of nonessential antibiotic use.
Eili Klein, PhD, is assistant professor in the department of emergency medicine at Johns Hopkins Medicine, Baltimore.
Treatment of patients admitted to the hospital with an upper respiratory infection is often complicated by the lack of diagnostics. Even in cases where a patient has a confirmed case of influenza, there is still the possibility that they may have, or become infected by, a secondary bacterial infection. This leads clinicians to treat patients empirically with antibiotics, which can result in unnecessary antibiotic use among patients without a bacterial infection.
Though antibiotics can be a lifesaving drug, their use is not without risks. Estimates suggest that 20% of patients taking common antibiotics experience some side effect. While most side effects are not life-threatening gastrointestinal effects, other nonnegligible side effects include anaphylactic shock, drug‐induced liver injury, increases in the risk of retinal detachment, serious arrhythmias, and superinfection with resistant bacteria. Antibiotics can also lead to secondary infections, such as Clostridium difficile.
Yet, despite these risks, there has been limited research on the percentage of patients with influenza who actually have a bacterial coinfection. A recent systematic review and meta-analysis conducted by my colleagues at Johns Hopkins University and the Center for Disease Dynamics, Economics & Policy examined the frequency of bacterial coinfection among hospitalized patients with influenza and identified the most common infecting bacterial species.
The findings, published in the journal Influenza and Other Respiratory Viruses, found that in the majority of studies, between 11% and 35% of patients with confirmed influenza had a bacterial coinfection. The most common coinfecting bacteria were found to be Streptococcus pneumoniae and Staphylococcus aureus. Combined, S. pneumoniae and S. aureus accounted for more than 60% of the identified coinfecting bacteria; however, many other bacterial species were found to cause infections as well.
The results suggest that while bacterial infection is common in influenza patients, only about a quarter of patients are likely to be infected. However, the studies were widely heterogeneous, both in patient makeup and results. Analyses of age, setting, enrollment year, study type, study size, and bacterial collection methods did not reveal a source for the heterogeneity in results. Thus, additional factors, such as patient comorbidities or prior antibiotic use, which could not be systematically assessed, may affect the likelihood of coinfection.
Given that the symptoms of influenza and bacterial infection often overlap, correctly diagnosing bacterial coinfection without a laboratory culture can present a challenge. This diagnostic uncertainty leads to significant overuse of antibiotics in patients with influenza alone. Most influenza cases will never result in serious bacterial infections (particularly in nonhospitalized patients), and thus a lot of antibiotic use is unnecessary. As mentioned earlier, unnecessary antibiotic use poses a nonnegligible risk to patients, but it also contributes significantly to rising rates of antibiotic resistance, a major public health issue.
The results from this study highlight that the majority of patients hospitalized with influenza are unlikely to be coinfected with a bacterial pathogen. Thus, it is important for clinicians to appropriately treat patients with antiviral drugs, and ensure that bacterial testing is done when presumptively starting patients on antibiotics. Based on the microbiology results, antibiotics can be stopped if no pathogen is identified or altered to be more appropriate depending on the pathogen found.
Although the findings of this study suggest we need a more thorough analysis of the issue, the results should still aid clinicians by improving their understanding of the likelihood of bacterial coinfection in hospitalized patients with influenza, and thus help them balance the need to minimize patient risks as well as the individual and societal risks of nonessential antibiotic use.
Eili Klein, PhD, is assistant professor in the department of emergency medicine at Johns Hopkins Medicine, Baltimore.
Getting prior lab results is worth the effort
Many patients we see need blood work as part of their evaluation. Although labs are cheap compared with other tests we order, they can still be frustrating to get.
It’s not hard to order them. Ordering any test is pretty easy.
But I hate duplicating tests. Patients often say they just had labs done, which “were all fine,” but that tells me nothing. For all I know, it was a lipid panel and PSA, entirely unrelated to what I’m seeing them for.
Occasionally, they bring labs in with them, or I’ve gotten them in advance, but usually I’m working blind.
Back when I was new to practice, I just ordered everything I wanted. I figured it was easier than trying to get the previous ones. I think we all do that sometimes. And there’s kind of an ivory-tower mentality we all have early in our careers that “I’m the doctor, and I’ll do what I want.”
I quickly learned that often backfires. If the same labs were done recently, many insurance companies won’t pay for them ... and the patients get a bill. Then they call my office and complain. It didn’t take me long to realize this approach was a waste of their time, money, and blood.
So now I always ask if they’ve had labs done since the symptoms started. If the answer is yes, I’ll call or fax the other doctor to get them. This can take (depending on the other office) a few hours to days. But the majority of outpatient neurology is nonurgent, and a extra few days usually doesn’t matter in the things I treat.
When I get the labs, it’s easy to make some quick notes on what was done and what still needs to be checked. I scribble out a lab order, mail or fax it, and have my staff notify the patient the ball is rolling. It’s not hard.
Patients appreciate it. I’m saving them time, blood, money, and maybe even a venipuncture. I get the tests I want, still in a timely fashion. It also keeps insurance costs down for all of us.
Obviously, there are some cases where urgency has to take priority. But for the majority of them, duplicating tests needlessly is a bad idea for all involved.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Many patients we see need blood work as part of their evaluation. Although labs are cheap compared with other tests we order, they can still be frustrating to get.
It’s not hard to order them. Ordering any test is pretty easy.
But I hate duplicating tests. Patients often say they just had labs done, which “were all fine,” but that tells me nothing. For all I know, it was a lipid panel and PSA, entirely unrelated to what I’m seeing them for.
Occasionally, they bring labs in with them, or I’ve gotten them in advance, but usually I’m working blind.
Back when I was new to practice, I just ordered everything I wanted. I figured it was easier than trying to get the previous ones. I think we all do that sometimes. And there’s kind of an ivory-tower mentality we all have early in our careers that “I’m the doctor, and I’ll do what I want.”
I quickly learned that often backfires. If the same labs were done recently, many insurance companies won’t pay for them ... and the patients get a bill. Then they call my office and complain. It didn’t take me long to realize this approach was a waste of their time, money, and blood.
So now I always ask if they’ve had labs done since the symptoms started. If the answer is yes, I’ll call or fax the other doctor to get them. This can take (depending on the other office) a few hours to days. But the majority of outpatient neurology is nonurgent, and a extra few days usually doesn’t matter in the things I treat.
When I get the labs, it’s easy to make some quick notes on what was done and what still needs to be checked. I scribble out a lab order, mail or fax it, and have my staff notify the patient the ball is rolling. It’s not hard.
Patients appreciate it. I’m saving them time, blood, money, and maybe even a venipuncture. I get the tests I want, still in a timely fashion. It also keeps insurance costs down for all of us.
Obviously, there are some cases where urgency has to take priority. But for the majority of them, duplicating tests needlessly is a bad idea for all involved.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Many patients we see need blood work as part of their evaluation. Although labs are cheap compared with other tests we order, they can still be frustrating to get.
It’s not hard to order them. Ordering any test is pretty easy.
But I hate duplicating tests. Patients often say they just had labs done, which “were all fine,” but that tells me nothing. For all I know, it was a lipid panel and PSA, entirely unrelated to what I’m seeing them for.
Occasionally, they bring labs in with them, or I’ve gotten them in advance, but usually I’m working blind.
Back when I was new to practice, I just ordered everything I wanted. I figured it was easier than trying to get the previous ones. I think we all do that sometimes. And there’s kind of an ivory-tower mentality we all have early in our careers that “I’m the doctor, and I’ll do what I want.”
I quickly learned that often backfires. If the same labs were done recently, many insurance companies won’t pay for them ... and the patients get a bill. Then they call my office and complain. It didn’t take me long to realize this approach was a waste of their time, money, and blood.
So now I always ask if they’ve had labs done since the symptoms started. If the answer is yes, I’ll call or fax the other doctor to get them. This can take (depending on the other office) a few hours to days. But the majority of outpatient neurology is nonurgent, and a extra few days usually doesn’t matter in the things I treat.
When I get the labs, it’s easy to make some quick notes on what was done and what still needs to be checked. I scribble out a lab order, mail or fax it, and have my staff notify the patient the ball is rolling. It’s not hard.
Patients appreciate it. I’m saving them time, blood, money, and maybe even a venipuncture. I get the tests I want, still in a timely fashion. It also keeps insurance costs down for all of us.
Obviously, there are some cases where urgency has to take priority. But for the majority of them, duplicating tests needlessly is a bad idea for all involved.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Should clopidogrel be discontinued prior to open vascular procedures?
The continued use of perioperative clopidogrel is appropriate
Surgeons have always worried about bleeding risks for procedures we do. Complex vascular procedures are further complicated by the myriad of available antiplatelet agents designed to reduce ischemic events from cardiovascular disease burden at the expense of potential bleeding complications if antiplatelet medications are continued. Rather than relying on anecdotal reports by historical vignettes, let’s look at the evidence.
There probably is no other drug available in our vascular toolbox which has been studied more in the last 20 years than clopidogrel. Multiple randomized and double blinded studies such as CASPAR1 and CHARISMA2 have amplified what was known since the early CAPRIE trial in the 1990’s and that is that clopidogrel is safe when used as a single medication or as a dual agent with aspirin (duel antiplatelet therapy [DAPT]).
But not all our patients need DAPT. There is no level 1 evidence demonstrating the need for any antiplatelet therapy in the primary prevention of cardiovascular events for patients deemed at low or moderate risk of cardiovascular disease from a large meta-analysis review of six primary prevention trials encompassing over 95,000 patients.3
If our patients do present with vascular disease, current ACCP guidelines recommend single-agent antiplatelet medication (either ASA or clopidogrel) for symptomatic peripheral arterial disease (PAD) whether planning LE revascularization with bypass or via endovascular means with grade 1A evidence.4 This works fine for single-focus vascular disease and each antiplatelet agent have proponents but either works well.
That’s great, but what about all those sick cardiac patients we see the most of? First, CHARISMA subgroup analysis of patients with preexisting coronary and/or cerebrovascular disease demonstrate a 7.1% risk reduction in MI, cerebrovascular events, and cardiac ischemic deaths when continuing DAPT over aspirin alone, and similar risk reduction is found in PAD patients for endpoints of MI and ischemic cardiovascular events. Second, there was no significant difference in severe, fatal, or moderate bleeding in those receiving DAPT vs. aspirin alone with only minor bleeding increased using DAPT. Third, real-life practice echoes multiple trial experiences such as the Vascular Study Group of New England study group confirmed in reviewing 16 centers and 66 surgeons with more than 10,000 patients. Approximately 39% underwent major aortic or lower extremity bypass operations.
No statistical difference could be found for reoperation (P = .74), transfusion (P = .1) or operative type between DAPT or aspirin use alone.5 This is rediscovered once again by Saadeh and Sfeir in their prospective study of 647 major arterial procedures over 7 years finding no significant difference in reoperation for bleeding or bleeding mortality between DAPT vs. aspirin alone.6
So can we stop bashing clopidogrel as an evil agent of bleeding as Dr. Dalsing wishes to do? After all, he has been on record as stating, “I don’t know if our bleeding risk is worse or better … something we have to do to keep our grafts going.” Evidence tells us the benefits for continuing DAPT as seen in risk reduction in primary cardiovascular outcomes far outweigh the risk of minor bleeding associated with continued use.
Let the science dictate practice. Patients with low or moderate risk for cardiovascular disease need no antiplatelet medication unless undergoing PAD treatment where a single agent, either aspirin or clopidogrel alone, is sufficient. In those patients having a large cardiovascular burden of disease, combination of aspirin and clopidogrel improves survival benefit and reduces ischemic events without a significant risk of reoperation, transfusion, or bleeding-related mortality. As many of our patients require DAPT for drug eluting coronary stents, withholding clopidogrel preoperatively increases overall risk beyond acceptable limits. Improving surgical skills and paying attention to hemostasis during the operation will allow naysayers to achieve improved patient survival without fear of bleeding when continuing best medical therapy such as DAPT.
Gary Lemmon, MD, is professor of vascular surgery at Indiana University, Indianapolis, and chief, vascular surgery, Indianapolis VA Medical Center. He reported no relevant conflicts.
References
1. J Vasc Surg. 2010;52:825-33
2. Eur Heart J. 2009;30:192-201
3. Lancet. 2009;373:1849-604. Chest. 2012;141:e669s-90s
5. J Vasc Surg. 2011;54: 779-84
6. J Vasc Surg. 2013;58: 1586-92
The continued use of perioperative clopidogrel is debatable!
There are cases in which clopidogrel should not be discontinued for a needed vascular intervention. Delaying operation or maintaining clopidogrel during operation if your patient required a recent coronary stent is warranted unless you are willing to accept an acute coronary thrombosis.
However, in other cases, for example infrainguinal grafts, the risk of potential increased bleeding when adding clopidogrel to aspirin may outweigh potential improvements in graft patency. This is especially true of below-knee vein bypass grafts where data do not support improved patency. However, in the CASPAR trial, prosthetic graft patency did appear to be beneficial, but only in subgroup analysis.1
It is true that severe bleeding was not increased (intracranial hemorrhage, or hemodynamic compromise: 1 vs 2.7%, P = NS) but moderate bleeding (transfusion required: 0.7 vs 3.7%, P = .012) and mild bleeding (5.4 vs 12.1%, P = .004) was increased when this agent was used especially in vein graft surgery. This risk of bleeding was present even when clopidogrel was begun 2 or more days after surgery.1
To complicate this decision, a Cochrane review did not consider subgroup analysis as statistically valid and so the authors considered infrainguinal graft patency as not improved with clopidogrel but bleeding risk was increased. One might even question the use of acetylsalicylic acid (ASA) for vein graft bypasses based on the results of this metanalysis.2 Carotid endarterectomy is a common vascular surgery procedure in which antiplatelet use has been evaluated in the real-world situation and with large cohorts. As is always the case when dealing with patient issues, the addition of one agent does not tell the entire story and patient demographics can have a significant influence on the outcome. A report from the Vascular Quality Initiative (VQI) database controlled for patient differences by propensity matching with more than 4,500 patients in each of the two groups; ASA vs. ASA + clopidogrel; demonstrated that major bleeding, defined as return to the OR for bleeding, was statistically more common with dual therapy (1.3% vs. 0.7%, P = .004).3
The addition of clopidogrel did statistically decrease the risk of ipsilateral TIA or stroke (0.8% vs. 1.2%, P = .02) but not the risk of death (0.2% vs. 0.3%, P = .3) or postoperative MI (1% vs. 0.8%, P = .4). Reoperation for bleeding is not inconsequential since in patients requiring this intervention, there is a significantly worse outcome in regard to stroke (3.7% vs. 0.8%, P = .001), MI (6.2% vs. 0.8%, P = .001), and death (2.5% vs. 0.2%,P = .001). Further drill down involving propensity score–matched analysis stratified by symptom status (asymptomatic vs. symptomatic) was quite interesting in that in only asymptomatic patients did the addition of clopidogrel actually demonstrate a statistically significant reduction in TIA or stroke, any stroke, or composite stroke/death. Symptomatic patients taking dual therapy demonstrated a slight reduction in TIA or stroke (1.4% vs. 1.7%, P = .6), any stroke (1.1% vs. 1.2%, P = .9) and composite stroke/death (1.2% vs. 1.5%, P = .5) but in no instance was statistical significance reached. The use of protamine did help to decrease the risk of bleeding.
Regarding the use of dual therapy during open aortic operations, an earlier report of the VQI database demonstrated no significant difference in bleeding risk statistically, but if one delves deeper the data indicate something different. In the majority of cases, vascular surgeons do not feel comfortable preforming this extensive dissection on dual therapy. Of the cases reported, 1,074 were preformed either free of either drug or only on ASA while 42 were on dual therapy and only 12 on clopidogrel only. In fact, in the conclusions, the authors note that they do not believe that conclusions regarding clopidogrel use in patient undergoing open abdominal aortic aneurysm repair can be drawn based on their results since the potential for a type II error was too great.4
It may be that our current level of sophistication is not sufficiently mature to determine the actual effect that clopidogrel is having on our patients. Clopidogrel, a thienopyridine, inhibits platelet activation by blocking the ADP-binding site for the P2Y12 receptor. Over 85% of ingested drug is metabolized into inactive metabolites while 15% is metabolized by the liver via a two-step oxidative process into the active thiol metabolite. Inter-individual variability in the antiplatelet response to thienopyridines is noted and partially caused by genetic mutations in the CP isoenzymes. Platelet reactivity testing is possible but most of the work has been conducted for those patients requiring coronary artery revascularization. Results of tailoring intervention to maximize therapeutic benefit and decrease the risk of bleeding have been inconsistent but, in some studies, appear to be promising.5 This approach may ultimately be found superior to determining how effective clopidogrel actually is in a particular case with some insight into the bleeding risk as well. With this determination, whether or not to hold clopidogrel perioperatively can be made with some science behind the decision.
Clearly, a blanket statement that the risk of bleeding should be accepted or ignored because of the demonstrated benefits of clopidogrel in patients requiring vascular surgery is not accurate. In some cases, there is no clear benefit, so eliminating the bleeding risk may well be the appropriate decision. The astute vascular surgeon understands the details of the written word in order to make an educated decision and understands that new information such as determining platelet reactivity may provide more clarity to such decisions in the future.
Michael C. Dalsing, MD, is chief of vascular surgery at Indiana University, Indianapolis. He reported no relevant conflicts.
References
1. J Vasc Surg. 2010;52:825-33
2. Cochrane Database Syst Rev. 2015, Issue 2. Art. No.: CD000535
The continued use of perioperative clopidogrel is appropriate
Surgeons have always worried about bleeding risks for procedures we do. Complex vascular procedures are further complicated by the myriad of available antiplatelet agents designed to reduce ischemic events from cardiovascular disease burden at the expense of potential bleeding complications if antiplatelet medications are continued. Rather than relying on anecdotal reports by historical vignettes, let’s look at the evidence.
There probably is no other drug available in our vascular toolbox which has been studied more in the last 20 years than clopidogrel. Multiple randomized and double blinded studies such as CASPAR1 and CHARISMA2 have amplified what was known since the early CAPRIE trial in the 1990’s and that is that clopidogrel is safe when used as a single medication or as a dual agent with aspirin (duel antiplatelet therapy [DAPT]).
But not all our patients need DAPT. There is no level 1 evidence demonstrating the need for any antiplatelet therapy in the primary prevention of cardiovascular events for patients deemed at low or moderate risk of cardiovascular disease from a large meta-analysis review of six primary prevention trials encompassing over 95,000 patients.3
If our patients do present with vascular disease, current ACCP guidelines recommend single-agent antiplatelet medication (either ASA or clopidogrel) for symptomatic peripheral arterial disease (PAD) whether planning LE revascularization with bypass or via endovascular means with grade 1A evidence.4 This works fine for single-focus vascular disease and each antiplatelet agent have proponents but either works well.
That’s great, but what about all those sick cardiac patients we see the most of? First, CHARISMA subgroup analysis of patients with preexisting coronary and/or cerebrovascular disease demonstrate a 7.1% risk reduction in MI, cerebrovascular events, and cardiac ischemic deaths when continuing DAPT over aspirin alone, and similar risk reduction is found in PAD patients for endpoints of MI and ischemic cardiovascular events. Second, there was no significant difference in severe, fatal, or moderate bleeding in those receiving DAPT vs. aspirin alone with only minor bleeding increased using DAPT. Third, real-life practice echoes multiple trial experiences such as the Vascular Study Group of New England study group confirmed in reviewing 16 centers and 66 surgeons with more than 10,000 patients. Approximately 39% underwent major aortic or lower extremity bypass operations.
No statistical difference could be found for reoperation (P = .74), transfusion (P = .1) or operative type between DAPT or aspirin use alone.5 This is rediscovered once again by Saadeh and Sfeir in their prospective study of 647 major arterial procedures over 7 years finding no significant difference in reoperation for bleeding or bleeding mortality between DAPT vs. aspirin alone.6
So can we stop bashing clopidogrel as an evil agent of bleeding as Dr. Dalsing wishes to do? After all, he has been on record as stating, “I don’t know if our bleeding risk is worse or better … something we have to do to keep our grafts going.” Evidence tells us the benefits for continuing DAPT as seen in risk reduction in primary cardiovascular outcomes far outweigh the risk of minor bleeding associated with continued use.
Let the science dictate practice. Patients with low or moderate risk for cardiovascular disease need no antiplatelet medication unless undergoing PAD treatment where a single agent, either aspirin or clopidogrel alone, is sufficient. In those patients having a large cardiovascular burden of disease, combination of aspirin and clopidogrel improves survival benefit and reduces ischemic events without a significant risk of reoperation, transfusion, or bleeding-related mortality. As many of our patients require DAPT for drug eluting coronary stents, withholding clopidogrel preoperatively increases overall risk beyond acceptable limits. Improving surgical skills and paying attention to hemostasis during the operation will allow naysayers to achieve improved patient survival without fear of bleeding when continuing best medical therapy such as DAPT.
Gary Lemmon, MD, is professor of vascular surgery at Indiana University, Indianapolis, and chief, vascular surgery, Indianapolis VA Medical Center. He reported no relevant conflicts.
References
1. J Vasc Surg. 2010;52:825-33
2. Eur Heart J. 2009;30:192-201
3. Lancet. 2009;373:1849-604. Chest. 2012;141:e669s-90s
5. J Vasc Surg. 2011;54: 779-84
6. J Vasc Surg. 2013;58: 1586-92
The continued use of perioperative clopidogrel is debatable!
There are cases in which clopidogrel should not be discontinued for a needed vascular intervention. Delaying operation or maintaining clopidogrel during operation if your patient required a recent coronary stent is warranted unless you are willing to accept an acute coronary thrombosis.
However, in other cases, for example infrainguinal grafts, the risk of potential increased bleeding when adding clopidogrel to aspirin may outweigh potential improvements in graft patency. This is especially true of below-knee vein bypass grafts where data do not support improved patency. However, in the CASPAR trial, prosthetic graft patency did appear to be beneficial, but only in subgroup analysis.1
It is true that severe bleeding was not increased (intracranial hemorrhage, or hemodynamic compromise: 1 vs 2.7%, P = NS) but moderate bleeding (transfusion required: 0.7 vs 3.7%, P = .012) and mild bleeding (5.4 vs 12.1%, P = .004) was increased when this agent was used especially in vein graft surgery. This risk of bleeding was present even when clopidogrel was begun 2 or more days after surgery.1
To complicate this decision, a Cochrane review did not consider subgroup analysis as statistically valid and so the authors considered infrainguinal graft patency as not improved with clopidogrel but bleeding risk was increased. One might even question the use of acetylsalicylic acid (ASA) for vein graft bypasses based on the results of this metanalysis.2 Carotid endarterectomy is a common vascular surgery procedure in which antiplatelet use has been evaluated in the real-world situation and with large cohorts. As is always the case when dealing with patient issues, the addition of one agent does not tell the entire story and patient demographics can have a significant influence on the outcome. A report from the Vascular Quality Initiative (VQI) database controlled for patient differences by propensity matching with more than 4,500 patients in each of the two groups; ASA vs. ASA + clopidogrel; demonstrated that major bleeding, defined as return to the OR for bleeding, was statistically more common with dual therapy (1.3% vs. 0.7%, P = .004).3
The addition of clopidogrel did statistically decrease the risk of ipsilateral TIA or stroke (0.8% vs. 1.2%, P = .02) but not the risk of death (0.2% vs. 0.3%, P = .3) or postoperative MI (1% vs. 0.8%, P = .4). Reoperation for bleeding is not inconsequential since in patients requiring this intervention, there is a significantly worse outcome in regard to stroke (3.7% vs. 0.8%, P = .001), MI (6.2% vs. 0.8%, P = .001), and death (2.5% vs. 0.2%,P = .001). Further drill down involving propensity score–matched analysis stratified by symptom status (asymptomatic vs. symptomatic) was quite interesting in that in only asymptomatic patients did the addition of clopidogrel actually demonstrate a statistically significant reduction in TIA or stroke, any stroke, or composite stroke/death. Symptomatic patients taking dual therapy demonstrated a slight reduction in TIA or stroke (1.4% vs. 1.7%, P = .6), any stroke (1.1% vs. 1.2%, P = .9) and composite stroke/death (1.2% vs. 1.5%, P = .5) but in no instance was statistical significance reached. The use of protamine did help to decrease the risk of bleeding.
Regarding the use of dual therapy during open aortic operations, an earlier report of the VQI database demonstrated no significant difference in bleeding risk statistically, but if one delves deeper the data indicate something different. In the majority of cases, vascular surgeons do not feel comfortable preforming this extensive dissection on dual therapy. Of the cases reported, 1,074 were preformed either free of either drug or only on ASA while 42 were on dual therapy and only 12 on clopidogrel only. In fact, in the conclusions, the authors note that they do not believe that conclusions regarding clopidogrel use in patient undergoing open abdominal aortic aneurysm repair can be drawn based on their results since the potential for a type II error was too great.4
It may be that our current level of sophistication is not sufficiently mature to determine the actual effect that clopidogrel is having on our patients. Clopidogrel, a thienopyridine, inhibits platelet activation by blocking the ADP-binding site for the P2Y12 receptor. Over 85% of ingested drug is metabolized into inactive metabolites while 15% is metabolized by the liver via a two-step oxidative process into the active thiol metabolite. Inter-individual variability in the antiplatelet response to thienopyridines is noted and partially caused by genetic mutations in the CP isoenzymes. Platelet reactivity testing is possible but most of the work has been conducted for those patients requiring coronary artery revascularization. Results of tailoring intervention to maximize therapeutic benefit and decrease the risk of bleeding have been inconsistent but, in some studies, appear to be promising.5 This approach may ultimately be found superior to determining how effective clopidogrel actually is in a particular case with some insight into the bleeding risk as well. With this determination, whether or not to hold clopidogrel perioperatively can be made with some science behind the decision.
Clearly, a blanket statement that the risk of bleeding should be accepted or ignored because of the demonstrated benefits of clopidogrel in patients requiring vascular surgery is not accurate. In some cases, there is no clear benefit, so eliminating the bleeding risk may well be the appropriate decision. The astute vascular surgeon understands the details of the written word in order to make an educated decision and understands that new information such as determining platelet reactivity may provide more clarity to such decisions in the future.
Michael C. Dalsing, MD, is chief of vascular surgery at Indiana University, Indianapolis. He reported no relevant conflicts.
References
1. J Vasc Surg. 2010;52:825-33
2. Cochrane Database Syst Rev. 2015, Issue 2. Art. No.: CD000535
The continued use of perioperative clopidogrel is appropriate
Surgeons have always worried about bleeding risks for procedures we do. Complex vascular procedures are further complicated by the myriad of available antiplatelet agents designed to reduce ischemic events from cardiovascular disease burden at the expense of potential bleeding complications if antiplatelet medications are continued. Rather than relying on anecdotal reports by historical vignettes, let’s look at the evidence.
There probably is no other drug available in our vascular toolbox which has been studied more in the last 20 years than clopidogrel. Multiple randomized and double blinded studies such as CASPAR1 and CHARISMA2 have amplified what was known since the early CAPRIE trial in the 1990’s and that is that clopidogrel is safe when used as a single medication or as a dual agent with aspirin (duel antiplatelet therapy [DAPT]).
But not all our patients need DAPT. There is no level 1 evidence demonstrating the need for any antiplatelet therapy in the primary prevention of cardiovascular events for patients deemed at low or moderate risk of cardiovascular disease from a large meta-analysis review of six primary prevention trials encompassing over 95,000 patients.3
If our patients do present with vascular disease, current ACCP guidelines recommend single-agent antiplatelet medication (either ASA or clopidogrel) for symptomatic peripheral arterial disease (PAD) whether planning LE revascularization with bypass or via endovascular means with grade 1A evidence.4 This works fine for single-focus vascular disease and each antiplatelet agent have proponents but either works well.
That’s great, but what about all those sick cardiac patients we see the most of? First, CHARISMA subgroup analysis of patients with preexisting coronary and/or cerebrovascular disease demonstrate a 7.1% risk reduction in MI, cerebrovascular events, and cardiac ischemic deaths when continuing DAPT over aspirin alone, and similar risk reduction is found in PAD patients for endpoints of MI and ischemic cardiovascular events. Second, there was no significant difference in severe, fatal, or moderate bleeding in those receiving DAPT vs. aspirin alone with only minor bleeding increased using DAPT. Third, real-life practice echoes multiple trial experiences such as the Vascular Study Group of New England study group confirmed in reviewing 16 centers and 66 surgeons with more than 10,000 patients. Approximately 39% underwent major aortic or lower extremity bypass operations.
No statistical difference could be found for reoperation (P = .74), transfusion (P = .1) or operative type between DAPT or aspirin use alone.5 This is rediscovered once again by Saadeh and Sfeir in their prospective study of 647 major arterial procedures over 7 years finding no significant difference in reoperation for bleeding or bleeding mortality between DAPT vs. aspirin alone.6
So can we stop bashing clopidogrel as an evil agent of bleeding as Dr. Dalsing wishes to do? After all, he has been on record as stating, “I don’t know if our bleeding risk is worse or better … something we have to do to keep our grafts going.” Evidence tells us the benefits for continuing DAPT as seen in risk reduction in primary cardiovascular outcomes far outweigh the risk of minor bleeding associated with continued use.
Let the science dictate practice. Patients with low or moderate risk for cardiovascular disease need no antiplatelet medication unless undergoing PAD treatment where a single agent, either aspirin or clopidogrel alone, is sufficient. In those patients having a large cardiovascular burden of disease, combination of aspirin and clopidogrel improves survival benefit and reduces ischemic events without a significant risk of reoperation, transfusion, or bleeding-related mortality. As many of our patients require DAPT for drug eluting coronary stents, withholding clopidogrel preoperatively increases overall risk beyond acceptable limits. Improving surgical skills and paying attention to hemostasis during the operation will allow naysayers to achieve improved patient survival without fear of bleeding when continuing best medical therapy such as DAPT.
Gary Lemmon, MD, is professor of vascular surgery at Indiana University, Indianapolis, and chief, vascular surgery, Indianapolis VA Medical Center. He reported no relevant conflicts.
References
1. J Vasc Surg. 2010;52:825-33
2. Eur Heart J. 2009;30:192-201
3. Lancet. 2009;373:1849-604. Chest. 2012;141:e669s-90s
5. J Vasc Surg. 2011;54: 779-84
6. J Vasc Surg. 2013;58: 1586-92
The continued use of perioperative clopidogrel is debatable!
There are cases in which clopidogrel should not be discontinued for a needed vascular intervention. Delaying operation or maintaining clopidogrel during operation if your patient required a recent coronary stent is warranted unless you are willing to accept an acute coronary thrombosis.
However, in other cases, for example infrainguinal grafts, the risk of potential increased bleeding when adding clopidogrel to aspirin may outweigh potential improvements in graft patency. This is especially true of below-knee vein bypass grafts where data do not support improved patency. However, in the CASPAR trial, prosthetic graft patency did appear to be beneficial, but only in subgroup analysis.1
It is true that severe bleeding was not increased (intracranial hemorrhage, or hemodynamic compromise: 1 vs 2.7%, P = NS) but moderate bleeding (transfusion required: 0.7 vs 3.7%, P = .012) and mild bleeding (5.4 vs 12.1%, P = .004) was increased when this agent was used especially in vein graft surgery. This risk of bleeding was present even when clopidogrel was begun 2 or more days after surgery.1
To complicate this decision, a Cochrane review did not consider subgroup analysis as statistically valid and so the authors considered infrainguinal graft patency as not improved with clopidogrel but bleeding risk was increased. One might even question the use of acetylsalicylic acid (ASA) for vein graft bypasses based on the results of this metanalysis.2 Carotid endarterectomy is a common vascular surgery procedure in which antiplatelet use has been evaluated in the real-world situation and with large cohorts. As is always the case when dealing with patient issues, the addition of one agent does not tell the entire story and patient demographics can have a significant influence on the outcome. A report from the Vascular Quality Initiative (VQI) database controlled for patient differences by propensity matching with more than 4,500 patients in each of the two groups; ASA vs. ASA + clopidogrel; demonstrated that major bleeding, defined as return to the OR for bleeding, was statistically more common with dual therapy (1.3% vs. 0.7%, P = .004).3
The addition of clopidogrel did statistically decrease the risk of ipsilateral TIA or stroke (0.8% vs. 1.2%, P = .02) but not the risk of death (0.2% vs. 0.3%, P = .3) or postoperative MI (1% vs. 0.8%, P = .4). Reoperation for bleeding is not inconsequential since in patients requiring this intervention, there is a significantly worse outcome in regard to stroke (3.7% vs. 0.8%, P = .001), MI (6.2% vs. 0.8%, P = .001), and death (2.5% vs. 0.2%,P = .001). Further drill down involving propensity score–matched analysis stratified by symptom status (asymptomatic vs. symptomatic) was quite interesting in that in only asymptomatic patients did the addition of clopidogrel actually demonstrate a statistically significant reduction in TIA or stroke, any stroke, or composite stroke/death. Symptomatic patients taking dual therapy demonstrated a slight reduction in TIA or stroke (1.4% vs. 1.7%, P = .6), any stroke (1.1% vs. 1.2%, P = .9) and composite stroke/death (1.2% vs. 1.5%, P = .5) but in no instance was statistical significance reached. The use of protamine did help to decrease the risk of bleeding.
Regarding the use of dual therapy during open aortic operations, an earlier report of the VQI database demonstrated no significant difference in bleeding risk statistically, but if one delves deeper the data indicate something different. In the majority of cases, vascular surgeons do not feel comfortable preforming this extensive dissection on dual therapy. Of the cases reported, 1,074 were preformed either free of either drug or only on ASA while 42 were on dual therapy and only 12 on clopidogrel only. In fact, in the conclusions, the authors note that they do not believe that conclusions regarding clopidogrel use in patient undergoing open abdominal aortic aneurysm repair can be drawn based on their results since the potential for a type II error was too great.4
It may be that our current level of sophistication is not sufficiently mature to determine the actual effect that clopidogrel is having on our patients. Clopidogrel, a thienopyridine, inhibits platelet activation by blocking the ADP-binding site for the P2Y12 receptor. Over 85% of ingested drug is metabolized into inactive metabolites while 15% is metabolized by the liver via a two-step oxidative process into the active thiol metabolite. Inter-individual variability in the antiplatelet response to thienopyridines is noted and partially caused by genetic mutations in the CP isoenzymes. Platelet reactivity testing is possible but most of the work has been conducted for those patients requiring coronary artery revascularization. Results of tailoring intervention to maximize therapeutic benefit and decrease the risk of bleeding have been inconsistent but, in some studies, appear to be promising.5 This approach may ultimately be found superior to determining how effective clopidogrel actually is in a particular case with some insight into the bleeding risk as well. With this determination, whether or not to hold clopidogrel perioperatively can be made with some science behind the decision.
Clearly, a blanket statement that the risk of bleeding should be accepted or ignored because of the demonstrated benefits of clopidogrel in patients requiring vascular surgery is not accurate. In some cases, there is no clear benefit, so eliminating the bleeding risk may well be the appropriate decision. The astute vascular surgeon understands the details of the written word in order to make an educated decision and understands that new information such as determining platelet reactivity may provide more clarity to such decisions in the future.
Michael C. Dalsing, MD, is chief of vascular surgery at Indiana University, Indianapolis. He reported no relevant conflicts.
References
1. J Vasc Surg. 2010;52:825-33
2. Cochrane Database Syst Rev. 2015, Issue 2. Art. No.: CD000535
Trials offer lessons despite negative primary endpoints
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
Conventional wisdom holds that for randomized, controlled trials, it’s all about the primary endpoint. If it’s negative or neutral, then none of the other results means much beyond “hypothesis generating.”
This strict-constructionist thinking has now been called into question. A recent article in the New England Journal of Medicine declared “an unreasonable yet widespread practice is the labeling of all randomized trials as either positive or negative on the basis of whether the P value for the primary outcome is less than .05. This view is overly simplistic.” (2016 Sept 1;375[9]:861-70).
The article, by the highly experienced and respected trialists Stuart J. Pocock, PhD, and Gregg W. Stone, MD, adds this: “If the primary outcome is negative, positive findings for secondary outcomes are usually considered to be hypothesis generating. Certainly, regulatory approval of a new drug is unlikely to follow. However, in some instances, secondary findings are compelling enough to affect guidelines and practice.”
This unconventional take from a pair of high-level trialists was especially timely given the buzz around the results from two studies reported at the European Society of Cardiology annual congress in late August, DANISH and NORSTENT.
The DANISH trial compared the impact of implantable cardioverter-defibrillators (ICDs) plus optimal care against optimal care without ICDs in 1,116 patients with nonischemic systolic heart failure. The primary outcome, all-cause death during more than 5 years of follow-up, was a relative 13% less with ICD use, a difference that was not statistically significant, and one secondary outcome, cardiovascular death, was cut by a relative 25% with ICD use, also not statistically significant.
But for the study’s second prespecified secondary endpoint of sudden cardiac death, treatment with ICDs cut the rate in half, compared with nonischemic heart failure patients who did not receive an ICD, a 4-percentage-point difference that was statistically significant.
And in a prespecified secondary analysis of the primary endpoint that broke down the study group by age, the two-thirds of patients younger than 68 years had a significant reduction in all-cause mortality with ICD use, a benefit not seen in patients aged 68 or older.
Discussion of the results at the meeting mainly focused on what meaning, if any, could be drawn from these strongly positive secondary outcomes in a trial neutral for its primary outcome.
“The ICDs did what they were supposed to, prevent sudden cardiac death,” said the lead investigator of the study, Lars Køber, MD. “As a principle I say don’t believe in a subgroup, but guidelines are often based on subgroup analyses.”
“The primary outcome was neutral, but the reduction in sudden cardiac death, the primary objective of an ICD, was significant, so an ICD should be taken into consideration,” commented Michel Komajda, MD, a discussant for the report.
After I wrote a news article about the DANISH report at ESC, I received an email from a reader who objected to spinning the results this way and insisted that no valid lessons can be drawn from the DANISH results because the study’s primary endpoint failed to show a statistical significance. This purist view misses the important, relevant lessons from the DANISH results. The DANISH trial was not designed to provide pivotal data for regulatory approval of ICDs in these patients. Rather, Dr. Køber and his associates designed DANISH to see whether ICD use in these patients could cut all-cause death over a fairly long follow-up. It was a very high bar and ICDs failed, but the deck was stacked against an ICD win. Enrolled patients averaged 64 years old at entry into the study, and they all had New York Heart Association class II or III heart failure. “The overall survival curves start to diverge, but then converge after 5 years because of the comorbidities and patients dying for other reasons,” Dr. Køber noted.
“The message is, in younger patients with less morbidity and more life expectancy, sudden cardiac death is a bigger problem, and they had a substantial drop in mortality” with ICD use, commented heart failure specialist Javed Butler, MD. “It’s very consistent with the way we think about providing ICD treatment to patients.”
In other words, the DANISH results showed that all patients with nonischemic systolic heart failure can’t expect to live substantially longer during extended follow-up if they get an ICD, because the cut in sudden cardiac death the devices provide eventually gets washed out by the many other risks for death these patients face. But younger, relatively healthier patients might very well see their reduced rate of sudden cardiac death translate into an overall mortality benefit even when they are followed for at least 5 years. That’s important information to help an individual patient decide whether to have an ICD placed, and an important message from the DANISH trial despite the neutral primary endpoint.
NORSTENT involved a similar scenario in a trial that addressed a totally different issue: Should patients with either stable or unstable coronary artery disease who are undergoing coronary stenting receive a drug-eluting stent (DES) or a bare metal stent (BMS)? The trial randomized 9,013 patients to receive either of the two stent types plus optimal medical therapy. The primary endpoint was the rate of all-cause death or nonfatal MI during 5 years of follow-up, and the results showed no statistically significant difference between the patients who received a DES and those who got a BMS (N Engl J Med. 2016 Aug 30. doi: 10.1056/NEJMoa1607991).
But for the secondary endpoint of repeat revascularizations performed during follow-up, the use of a DES cut the procedure rate by 3.3 percentage points, a 17% relative risk reduction that was statistically significant. The use of a DES also cut the stent thrombosis rate by 0.4 percentage points, a one-third relative drop in these events that was also statistically significant.
In short, despite the neutral primary endpoint for the trial, the results showed that drug-eluting stents did what they were designed to do relative to bare metal stents: cut the rate of target lesion restenosis and the need for repeat revascularization. Several interventional cardiologists who heard the results at the meeting said that the findings would not change their practice and that they would continue to use the DES as their default device for percutaneous coronary interventions. Although “the long-term benefit of contemporary DES over BMS was less than expected,” said Kaare H. Bønaa, MD, lead investigator for the NORSTENT trial, the secondary benefit of significantly reduced repeat revascularization and the very modest price difference that now exists between drug-eluting stents and bare metal stents means that many interventionalists will continue to use a DES for most patients.
The message from Dr. Pocock and Dr. Stone, underscored by the DANISH and NORSTENT results, is that large and well-run randomized trials can yield important evidence to inform practice that transcends a simple black or white statistical assessment of the primary endpoint.
On Twitter @mitchelzoler
