Today’s cosmetic patient wants to look more youthful every day without spending a lot of money, feeling any pain, or having any postprocedure downtime. With continued technological improvements, dermatologists have been able to provide our patients with the more youthful appearance they desire; however, many of these procedures still are costly, painful, and may require some downtime. New cosmeceutical therapies can be used as adjuncts to these procedures, making antiaging regimens less painful for patients and requiring less postprocedure healing time. In this article, the use of cosmeceuticals in conjunction with chemical peels, lasers, and injectables will be discussed.

Chemical Peels

Chemical peels are used to create an injury of specific skin depth with a goal of stimulating new skin growth and improving surface texture and appearance. They generally are classified as superficial, medium, or deep according to the depth of action. Currently available agents for superficial chemical peels include α-hydroxy acids (AHAs)(eg, glycolic acid [GA]) and β-hydroxy acids (BHAs)(eg, salicylic acid). β-Lipohydroxy acid (up to 10%), a derivative of salicylic acid, is widely used in Europe. Trichloroacetic acid (TCA) can be used for superficial peels (10%–20%) and for medium-depth peels (35%). Combination peels such as Monheit combination (Jessner solution plus TCA), Brody combination (solid CO₂ plus TCA), Coleman combination (GA 70% plus TCA), and Jessner solution with GA can be used as medium-depth peels. Deep peels typically are performed with phenol-based solutions, including the Baker-Gordon phenol peel and the Hetter peel (phenol or croton oil peel).

Specific agents for chemical peels should be selected based on the disorder being treated and should be administered using an appropriate peel depth determined by the histologic level or severity of skin pathology to maximize treatment success.¹ However, other considerations, such as skin characteristics, area of skin to be treated, safety concerns, healing time, and patient adherence also should be taken into account to achieve the best overall results. Although many of the deeper peels recently have been replaced by laser-based ablative treatments, superficial to medium-depth peels still are commonly used in the treatment of fine lines, uneven texture, and dyspigmentation.²

Superficial peels are reasonably safe and well tolerated, usually with only mild discomfort (eg, transient burning, irritation, erythema). Scarring, postinflammatory hyperpigmentation (PIH), and infection are rare with superficial peels.¹ Postinflammatory hyperpigmentation can be exacerbated by sun exposure, making it important for patients to be educated about sun protection and closely monitored during the recovery phase. In medium and deep peels, lines of demarcation related to the administration technique can occur. Feathering the chemical peel solution at junctions with nonpeeled skin can help to avoid this effect.¹ Side effects associated with deeper chemical peels can include pigmentary changes, infections, allergic reactions, improper healing, hypersensitivity, and underlying disease exacerbation. The best way to prevent complications is to identify patients who are at risk and maintain an appropriate peel depth that balances efficacy with known adverse events.¹ 

Many adjunctive agents (eg, AHAs, BHAs, retinoids, skin-bleaching preparations) can be used to enhance chemical peels and decrease the incidence of PIH. α-Hydroxy acids and BHAs can be beneficial when applied prior to chemical peels. Moisturizers containing AHAs and BHAs can be used for 2 to 3 weeks before superficial or medium-depth chemical peels.² These agents cause thinning of the stratum corneum, thereby creating a more uniform cutaneous surface and allowing for deeper penetration of the chemical peeling agent. Retinoids also are superior prepeeling agents; however, retinoids also can increase the likelihood of irritation, which can be minimized by discontinuing retinoids for 1 week following chemical peels.² A combination of chemical peels and topical bleaching agents has been shown to be effective in treating hyperpigmentation. The chemical peel causes superficial exfoliation, which allows the lightening agent to penetrate more deeply.²

Hydroquinone (HQ) is the gold standard for improvement of existing pigmentation.³ It is one of the most effective inhibitors of melanogenesis both in vitro and in vivo and is widely used for the treatment of melanosis and other hyperpigmentary disorders. It is widely accepted that the depigmentation activity of HQ may partly be related to its ability to act as an alternate substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.³ Using HQ at a 4% concentration and combining it with retinoids is quite efficacious.² Other commonly used depigmenting agents include kojic acid, ascorbic acid (vitamin C), and niacinamide, which often can be used as adjuncts with or maintenance therapy after HQ treatment.^2,3

The risk for PIH is imminent for chemical peels and cosmetic laser treatments; therefore, it is crucial to educate patients about the importance of daily and aggressive sun protection. There are several methods of reducing or eliminating postprocedure melanin formation, such as inhibiting tyrosinase synthesis, using complex copper to inhibit tyrosinase function, eliminating oxidation reactions that lead to polymer formation, slowing down the transfer of melanosomes to keratinocytes, or acting upstream on the hormone that stimulates melanogenesis.³ Most of the depigmenting agents presently on the market act by inhibiting tyrosinase via one of these mechanisms. 

Skin-lightening agents are primarily formulated as emulsions that have a higher aesthetic appeal. Many of the ingredients get better dispersions with emulsions, which is an added feature of these products. Recently, gel-based formulations also are being considered for their suitability in certain skin types. Efficacy studies for skin-lightening formulations are being carried out through clinical trials that utilize devices that measure skin color in addition to the dermatologist’s assessment.⁴ Other skin parameters (eg, moisturization, texture, barrier integrity, pH) also are being evaluated to give physicians a picture of skin health after the use of skin-lightening agents. With advances in technology and measurement techniques, it is becoming easier to identify the efficacy of these formulations in different skin types.⁴

Lasers

The ultimate goal of laser therapy often is to improve the canvas and color of the skin. Ablative laser resurfacing is reliably the most effective procedure for sun-damaged skin.² This technique causes thermally induced full-thickness epidermal and dermal denudation, which in turn facilitates cytokine-led dermal collagen formation and reepithelialization. Various nonablative modalities also are used for treating photodamaged skin. The epidermis remains unaffected by these nonablative methods, thus decreasing the need for extensive wound care and downtime that is required with ablative treatments. Combining nonablative laser treatments with topical cosmeceuticals has been proven more effective than using either method alone.² The use of topical retinoids prior to ablative laser resurfacing often results in remarkably faster postprocedure healing and reepithelialization (Figure). Retinoids are best applied nightly for at least 2 weeks and optimally for 3 months before ablative laser treatment. Application should be discontinued for 1 week immediately prior to the procedure.

Before (A) and after (B) treatment with a fractional laser in combination with a pre- and postprocedure skin care regimen consisting of retinoids and sunscreen.

Topical retinoids also are effective in reducing erythema and increasing dermal thickness after nonablative treatments. When used prior to laser treatments, retinoids have been shown to decrease the risk for postoperative milia and hyperpigmentation as well as to allow for better penetration of the laser beam secondary to a thinner stratum corneum.² Following ablative resurfacing, retinoid use should be discontinued for several weeks to allow for reepithelialization and adequate healing.

Postprocedure Wound Healing

Most of the recommended products that help decrease postprocedural inflammation are cosmeceuticals containing both antioxidants and anti-inflammatories to help decrease redness and inflammation, including various barrier repair moisturizers. Restoring barrier integrity improves the overall appearance of the skin. The ingredients normally recommended in barrier repair moisturizers are epidermal lipids such as ceramides; hyaluronic acid (HA), which is a humectant; and occlusives for patients with very dry skin. Some of the ingredients in over-the-counter cosmeceuticals that can help decrease redness and inflammation include vitamin C, vitamin E, and vitamin B or niacinamide, which will help plump the barrier and also have anti-inflammatory properties. Additionally, polyphenolic flavonoids such as soy and green tea can help decrease inflammation, along with a number of other organic ingredients, such as caffeine, feverfew, and licorice.⁵ If topical vitamin C is being considered for postprocedure use, the non–ascorbic acid variant should be administered. The magnesium ascorbyl phosphate and ascorbyl palmitate forms of vitamin C have a neutral pH and tend to be better tolerated by patients.

In addition to current prescription and over-the-counter cosmeceuticals used for postprocedure irritation and inflammation, copper peptides and other well-tolerated and effective naturally occurring compounds are being investigated and tried. Copper is a biocide that regulates keratinocyte integrins for epithelization and extracellular matrix remodeling. The extracellular matrix consists of the structural fibrillar collagens and is remodeled or degraded by matrix metalloproteinases (MMPs) that facilitate epithelization. The predominant classes of MMPs include collagenases (ie, MMP-1) and gelatinases (ie, MMP-2, MMP-9) that degrade interstitial collagen and basement membrane proteins.⁶ The MMPs are endogenously inhibited by tissue inhibitors of metalloproteinases (TIMPs). Copper is a cofactor to lysyl oxidase, which cross-links collagen and stimulates expression of MMP-2 and collagen in a complex with a matrix-derived tripeptide (glycyl-histidyl-lysine or Gly-His-Lys [GHK]) in fibroblasts.⁶ Much attention has been focused on the tripeptides, such as GHK and Gly-Gly-His, and their copper complexes, which have high activity and good skin tolerance. These complexes have been shown to play a physiological role in the process of wound healing, tissue repair, and skin inflammation. Gly-Gly-His, GHK, copper chloride, and their copper complexes decrease tumor necrosis factor α–dependent IL-6 secretion in fibroblasts.⁷ IL-6 is crucial for normal wound healing, skin inflammation, and UVB-induced erythema. Because of their anti-inflammatory properties, these copper peptides could potentially be used in place of corticosteroids or nonsteroidal anti-inflammatory drugs, which have more side effects.

Botulinum Neurotoxin and Other Injectable Fillers

Acetyl Hexapeptide-3: A Topical Complement to Botulinum Neurotoxin

Acetyl hexapeptide-3 (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂) was discovered when looking for a less toxic variation of botulinum neurotoxin (BoNT) to treat aging skin.⁸ It is patterned from the N-terminal end of the synaptosome-associated protein of molecular weight 25 kDa (SNAP-25), which is essential for docking and fusion of synaptic vesicles to the presynaptic membrane for acetylcholine release.⁹ It prevents formation and stability of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex, inhibiting vesicle docking and calcium-dependent catecholamine exocytosis.⁸ It also has been found to substantially inhibit the repetitive muscular contraction of facial expression similar to BoNT type A but with somewhat lower efficacy. Acetyl hexapeptide-3 was shown to inhibit 30% of total catecholamine exocytosis and had a remarkable capacity to permeate the skin.¹⁰ Thus this topical form of BoNT is a useful complement to intramuscular BoNT.

Studies showing the efficacy and safety of acetyl hexapeptide-3 have demonstrated reductions in wrinkle intensity, mainly in the lateral periorbital areas. In one early study, 10 women applied an emulsion containing 10% of the hexapeptide to one lateral periorbital region and the same emulsion without the hexapeptide to the contralateral side, both twice daily for 30 days.¹⁰ A 30% decrease in the depth of skin wrinkles was seen on the hexapeptide side compared with a 10% decrease in the depth of wrinkles on the side treated without hexapeptide. No irritation or toxicity was noted.¹⁰ In another trial, 10 women applied an acetyl hexapeptide-3 cream 5% twice daily to lateral periorbital rhytides, with a 27% improvement in wrinkle depth after a 30-day treatment period.⁹ A double-blind, placebo-controlled study of 60 women assessing the safety and efficacy of topical hexapeptide showed a total antiwrinkle efficacy of 48.9% on the side treated with an emulsion containing 10% of the hexapeptide compared with 0% efficacy on the placebo side.⁸ Similar to Blanes-Mira et al,¹⁰ no adverse events such as skin irritation or toxicity were seen.⁸ In all of these studies, wrinkle depth was measured by silicone replica analysis.

Topical acetyl hexapeptide-3 is effective in decreasing wrinkles, and its best use will likely be as an adjunct to intramuscular BoNT, as the intramuscular form likely has higher efficacy with the toxin injected directly into the target muscle; however, patients who want the effects of BoNT without the pain of injections may choose to use topical acetyl hexapeptide-3 alone. Patients who do use acetyl hexapeptide-3 as a complement to their intramuscular BoNT regimen may not need as many units of BoNT with each treatment or may not need certain areas injected as often, leading to fewer injections and less pain with each visit. Skin irritation was not seen as a side effect in these trials. Additionally, the topical form has insignificant acute toxicity (≥2000 mg/kg) compared to BoNT type A (20 ng/kg), and genotoxicity was not seen with testing, making it a safe complementary option to an injectable regimen.⁸

Topical Hyaluronic Acid: A Complement to Injectable Fillers

Hyaluronic acid (HA) is a glycosaminoglycan found in the extracellular matrix of the skin that greatly contributes to tissue hydration. Additionally, it plays a crucial role in the synthesis of extracellular matrix molecules and epidermal cell interaction with the environment.¹¹ The water-binding capacity of HA approximates 1000 times its volume or 6 L of water per gram of HA; however, once an individual reaches adulthood, the amount of HA decreases to 5% of baseline levels, thus contributing to xerosis, loss of skin elasticity, and atrophy.^11,12 Although photoaged skin can have increased glycosaminoglycans due to an increase in chondroitin sulfate proteoglycans, they are abnormally deposited on elastotic material in the superficial dermis rather than diffusely scattered, as seen in youthful skin.¹²

Many topical antiaging products contain HA, though evidence for efficacy in reducing wrinkles has been lacking, along with concerns that HA cannot penetrate the skin. This concern stems from the fact that the original molecule is 3000 nm in diameter and the intercellular space is only 15 to 50 nm. This space is only 6 to 10 nm at the hyaline membrane. Recently, scientists in Japan found a way to reduce the size of HA molecules to 5 nm (nano-HA) without changing its structure. A study of 33 women who applied the topical nano-HA twice daily for 8 weeks to one periorbital area while the contralateral side was left untreated showed improved hydration of the treated side that continued to increase when measured at 2, 4, and 8 weeks using corneometry.¹¹ Roughness decreased and elasticity increased after week 2, which were maintained throughout the study. Additionally, erythema was measured using a chroma meter, which was found to have decreased at day 57 versus day 1.¹¹ An earlier study by Pavicic et al¹² evaluated the efficacy of topical hyalu-ronan 0.1% formulations of different molecular weights—50, 130, 300, 800, or 2000 kDa—in the periocular area. A randomized group of 76 women were treated twice daily for 2 months with HA cream on one side of the periocular area and placebo cream on the other. With regard to antiwrinkle properties, only the 50- and 130-kDa HA formulations showed marked effects compared with placebo after 2 months.¹²

Topical HA would be an effective addition to an antiwrinkle regimen, especially in patients who are averse to needles or are just starting to get wrinkles and are looking for a noninvasive therapy. Additionally, it would be beneficial for patients who have an injectable filler and BoNT regimen, as these patients will be able to target wrinkles simultaneously with both topical cosmeceuticals and injectables and likely will need fewer units of BoNT and/or filler and possibly fewer injections over time, which translates to decreased pain and adverse outcomes for patients.

Conclusion

The myriad of options dermatologists have to offer patients for cosmetic enhancement provides alternatives for patients who have contraindications to certain treatments, are needle averse, or have lifestyles that do not afford them a great deal of postprocedural healing time. Being knowledgeable about these options and how to combine them for improved outcomes is essential to any cosmetic practice.

Today’s cosmetic patient wants to look more youthful every day without spending a lot of money, feeling any pain, or having any postprocedure downtime. With continued technological improvements, dermatologists have been able to provide our patients with the more youthful appearance they desire; however, many of these procedures still are costly, painful, and may require some downtime. New cosmeceutical therapies can be used as adjuncts to these procedures, making antiaging regimens less painful for patients and requiring less postprocedure healing time. In this article, the use of cosmeceuticals in conjunction with chemical peels, lasers, and injectables will be discussed.

Chemical Peels

Chemical peels are used to create an injury of specific skin depth with a goal of stimulating new skin growth and improving surface texture and appearance. They generally are classified as superficial, medium, or deep according to the depth of action. Currently available agents for superficial chemical peels include α-hydroxy acids (AHAs)(eg, glycolic acid [GA]) and β-hydroxy acids (BHAs)(eg, salicylic acid). β-Lipohydroxy acid (up to 10%), a derivative of salicylic acid, is widely used in Europe. Trichloroacetic acid (TCA) can be used for superficial peels (10%–20%) and for medium-depth peels (35%). Combination peels such as Monheit combination (Jessner solution plus TCA), Brody combination (solid CO₂ plus TCA), Coleman combination (GA 70% plus TCA), and Jessner solution with GA can be used as medium-depth peels. Deep peels typically are performed with phenol-based solutions, including the Baker-Gordon phenol peel and the Hetter peel (phenol or croton oil peel).

Specific agents for chemical peels should be selected based on the disorder being treated and should be administered using an appropriate peel depth determined by the histologic level or severity of skin pathology to maximize treatment success.¹ However, other considerations, such as skin characteristics, area of skin to be treated, safety concerns, healing time, and patient adherence also should be taken into account to achieve the best overall results. Although many of the deeper peels recently have been replaced by laser-based ablative treatments, superficial to medium-depth peels still are commonly used in the treatment of fine lines, uneven texture, and dyspigmentation.²

Superficial peels are reasonably safe and well tolerated, usually with only mild discomfort (eg, transient burning, irritation, erythema). Scarring, postinflammatory hyperpigmentation (PIH), and infection are rare with superficial peels.¹ Postinflammatory hyperpigmentation can be exacerbated by sun exposure, making it important for patients to be educated about sun protection and closely monitored during the recovery phase. In medium and deep peels, lines of demarcation related to the administration technique can occur. Feathering the chemical peel solution at junctions with nonpeeled skin can help to avoid this effect.¹ Side effects associated with deeper chemical peels can include pigmentary changes, infections, allergic reactions, improper healing, hypersensitivity, and underlying disease exacerbation. The best way to prevent complications is to identify patients who are at risk and maintain an appropriate peel depth that balances efficacy with known adverse events.¹ 

Many adjunctive agents (eg, AHAs, BHAs, retinoids, skin-bleaching preparations) can be used to enhance chemical peels and decrease the incidence of PIH. α-Hydroxy acids and BHAs can be beneficial when applied prior to chemical peels. Moisturizers containing AHAs and BHAs can be used for 2 to 3 weeks before superficial or medium-depth chemical peels.² These agents cause thinning of the stratum corneum, thereby creating a more uniform cutaneous surface and allowing for deeper penetration of the chemical peeling agent. Retinoids also are superior prepeeling agents; however, retinoids also can increase the likelihood of irritation, which can be minimized by discontinuing retinoids for 1 week following chemical peels.² A combination of chemical peels and topical bleaching agents has been shown to be effective in treating hyperpigmentation. The chemical peel causes superficial exfoliation, which allows the lightening agent to penetrate more deeply.²

Hydroquinone (HQ) is the gold standard for improvement of existing pigmentation.³ It is one of the most effective inhibitors of melanogenesis both in vitro and in vivo and is widely used for the treatment of melanosis and other hyperpigmentary disorders. It is widely accepted that the depigmentation activity of HQ may partly be related to its ability to act as an alternate substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.³ Using HQ at a 4% concentration and combining it with retinoids is quite efficacious.² Other commonly used depigmenting agents include kojic acid, ascorbic acid (vitamin C), and niacinamide, which often can be used as adjuncts with or maintenance therapy after HQ treatment.^2,3

The risk for PIH is imminent for chemical peels and cosmetic laser treatments; therefore, it is crucial to educate patients about the importance of daily and aggressive sun protection. There are several methods of reducing or eliminating postprocedure melanin formation, such as inhibiting tyrosinase synthesis, using complex copper to inhibit tyrosinase function, eliminating oxidation reactions that lead to polymer formation, slowing down the transfer of melanosomes to keratinocytes, or acting upstream on the hormone that stimulates melanogenesis.³ Most of the depigmenting agents presently on the market act by inhibiting tyrosinase via one of these mechanisms. 

Skin-lightening agents are primarily formulated as emulsions that have a higher aesthetic appeal. Many of the ingredients get better dispersions with emulsions, which is an added feature of these products. Recently, gel-based formulations also are being considered for their suitability in certain skin types. Efficacy studies for skin-lightening formulations are being carried out through clinical trials that utilize devices that measure skin color in addition to the dermatologist’s assessment.⁴ Other skin parameters (eg, moisturization, texture, barrier integrity, pH) also are being evaluated to give physicians a picture of skin health after the use of skin-lightening agents. With advances in technology and measurement techniques, it is becoming easier to identify the efficacy of these formulations in different skin types.⁴

Lasers

The ultimate goal of laser therapy often is to improve the canvas and color of the skin. Ablative laser resurfacing is reliably the most effective procedure for sun-damaged skin.² This technique causes thermally induced full-thickness epidermal and dermal denudation, which in turn facilitates cytokine-led dermal collagen formation and reepithelialization. Various nonablative modalities also are used for treating photodamaged skin. The epidermis remains unaffected by these nonablative methods, thus decreasing the need for extensive wound care and downtime that is required with ablative treatments. Combining nonablative laser treatments with topical cosmeceuticals has been proven more effective than using either method alone.² The use of topical retinoids prior to ablative laser resurfacing often results in remarkably faster postprocedure healing and reepithelialization (Figure). Retinoids are best applied nightly for at least 2 weeks and optimally for 3 months before ablative laser treatment. Application should be discontinued for 1 week immediately prior to the procedure.

Before (A) and after (B) treatment with a fractional laser in combination with a pre- and postprocedure skin care regimen consisting of retinoids and sunscreen.

Topical retinoids also are effective in reducing erythema and increasing dermal thickness after nonablative treatments. When used prior to laser treatments, retinoids have been shown to decrease the risk for postoperative milia and hyperpigmentation as well as to allow for better penetration of the laser beam secondary to a thinner stratum corneum.² Following ablative resurfacing, retinoid use should be discontinued for several weeks to allow for reepithelialization and adequate healing.

Postprocedure Wound Healing

Most of the recommended products that help decrease postprocedural inflammation are cosmeceuticals containing both antioxidants and anti-inflammatories to help decrease redness and inflammation, including various barrier repair moisturizers. Restoring barrier integrity improves the overall appearance of the skin. The ingredients normally recommended in barrier repair moisturizers are epidermal lipids such as ceramides; hyaluronic acid (HA), which is a humectant; and occlusives for patients with very dry skin. Some of the ingredients in over-the-counter cosmeceuticals that can help decrease redness and inflammation include vitamin C, vitamin E, and vitamin B or niacinamide, which will help plump the barrier and also have anti-inflammatory properties. Additionally, polyphenolic flavonoids such as soy and green tea can help decrease inflammation, along with a number of other organic ingredients, such as caffeine, feverfew, and licorice.⁵ If topical vitamin C is being considered for postprocedure use, the non–ascorbic acid variant should be administered. The magnesium ascorbyl phosphate and ascorbyl palmitate forms of vitamin C have a neutral pH and tend to be better tolerated by patients.

In addition to current prescription and over-the-counter cosmeceuticals used for postprocedure irritation and inflammation, copper peptides and other well-tolerated and effective naturally occurring compounds are being investigated and tried. Copper is a biocide that regulates keratinocyte integrins for epithelization and extracellular matrix remodeling. The extracellular matrix consists of the structural fibrillar collagens and is remodeled or degraded by matrix metalloproteinases (MMPs) that facilitate epithelization. The predominant classes of MMPs include collagenases (ie, MMP-1) and gelatinases (ie, MMP-2, MMP-9) that degrade interstitial collagen and basement membrane proteins.⁶ The MMPs are endogenously inhibited by tissue inhibitors of metalloproteinases (TIMPs). Copper is a cofactor to lysyl oxidase, which cross-links collagen and stimulates expression of MMP-2 and collagen in a complex with a matrix-derived tripeptide (glycyl-histidyl-lysine or Gly-His-Lys [GHK]) in fibroblasts.⁶ Much attention has been focused on the tripeptides, such as GHK and Gly-Gly-His, and their copper complexes, which have high activity and good skin tolerance. These complexes have been shown to play a physiological role in the process of wound healing, tissue repair, and skin inflammation. Gly-Gly-His, GHK, copper chloride, and their copper complexes decrease tumor necrosis factor α–dependent IL-6 secretion in fibroblasts.⁷ IL-6 is crucial for normal wound healing, skin inflammation, and UVB-induced erythema. Because of their anti-inflammatory properties, these copper peptides could potentially be used in place of corticosteroids or nonsteroidal anti-inflammatory drugs, which have more side effects.

Botulinum Neurotoxin and Other Injectable Fillers

Acetyl Hexapeptide-3: A Topical Complement to Botulinum Neurotoxin

Acetyl hexapeptide-3 (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂) was discovered when looking for a less toxic variation of botulinum neurotoxin (BoNT) to treat aging skin.⁸ It is patterned from the N-terminal end of the synaptosome-associated protein of molecular weight 25 kDa (SNAP-25), which is essential for docking and fusion of synaptic vesicles to the presynaptic membrane for acetylcholine release.⁹ It prevents formation and stability of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex, inhibiting vesicle docking and calcium-dependent catecholamine exocytosis.⁸ It also has been found to substantially inhibit the repetitive muscular contraction of facial expression similar to BoNT type A but with somewhat lower efficacy. Acetyl hexapeptide-3 was shown to inhibit 30% of total catecholamine exocytosis and had a remarkable capacity to permeate the skin.¹⁰ Thus this topical form of BoNT is a useful complement to intramuscular BoNT.

Studies showing the efficacy and safety of acetyl hexapeptide-3 have demonstrated reductions in wrinkle intensity, mainly in the lateral periorbital areas. In one early study, 10 women applied an emulsion containing 10% of the hexapeptide to one lateral periorbital region and the same emulsion without the hexapeptide to the contralateral side, both twice daily for 30 days.¹⁰ A 30% decrease in the depth of skin wrinkles was seen on the hexapeptide side compared with a 10% decrease in the depth of wrinkles on the side treated without hexapeptide. No irritation or toxicity was noted.¹⁰ In another trial, 10 women applied an acetyl hexapeptide-3 cream 5% twice daily to lateral periorbital rhytides, with a 27% improvement in wrinkle depth after a 30-day treatment period.⁹ A double-blind, placebo-controlled study of 60 women assessing the safety and efficacy of topical hexapeptide showed a total antiwrinkle efficacy of 48.9% on the side treated with an emulsion containing 10% of the hexapeptide compared with 0% efficacy on the placebo side.⁸ Similar to Blanes-Mira et al,¹⁰ no adverse events such as skin irritation or toxicity were seen.⁸ In all of these studies, wrinkle depth was measured by silicone replica analysis.

Topical acetyl hexapeptide-3 is effective in decreasing wrinkles, and its best use will likely be as an adjunct to intramuscular BoNT, as the intramuscular form likely has higher efficacy with the toxin injected directly into the target muscle; however, patients who want the effects of BoNT without the pain of injections may choose to use topical acetyl hexapeptide-3 alone. Patients who do use acetyl hexapeptide-3 as a complement to their intramuscular BoNT regimen may not need as many units of BoNT with each treatment or may not need certain areas injected as often, leading to fewer injections and less pain with each visit. Skin irritation was not seen as a side effect in these trials. Additionally, the topical form has insignificant acute toxicity (≥2000 mg/kg) compared to BoNT type A (20 ng/kg), and genotoxicity was not seen with testing, making it a safe complementary option to an injectable regimen.⁸

Topical Hyaluronic Acid: A Complement to Injectable Fillers

Hyaluronic acid (HA) is a glycosaminoglycan found in the extracellular matrix of the skin that greatly contributes to tissue hydration. Additionally, it plays a crucial role in the synthesis of extracellular matrix molecules and epidermal cell interaction with the environment.¹¹ The water-binding capacity of HA approximates 1000 times its volume or 6 L of water per gram of HA; however, once an individual reaches adulthood, the amount of HA decreases to 5% of baseline levels, thus contributing to xerosis, loss of skin elasticity, and atrophy.^11,12 Although photoaged skin can have increased glycosaminoglycans due to an increase in chondroitin sulfate proteoglycans, they are abnormally deposited on elastotic material in the superficial dermis rather than diffusely scattered, as seen in youthful skin.¹²

Many topical antiaging products contain HA, though evidence for efficacy in reducing wrinkles has been lacking, along with concerns that HA cannot penetrate the skin. This concern stems from the fact that the original molecule is 3000 nm in diameter and the intercellular space is only 15 to 50 nm. This space is only 6 to 10 nm at the hyaline membrane. Recently, scientists in Japan found a way to reduce the size of HA molecules to 5 nm (nano-HA) without changing its structure. A study of 33 women who applied the topical nano-HA twice daily for 8 weeks to one periorbital area while the contralateral side was left untreated showed improved hydration of the treated side that continued to increase when measured at 2, 4, and 8 weeks using corneometry.¹¹ Roughness decreased and elasticity increased after week 2, which were maintained throughout the study. Additionally, erythema was measured using a chroma meter, which was found to have decreased at day 57 versus day 1.¹¹ An earlier study by Pavicic et al¹² evaluated the efficacy of topical hyalu-ronan 0.1% formulations of different molecular weights—50, 130, 300, 800, or 2000 kDa—in the periocular area. A randomized group of 76 women were treated twice daily for 2 months with HA cream on one side of the periocular area and placebo cream on the other. With regard to antiwrinkle properties, only the 50- and 130-kDa HA formulations showed marked effects compared with placebo after 2 months.¹²

Topical HA would be an effective addition to an antiwrinkle regimen, especially in patients who are averse to needles or are just starting to get wrinkles and are looking for a noninvasive therapy. Additionally, it would be beneficial for patients who have an injectable filler and BoNT regimen, as these patients will be able to target wrinkles simultaneously with both topical cosmeceuticals and injectables and likely will need fewer units of BoNT and/or filler and possibly fewer injections over time, which translates to decreased pain and adverse outcomes for patients.

Conclusion

The myriad of options dermatologists have to offer patients for cosmetic enhancement provides alternatives for patients who have contraindications to certain treatments, are needle averse, or have lifestyles that do not afford them a great deal of postprocedural healing time. Being knowledgeable about these options and how to combine them for improved outcomes is essential to any cosmetic practice.

Today’s cosmetic patient wants to look more youthful every day without spending a lot of money, feeling any pain, or having any postprocedure downtime. With continued technological improvements, dermatologists have been able to provide our patients with the more youthful appearance they desire; however, many of these procedures still are costly, painful, and may require some downtime. New cosmeceutical therapies can be used as adjuncts to these procedures, making antiaging regimens less painful for patients and requiring less postprocedure healing time. In this article, the use of cosmeceuticals in conjunction with chemical peels, lasers, and injectables will be discussed.

Chemical Peels

Chemical peels are used to create an injury of specific skin depth with a goal of stimulating new skin growth and improving surface texture and appearance. They generally are classified as superficial, medium, or deep according to the depth of action. Currently available agents for superficial chemical peels include α-hydroxy acids (AHAs)(eg, glycolic acid [GA]) and β-hydroxy acids (BHAs)(eg, salicylic acid). β-Lipohydroxy acid (up to 10%), a derivative of salicylic acid, is widely used in Europe. Trichloroacetic acid (TCA) can be used for superficial peels (10%–20%) and for medium-depth peels (35%). Combination peels such as Monheit combination (Jessner solution plus TCA), Brody combination (solid CO₂ plus TCA), Coleman combination (GA 70% plus TCA), and Jessner solution with GA can be used as medium-depth peels. Deep peels typically are performed with phenol-based solutions, including the Baker-Gordon phenol peel and the Hetter peel (phenol or croton oil peel).

Specific agents for chemical peels should be selected based on the disorder being treated and should be administered using an appropriate peel depth determined by the histologic level or severity of skin pathology to maximize treatment success.¹ However, other considerations, such as skin characteristics, area of skin to be treated, safety concerns, healing time, and patient adherence also should be taken into account to achieve the best overall results. Although many of the deeper peels recently have been replaced by laser-based ablative treatments, superficial to medium-depth peels still are commonly used in the treatment of fine lines, uneven texture, and dyspigmentation.²

Superficial peels are reasonably safe and well tolerated, usually with only mild discomfort (eg, transient burning, irritation, erythema). Scarring, postinflammatory hyperpigmentation (PIH), and infection are rare with superficial peels.¹ Postinflammatory hyperpigmentation can be exacerbated by sun exposure, making it important for patients to be educated about sun protection and closely monitored during the recovery phase. In medium and deep peels, lines of demarcation related to the administration technique can occur. Feathering the chemical peel solution at junctions with nonpeeled skin can help to avoid this effect.¹ Side effects associated with deeper chemical peels can include pigmentary changes, infections, allergic reactions, improper healing, hypersensitivity, and underlying disease exacerbation. The best way to prevent complications is to identify patients who are at risk and maintain an appropriate peel depth that balances efficacy with known adverse events.¹ 

Many adjunctive agents (eg, AHAs, BHAs, retinoids, skin-bleaching preparations) can be used to enhance chemical peels and decrease the incidence of PIH. α-Hydroxy acids and BHAs can be beneficial when applied prior to chemical peels. Moisturizers containing AHAs and BHAs can be used for 2 to 3 weeks before superficial or medium-depth chemical peels.² These agents cause thinning of the stratum corneum, thereby creating a more uniform cutaneous surface and allowing for deeper penetration of the chemical peeling agent. Retinoids also are superior prepeeling agents; however, retinoids also can increase the likelihood of irritation, which can be minimized by discontinuing retinoids for 1 week following chemical peels.² A combination of chemical peels and topical bleaching agents has been shown to be effective in treating hyperpigmentation. The chemical peel causes superficial exfoliation, which allows the lightening agent to penetrate more deeply.²

Hydroquinone (HQ) is the gold standard for improvement of existing pigmentation.³ It is one of the most effective inhibitors of melanogenesis both in vitro and in vivo and is widely used for the treatment of melanosis and other hyperpigmentary disorders. It is widely accepted that the depigmentation activity of HQ may partly be related to its ability to act as an alternate substrate of tyrosinase, thereby competing for tyrosine oxidation in active melanocytes.³ Using HQ at a 4% concentration and combining it with retinoids is quite efficacious.² Other commonly used depigmenting agents include kojic acid, ascorbic acid (vitamin C), and niacinamide, which often can be used as adjuncts with or maintenance therapy after HQ treatment.^2,3

The risk for PIH is imminent for chemical peels and cosmetic laser treatments; therefore, it is crucial to educate patients about the importance of daily and aggressive sun protection. There are several methods of reducing or eliminating postprocedure melanin formation, such as inhibiting tyrosinase synthesis, using complex copper to inhibit tyrosinase function, eliminating oxidation reactions that lead to polymer formation, slowing down the transfer of melanosomes to keratinocytes, or acting upstream on the hormone that stimulates melanogenesis.³ Most of the depigmenting agents presently on the market act by inhibiting tyrosinase via one of these mechanisms. 

Skin-lightening agents are primarily formulated as emulsions that have a higher aesthetic appeal. Many of the ingredients get better dispersions with emulsions, which is an added feature of these products. Recently, gel-based formulations also are being considered for their suitability in certain skin types. Efficacy studies for skin-lightening formulations are being carried out through clinical trials that utilize devices that measure skin color in addition to the dermatologist’s assessment.⁴ Other skin parameters (eg, moisturization, texture, barrier integrity, pH) also are being evaluated to give physicians a picture of skin health after the use of skin-lightening agents. With advances in technology and measurement techniques, it is becoming easier to identify the efficacy of these formulations in different skin types.⁴

Lasers

The ultimate goal of laser therapy often is to improve the canvas and color of the skin. Ablative laser resurfacing is reliably the most effective procedure for sun-damaged skin.² This technique causes thermally induced full-thickness epidermal and dermal denudation, which in turn facilitates cytokine-led dermal collagen formation and reepithelialization. Various nonablative modalities also are used for treating photodamaged skin. The epidermis remains unaffected by these nonablative methods, thus decreasing the need for extensive wound care and downtime that is required with ablative treatments. Combining nonablative laser treatments with topical cosmeceuticals has been proven more effective than using either method alone.² The use of topical retinoids prior to ablative laser resurfacing often results in remarkably faster postprocedure healing and reepithelialization (Figure). Retinoids are best applied nightly for at least 2 weeks and optimally for 3 months before ablative laser treatment. Application should be discontinued for 1 week immediately prior to the procedure.

Before (A) and after (B) treatment with a fractional laser in combination with a pre- and postprocedure skin care regimen consisting of retinoids and sunscreen.

Topical retinoids also are effective in reducing erythema and increasing dermal thickness after nonablative treatments. When used prior to laser treatments, retinoids have been shown to decrease the risk for postoperative milia and hyperpigmentation as well as to allow for better penetration of the laser beam secondary to a thinner stratum corneum.² Following ablative resurfacing, retinoid use should be discontinued for several weeks to allow for reepithelialization and adequate healing.

Postprocedure Wound Healing

Most of the recommended products that help decrease postprocedural inflammation are cosmeceuticals containing both antioxidants and anti-inflammatories to help decrease redness and inflammation, including various barrier repair moisturizers. Restoring barrier integrity improves the overall appearance of the skin. The ingredients normally recommended in barrier repair moisturizers are epidermal lipids such as ceramides; hyaluronic acid (HA), which is a humectant; and occlusives for patients with very dry skin. Some of the ingredients in over-the-counter cosmeceuticals that can help decrease redness and inflammation include vitamin C, vitamin E, and vitamin B or niacinamide, which will help plump the barrier and also have anti-inflammatory properties. Additionally, polyphenolic flavonoids such as soy and green tea can help decrease inflammation, along with a number of other organic ingredients, such as caffeine, feverfew, and licorice.⁵ If topical vitamin C is being considered for postprocedure use, the non–ascorbic acid variant should be administered. The magnesium ascorbyl phosphate and ascorbyl palmitate forms of vitamin C have a neutral pH and tend to be better tolerated by patients.

In addition to current prescription and over-the-counter cosmeceuticals used for postprocedure irritation and inflammation, copper peptides and other well-tolerated and effective naturally occurring compounds are being investigated and tried. Copper is a biocide that regulates keratinocyte integrins for epithelization and extracellular matrix remodeling. The extracellular matrix consists of the structural fibrillar collagens and is remodeled or degraded by matrix metalloproteinases (MMPs) that facilitate epithelization. The predominant classes of MMPs include collagenases (ie, MMP-1) and gelatinases (ie, MMP-2, MMP-9) that degrade interstitial collagen and basement membrane proteins.⁶ The MMPs are endogenously inhibited by tissue inhibitors of metalloproteinases (TIMPs). Copper is a cofactor to lysyl oxidase, which cross-links collagen and stimulates expression of MMP-2 and collagen in a complex with a matrix-derived tripeptide (glycyl-histidyl-lysine or Gly-His-Lys [GHK]) in fibroblasts.⁶ Much attention has been focused on the tripeptides, such as GHK and Gly-Gly-His, and their copper complexes, which have high activity and good skin tolerance. These complexes have been shown to play a physiological role in the process of wound healing, tissue repair, and skin inflammation. Gly-Gly-His, GHK, copper chloride, and their copper complexes decrease tumor necrosis factor α–dependent IL-6 secretion in fibroblasts.⁷ IL-6 is crucial for normal wound healing, skin inflammation, and UVB-induced erythema. Because of their anti-inflammatory properties, these copper peptides could potentially be used in place of corticosteroids or nonsteroidal anti-inflammatory drugs, which have more side effects.

Botulinum Neurotoxin and Other Injectable Fillers

Acetyl Hexapeptide-3: A Topical Complement to Botulinum Neurotoxin

Acetyl hexapeptide-3 (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH₂) was discovered when looking for a less toxic variation of botulinum neurotoxin (BoNT) to treat aging skin.⁸ It is patterned from the N-terminal end of the synaptosome-associated protein of molecular weight 25 kDa (SNAP-25), which is essential for docking and fusion of synaptic vesicles to the presynaptic membrane for acetylcholine release.⁹ It prevents formation and stability of the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex, inhibiting vesicle docking and calcium-dependent catecholamine exocytosis.⁸ It also has been found to substantially inhibit the repetitive muscular contraction of facial expression similar to BoNT type A but with somewhat lower efficacy. Acetyl hexapeptide-3 was shown to inhibit 30% of total catecholamine exocytosis and had a remarkable capacity to permeate the skin.¹⁰ Thus this topical form of BoNT is a useful complement to intramuscular BoNT.

Studies showing the efficacy and safety of acetyl hexapeptide-3 have demonstrated reductions in wrinkle intensity, mainly in the lateral periorbital areas. In one early study, 10 women applied an emulsion containing 10% of the hexapeptide to one lateral periorbital region and the same emulsion without the hexapeptide to the contralateral side, both twice daily for 30 days.¹⁰ A 30% decrease in the depth of skin wrinkles was seen on the hexapeptide side compared with a 10% decrease in the depth of wrinkles on the side treated without hexapeptide. No irritation or toxicity was noted.¹⁰ In another trial, 10 women applied an acetyl hexapeptide-3 cream 5% twice daily to lateral periorbital rhytides, with a 27% improvement in wrinkle depth after a 30-day treatment period.⁹ A double-blind, placebo-controlled study of 60 women assessing the safety and efficacy of topical hexapeptide showed a total antiwrinkle efficacy of 48.9% on the side treated with an emulsion containing 10% of the hexapeptide compared with 0% efficacy on the placebo side.⁸ Similar to Blanes-Mira et al,¹⁰ no adverse events such as skin irritation or toxicity were seen.⁸ In all of these studies, wrinkle depth was measured by silicone replica analysis.

Topical acetyl hexapeptide-3 is effective in decreasing wrinkles, and its best use will likely be as an adjunct to intramuscular BoNT, as the intramuscular form likely has higher efficacy with the toxin injected directly into the target muscle; however, patients who want the effects of BoNT without the pain of injections may choose to use topical acetyl hexapeptide-3 alone. Patients who do use acetyl hexapeptide-3 as a complement to their intramuscular BoNT regimen may not need as many units of BoNT with each treatment or may not need certain areas injected as often, leading to fewer injections and less pain with each visit. Skin irritation was not seen as a side effect in these trials. Additionally, the topical form has insignificant acute toxicity (≥2000 mg/kg) compared to BoNT type A (20 ng/kg), and genotoxicity was not seen with testing, making it a safe complementary option to an injectable regimen.⁸

Topical Hyaluronic Acid: A Complement to Injectable Fillers

Hyaluronic acid (HA) is a glycosaminoglycan found in the extracellular matrix of the skin that greatly contributes to tissue hydration. Additionally, it plays a crucial role in the synthesis of extracellular matrix molecules and epidermal cell interaction with the environment.¹¹ The water-binding capacity of HA approximates 1000 times its volume or 6 L of water per gram of HA; however, once an individual reaches adulthood, the amount of HA decreases to 5% of baseline levels, thus contributing to xerosis, loss of skin elasticity, and atrophy.^11,12 Although photoaged skin can have increased glycosaminoglycans due to an increase in chondroitin sulfate proteoglycans, they are abnormally deposited on elastotic material in the superficial dermis rather than diffusely scattered, as seen in youthful skin.¹²

Many topical antiaging products contain HA, though evidence for efficacy in reducing wrinkles has been lacking, along with concerns that HA cannot penetrate the skin. This concern stems from the fact that the original molecule is 3000 nm in diameter and the intercellular space is only 15 to 50 nm. This space is only 6 to 10 nm at the hyaline membrane. Recently, scientists in Japan found a way to reduce the size of HA molecules to 5 nm (nano-HA) without changing its structure. A study of 33 women who applied the topical nano-HA twice daily for 8 weeks to one periorbital area while the contralateral side was left untreated showed improved hydration of the treated side that continued to increase when measured at 2, 4, and 8 weeks using corneometry.¹¹ Roughness decreased and elasticity increased after week 2, which were maintained throughout the study. Additionally, erythema was measured using a chroma meter, which was found to have decreased at day 57 versus day 1.¹¹ An earlier study by Pavicic et al¹² evaluated the efficacy of topical hyalu-ronan 0.1% formulations of different molecular weights—50, 130, 300, 800, or 2000 kDa—in the periocular area. A randomized group of 76 women were treated twice daily for 2 months with HA cream on one side of the periocular area and placebo cream on the other. With regard to antiwrinkle properties, only the 50- and 130-kDa HA formulations showed marked effects compared with placebo after 2 months.¹²

Topical HA would be an effective addition to an antiwrinkle regimen, especially in patients who are averse to needles or are just starting to get wrinkles and are looking for a noninvasive therapy. Additionally, it would be beneficial for patients who have an injectable filler and BoNT regimen, as these patients will be able to target wrinkles simultaneously with both topical cosmeceuticals and injectables and likely will need fewer units of BoNT and/or filler and possibly fewer injections over time, which translates to decreased pain and adverse outcomes for patients.

Conclusion

The myriad of options dermatologists have to offer patients for cosmetic enhancement provides alternatives for patients who have contraindications to certain treatments, are needle averse, or have lifestyles that do not afford them a great deal of postprocedural healing time. Being knowledgeable about these options and how to combine them for improved outcomes is essential to any cosmetic practice.

BARCELONA – More extensive catheter ablation procedures offered no benefit over pulmonary vein isolation alone for persistent atrial fibrillation in the largest-ever randomized trial examining outcomes of the three most popular ablation strategies.

"This study, the STAR AF 2 trial, will force a change in thinking both in the guidelines as well as in clinical practice," Dr. Atul Verma predicted, in presenting the study findings at the annual congress of the European Society of Cardiology.

Because of a widespread belief that catheter ablation success rates are probably lower in persistent AF than in paroxysmal AF, guidelines suggest "operators should consider more ablation based on linear lesions or complex fractionated electrograms," in addition to pulmonary vein isolation, in treating patients with persistent AF (Heart Rhythm 2012;9:632-96). The guidelines noted, however, that there is little evidence to support this recommendation.

The STAR AF 2 trial was conducted to learn if more complex ablation procedures really do provide greater efficacy than pulmonary vein isolation (PVI) alone. The study included 589 patients at 48 centers in 12 countries. All patients had persistent AF refractory to at least one antiarrhythmic drug and were about to undergo their first-ever catheter ablation.

Participants were randomized 1:4:4 to PVI alone with the procedural endpoint of entrance and exit block by circular mapping catheter, or PVI plus mapping and ablation of complex fractionated electrograms during AF identified using a validated 3-D mapping system, or PVI plus a left atrial roof line and another line along the mitral valve isthmus with the endpoint of bidirectional block confirmed by prespecified pacing maneuvers.

Patients remained blinded as to which of the three treatments they received. They were prospectively followed with 24-hour Holter monitoring at 3, 6, 9, 12, and 18 months along with weekly transtelephonic monitoring transmissions or at any time they felt symptoms.

Successful PVI was achieved in 97% of patients, complex fractionated electrograms were eliminated in 80% of patients assigned to that strategy, and both target lines were blocked in 74% of patients who underwent linear ablation.

The primary outcome was freedom from a documented episode of AF lasting more than 30 seconds after one procedure with or without antiarrhythmic medication through 18 months. The rates were 59% with PVI only, 48% with PVI plus complex fractionated electrograms, and 44% with PVI and linear ablation. These rates weren’t significantly different.

There were downsides to the two more elaborate ablation strategies. Procedural times were roughly 1 hour longer. Moreover, mean fluoroscopy time was 29 minutes in the PVI-only group, compared with 41 and 42 minutes with the more complex procedures. That translates to 44% more radiation exposure for both operators and patients, with absolutely no resultant added benefit over PVI alone, noted Dr. Verma, an electrophysiologist at Southlake Regional Health Center in Newmarket, Ont.

Complication rates across the board in STAR AF 2 were among the lowest ever reported in a multicenter clinical trial of catheter ablation. Of note, however, the sole fatal complication was the result of an atrial esophageal fistula in a patient assigned to PVI plus electrogram ablation.

Discussant Dr. Jagmeet P. Singh, director of the cardiac resynchronization therapy program at Massachusetts General Hospital, Boston, called STAR AF 2 "a fantastic trial."

"This study surely advocates that less ablation is more – and less works quite well," he said, noting that the roughly 50% success rate at 18 months with PVI alone is comparable to prior published success rates in paroxysmal AF.

Discussant Dr. Paulus Kirchhof said his own recent informal survey of high-volume catheter ablation centers in the United States and Europe indicated roughly one-third do PVI alone for patients with persistent AF, one-third do PVI plus ablation of complex fractionated electrograms, and one-third do PVI plus linear ablation.

"So I would say this was a question at equipoise," added Dr. Kirchhof, professor of cardiovascular sciences at the University of Birmingham (England).

Zeroing in on the added fluoroscopy time associated with the more complex ablation procedures, he noted that observational data suggest lengthier fluoroscopy may be associated with silent, subclinical brain lesions. Based upon the STAR 2 AF results, therefore, a reasonable strategy now for persistent AF is to do PVI alone, then wait and see what happens before considering additional ablation procedures later, he said.

"More importantly, I think this study shows we have to go back to the drawing board. The time pattern of AF – its duration, whether it’s paroxysmal or persistent, the left atrial size – all these things we believe identify patients who need more therapy, they may not actually help us. We just have to accept that not all patients with AF are the same, and that the pattern of AF does not discriminate so well. I think what we can really learn from this trial moving forward is that we need a clinical classification of AF patients. We have to define the patient who would benefit before we continue to develop ever-more intensive interventional strategies," he commented.

Factors worthy of further study as potential tools for separating AF patients into subgroups for treatment purposes include markers of atrial fibrosis, whether by imaging, blood, or ECG patterns; markers of parasympathetic/sympathetic imbalance; clinical markers of abnormal calcium metabolism; or blood markers, Dr. Kirchhof added.

The STAR AF 2 trial was funded by St. Jude Medical. Dr. Verma, Dr. Singh, and Dr. Kirchhof reported receiving grant support from St. Jude Medical as well as other pharmaceutical and medical device companies. In addition, Dr. Verma and Dr. Singh have served on advisory boards for St. Jude.

bjancin@frontlinemedcom.com

BARCELONA – More extensive catheter ablation procedures offered no benefit over pulmonary vein isolation alone for persistent atrial fibrillation in the largest-ever randomized trial examining outcomes of the three most popular ablation strategies.

"This study, the STAR AF 2 trial, will force a change in thinking both in the guidelines as well as in clinical practice," Dr. Atul Verma predicted, in presenting the study findings at the annual congress of the European Society of Cardiology.

Because of a widespread belief that catheter ablation success rates are probably lower in persistent AF than in paroxysmal AF, guidelines suggest "operators should consider more ablation based on linear lesions or complex fractionated electrograms," in addition to pulmonary vein isolation, in treating patients with persistent AF (Heart Rhythm 2012;9:632-96). The guidelines noted, however, that there is little evidence to support this recommendation.

The STAR AF 2 trial was conducted to learn if more complex ablation procedures really do provide greater efficacy than pulmonary vein isolation (PVI) alone. The study included 589 patients at 48 centers in 12 countries. All patients had persistent AF refractory to at least one antiarrhythmic drug and were about to undergo their first-ever catheter ablation.

Participants were randomized 1:4:4 to PVI alone with the procedural endpoint of entrance and exit block by circular mapping catheter, or PVI plus mapping and ablation of complex fractionated electrograms during AF identified using a validated 3-D mapping system, or PVI plus a left atrial roof line and another line along the mitral valve isthmus with the endpoint of bidirectional block confirmed by prespecified pacing maneuvers.

Patients remained blinded as to which of the three treatments they received. They were prospectively followed with 24-hour Holter monitoring at 3, 6, 9, 12, and 18 months along with weekly transtelephonic monitoring transmissions or at any time they felt symptoms.

Successful PVI was achieved in 97% of patients, complex fractionated electrograms were eliminated in 80% of patients assigned to that strategy, and both target lines were blocked in 74% of patients who underwent linear ablation.

The primary outcome was freedom from a documented episode of AF lasting more than 30 seconds after one procedure with or without antiarrhythmic medication through 18 months. The rates were 59% with PVI only, 48% with PVI plus complex fractionated electrograms, and 44% with PVI and linear ablation. These rates weren’t significantly different.

There were downsides to the two more elaborate ablation strategies. Procedural times were roughly 1 hour longer. Moreover, mean fluoroscopy time was 29 minutes in the PVI-only group, compared with 41 and 42 minutes with the more complex procedures. That translates to 44% more radiation exposure for both operators and patients, with absolutely no resultant added benefit over PVI alone, noted Dr. Verma, an electrophysiologist at Southlake Regional Health Center in Newmarket, Ont.

Complication rates across the board in STAR AF 2 were among the lowest ever reported in a multicenter clinical trial of catheter ablation. Of note, however, the sole fatal complication was the result of an atrial esophageal fistula in a patient assigned to PVI plus electrogram ablation.

Discussant Dr. Jagmeet P. Singh, director of the cardiac resynchronization therapy program at Massachusetts General Hospital, Boston, called STAR AF 2 "a fantastic trial."

"This study surely advocates that less ablation is more – and less works quite well," he said, noting that the roughly 50% success rate at 18 months with PVI alone is comparable to prior published success rates in paroxysmal AF.

Discussant Dr. Paulus Kirchhof said his own recent informal survey of high-volume catheter ablation centers in the United States and Europe indicated roughly one-third do PVI alone for patients with persistent AF, one-third do PVI plus ablation of complex fractionated electrograms, and one-third do PVI plus linear ablation.

"So I would say this was a question at equipoise," added Dr. Kirchhof, professor of cardiovascular sciences at the University of Birmingham (England).

Zeroing in on the added fluoroscopy time associated with the more complex ablation procedures, he noted that observational data suggest lengthier fluoroscopy may be associated with silent, subclinical brain lesions. Based upon the STAR 2 AF results, therefore, a reasonable strategy now for persistent AF is to do PVI alone, then wait and see what happens before considering additional ablation procedures later, he said.

"More importantly, I think this study shows we have to go back to the drawing board. The time pattern of AF – its duration, whether it’s paroxysmal or persistent, the left atrial size – all these things we believe identify patients who need more therapy, they may not actually help us. We just have to accept that not all patients with AF are the same, and that the pattern of AF does not discriminate so well. I think what we can really learn from this trial moving forward is that we need a clinical classification of AF patients. We have to define the patient who would benefit before we continue to develop ever-more intensive interventional strategies," he commented.

Factors worthy of further study as potential tools for separating AF patients into subgroups for treatment purposes include markers of atrial fibrosis, whether by imaging, blood, or ECG patterns; markers of parasympathetic/sympathetic imbalance; clinical markers of abnormal calcium metabolism; or blood markers, Dr. Kirchhof added.

The STAR AF 2 trial was funded by St. Jude Medical. Dr. Verma, Dr. Singh, and Dr. Kirchhof reported receiving grant support from St. Jude Medical as well as other pharmaceutical and medical device companies. In addition, Dr. Verma and Dr. Singh have served on advisory boards for St. Jude.

bjancin@frontlinemedcom.com

BARCELONA – More extensive catheter ablation procedures offered no benefit over pulmonary vein isolation alone for persistent atrial fibrillation in the largest-ever randomized trial examining outcomes of the three most popular ablation strategies.

"This study, the STAR AF 2 trial, will force a change in thinking both in the guidelines as well as in clinical practice," Dr. Atul Verma predicted, in presenting the study findings at the annual congress of the European Society of Cardiology.

Because of a widespread belief that catheter ablation success rates are probably lower in persistent AF than in paroxysmal AF, guidelines suggest "operators should consider more ablation based on linear lesions or complex fractionated electrograms," in addition to pulmonary vein isolation, in treating patients with persistent AF (Heart Rhythm 2012;9:632-96). The guidelines noted, however, that there is little evidence to support this recommendation.

The STAR AF 2 trial was conducted to learn if more complex ablation procedures really do provide greater efficacy than pulmonary vein isolation (PVI) alone. The study included 589 patients at 48 centers in 12 countries. All patients had persistent AF refractory to at least one antiarrhythmic drug and were about to undergo their first-ever catheter ablation.

Participants were randomized 1:4:4 to PVI alone with the procedural endpoint of entrance and exit block by circular mapping catheter, or PVI plus mapping and ablation of complex fractionated electrograms during AF identified using a validated 3-D mapping system, or PVI plus a left atrial roof line and another line along the mitral valve isthmus with the endpoint of bidirectional block confirmed by prespecified pacing maneuvers.

Patients remained blinded as to which of the three treatments they received. They were prospectively followed with 24-hour Holter monitoring at 3, 6, 9, 12, and 18 months along with weekly transtelephonic monitoring transmissions or at any time they felt symptoms.

Successful PVI was achieved in 97% of patients, complex fractionated electrograms were eliminated in 80% of patients assigned to that strategy, and both target lines were blocked in 74% of patients who underwent linear ablation.

The primary outcome was freedom from a documented episode of AF lasting more than 30 seconds after one procedure with or without antiarrhythmic medication through 18 months. The rates were 59% with PVI only, 48% with PVI plus complex fractionated electrograms, and 44% with PVI and linear ablation. These rates weren’t significantly different.

There were downsides to the two more elaborate ablation strategies. Procedural times were roughly 1 hour longer. Moreover, mean fluoroscopy time was 29 minutes in the PVI-only group, compared with 41 and 42 minutes with the more complex procedures. That translates to 44% more radiation exposure for both operators and patients, with absolutely no resultant added benefit over PVI alone, noted Dr. Verma, an electrophysiologist at Southlake Regional Health Center in Newmarket, Ont.

Complication rates across the board in STAR AF 2 were among the lowest ever reported in a multicenter clinical trial of catheter ablation. Of note, however, the sole fatal complication was the result of an atrial esophageal fistula in a patient assigned to PVI plus electrogram ablation.

Discussant Dr. Jagmeet P. Singh, director of the cardiac resynchronization therapy program at Massachusetts General Hospital, Boston, called STAR AF 2 "a fantastic trial."

"This study surely advocates that less ablation is more – and less works quite well," he said, noting that the roughly 50% success rate at 18 months with PVI alone is comparable to prior published success rates in paroxysmal AF.

Discussant Dr. Paulus Kirchhof said his own recent informal survey of high-volume catheter ablation centers in the United States and Europe indicated roughly one-third do PVI alone for patients with persistent AF, one-third do PVI plus ablation of complex fractionated electrograms, and one-third do PVI plus linear ablation.

"So I would say this was a question at equipoise," added Dr. Kirchhof, professor of cardiovascular sciences at the University of Birmingham (England).

Zeroing in on the added fluoroscopy time associated with the more complex ablation procedures, he noted that observational data suggest lengthier fluoroscopy may be associated with silent, subclinical brain lesions. Based upon the STAR 2 AF results, therefore, a reasonable strategy now for persistent AF is to do PVI alone, then wait and see what happens before considering additional ablation procedures later, he said.

"More importantly, I think this study shows we have to go back to the drawing board. The time pattern of AF – its duration, whether it’s paroxysmal or persistent, the left atrial size – all these things we believe identify patients who need more therapy, they may not actually help us. We just have to accept that not all patients with AF are the same, and that the pattern of AF does not discriminate so well. I think what we can really learn from this trial moving forward is that we need a clinical classification of AF patients. We have to define the patient who would benefit before we continue to develop ever-more intensive interventional strategies," he commented.

Factors worthy of further study as potential tools for separating AF patients into subgroups for treatment purposes include markers of atrial fibrosis, whether by imaging, blood, or ECG patterns; markers of parasympathetic/sympathetic imbalance; clinical markers of abnormal calcium metabolism; or blood markers, Dr. Kirchhof added.

The STAR AF 2 trial was funded by St. Jude Medical. Dr. Verma, Dr. Singh, and Dr. Kirchhof reported receiving grant support from St. Jude Medical as well as other pharmaceutical and medical device companies. In addition, Dr. Verma and Dr. Singh have served on advisory boards for St. Jude.

bjancin@frontlinemedcom.com

BARCELONA – Intensive perioperative statin therapy in patients undergoing CABG surgery doesn’t protect against postop atrial fibrillation or myocardial injury, according to a large randomized clinical trial hailed as the "definitive" study addressing this issue.

"There are many reasons why these patients should be put on statin treatment, but the prevention of postop complications is not one of them," Dr. Barbara Casadei said in presenting the findings of the Statin Therapy in Cardiac Surgery (STICS) trial at the annual congress of the European Society of Cardiology.

The STICS results are at odds with conventional wisdom. ESC guidelines give a favorable class IIa, level of evidence B recommendation that "statins should be considered for prevention of new-onset atrial fibrillation after coronary artery bypass grafting, either isolated or in combination with valvular interventions."

"STICS was a very carefully conducted, large scale, robust study that I think has definitely closed the door on this issue," commented Dr. Keith A.A. Fox, professor of cardiology at the University of Edinburgh and chair of the scientific and clinical program committee at ESC Congress 2014.

STICS was a double-blind prospective trial in which 1,922 patients scheduled for elective CABG were randomized to 20 mg per day of rosuvastatin (Crestor) or placebo starting up to 8 days prior to surgery and continued for 5 days postop. All participants were in sinus rhythm preoperatively, with no history of AF, said Dr. Casadei, professor of cardiovascular medicine at the University of Oxford, England.

The two coprimary endpoints in STICS were the incidence of new-onset AF during 5 days of postop Holter monitoring, and evidence of postop myocardial injury as demonstrated in serial troponin I assays.

Postop AF occurred in 21% of those given high-intensity therapy with rosuvastatin and 20% of placebo-treated controls. There was no subgroup where rosuvastatin was protective (see graphic).

Troponin I measurements obtained 6, 24, 48, and 120 hours postop showed areas under the curve that were superimposable in the two study groups, meaning perioperative high-dose statin therapy provided absolutely no protection against postop cardiac muscle injury.

Mean hospital length of stay and ICU time didn’t differ between the two groups, either.

The impetus for conducting STICS was recognition that the guidelines’ endorsement of perioperative high-dose statin therapy in conjunction with cardiac surgery was based upon a series of small randomized trials with serious limitations. Although the results of a meta-analysis of the 14 prior trials looked impressive at first glance – a 17% incidence of postop AF in statin-treated patients, compared with 30% in controls, for a near-halving of the risk of this important complication – these 14 studies totaled 1,300 patients, and there were many methodologic shortcomings.

The STICS researchers hypothesized that a large, well-designed trial – bigger than all previous studies combined – would shore up the previously shaky supporting evidence and perhaps provide grounds for statins to win a new indication from regulatory agencies. Post-CABG AF is associated with a doubled risk of stroke and mortality, and excess hospital costs of $8,000-$18,000 dollars per patient.

Discussant Dr. Paulus Kirchhof, a member of the task force that developed the current ESC guidelines (Europace 2010;12:1360-420), said those guidelines now clearly need to be revisited. Beyond that, he added, STICS provides important new contributions in understanding the pathophysiology of AF.

Bruce Jancin/Frontline Medical News

"We know that AF is caused by several vicious circles, and we believe that inflammation could influence those and cause AF. And we also thought that postop AF was the condition where inflammation plays the biggest role. Based upon the negative results with this anti-inflammatory intervention, I think we have to question this concept a bit," said Dr. Kirchhof, professor of cardiovascular sciences at the University of Birmingham, England.

Dr. Casadei countered that she’s not ready to write off postop inflammation entirely as a major trigger of new-onset AF following CABG.

"The inflammation is there. We know from experimental work in animals that there is a strong association between inflammation and postop atrial fibrillation, but whether the association is causal, I think, is still debated. However, it may be that the anti-inflammatory effect of statins is not sufficiently strong to actually prevent this complication," she said.

Discussant Dr. Steven Nissen praised STICS as "an outstanding trial."

"I also think there’s a terribly important lesson here, which is the power of self-delusion in medicine. When we base our guidelines on small, poorly controlled trials, we are often making mistakes. This is one of countless examples where when someone finally does a careful, thoughtful trial, we find out that something that people believe just isn’t true. We can’t cut corners with evidence. We need good randomized trials," declared Dr. Nissen, chair of the department of cardiovascular medicine at the Cleveland Clinic.

The STICS trial was funded primarily by the British Heart Foundation, the Oxford Biomedical Research Center, and the UK Medical Research Council. In addition, Dr. Casadei reported receiving an unrestricted grant from AstraZeneca in conjunction with the trial.

bjancin@frontlinemedcom.com

BARCELONA – Intensive perioperative statin therapy in patients undergoing CABG surgery doesn’t protect against postop atrial fibrillation or myocardial injury, according to a large randomized clinical trial hailed as the "definitive" study addressing this issue.

"There are many reasons why these patients should be put on statin treatment, but the prevention of postop complications is not one of them," Dr. Barbara Casadei said in presenting the findings of the Statin Therapy in Cardiac Surgery (STICS) trial at the annual congress of the European Society of Cardiology.

The STICS results are at odds with conventional wisdom. ESC guidelines give a favorable class IIa, level of evidence B recommendation that "statins should be considered for prevention of new-onset atrial fibrillation after coronary artery bypass grafting, either isolated or in combination with valvular interventions."

"STICS was a very carefully conducted, large scale, robust study that I think has definitely closed the door on this issue," commented Dr. Keith A.A. Fox, professor of cardiology at the University of Edinburgh and chair of the scientific and clinical program committee at ESC Congress 2014.

STICS was a double-blind prospective trial in which 1,922 patients scheduled for elective CABG were randomized to 20 mg per day of rosuvastatin (Crestor) or placebo starting up to 8 days prior to surgery and continued for 5 days postop. All participants were in sinus rhythm preoperatively, with no history of AF, said Dr. Casadei, professor of cardiovascular medicine at the University of Oxford, England.

The two coprimary endpoints in STICS were the incidence of new-onset AF during 5 days of postop Holter monitoring, and evidence of postop myocardial injury as demonstrated in serial troponin I assays.

Postop AF occurred in 21% of those given high-intensity therapy with rosuvastatin and 20% of placebo-treated controls. There was no subgroup where rosuvastatin was protective (see graphic).

Troponin I measurements obtained 6, 24, 48, and 120 hours postop showed areas under the curve that were superimposable in the two study groups, meaning perioperative high-dose statin therapy provided absolutely no protection against postop cardiac muscle injury.

Mean hospital length of stay and ICU time didn’t differ between the two groups, either.

The impetus for conducting STICS was recognition that the guidelines’ endorsement of perioperative high-dose statin therapy in conjunction with cardiac surgery was based upon a series of small randomized trials with serious limitations. Although the results of a meta-analysis of the 14 prior trials looked impressive at first glance – a 17% incidence of postop AF in statin-treated patients, compared with 30% in controls, for a near-halving of the risk of this important complication – these 14 studies totaled 1,300 patients, and there were many methodologic shortcomings.

The STICS researchers hypothesized that a large, well-designed trial – bigger than all previous studies combined – would shore up the previously shaky supporting evidence and perhaps provide grounds for statins to win a new indication from regulatory agencies. Post-CABG AF is associated with a doubled risk of stroke and mortality, and excess hospital costs of $8,000-$18,000 dollars per patient.

Discussant Dr. Paulus Kirchhof, a member of the task force that developed the current ESC guidelines (Europace 2010;12:1360-420), said those guidelines now clearly need to be revisited. Beyond that, he added, STICS provides important new contributions in understanding the pathophysiology of AF.

Bruce Jancin/Frontline Medical News

"We know that AF is caused by several vicious circles, and we believe that inflammation could influence those and cause AF. And we also thought that postop AF was the condition where inflammation plays the biggest role. Based upon the negative results with this anti-inflammatory intervention, I think we have to question this concept a bit," said Dr. Kirchhof, professor of cardiovascular sciences at the University of Birmingham, England.

Dr. Casadei countered that she’s not ready to write off postop inflammation entirely as a major trigger of new-onset AF following CABG.

"The inflammation is there. We know from experimental work in animals that there is a strong association between inflammation and postop atrial fibrillation, but whether the association is causal, I think, is still debated. However, it may be that the anti-inflammatory effect of statins is not sufficiently strong to actually prevent this complication," she said.

Discussant Dr. Steven Nissen praised STICS as "an outstanding trial."

"I also think there’s a terribly important lesson here, which is the power of self-delusion in medicine. When we base our guidelines on small, poorly controlled trials, we are often making mistakes. This is one of countless examples where when someone finally does a careful, thoughtful trial, we find out that something that people believe just isn’t true. We can’t cut corners with evidence. We need good randomized trials," declared Dr. Nissen, chair of the department of cardiovascular medicine at the Cleveland Clinic.

The STICS trial was funded primarily by the British Heart Foundation, the Oxford Biomedical Research Center, and the UK Medical Research Council. In addition, Dr. Casadei reported receiving an unrestricted grant from AstraZeneca in conjunction with the trial.

bjancin@frontlinemedcom.com

BARCELONA – Intensive perioperative statin therapy in patients undergoing CABG surgery doesn’t protect against postop atrial fibrillation or myocardial injury, according to a large randomized clinical trial hailed as the "definitive" study addressing this issue.

"There are many reasons why these patients should be put on statin treatment, but the prevention of postop complications is not one of them," Dr. Barbara Casadei said in presenting the findings of the Statin Therapy in Cardiac Surgery (STICS) trial at the annual congress of the European Society of Cardiology.

The STICS results are at odds with conventional wisdom. ESC guidelines give a favorable class IIa, level of evidence B recommendation that "statins should be considered for prevention of new-onset atrial fibrillation after coronary artery bypass grafting, either isolated or in combination with valvular interventions."

"STICS was a very carefully conducted, large scale, robust study that I think has definitely closed the door on this issue," commented Dr. Keith A.A. Fox, professor of cardiology at the University of Edinburgh and chair of the scientific and clinical program committee at ESC Congress 2014.

STICS was a double-blind prospective trial in which 1,922 patients scheduled for elective CABG were randomized to 20 mg per day of rosuvastatin (Crestor) or placebo starting up to 8 days prior to surgery and continued for 5 days postop. All participants were in sinus rhythm preoperatively, with no history of AF, said Dr. Casadei, professor of cardiovascular medicine at the University of Oxford, England.

The two coprimary endpoints in STICS were the incidence of new-onset AF during 5 days of postop Holter monitoring, and evidence of postop myocardial injury as demonstrated in serial troponin I assays.

Postop AF occurred in 21% of those given high-intensity therapy with rosuvastatin and 20% of placebo-treated controls. There was no subgroup where rosuvastatin was protective (see graphic).

Troponin I measurements obtained 6, 24, 48, and 120 hours postop showed areas under the curve that were superimposable in the two study groups, meaning perioperative high-dose statin therapy provided absolutely no protection against postop cardiac muscle injury.

Mean hospital length of stay and ICU time didn’t differ between the two groups, either.

The impetus for conducting STICS was recognition that the guidelines’ endorsement of perioperative high-dose statin therapy in conjunction with cardiac surgery was based upon a series of small randomized trials with serious limitations. Although the results of a meta-analysis of the 14 prior trials looked impressive at first glance – a 17% incidence of postop AF in statin-treated patients, compared with 30% in controls, for a near-halving of the risk of this important complication – these 14 studies totaled 1,300 patients, and there were many methodologic shortcomings.

The STICS researchers hypothesized that a large, well-designed trial – bigger than all previous studies combined – would shore up the previously shaky supporting evidence and perhaps provide grounds for statins to win a new indication from regulatory agencies. Post-CABG AF is associated with a doubled risk of stroke and mortality, and excess hospital costs of $8,000-$18,000 dollars per patient.

Discussant Dr. Paulus Kirchhof, a member of the task force that developed the current ESC guidelines (Europace 2010;12:1360-420), said those guidelines now clearly need to be revisited. Beyond that, he added, STICS provides important new contributions in understanding the pathophysiology of AF.

Bruce Jancin/Frontline Medical News

"We know that AF is caused by several vicious circles, and we believe that inflammation could influence those and cause AF. And we also thought that postop AF was the condition where inflammation plays the biggest role. Based upon the negative results with this anti-inflammatory intervention, I think we have to question this concept a bit," said Dr. Kirchhof, professor of cardiovascular sciences at the University of Birmingham, England.

Dr. Casadei countered that she’s not ready to write off postop inflammation entirely as a major trigger of new-onset AF following CABG.

"The inflammation is there. We know from experimental work in animals that there is a strong association between inflammation and postop atrial fibrillation, but whether the association is causal, I think, is still debated. However, it may be that the anti-inflammatory effect of statins is not sufficiently strong to actually prevent this complication," she said.

Discussant Dr. Steven Nissen praised STICS as "an outstanding trial."

"I also think there’s a terribly important lesson here, which is the power of self-delusion in medicine. When we base our guidelines on small, poorly controlled trials, we are often making mistakes. This is one of countless examples where when someone finally does a careful, thoughtful trial, we find out that something that people believe just isn’t true. We can’t cut corners with evidence. We need good randomized trials," declared Dr. Nissen, chair of the department of cardiovascular medicine at the Cleveland Clinic.

The STICS trial was funded primarily by the British Heart Foundation, the Oxford Biomedical Research Center, and the UK Medical Research Council. In addition, Dr. Casadei reported receiving an unrestricted grant from AstraZeneca in conjunction with the trial.

bjancin@frontlinemedcom.com

Case Report

A 65-year-old man presented to the dermatology department for treatment of a scaly rash on the face and scalp. A diagnosis of seborrheic dermatitis was made, and he was prescribed ketoconazole cream 2% and shampoo 2%. Two days later, the patient presented to the emergency department for facial swelling and pruritus, which began 1 day after he began using the ketoconazole cream and shampoo. He reported itching and burning on the face that began within several hours of application followed by progressive facial edema. The patient denied shortness of breath or swelling of the tongue. Physical examination revealed mild facial induration with erythematous plaques on the bilateral cheeks, forehead, and eyelids. The patient was instructed to stop using the ketoconazole cream and shampoo. Within several days of discontinuing use of the ketoconazole products, the dermatitis resolved following treatment with oral diphenhydramine and topical desonide.

Review of the patient’s medical record revealed several likely relevant incidences of undiagnosed recurrent dermatitis. Approximately 2 years earlier, the patient had called his primary care provider to report pain, burning, redness, and itching in the right buttock area following use of ketoconazole cream that the physician had prescribed. Allergic contact dermatitis also had been documented in the patient’s dermatology problem list approximately 1.5 years prior to the current presentation, though a likely causative agent was not listed. Approximately 3 months prior to the current presentation, the patient presented with lower leg rash and edema with documentation of possible allergic reaction to ketoconazole cream.

The patient was patch tested several weeks after discontinuation of the ketoconazole products using the 2012 North American Contact Dermatitis Group series (70 allergens), a supplemental series (36 allergens), an antifungal series (10 allergens), and personal products including ketoconazole cream and shampoo (diluted 1:100). Clinically relevant reactions at 72 hours included an extreme reaction (+++) to the patient’s personal ketoconazole cream 2% (E. Fougera & Co)(Figure 1), and strong reactions (++) to purified ketoconazole 5% in petrolatum and ketoconazole cream 2% (E. Fougera & Co) in an antifungal series (Figure 2). A doubtful reaction to methyl methacrylate was not deemed clinically relevant. No reactions were noted to terbinafine cream 1%, clotrimazole cream 1%, nystatin cream, nystatin ointment, econazole nitrate cream 1%, miconazole nitrate cream 2%, tolnaftate cream 1%, or purified clotrimazole 1% in petrolatum.

Figure 1. Reading at 72 hours of patient’s personal products (ketoconazole cream 2% and ketoconazole shampoo 2%).

Figure 2. Reading at 72 hours of an antifungal series (ketoconazole cream 2% and purified ketocona-zole 5% in petrolatum).

Comment

Ketoconazole is a widely used antifungal but rarely is reported as a cause of allergic contact dermatitis. Allergies to inactive ingredients, especially vehicles and preservatives, are more common than allergies to ketoconazole itself. In our patient, allergy to inactive ingredients was ruled out by negative reactions to individual constituents and/or negative reactions to other products containing those ingredients. A literature review via Ovid using the search terms ketoconazole, allergic contact dermatitis, and allergy found 4 reports involving 9 documented patients with type IV hypersensitivity to ketoconazole,^1-4 and 1 report of 2 patients who developed anaphylaxis from oral ketoconazole.¹ Of the 9 dermatitis cases, 3 patients had positive patch tests to only ketoconazole with no reactions to other imidazoles.^2,3 Monoallergy to clotrimazole also has been reported.⁵ A study by Dooms-Goossens et al⁴ showed that ketoconazole ranked seventh of 11 imidazole derivatives in its frequency to cause allergic contact dermatitis and did not demonstrate statistically significant cross-reactivity with other imidazoles; cross-reactivity usually occurred with miconazole and sulconazole.

Conclusion

This case of contact dermatitis to ketoconazole demonstrates the importance of patch testing with personal products as well as the unpredictability of cross-reactions within the imidazole class of antifungals.

Acknowledgment

This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Health Care System.

Case Report

A 65-year-old man presented to the dermatology department for treatment of a scaly rash on the face and scalp. A diagnosis of seborrheic dermatitis was made, and he was prescribed ketoconazole cream 2% and shampoo 2%. Two days later, the patient presented to the emergency department for facial swelling and pruritus, which began 1 day after he began using the ketoconazole cream and shampoo. He reported itching and burning on the face that began within several hours of application followed by progressive facial edema. The patient denied shortness of breath or swelling of the tongue. Physical examination revealed mild facial induration with erythematous plaques on the bilateral cheeks, forehead, and eyelids. The patient was instructed to stop using the ketoconazole cream and shampoo. Within several days of discontinuing use of the ketoconazole products, the dermatitis resolved following treatment with oral diphenhydramine and topical desonide.

Review of the patient’s medical record revealed several likely relevant incidences of undiagnosed recurrent dermatitis. Approximately 2 years earlier, the patient had called his primary care provider to report pain, burning, redness, and itching in the right buttock area following use of ketoconazole cream that the physician had prescribed. Allergic contact dermatitis also had been documented in the patient’s dermatology problem list approximately 1.5 years prior to the current presentation, though a likely causative agent was not listed. Approximately 3 months prior to the current presentation, the patient presented with lower leg rash and edema with documentation of possible allergic reaction to ketoconazole cream.

The patient was patch tested several weeks after discontinuation of the ketoconazole products using the 2012 North American Contact Dermatitis Group series (70 allergens), a supplemental series (36 allergens), an antifungal series (10 allergens), and personal products including ketoconazole cream and shampoo (diluted 1:100). Clinically relevant reactions at 72 hours included an extreme reaction (+++) to the patient’s personal ketoconazole cream 2% (E. Fougera & Co)(Figure 1), and strong reactions (++) to purified ketoconazole 5% in petrolatum and ketoconazole cream 2% (E. Fougera & Co) in an antifungal series (Figure 2). A doubtful reaction to methyl methacrylate was not deemed clinically relevant. No reactions were noted to terbinafine cream 1%, clotrimazole cream 1%, nystatin cream, nystatin ointment, econazole nitrate cream 1%, miconazole nitrate cream 2%, tolnaftate cream 1%, or purified clotrimazole 1% in petrolatum.

Figure 1. Reading at 72 hours of patient’s personal products (ketoconazole cream 2% and ketoconazole shampoo 2%).

Figure 2. Reading at 72 hours of an antifungal series (ketoconazole cream 2% and purified ketocona-zole 5% in petrolatum).

Comment

Ketoconazole is a widely used antifungal but rarely is reported as a cause of allergic contact dermatitis. Allergies to inactive ingredients, especially vehicles and preservatives, are more common than allergies to ketoconazole itself. In our patient, allergy to inactive ingredients was ruled out by negative reactions to individual constituents and/or negative reactions to other products containing those ingredients. A literature review via Ovid using the search terms ketoconazole, allergic contact dermatitis, and allergy found 4 reports involving 9 documented patients with type IV hypersensitivity to ketoconazole,^1-4 and 1 report of 2 patients who developed anaphylaxis from oral ketoconazole.¹ Of the 9 dermatitis cases, 3 patients had positive patch tests to only ketoconazole with no reactions to other imidazoles.^2,3 Monoallergy to clotrimazole also has been reported.⁵ A study by Dooms-Goossens et al⁴ showed that ketoconazole ranked seventh of 11 imidazole derivatives in its frequency to cause allergic contact dermatitis and did not demonstrate statistically significant cross-reactivity with other imidazoles; cross-reactivity usually occurred with miconazole and sulconazole.

Conclusion

This case of contact dermatitis to ketoconazole demonstrates the importance of patch testing with personal products as well as the unpredictability of cross-reactions within the imidazole class of antifungals.

Acknowledgment

This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Health Care System.

Case Report

A 65-year-old man presented to the dermatology department for treatment of a scaly rash on the face and scalp. A diagnosis of seborrheic dermatitis was made, and he was prescribed ketoconazole cream 2% and shampoo 2%. Two days later, the patient presented to the emergency department for facial swelling and pruritus, which began 1 day after he began using the ketoconazole cream and shampoo. He reported itching and burning on the face that began within several hours of application followed by progressive facial edema. The patient denied shortness of breath or swelling of the tongue. Physical examination revealed mild facial induration with erythematous plaques on the bilateral cheeks, forehead, and eyelids. The patient was instructed to stop using the ketoconazole cream and shampoo. Within several days of discontinuing use of the ketoconazole products, the dermatitis resolved following treatment with oral diphenhydramine and topical desonide.

Review of the patient’s medical record revealed several likely relevant incidences of undiagnosed recurrent dermatitis. Approximately 2 years earlier, the patient had called his primary care provider to report pain, burning, redness, and itching in the right buttock area following use of ketoconazole cream that the physician had prescribed. Allergic contact dermatitis also had been documented in the patient’s dermatology problem list approximately 1.5 years prior to the current presentation, though a likely causative agent was not listed. Approximately 3 months prior to the current presentation, the patient presented with lower leg rash and edema with documentation of possible allergic reaction to ketoconazole cream.

The patient was patch tested several weeks after discontinuation of the ketoconazole products using the 2012 North American Contact Dermatitis Group series (70 allergens), a supplemental series (36 allergens), an antifungal series (10 allergens), and personal products including ketoconazole cream and shampoo (diluted 1:100). Clinically relevant reactions at 72 hours included an extreme reaction (+++) to the patient’s personal ketoconazole cream 2% (E. Fougera & Co)(Figure 1), and strong reactions (++) to purified ketoconazole 5% in petrolatum and ketoconazole cream 2% (E. Fougera & Co) in an antifungal series (Figure 2). A doubtful reaction to methyl methacrylate was not deemed clinically relevant. No reactions were noted to terbinafine cream 1%, clotrimazole cream 1%, nystatin cream, nystatin ointment, econazole nitrate cream 1%, miconazole nitrate cream 2%, tolnaftate cream 1%, or purified clotrimazole 1% in petrolatum.

Figure 1. Reading at 72 hours of patient’s personal products (ketoconazole cream 2% and ketoconazole shampoo 2%).

Figure 2. Reading at 72 hours of an antifungal series (ketoconazole cream 2% and purified ketocona-zole 5% in petrolatum).

Comment

Ketoconazole is a widely used antifungal but rarely is reported as a cause of allergic contact dermatitis. Allergies to inactive ingredients, especially vehicles and preservatives, are more common than allergies to ketoconazole itself. In our patient, allergy to inactive ingredients was ruled out by negative reactions to individual constituents and/or negative reactions to other products containing those ingredients. A literature review via Ovid using the search terms ketoconazole, allergic contact dermatitis, and allergy found 4 reports involving 9 documented patients with type IV hypersensitivity to ketoconazole,^1-4 and 1 report of 2 patients who developed anaphylaxis from oral ketoconazole.¹ Of the 9 dermatitis cases, 3 patients had positive patch tests to only ketoconazole with no reactions to other imidazoles.^2,3 Monoallergy to clotrimazole also has been reported.⁵ A study by Dooms-Goossens et al⁴ showed that ketoconazole ranked seventh of 11 imidazole derivatives in its frequency to cause allergic contact dermatitis and did not demonstrate statistically significant cross-reactivity with other imidazoles; cross-reactivity usually occurred with miconazole and sulconazole.

Conclusion

This case of contact dermatitis to ketoconazole demonstrates the importance of patch testing with personal products as well as the unpredictability of cross-reactions within the imidazole class of antifungals.

Acknowledgment

This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Health Care System.

Thomas Barker, PhD, with

bacteria needed to create

the platelet-like particles

Credit: Gary Meek

Researchers say they’ve developed a new class of synthetic platelet-like particles that can augment natural blood clotting.

The particles are based on soft and deformable hydrogel materials and measure about 1 micron in diameter.

Testing in animal models and a simulated circulatory system suggested the particles are effective at slowing bleeding and can safely circulate in the bloodstream.

The particles have been tested in human blood but not in clinical trials.

Ashley Brown, PhD, of the Georgia Institute of Technology and Emory University in Atlanta, and her colleagues described the research involving these particles in Nature Materials.

The team noted that, when fibrinogen proteins receive the right signals from thrombin, they polymerize at the site of bleeding to form a clot. The synthetic platelet-like particles use the same trigger, so they are activated only when the body’s natural clotting process is initiated.

To create that trigger, the researchers employed molecular evolution. They developed an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.

“Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it,” said study author Thomas Barker, PhD, of Georgia Tech and Emory University.

“The specificity of this material provides a very important advantage in triggering clotting at just the right time.”

The researchers tested the platelet-like particles in an animal model and a microfluidic chamber designed to simulate conditions within the body’s circulatory system.

The team used the chamber to study normal human blood, as well as blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.

The researchers also tested blood from infants who had received anticoagulant treatment prior to undergoing open heart surgery. When platelet-like particles were added to this blood, it was able to form clots.

Finally, the team performed safety testing on blood from hemophilia patients. Because their blood lacked the triggers needed to cause fibrin formation, the particles had no effect.

What ultimately happens to the particles circulating in the bloodstream will be the topic of future research, Dr Brown said. Particles of similar size and composition are normally eliminated from the body.

While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body’s repair process. Clots formed from the synthetic particles also contract, but over a longer period of time.

These particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.

“For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain,” said study author Wilbur Lam, MD, PhD, of the Georgia Institute of Technology and Emory University.

“These particles could potentially be a way to obviate the need for a transfusion. Though they don’t have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process.”

Thomas Barker, PhD, with

bacteria needed to create

the platelet-like particles

Credit: Gary Meek

Researchers say they’ve developed a new class of synthetic platelet-like particles that can augment natural blood clotting.

The particles are based on soft and deformable hydrogel materials and measure about 1 micron in diameter.

Testing in animal models and a simulated circulatory system suggested the particles are effective at slowing bleeding and can safely circulate in the bloodstream.

The particles have been tested in human blood but not in clinical trials.

Ashley Brown, PhD, of the Georgia Institute of Technology and Emory University in Atlanta, and her colleagues described the research involving these particles in Nature Materials.

The team noted that, when fibrinogen proteins receive the right signals from thrombin, they polymerize at the site of bleeding to form a clot. The synthetic platelet-like particles use the same trigger, so they are activated only when the body’s natural clotting process is initiated.

To create that trigger, the researchers employed molecular evolution. They developed an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.

“Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it,” said study author Thomas Barker, PhD, of Georgia Tech and Emory University.

“The specificity of this material provides a very important advantage in triggering clotting at just the right time.”

The researchers tested the platelet-like particles in an animal model and a microfluidic chamber designed to simulate conditions within the body’s circulatory system.

The team used the chamber to study normal human blood, as well as blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.

The researchers also tested blood from infants who had received anticoagulant treatment prior to undergoing open heart surgery. When platelet-like particles were added to this blood, it was able to form clots.

Finally, the team performed safety testing on blood from hemophilia patients. Because their blood lacked the triggers needed to cause fibrin formation, the particles had no effect.

What ultimately happens to the particles circulating in the bloodstream will be the topic of future research, Dr Brown said. Particles of similar size and composition are normally eliminated from the body.

While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body’s repair process. Clots formed from the synthetic particles also contract, but over a longer period of time.

These particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.

“For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain,” said study author Wilbur Lam, MD, PhD, of the Georgia Institute of Technology and Emory University.

“These particles could potentially be a way to obviate the need for a transfusion. Though they don’t have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process.”

Thomas Barker, PhD, with

bacteria needed to create

the platelet-like particles

Credit: Gary Meek

Researchers say they’ve developed a new class of synthetic platelet-like particles that can augment natural blood clotting.

The particles are based on soft and deformable hydrogel materials and measure about 1 micron in diameter.

Testing in animal models and a simulated circulatory system suggested the particles are effective at slowing bleeding and can safely circulate in the bloodstream.

The particles have been tested in human blood but not in clinical trials.

Ashley Brown, PhD, of the Georgia Institute of Technology and Emory University in Atlanta, and her colleagues described the research involving these particles in Nature Materials.

The team noted that, when fibrinogen proteins receive the right signals from thrombin, they polymerize at the site of bleeding to form a clot. The synthetic platelet-like particles use the same trigger, so they are activated only when the body’s natural clotting process is initiated.

To create that trigger, the researchers employed molecular evolution. They developed an antibody that could be attached to the hydrogel particles to change their form when they encounter thrombin-activated fibrin. The resulting antibody has a high affinity for the polymerized form of fibrin and a low affinity for the precursor material.

“Fibrin production is on the back end of the clotting process, so we feel that it is a safer place to try to interact with it,” said study author Thomas Barker, PhD, of Georgia Tech and Emory University.

“The specificity of this material provides a very important advantage in triggering clotting at just the right time.”

The researchers tested the platelet-like particles in an animal model and a microfluidic chamber designed to simulate conditions within the body’s circulatory system.

The team used the chamber to study normal human blood, as well as blood that had been depleted of its natural platelets. In platelet-rich blood, clots formed as expected, and blood without platelets did not form clots. When the platelet-like particles were added to the platelet-depleted blood, it was able to clot.

The researchers also tested blood from infants who had received anticoagulant treatment prior to undergoing open heart surgery. When platelet-like particles were added to this blood, it was able to form clots.

Finally, the team performed safety testing on blood from hemophilia patients. Because their blood lacked the triggers needed to cause fibrin formation, the particles had no effect.

What ultimately happens to the particles circulating in the bloodstream will be the topic of future research, Dr Brown said. Particles of similar size and composition are normally eliminated from the body.

While the platelet-like particles lack many features of natural platelets, the researchers were surprised to find one property in common. Clots formed by natural platelets begin to contract over a period of hours, beginning the body’s repair process. Clots formed from the synthetic particles also contract, but over a longer period of time.

These particles were originally developed to be used on the battlefield by wounded soldiers, who might self-administer them using a device about the size of a smartphone. But the researchers believe the particles could also reduce the need for platelet transfusions in patients undergoing chemotherapy or bypass surgery, and in those with certain blood disorders.

“For a patient with insufficient platelets due to bleeding or an inherited disorder, physicians often have to resort to platelet transfusions, which can be difficult to obtain,” said study author Wilbur Lam, MD, PhD, of the Georgia Institute of Technology and Emory University.

“These particles could potentially be a way to obviate the need for a transfusion. Though they don’t have all the assets of natural platelets, a number of intriguing experiments have shown that the particles help augment the clotting process.”

Doctor and cancer patient

Credit: NCI and

Mathews Media Group

A new study suggests many patients in cancer centers do not experience a dignified death.

Study investigators surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Württemberg, Germany.

The results revealed a need for cancer centers to invest more in palliative care services, adequate rooms for dying patients, staff training in end-of-life care, and advance-care-planning standards.

Karin Jors, of the University Medical Center Freiburg, and her colleagues reported these findings in Cancer.

Previous research has shown that hospitals are often ill-prepared to provide care for dying patients.

To investigate whether the circumstances for dying on cancer center wards allow for a dignified death, Jors and her colleagues surveyed physicians and nurses in German cancer centers.

Among 1131 survey respondents, 57% believed that patients could die with dignity on their ward.

Half of the surveyed staff members indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory.

Only 19% of respondents felt they had been well-prepared to care for dying patients, and only 6% of physicians felt that way.

On the other hand, physicians perceived the circumstances for dying patients much more positively than nurses, especially regarding communication and life-prolonging measures.

While 72% of physicians reported that patients can usually die a dignified death on their ward, only 52% of nurses shared this opinion.

Palliative care staff reported much better conditions for dying patients than staff from other wards, with 95% of palliative care staff indicating that patients die with dignity on their wards.

“In our aging society, it is predicted that the number of hospital deaths will continue to rise in the coming years, and many of these deaths will be attributable to cancer,” Jors said.

“For this reason, it is particularly important that cancer centers strive to create a comfortable, dignified experience for dying patients and their families. Above all, this requires that staff members are provided with the adequate resources to care for these patients.”

The investigators therefore encourage the integration of palliative care into standard oncology care, beginning as early as diagnosis. They also believe physicians and nurses would benefit from increased education and training in end-of-life care.

Doctor and cancer patient

Credit: NCI and

Mathews Media Group

A new study suggests many patients in cancer centers do not experience a dignified death.

Study investigators surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Württemberg, Germany.

The results revealed a need for cancer centers to invest more in palliative care services, adequate rooms for dying patients, staff training in end-of-life care, and advance-care-planning standards.

Karin Jors, of the University Medical Center Freiburg, and her colleagues reported these findings in Cancer.

Previous research has shown that hospitals are often ill-prepared to provide care for dying patients.

To investigate whether the circumstances for dying on cancer center wards allow for a dignified death, Jors and her colleagues surveyed physicians and nurses in German cancer centers.

Among 1131 survey respondents, 57% believed that patients could die with dignity on their ward.

Half of the surveyed staff members indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory.

Only 19% of respondents felt they had been well-prepared to care for dying patients, and only 6% of physicians felt that way.

On the other hand, physicians perceived the circumstances for dying patients much more positively than nurses, especially regarding communication and life-prolonging measures.

While 72% of physicians reported that patients can usually die a dignified death on their ward, only 52% of nurses shared this opinion.

Palliative care staff reported much better conditions for dying patients than staff from other wards, with 95% of palliative care staff indicating that patients die with dignity on their wards.

“In our aging society, it is predicted that the number of hospital deaths will continue to rise in the coming years, and many of these deaths will be attributable to cancer,” Jors said.

“For this reason, it is particularly important that cancer centers strive to create a comfortable, dignified experience for dying patients and their families. Above all, this requires that staff members are provided with the adequate resources to care for these patients.”

The investigators therefore encourage the integration of palliative care into standard oncology care, beginning as early as diagnosis. They also believe physicians and nurses would benefit from increased education and training in end-of-life care.

Doctor and cancer patient

Credit: NCI and

Mathews Media Group

A new study suggests many patients in cancer centers do not experience a dignified death.

Study investigators surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Württemberg, Germany.

The results revealed a need for cancer centers to invest more in palliative care services, adequate rooms for dying patients, staff training in end-of-life care, and advance-care-planning standards.

Karin Jors, of the University Medical Center Freiburg, and her colleagues reported these findings in Cancer.

Previous research has shown that hospitals are often ill-prepared to provide care for dying patients.

To investigate whether the circumstances for dying on cancer center wards allow for a dignified death, Jors and her colleagues surveyed physicians and nurses in German cancer centers.

Among 1131 survey respondents, 57% believed that patients could die with dignity on their ward.

Half of the surveyed staff members indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory.

Only 19% of respondents felt they had been well-prepared to care for dying patients, and only 6% of physicians felt that way.

On the other hand, physicians perceived the circumstances for dying patients much more positively than nurses, especially regarding communication and life-prolonging measures.

While 72% of physicians reported that patients can usually die a dignified death on their ward, only 52% of nurses shared this opinion.

Palliative care staff reported much better conditions for dying patients than staff from other wards, with 95% of palliative care staff indicating that patients die with dignity on their wards.

“In our aging society, it is predicted that the number of hospital deaths will continue to rise in the coming years, and many of these deaths will be attributable to cancer,” Jors said.

“For this reason, it is particularly important that cancer centers strive to create a comfortable, dignified experience for dying patients and their families. Above all, this requires that staff members are provided with the adequate resources to care for these patients.”

The investigators therefore encourage the integration of palliative care into standard oncology care, beginning as early as diagnosis. They also believe physicians and nurses would benefit from increased education and training in end-of-life care.

Blood for transfusion

Credit: Elise Amendola

Experts from the World Health Organization (WHO) have identified several interventions that should be the focus of clinical evaluation for treating and preventing Ebola.

Transfusions of blood products from Ebola survivors topped this list.

Of course, such blood preparations, like the other interventions the WHO discussed, have not been approved to treat or prevent Ebola.

However, they could be available before the year is out, according to WHO estimates. The organization is exploring options to conduct clinical trials of blood products in Ebola patients.

Previous studies have suggested blood transfusions from Ebola survivors might prevent or treat Ebola virus infection. However, it is unclear whether antibodies in the plasma of survivors are sufficient to treat or prevent the disease.

Safety is also a concern, although the WHO said transfusions should be safe if they are provided by well-managed blood banks. Still, there is a risk of transmitting blood-borne pathogens and a theoretical concern about antibody-dependent enhancement of Ebola virus infection.

“[T]here was a lot of discussion and emphasis on blood, on blood transfusion, whole-blood transfusion, as well as on plasma that can be purified from convalescent serum,” said Marie-Paule Kieny, Assistant Director-General at the WHO.

“There was consensus that this has a good chance to work and that, also, this is something that can be produced now from the affected countries themselves.”

The experts also agreed that the international community needs to help affected countries create the necessary infrastructure to draw blood safely and prepare the blood products safely.

Aside from blood transfusions, the WHO experts mentioned 2 potential Ebola vaccines that should be a priority. Safety studies of these vaccines—based on vesicular stomatitis virus (VSV-EBO) and chimpanzee adenovirus (ChAd-EBO)—are beginning in the US and are slated to begin in Africa and Europe in mid-September.

If proven safe, a vaccine could be available in November 2014 for priority use in healthcare workers.

The WHO experts also discussed the availability and evidence supporting the use of novel therapeutic drugs, including monoclonal antibodies, RNA-based drugs, and small antiviral molecules. They considered the potential use of existing drugs approved for other diseases and conditions as well.

Of the novel products discussed, some have shown great promise in monkey models. Others have been used in a few Ebola patients and appear safe, but the numbers are too small to permit any definitive conclusions about efficacy.

Existing supplies of all experimental medicines are limited, the WHO said. While many efforts are underway to accelerate production, supplies will not be sufficient for several months to come. The prospects of having augmented supplies of vaccines rapidly look slightly better.

The WHO also cautioned that the investigation of the aforementioned interventions should not detract attention from measures to prevent Ebola from spreading.

Blood for transfusion

Credit: Elise Amendola

Experts from the World Health Organization (WHO) have identified several interventions that should be the focus of clinical evaluation for treating and preventing Ebola.

Transfusions of blood products from Ebola survivors topped this list.

Of course, such blood preparations, like the other interventions the WHO discussed, have not been approved to treat or prevent Ebola.

However, they could be available before the year is out, according to WHO estimates. The organization is exploring options to conduct clinical trials of blood products in Ebola patients.

Previous studies have suggested blood transfusions from Ebola survivors might prevent or treat Ebola virus infection. However, it is unclear whether antibodies in the plasma of survivors are sufficient to treat or prevent the disease.

Safety is also a concern, although the WHO said transfusions should be safe if they are provided by well-managed blood banks. Still, there is a risk of transmitting blood-borne pathogens and a theoretical concern about antibody-dependent enhancement of Ebola virus infection.

“[T]here was a lot of discussion and emphasis on blood, on blood transfusion, whole-blood transfusion, as well as on plasma that can be purified from convalescent serum,” said Marie-Paule Kieny, Assistant Director-General at the WHO.

“There was consensus that this has a good chance to work and that, also, this is something that can be produced now from the affected countries themselves.”

The experts also agreed that the international community needs to help affected countries create the necessary infrastructure to draw blood safely and prepare the blood products safely.

Aside from blood transfusions, the WHO experts mentioned 2 potential Ebola vaccines that should be a priority. Safety studies of these vaccines—based on vesicular stomatitis virus (VSV-EBO) and chimpanzee adenovirus (ChAd-EBO)—are beginning in the US and are slated to begin in Africa and Europe in mid-September.

If proven safe, a vaccine could be available in November 2014 for priority use in healthcare workers.

The WHO experts also discussed the availability and evidence supporting the use of novel therapeutic drugs, including monoclonal antibodies, RNA-based drugs, and small antiviral molecules. They considered the potential use of existing drugs approved for other diseases and conditions as well.

Of the novel products discussed, some have shown great promise in monkey models. Others have been used in a few Ebola patients and appear safe, but the numbers are too small to permit any definitive conclusions about efficacy.

Existing supplies of all experimental medicines are limited, the WHO said. While many efforts are underway to accelerate production, supplies will not be sufficient for several months to come. The prospects of having augmented supplies of vaccines rapidly look slightly better.

The WHO also cautioned that the investigation of the aforementioned interventions should not detract attention from measures to prevent Ebola from spreading.

Blood for transfusion

Credit: Elise Amendola

Experts from the World Health Organization (WHO) have identified several interventions that should be the focus of clinical evaluation for treating and preventing Ebola.

Transfusions of blood products from Ebola survivors topped this list.

Of course, such blood preparations, like the other interventions the WHO discussed, have not been approved to treat or prevent Ebola.

However, they could be available before the year is out, according to WHO estimates. The organization is exploring options to conduct clinical trials of blood products in Ebola patients.

Previous studies have suggested blood transfusions from Ebola survivors might prevent or treat Ebola virus infection. However, it is unclear whether antibodies in the plasma of survivors are sufficient to treat or prevent the disease.

Safety is also a concern, although the WHO said transfusions should be safe if they are provided by well-managed blood banks. Still, there is a risk of transmitting blood-borne pathogens and a theoretical concern about antibody-dependent enhancement of Ebola virus infection.

“[T]here was a lot of discussion and emphasis on blood, on blood transfusion, whole-blood transfusion, as well as on plasma that can be purified from convalescent serum,” said Marie-Paule Kieny, Assistant Director-General at the WHO.

“There was consensus that this has a good chance to work and that, also, this is something that can be produced now from the affected countries themselves.”

The experts also agreed that the international community needs to help affected countries create the necessary infrastructure to draw blood safely and prepare the blood products safely.

Aside from blood transfusions, the WHO experts mentioned 2 potential Ebola vaccines that should be a priority. Safety studies of these vaccines—based on vesicular stomatitis virus (VSV-EBO) and chimpanzee adenovirus (ChAd-EBO)—are beginning in the US and are slated to begin in Africa and Europe in mid-September.

If proven safe, a vaccine could be available in November 2014 for priority use in healthcare workers.

The WHO experts also discussed the availability and evidence supporting the use of novel therapeutic drugs, including monoclonal antibodies, RNA-based drugs, and small antiviral molecules. They considered the potential use of existing drugs approved for other diseases and conditions as well.

Of the novel products discussed, some have shown great promise in monkey models. Others have been used in a few Ebola patients and appear safe, but the numbers are too small to permit any definitive conclusions about efficacy.

Existing supplies of all experimental medicines are limited, the WHO said. While many efforts are underway to accelerate production, supplies will not be sufficient for several months to come. The prospects of having augmented supplies of vaccines rapidly look slightly better.

The WHO also cautioned that the investigation of the aforementioned interventions should not detract attention from measures to prevent Ebola from spreading.

A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.

The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.

CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.

These results appear in Clinical Cancer Research.

“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.

“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”

Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.

The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).

Treatment dosing and toxicity

Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.

When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m², there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m² over 2 hours, so this was considered the maximum-tolerated dose.

The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).

Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.

Response data

Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.

Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.

One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.

A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.

A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.

The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.

Two patients died from disease progression while on study.

The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.

Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.

A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.

The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.

CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.

These results appear in Clinical Cancer Research.

“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.

“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”

Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.

The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).

Treatment dosing and toxicity

Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.

When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m², there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m² over 2 hours, so this was considered the maximum-tolerated dose.

The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).

Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.

Response data

Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.

Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.

One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.

A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.

A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.

The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.

Two patients died from disease progression while on study.

The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.

Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.

A drug that targets mitochondrial function is largely safe and can be active in heavily pretreated patients with hematologic malignancies, a phase 1 trial indicates.

The drug, CPI-613, prompted responses in only 4 of 21 evaluable patients. However, 2 of those responses lasted more than 2 years.

CPI-613 was generally well-tolerated and did not induce bone marrow suppression. Four patients experienced renal failure, but it was reversed in 3 of them.

These results appear in Clinical Cancer Research.

“This drug is selectively taken up by cancer cells and then shuts down the production of energy in the mitochondria,” said study author Timothy Pardee, MD, PhD, of the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, North Carolina.

“This is the first drug to inhibit mitochondria in this way, and, if it proves effective in further clinical trials, it will open up a whole new approach to fighting cancer.”

Dr Pardee and his colleagues evaluated CPI-613 in 26 patients with relapsed or refractory hematologic malignancies—11 with acute myeloid leukemia, 6 with non-Hodgkin lymphoma, 4 with multiple myeloma, 4 with myelodysplastic syndrome (MDS), and 1 with Hodgkin lymphoma.

The median patient age was 65 years (range, 19-81), and the median number of prior therapies was 3 (range, 1-9).

Treatment dosing and toxicity

Patients received CPI-613 as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.

When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3780 mg/m², there were 2 dose-limiting toxicities. There were no such toxicities at a dose of 2940 mg/m² over 2 hours, so this was considered the maximum-tolerated dose.

The following grade 2 or higher toxicities were probably or definitely related to treatment: nausea (1 grade 2), vomiting (1 grade 3), diarrhea (3 grade 2), proteinuria (1 grade 2), renal failure (4 grade 3), hypotension (1 grade 2), hypocalcemia (1 grade 2), hypoalbuminemia (1 grade 2), and hyperkalemia (1 grade 3).

Renal failure was resolved in 3 of the 4 patients. The remaining patient chose hospice care.

Response data

Five patients discontinued treatment—1 refused therapy, 1 acquired an infection, and 3 developed acute kidney failure.

Of the 21 patients evaluable for response, 4 had an objective response following CPI-613 treatment, and 2 had prolonged stable disease.

One patient with MDS achieved a complete response that has been maintained for more than 3 years. A patient with acute myeloid leukemia achieved a morphologically leukemia-free state, went on to transplant, and is still alive and leukemia-free.

A patient with Burkitt lymphoma achieved a partial response after 3 cycles of therapy that was maintained for 17 cycles. She discontinued CPI-613 to have her residual disease resected, and has not received any treatment since. She is now disease-free more than 12 months later.

A patient with cutaneous T-cell lymphoma achieved a partial response that has been sustained for more than 2 years. At her request, she started to receive continuous therapy (no 1-week rest period), and she remains on treatment without significant toxicities and no evidence of marrow suppression.

The 2 patients with prolonged stable disease had MDS. Their disease was stable for 8 and 12 cycles, respectively. Two patients with multiple myeloma also initially had stable disease, but they progressed after 2 and 4 cycles, respectively.

Two patients died from disease progression while on study.

The researchers said these results suggest that agents targeting mitochondrial metabolism can be safe and active in hematologic malignancies. A phase 2 trial of CPI-613 is now underway.

Support for the phase 1 trial was provided by National Cancer Institute grants P30CA012197 and 1K08CA169809, the Doug Coley Foundation for Leukemia Research, the Frances P. Tutwiler Fund, The MacKay Foundation for Cancer Research, and Cornerstone Pharmaceuticals, which manufactured and provided CPI-613.

The use of low-dose aspirin is advisable after 12 weeks of gestation in asymptomatic pregnant women at high risk for developing preeclampsia, according to a recommendation from the U.S. Preventive Services Task Force.

The recommendation, published online Sept. 8 in the Annals of Internal Medicine, is based on a review of new evidence suggesting that the net benefit of low-dose aspirin for preventing preeclampsia is of substantial magnitude. It updates a 1996 recommendation from the USPSTF, which concluded that there was insufficient evidence at that time to recommend for or against the routine use of aspirin for the prevention of preeclampsia.

Louise Koenig/Frontline Medical News

The current evidence – including 15 randomized controlled trials used to assess the health benefits of low-dose aspirin, 13 randomized controlled trials used to evaluate preeclampsia incidence, and 19 randomized controlled trials and 2 good-quality observational studies used to evaluate harms associated with low-dose aspirin use – suggests that women at risk may benefit from low-dose aspirin beginning after 12 weeks of gestation.

Preeclampsia complicates 2%-8% of pregnancies worldwide, and accounts for 15% of preterm births and 12% of maternal deaths in the United States, according to the task force.

"The USPSTF found adequate evidence of a reduction in risk for preeclampsia, preterm birth, and IUGR [intrauterine growth restriction] in women at increased risk for preeclampsia who received low-dose aspirin, thus demonstrating substantial benefit. Low-dose aspirin (range, 60-150 mg/day) reduced the risk for preeclampsia by 24% in clinical trials [pooled relative risk, 0.76] and reduced the risk for preterm birth by 14% and IUGR by 20% [pooled relative risk, 0.86 and 0.80, respectively]," the updated recommendation stated (Ann. Intern. Med. 2014 Sept. 8 [doi:10.7326/m14-1884]).

Adequate evidence also indicates that low-dose aspirin is not associated with any increase in the risk of placental abruption, postpartum hemorrhage, fetal intracranial bleeding, or perinatal mortality.

"Evidence on long-term outcomes in offspring exposed in utero to low-dose aspirin is limited, but no developmental harms were identified by age 18 months in the one study reviewed," the task force wrote, concluding – with moderate certainty – that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, and IUGR in women at high risk.

The decision to initiate low-dose aspirin therapy in this population is typically based on medical history; there are no validated methods for identifying women at high risk based on biomarkers, clinical diagnostic tests, or medical history. However, as part of the recommendation, the USPSTF provided a pragmatic approach that may help identify those at risk.

"Women with one or more risk factors should receive low-dose aspirin. Women with several moderate risk factors may also benefit from low-dose aspirin," the task force noted, adding that the evidence for the latter approach is less certain, and that clinicians should use clinical judgment and discuss the risks and benefits with patients.

The recommendation applies to asymptomatic women at risk in whom low-dose aspirin is not contraindicated, and defines women at high risk as those with a history of preeclampsia, especially those with an adverse outcome; chronic hypertension, renal disease, type 1 or 2 diabetes, or an autoimmune disease; and those with multifetal gestation, according to the updated recommendation.

Moderate risk factors include nulliparity, obesity, a family history of preeclampsia, age greater than or equal to 35 years, African American race, low socioeconomic status, low birth rate or small for gestational age, greater than 10-year pregnancy interval, or previous adverse pregnancy outcome.

As for appropriate dosing, the most common dosage across studies was 100 mg, but the two largest trials contributing to benefit estimates used 60 mg.

An 81-mg dose was not specifically evaluated, but is commonly available in the United States in tablet form, and is a reasonable dosage for preeclampsia prophylaxis, the task force said.

The updated recommendation is generally in keeping with those of other organizations, including the American College of Obstetricians and Gynecologists, the World Health Organization, the National Institute for Health and Clinical Excellence, the American Heart Association/American Stroke Association, and the American Academy of Family Physicians. For example, ACOG recommends initiating daily low-dose aspirin during the late first trimester in those with a history of early-onset preeclampsia and preterm delivery, or with a history of preeclampsia in more than one prior pregnancy (<cf number="\"2\"">“</cf>American College of Obstetricians and Gynecologists: Hypertension in Pregnancy [Washington, D.C.: American College of Obstetricians and Gynecologists, 2013]), and WHO recommends daily low-dose aspirin as early as 12 weeks for those at high risk ("WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia" [Geneva: World Health Organization, 2011]).

The review by the USPSTF identified several research needs. For example, additional study is needed on the effects of low-dose aspirin on the development of preeclampsia and how patient response is affected by various risk factors. Research is also needed on how to improve clinicians’ ability to identify those at risk, and particularly those who would benefit most from prophylaxis. Study is needed on risk assessment tools, and on populations at particular risk, such as African American and nulliparous women.

Future trials should recruit adequate numbers of women from racial/ethnic populations that are at disproportionate risk.

"Larger studies on aspirin use in the first or early second trimester may improve the evidence base on optimal timing of low-dose aspirin preventive medication. Other areas of research include optimal therapies that individualize the aspirin dosage and timing of administration (e.g., morning vs. bedtime)," they concluded, noting that research is also needed to explore less-well-established risk factors, and to investigate whether preeclampsia prevention with low-dose aspirin affects long-term risk for cardiovascular disease, and whether there is any benefit to continuing low-dose aspirin after delivery in those at high risk.

The use of low-dose aspirin is advisable after 12 weeks of gestation in asymptomatic pregnant women at high risk for developing preeclampsia, according to a recommendation from the U.S. Preventive Services Task Force.

The recommendation, published online Sept. 8 in the Annals of Internal Medicine, is based on a review of new evidence suggesting that the net benefit of low-dose aspirin for preventing preeclampsia is of substantial magnitude. It updates a 1996 recommendation from the USPSTF, which concluded that there was insufficient evidence at that time to recommend for or against the routine use of aspirin for the prevention of preeclampsia.

Louise Koenig/Frontline Medical News

The current evidence – including 15 randomized controlled trials used to assess the health benefits of low-dose aspirin, 13 randomized controlled trials used to evaluate preeclampsia incidence, and 19 randomized controlled trials and 2 good-quality observational studies used to evaluate harms associated with low-dose aspirin use – suggests that women at risk may benefit from low-dose aspirin beginning after 12 weeks of gestation.

Preeclampsia complicates 2%-8% of pregnancies worldwide, and accounts for 15% of preterm births and 12% of maternal deaths in the United States, according to the task force.

"The USPSTF found adequate evidence of a reduction in risk for preeclampsia, preterm birth, and IUGR [intrauterine growth restriction] in women at increased risk for preeclampsia who received low-dose aspirin, thus demonstrating substantial benefit. Low-dose aspirin (range, 60-150 mg/day) reduced the risk for preeclampsia by 24% in clinical trials [pooled relative risk, 0.76] and reduced the risk for preterm birth by 14% and IUGR by 20% [pooled relative risk, 0.86 and 0.80, respectively]," the updated recommendation stated (Ann. Intern. Med. 2014 Sept. 8 [doi:10.7326/m14-1884]).

Adequate evidence also indicates that low-dose aspirin is not associated with any increase in the risk of placental abruption, postpartum hemorrhage, fetal intracranial bleeding, or perinatal mortality.

"Evidence on long-term outcomes in offspring exposed in utero to low-dose aspirin is limited, but no developmental harms were identified by age 18 months in the one study reviewed," the task force wrote, concluding – with moderate certainty – that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, and IUGR in women at high risk.

The decision to initiate low-dose aspirin therapy in this population is typically based on medical history; there are no validated methods for identifying women at high risk based on biomarkers, clinical diagnostic tests, or medical history. However, as part of the recommendation, the USPSTF provided a pragmatic approach that may help identify those at risk.

"Women with one or more risk factors should receive low-dose aspirin. Women with several moderate risk factors may also benefit from low-dose aspirin," the task force noted, adding that the evidence for the latter approach is less certain, and that clinicians should use clinical judgment and discuss the risks and benefits with patients.

The recommendation applies to asymptomatic women at risk in whom low-dose aspirin is not contraindicated, and defines women at high risk as those with a history of preeclampsia, especially those with an adverse outcome; chronic hypertension, renal disease, type 1 or 2 diabetes, or an autoimmune disease; and those with multifetal gestation, according to the updated recommendation.

Moderate risk factors include nulliparity, obesity, a family history of preeclampsia, age greater than or equal to 35 years, African American race, low socioeconomic status, low birth rate or small for gestational age, greater than 10-year pregnancy interval, or previous adverse pregnancy outcome.

As for appropriate dosing, the most common dosage across studies was 100 mg, but the two largest trials contributing to benefit estimates used 60 mg.

An 81-mg dose was not specifically evaluated, but is commonly available in the United States in tablet form, and is a reasonable dosage for preeclampsia prophylaxis, the task force said.

The updated recommendation is generally in keeping with those of other organizations, including the American College of Obstetricians and Gynecologists, the World Health Organization, the National Institute for Health and Clinical Excellence, the American Heart Association/American Stroke Association, and the American Academy of Family Physicians. For example, ACOG recommends initiating daily low-dose aspirin during the late first trimester in those with a history of early-onset preeclampsia and preterm delivery, or with a history of preeclampsia in more than one prior pregnancy (<cf number="\"2\"">“</cf>American College of Obstetricians and Gynecologists: Hypertension in Pregnancy [Washington, D.C.: American College of Obstetricians and Gynecologists, 2013]), and WHO recommends daily low-dose aspirin as early as 12 weeks for those at high risk ("WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia" [Geneva: World Health Organization, 2011]).

The review by the USPSTF identified several research needs. For example, additional study is needed on the effects of low-dose aspirin on the development of preeclampsia and how patient response is affected by various risk factors. Research is also needed on how to improve clinicians’ ability to identify those at risk, and particularly those who would benefit most from prophylaxis. Study is needed on risk assessment tools, and on populations at particular risk, such as African American and nulliparous women.

Future trials should recruit adequate numbers of women from racial/ethnic populations that are at disproportionate risk.

"Larger studies on aspirin use in the first or early second trimester may improve the evidence base on optimal timing of low-dose aspirin preventive medication. Other areas of research include optimal therapies that individualize the aspirin dosage and timing of administration (e.g., morning vs. bedtime)," they concluded, noting that research is also needed to explore less-well-established risk factors, and to investigate whether preeclampsia prevention with low-dose aspirin affects long-term risk for cardiovascular disease, and whether there is any benefit to continuing low-dose aspirin after delivery in those at high risk.

The use of low-dose aspirin is advisable after 12 weeks of gestation in asymptomatic pregnant women at high risk for developing preeclampsia, according to a recommendation from the U.S. Preventive Services Task Force.

The recommendation, published online Sept. 8 in the Annals of Internal Medicine, is based on a review of new evidence suggesting that the net benefit of low-dose aspirin for preventing preeclampsia is of substantial magnitude. It updates a 1996 recommendation from the USPSTF, which concluded that there was insufficient evidence at that time to recommend for or against the routine use of aspirin for the prevention of preeclampsia.

Louise Koenig/Frontline Medical News

The current evidence – including 15 randomized controlled trials used to assess the health benefits of low-dose aspirin, 13 randomized controlled trials used to evaluate preeclampsia incidence, and 19 randomized controlled trials and 2 good-quality observational studies used to evaluate harms associated with low-dose aspirin use – suggests that women at risk may benefit from low-dose aspirin beginning after 12 weeks of gestation.

Preeclampsia complicates 2%-8% of pregnancies worldwide, and accounts for 15% of preterm births and 12% of maternal deaths in the United States, according to the task force.

"The USPSTF found adequate evidence of a reduction in risk for preeclampsia, preterm birth, and IUGR [intrauterine growth restriction] in women at increased risk for preeclampsia who received low-dose aspirin, thus demonstrating substantial benefit. Low-dose aspirin (range, 60-150 mg/day) reduced the risk for preeclampsia by 24% in clinical trials [pooled relative risk, 0.76] and reduced the risk for preterm birth by 14% and IUGR by 20% [pooled relative risk, 0.86 and 0.80, respectively]," the updated recommendation stated (Ann. Intern. Med. 2014 Sept. 8 [doi:10.7326/m14-1884]).

Adequate evidence also indicates that low-dose aspirin is not associated with any increase in the risk of placental abruption, postpartum hemorrhage, fetal intracranial bleeding, or perinatal mortality.

"Evidence on long-term outcomes in offspring exposed in utero to low-dose aspirin is limited, but no developmental harms were identified by age 18 months in the one study reviewed," the task force wrote, concluding – with moderate certainty – that there is a substantial net benefit of daily low-dose aspirin use to reduce the risk for preeclampsia, preterm birth, and IUGR in women at high risk.

The decision to initiate low-dose aspirin therapy in this population is typically based on medical history; there are no validated methods for identifying women at high risk based on biomarkers, clinical diagnostic tests, or medical history. However, as part of the recommendation, the USPSTF provided a pragmatic approach that may help identify those at risk.

"Women with one or more risk factors should receive low-dose aspirin. Women with several moderate risk factors may also benefit from low-dose aspirin," the task force noted, adding that the evidence for the latter approach is less certain, and that clinicians should use clinical judgment and discuss the risks and benefits with patients.

The recommendation applies to asymptomatic women at risk in whom low-dose aspirin is not contraindicated, and defines women at high risk as those with a history of preeclampsia, especially those with an adverse outcome; chronic hypertension, renal disease, type 1 or 2 diabetes, or an autoimmune disease; and those with multifetal gestation, according to the updated recommendation.

Moderate risk factors include nulliparity, obesity, a family history of preeclampsia, age greater than or equal to 35 years, African American race, low socioeconomic status, low birth rate or small for gestational age, greater than 10-year pregnancy interval, or previous adverse pregnancy outcome.

As for appropriate dosing, the most common dosage across studies was 100 mg, but the two largest trials contributing to benefit estimates used 60 mg.

An 81-mg dose was not specifically evaluated, but is commonly available in the United States in tablet form, and is a reasonable dosage for preeclampsia prophylaxis, the task force said.

The updated recommendation is generally in keeping with those of other organizations, including the American College of Obstetricians and Gynecologists, the World Health Organization, the National Institute for Health and Clinical Excellence, the American Heart Association/American Stroke Association, and the American Academy of Family Physicians. For example, ACOG recommends initiating daily low-dose aspirin during the late first trimester in those with a history of early-onset preeclampsia and preterm delivery, or with a history of preeclampsia in more than one prior pregnancy (<cf number="\"2\"">“</cf>American College of Obstetricians and Gynecologists: Hypertension in Pregnancy [Washington, D.C.: American College of Obstetricians and Gynecologists, 2013]), and WHO recommends daily low-dose aspirin as early as 12 weeks for those at high risk ("WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia" [Geneva: World Health Organization, 2011]).

The review by the USPSTF identified several research needs. For example, additional study is needed on the effects of low-dose aspirin on the development of preeclampsia and how patient response is affected by various risk factors. Research is also needed on how to improve clinicians’ ability to identify those at risk, and particularly those who would benefit most from prophylaxis. Study is needed on risk assessment tools, and on populations at particular risk, such as African American and nulliparous women.

Future trials should recruit adequate numbers of women from racial/ethnic populations that are at disproportionate risk.

"Larger studies on aspirin use in the first or early second trimester may improve the evidence base on optimal timing of low-dose aspirin preventive medication. Other areas of research include optimal therapies that individualize the aspirin dosage and timing of administration (e.g., morning vs. bedtime)," they concluded, noting that research is also needed to explore less-well-established risk factors, and to investigate whether preeclampsia prevention with low-dose aspirin affects long-term risk for cardiovascular disease, and whether there is any benefit to continuing low-dose aspirin after delivery in those at high risk.

Over the past few days, an article has circulated about a 23-year-old middle school teacher in Cambridge, Md., who was suspended from his job because of two futuristic novels he wrote, including one about a school massacre 900 years in the future. The story was reported in The Atlantic under the headline, "In Maryland, a Soviet-Style Punishment for a Novelist."

The article, by Jeffrey Goldberg, said the young teacher had self-published his novels some time ago under a pseudonym. In addition to his being suspended, an "emergency medical evaluation" was ordered, his house was searched, and the school was swept for bombs by K-9 dogs. No charges have been filed as of this writing.

This response was deemed an "overreaction," and certainly has been good for book sales but probably not so much for the young man’s teaching career. The idea that artistic expression must conform to a specific standard or jeopardize one’s job leaves those with creative pursuits to worry and civil rights advocates to protest.

Soon after, the Los Angeles Times published an article stating that the issue was not the novels – the school knew about those in 2012 – but rather the content of a four-page letter the teacher had written to the school board suggesting that the teacher was suffering from some type of psychiatric condition and might have included indications that he was suicidal or dangerous. With this information, it was not as clear if the police response was an overreaction, and such determinations are generally made in hindsight: If a bomb is found, the decision was heroic, if not, it was an overreaction and a civil rights violation.

The case reminded me of the story about a New York City police officer who had Internet discussions about his desire to cook and eat women, including his ex-wife. While the officer never ate anyone, he was part of an online community called the Dark Fetish Network, which has of tens of thousands of registered users who discuss violent sexual fantasies. The officer, known in the media frenzy as Cannibal Cop, lost his job and was convicted of plotting to kidnap, a crime that could carry a life sentence. He reportedly had graphic discussions of plans to kill, roast, and eat specified victims, and he claimed that he had the means to do so. An investigation revealed that he did not own the implements that would enable him to carry out such a plan. His lawyer insisted that he was engaged in a role-playing fantasy, but he was convicted by a jury in 2012. In July, his conviction was overturned and he was released on bond. By that time, Cannibal Cop had served a year and a half in prison, with several months of it in solitary confinement.

Situations in which a person has done nothing illegal but has spoken or written words that indicate he or she might be a threat to public safety are fraught with concerns. While violent fantasies might be seen as "creepy" at a minimum, the criminal justice system is left to decide where the line is between fantasy and plan, and when a real threat exists. A person has the right to his dark fantasies, and the First Amendment right to free speech allows for discussion of those fantasies, while artistic endeavors allow for their expression. At the same time, if there are named or presumed victims, those individuals should not have to live with the terror of wondering if the fantasizer is going to act on the fantasies.

Invariably, psychiatrists end up being involved, even if the individual in question has no psychiatric history or obvious diagnosis. In a New York magazine article about the police officer titled, "A Dangerous Mind," Robert Kolker noted: "Pre-crime and psychiatry often go hand in hand. Legal instruments like institutionalization and sex-offender registration all share the goal of preventing crime from taking place, and for better or worse, they’re based on a psychiatric rationale."

As we all know, it can be difficult – if not impossible – to distinguish those who are having fantasies from those who are planning to commit a dangerous act. As psychiatrists, we deal with this uncertainty for patients who have suicidal thoughts on a regular basis. Often, even the patients don’t know for sure if they will act on their impulses. Fantasies that involve harming others are more unusual in clinical practice, and our risk assessment often begins with the stated intent of the individual. Our strongest predictor of future behavior continues to be past behavior, and neither the teacher nor the police officer in the stories above had criminal records.

To make it even more confusing, the Internet has added to the uncertainty; people have always had dangerous and fetishistic fantasies, but now there are ways others can learn the content of what was once very private. The risk, of course, is that fantasies and artistic endeavors become subject to both psychiatric scrutiny and criminal prosecution in a way that threatens civil rights and squelches creativity.

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore:The Johns Hopkins University Press, 2011).

Over the past few days, an article has circulated about a 23-year-old middle school teacher in Cambridge, Md., who was suspended from his job because of two futuristic novels he wrote, including one about a school massacre 900 years in the future. The story was reported in The Atlantic under the headline, "In Maryland, a Soviet-Style Punishment for a Novelist."

The article, by Jeffrey Goldberg, said the young teacher had self-published his novels some time ago under a pseudonym. In addition to his being suspended, an "emergency medical evaluation" was ordered, his house was searched, and the school was swept for bombs by K-9 dogs. No charges have been filed as of this writing.

This response was deemed an "overreaction," and certainly has been good for book sales but probably not so much for the young man’s teaching career. The idea that artistic expression must conform to a specific standard or jeopardize one’s job leaves those with creative pursuits to worry and civil rights advocates to protest.

Soon after, the Los Angeles Times published an article stating that the issue was not the novels – the school knew about those in 2012 – but rather the content of a four-page letter the teacher had written to the school board suggesting that the teacher was suffering from some type of psychiatric condition and might have included indications that he was suicidal or dangerous. With this information, it was not as clear if the police response was an overreaction, and such determinations are generally made in hindsight: If a bomb is found, the decision was heroic, if not, it was an overreaction and a civil rights violation.

The case reminded me of the story about a New York City police officer who had Internet discussions about his desire to cook and eat women, including his ex-wife. While the officer never ate anyone, he was part of an online community called the Dark Fetish Network, which has of tens of thousands of registered users who discuss violent sexual fantasies. The officer, known in the media frenzy as Cannibal Cop, lost his job and was convicted of plotting to kidnap, a crime that could carry a life sentence. He reportedly had graphic discussions of plans to kill, roast, and eat specified victims, and he claimed that he had the means to do so. An investigation revealed that he did not own the implements that would enable him to carry out such a plan. His lawyer insisted that he was engaged in a role-playing fantasy, but he was convicted by a jury in 2012. In July, his conviction was overturned and he was released on bond. By that time, Cannibal Cop had served a year and a half in prison, with several months of it in solitary confinement.

Situations in which a person has done nothing illegal but has spoken or written words that indicate he or she might be a threat to public safety are fraught with concerns. While violent fantasies might be seen as "creepy" at a minimum, the criminal justice system is left to decide where the line is between fantasy and plan, and when a real threat exists. A person has the right to his dark fantasies, and the First Amendment right to free speech allows for discussion of those fantasies, while artistic endeavors allow for their expression. At the same time, if there are named or presumed victims, those individuals should not have to live with the terror of wondering if the fantasizer is going to act on the fantasies.

Invariably, psychiatrists end up being involved, even if the individual in question has no psychiatric history or obvious diagnosis. In a New York magazine article about the police officer titled, "A Dangerous Mind," Robert Kolker noted: "Pre-crime and psychiatry often go hand in hand. Legal instruments like institutionalization and sex-offender registration all share the goal of preventing crime from taking place, and for better or worse, they’re based on a psychiatric rationale."

As we all know, it can be difficult – if not impossible – to distinguish those who are having fantasies from those who are planning to commit a dangerous act. As psychiatrists, we deal with this uncertainty for patients who have suicidal thoughts on a regular basis. Often, even the patients don’t know for sure if they will act on their impulses. Fantasies that involve harming others are more unusual in clinical practice, and our risk assessment often begins with the stated intent of the individual. Our strongest predictor of future behavior continues to be past behavior, and neither the teacher nor the police officer in the stories above had criminal records.

To make it even more confusing, the Internet has added to the uncertainty; people have always had dangerous and fetishistic fantasies, but now there are ways others can learn the content of what was once very private. The risk, of course, is that fantasies and artistic endeavors become subject to both psychiatric scrutiny and criminal prosecution in a way that threatens civil rights and squelches creativity.

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore:The Johns Hopkins University Press, 2011).

Over the past few days, an article has circulated about a 23-year-old middle school teacher in Cambridge, Md., who was suspended from his job because of two futuristic novels he wrote, including one about a school massacre 900 years in the future. The story was reported in The Atlantic under the headline, "In Maryland, a Soviet-Style Punishment for a Novelist."

The article, by Jeffrey Goldberg, said the young teacher had self-published his novels some time ago under a pseudonym. In addition to his being suspended, an "emergency medical evaluation" was ordered, his house was searched, and the school was swept for bombs by K-9 dogs. No charges have been filed as of this writing.

This response was deemed an "overreaction," and certainly has been good for book sales but probably not so much for the young man’s teaching career. The idea that artistic expression must conform to a specific standard or jeopardize one’s job leaves those with creative pursuits to worry and civil rights advocates to protest.

Soon after, the Los Angeles Times published an article stating that the issue was not the novels – the school knew about those in 2012 – but rather the content of a four-page letter the teacher had written to the school board suggesting that the teacher was suffering from some type of psychiatric condition and might have included indications that he was suicidal or dangerous. With this information, it was not as clear if the police response was an overreaction, and such determinations are generally made in hindsight: If a bomb is found, the decision was heroic, if not, it was an overreaction and a civil rights violation.

The case reminded me of the story about a New York City police officer who had Internet discussions about his desire to cook and eat women, including his ex-wife. While the officer never ate anyone, he was part of an online community called the Dark Fetish Network, which has of tens of thousands of registered users who discuss violent sexual fantasies. The officer, known in the media frenzy as Cannibal Cop, lost his job and was convicted of plotting to kidnap, a crime that could carry a life sentence. He reportedly had graphic discussions of plans to kill, roast, and eat specified victims, and he claimed that he had the means to do so. An investigation revealed that he did not own the implements that would enable him to carry out such a plan. His lawyer insisted that he was engaged in a role-playing fantasy, but he was convicted by a jury in 2012. In July, his conviction was overturned and he was released on bond. By that time, Cannibal Cop had served a year and a half in prison, with several months of it in solitary confinement.

Situations in which a person has done nothing illegal but has spoken or written words that indicate he or she might be a threat to public safety are fraught with concerns. While violent fantasies might be seen as "creepy" at a minimum, the criminal justice system is left to decide where the line is between fantasy and plan, and when a real threat exists. A person has the right to his dark fantasies, and the First Amendment right to free speech allows for discussion of those fantasies, while artistic endeavors allow for their expression. At the same time, if there are named or presumed victims, those individuals should not have to live with the terror of wondering if the fantasizer is going to act on the fantasies.

Invariably, psychiatrists end up being involved, even if the individual in question has no psychiatric history or obvious diagnosis. In a New York magazine article about the police officer titled, "A Dangerous Mind," Robert Kolker noted: "Pre-crime and psychiatry often go hand in hand. Legal instruments like institutionalization and sex-offender registration all share the goal of preventing crime from taking place, and for better or worse, they’re based on a psychiatric rationale."

As we all know, it can be difficult – if not impossible – to distinguish those who are having fantasies from those who are planning to commit a dangerous act. As psychiatrists, we deal with this uncertainty for patients who have suicidal thoughts on a regular basis. Often, even the patients don’t know for sure if they will act on their impulses. Fantasies that involve harming others are more unusual in clinical practice, and our risk assessment often begins with the stated intent of the individual. Our strongest predictor of future behavior continues to be past behavior, and neither the teacher nor the police officer in the stories above had criminal records.

To make it even more confusing, the Internet has added to the uncertainty; people have always had dangerous and fetishistic fantasies, but now there are ways others can learn the content of what was once very private. The risk, of course, is that fantasies and artistic endeavors become subject to both psychiatric scrutiny and criminal prosecution in a way that threatens civil rights and squelches creativity.

Dr. Miller is a coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work" (Baltimore:The Johns Hopkins University Press, 2011).