Mary Ann Moon

Premarketing approval of cardiovascular devices by the Food and Drug Administration often rests on a very shaky foundation, according to a review of 123 studies.

Most of the clinical studies the FDA has relied on to approve CV devices are neither blinded nor randomized. About half are not controlled or use only historical controls, which produces biased results favoring the devices, the study investigators reported. In addition, most of the studies exclude data on patients who have unfavorable outcomes; and are performed in subjects who are not representative of the patient populations that will be using the devices.

Moreover, the majority of such FDA approvals have rested on the results of a single study, reported Dr. Sanket S. Dhruva and associates at the University of California, San Francisco (JAMA 2009;302:2679–85).

The public assumes that the FDA's premarketing approval “is the most rigorous device approval process, and strict standards for cardiovascular devices are expected given their far-reaching effects, permanent nature, and use in critically ill patients.” Yet the type and quality of the evidence on which the FDA bases its approval have never been systematically examined until now, the investigators noted.

They reviewed the 123 clinical studies underlying FDA approval of 78 cardiovascular devices between 2000 and 2007.

The mean number of studies supporting each approval was only 1.6; fully 65% of the device approvals were supported by only a single study.

Most approvals did not cite even one blinded or one randomized study. Overall, only 27% of the supporting studies were randomized and only 14% were blinded.

Nearly half of the studies supporting FDA approval failed to include a control group for comparison. Of those that did include a control group, retrospectively selected controls were commonly used, which biases the results in favor of the device, the authors wrote.

Many studies excluded data from lead-in periods, which effectively excludes subjects who have immediate unfavorable outcomes. Most also showed large discrepancies between the number of subjects enrolled and the number included in final analyses, with no explanation of the missing data.

In all, data on 10,352 study subjects were excluded, which constitutes nearly a third of the total study population. Twenty percent of the studies did not even report the number of subjects participating.

In more than one-third of the device approvals, “we were not able to ascertain that even 1 study had been conducted in the United States. This results in uncertain generalizability of approved medical devices to the US population,” Dr. Dhruva and associates said.

In addition, many devices were approved “using a post hoc analysis of data,” which can bias the results in favor of the device, they said.

“The importance of the 'seal of FDA approval' cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the investigators noted.

The findings of this study are particularly disturbing given that FDA device approval effectively preempts consumers from bringing lawsuits because of problems with device safety or effectiveness. Moreover, manufacturers are not required to seek out and report device malfunctions, “so device-related adverse events are substantially underreported,” they said.

The investigators noted that a limitation of the study may be that the data source is primarily publicly available summaries of safety and effectiveness data.

Disclosures: Dr. Dhruva's associate in this study, Dr. Rita Redberg, reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other potential conflicts were reported.

Premarketing approval of cardiovascular devices by the Food and Drug Administration often rests on a very shaky foundation, according to a review of 123 studies.

Most of the clinical studies the FDA has relied on to approve CV devices are neither blinded nor randomized. About half are not controlled or use only historical controls, which produces biased results favoring the devices, the study investigators reported. In addition, most of the studies exclude data on patients who have unfavorable outcomes; and are performed in subjects who are not representative of the patient populations that will be using the devices.

Moreover, the majority of such FDA approvals have rested on the results of a single study, reported Dr. Sanket S. Dhruva and associates at the University of California, San Francisco (JAMA 2009;302:2679–85).

The public assumes that the FDA's premarketing approval “is the most rigorous device approval process, and strict standards for cardiovascular devices are expected given their far-reaching effects, permanent nature, and use in critically ill patients.” Yet the type and quality of the evidence on which the FDA bases its approval have never been systematically examined until now, the investigators noted.

They reviewed the 123 clinical studies underlying FDA approval of 78 cardiovascular devices between 2000 and 2007.

The mean number of studies supporting each approval was only 1.6; fully 65% of the device approvals were supported by only a single study.

Most approvals did not cite even one blinded or one randomized study. Overall, only 27% of the supporting studies were randomized and only 14% were blinded.

Nearly half of the studies supporting FDA approval failed to include a control group for comparison. Of those that did include a control group, retrospectively selected controls were commonly used, which biases the results in favor of the device, the authors wrote.

Many studies excluded data from lead-in periods, which effectively excludes subjects who have immediate unfavorable outcomes. Most also showed large discrepancies between the number of subjects enrolled and the number included in final analyses, with no explanation of the missing data.

In all, data on 10,352 study subjects were excluded, which constitutes nearly a third of the total study population. Twenty percent of the studies did not even report the number of subjects participating.

In more than one-third of the device approvals, “we were not able to ascertain that even 1 study had been conducted in the United States. This results in uncertain generalizability of approved medical devices to the US population,” Dr. Dhruva and associates said.

In addition, many devices were approved “using a post hoc analysis of data,” which can bias the results in favor of the device, they said.

“The importance of the 'seal of FDA approval' cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the investigators noted.

The findings of this study are particularly disturbing given that FDA device approval effectively preempts consumers from bringing lawsuits because of problems with device safety or effectiveness. Moreover, manufacturers are not required to seek out and report device malfunctions, “so device-related adverse events are substantially underreported,” they said.

The investigators noted that a limitation of the study may be that the data source is primarily publicly available summaries of safety and effectiveness data.

Disclosures: Dr. Dhruva's associate in this study, Dr. Rita Redberg, reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other potential conflicts were reported.

Premarketing approval of cardiovascular devices by the Food and Drug Administration often rests on a very shaky foundation, according to a review of 123 studies.

Most of the clinical studies the FDA has relied on to approve CV devices are neither blinded nor randomized. About half are not controlled or use only historical controls, which produces biased results favoring the devices, the study investigators reported. In addition, most of the studies exclude data on patients who have unfavorable outcomes; and are performed in subjects who are not representative of the patient populations that will be using the devices.

Moreover, the majority of such FDA approvals have rested on the results of a single study, reported Dr. Sanket S. Dhruva and associates at the University of California, San Francisco (JAMA 2009;302:2679–85).

The public assumes that the FDA's premarketing approval “is the most rigorous device approval process, and strict standards for cardiovascular devices are expected given their far-reaching effects, permanent nature, and use in critically ill patients.” Yet the type and quality of the evidence on which the FDA bases its approval have never been systematically examined until now, the investigators noted.

They reviewed the 123 clinical studies underlying FDA approval of 78 cardiovascular devices between 2000 and 2007.

The mean number of studies supporting each approval was only 1.6; fully 65% of the device approvals were supported by only a single study.

Most approvals did not cite even one blinded or one randomized study. Overall, only 27% of the supporting studies were randomized and only 14% were blinded.

Nearly half of the studies supporting FDA approval failed to include a control group for comparison. Of those that did include a control group, retrospectively selected controls were commonly used, which biases the results in favor of the device, the authors wrote.

Many studies excluded data from lead-in periods, which effectively excludes subjects who have immediate unfavorable outcomes. Most also showed large discrepancies between the number of subjects enrolled and the number included in final analyses, with no explanation of the missing data.

In all, data on 10,352 study subjects were excluded, which constitutes nearly a third of the total study population. Twenty percent of the studies did not even report the number of subjects participating.

In more than one-third of the device approvals, “we were not able to ascertain that even 1 study had been conducted in the United States. This results in uncertain generalizability of approved medical devices to the US population,” Dr. Dhruva and associates said.

In addition, many devices were approved “using a post hoc analysis of data,” which can bias the results in favor of the device, they said.

“The importance of the 'seal of FDA approval' cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the investigators noted.

The findings of this study are particularly disturbing given that FDA device approval effectively preempts consumers from bringing lawsuits because of problems with device safety or effectiveness. Moreover, manufacturers are not required to seek out and report device malfunctions, “so device-related adverse events are substantially underreported,” they said.

The investigators noted that a limitation of the study may be that the data source is primarily publicly available summaries of safety and effectiveness data.

Disclosures: Dr. Dhruva's associate in this study, Dr. Rita Redberg, reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other potential conflicts were reported.

Two unrelated preoperative treatments sharply reduced the number of surgical site infections in patients at facilities in the United States and the Netherlands, according to the results of two randomized trials.

In one study, preoperative cleansing of patients' skin with chlorhexidine-alcohol instead of standard povidone-iodine cut the risk of surgical site infection (SSI) by any organism by 41% and the risk of surgical site staph infection by 50%.

In the other study, rapid identification of surgical patients who are nasal carriers of Staphylococcus aureus, followed by immediate treatment with nasal mupirocin ointment, reduced the risk of hospital-acquired S. aureus infections by nearly 60%.

Dr. Rabih O. Darouiche of Baylor College of Medicine,´Houston, and his associates performed what they described as the first prospective, randomized trial that directly compared the efficacy of two skin antiseptics in preventing SSIs.

The study included 813 patients treated at six university-affiliated U.S. hospitals who were undergoing clean-contaminated surgery—colorectal, small intestinal, gastroesophageal, biliary, thoracic, gynecologic, or urologic procedures—performed under controlled conditions without substantial spillage or unusual contamination.

The patients were randomly assigned to undergo either the standard preoperative scrubbing followed by painting with an aqueous solution of 10% povidone-iodine (422 patients) or preoperative scrubbing with applicators containing 2% chlorhexidine gluconate and 70% isopropyl alcohol (391 patients). All subjects also received systemic prophylactic antibiotics preoperatively.

The overall rate of SSI was markedly lower with chlorhexidine (9.5%) than with povidone-iodine (16.1%). The chlorhexidine preparation reduced the rates of both superficial and deep incisional infections, regardless of the type of surgery.

Dr. Darouiche and his colleagues estimated that the number of patients who needed to undergo skin preparation with chlorhexidine-alcohol instead of povidone-iodine in order to prevent one case of SSI was 17.

The proportion of patients infected with an identifiable microorganism was similar between the two groups. There also were no significant differences in the types of microorganisms causing the infections, except that streptococcal infections were less common in patients who received chlorhexidine-alcohol than in those who received povidone-iodine.

The number of adverse events and serious adverse events also was similar between the two groups. Three patients in each group developed pruritus, erythema, or both around the surgical wound, outcomes that were considered to be possibly related to the antiseptic preparations.

“The superior clinical protection provided by chlorhexidine-alcohol is probably related to its more rapid action, persistent activity despite exposure to bodily fluids, and residual effect,” Dr. Darouiche and his associates wrote (N. Engl. J. Med. 2010;362:18–26).

Mupirocin nasal ointment had previously been shown to reduce hospital-associated staph infection, but the authors of the second study said that final proof would be needed from a prospective, randomized clinical trial.

In the study by Dr. Lonneke G.M. Bode of Erasmus University Medical Center, Rotterdam, the Netherlands, and her associates, more than 6,000 surgical patients at three academic and two general hospitals in the Netherlands initially were screened for nasal carriage of S. aureus at hospital admission using a real-time polymerase chain reaction assay. The 917 patients who tested positive were randomly assigned to receive mupirocin nasal ointment plus chlorhexidine gluconate soap for their skin (504 study subjects) or placebo ointment plus placebo soap (413 subjects) before undergoing surgery. The skin treatment was added because nasal carriers of the organism often have both skin and nasal colonization.

The patients, who underwent cardiothoracic, vascular, orthopedic, gastrointestinal, or general procedures, were treated for 5 days regardless of the timing of any interventions, and were followed for staphylococcal SSI for 6 weeks.

A total of 49 patients developed S. aureus infections at the surgical site. The rate was more than twice as high among placebo patients (7.7%) as among those who received active treatment (3.4%).

The treatment benefit was most pronounced in reducing the risk that patients would develop deep SSIs. The rate of such staph infections was 0.9% in patients who received mupirocin vs. 4.4% in those who received placebo.

Mean hospital stay also was significantly reduced—by nearly 2 days—with active treatment, compared with placebo. The only adverse effect of active treatment was local irritation, which resolved after mupirocin treatment was discontinued.

“The results of our trial provide solid evidence of the preventive effect of S. aureus decolonization and a good estimate of the size of this effect: The risk of hospital-associated S. aureus infections was reduced by nearly 60%,” Dr. Bode and her colleagues wrote (N. Engl. J. Med. 2010;362:9–17´. “It is plausible that this strategy would also be effective in carriers of methicillin-resistant strains of S. aureus that are susceptible to mupirocin.”

Disclosures: Dr. Darouiche reported receiving research and educational grants from Cardinal Health. Dr. Bode's study was supported by grants from ZonMw, Mölnlycke Health Care, GlaxoSmithKline, Roche, bioMérieux, and 3M.

My Take

Chlorhexidine Prep Clearly Superior

These are both high-quality studies, but I believe that the findings reported by Dr. Darouiche and colleagues will have more immediate impact. They convincingly demonstrate that a chlorhexidine-alcohol prep is superior to the traditional povidone-iodine solution. Chlorhexidine previously has been shown to be clearly superior to povidone-iodine when used as a skin prep for central venous catheter insertion.

The authors found that the chlorhexidine-alcohol product showed relatively greater superiority in the prevention of superficial incisional surgical site infections and relatively less in preventing more serious infections. Still, the overall benefit associated with the chlorhexidine solution suggests that hospitals not already using it as a surgical prep should begin doing so.

The study by Dr. Bode and colleagues is intriguing, showing that real-time PCR screening of primarily surgical patients on or before admission, coupled with a 5-day course of intranasal mupirocin and chlorhexidine baths, significantly decreased the incidence of nosocomial Staphylococcus aureus infections. This was particularly true of deep surgical site infections, a sometimes devastating complication.

However, the study has limitations that I believe will prevent the results from being immediately embraced in this country. None of the S. aureus isolates in the study were methicillin resistant, yet in the United States, a high percentage of colonizing isolates are community-associated MRSA, and an increasing percentage of those are mupirocin resistant. Also, a recent large Swiss study employing a similar “search and destroy” strategy for MRSA colonization before surgery failed to show benefit (JAMA 2008;299:1149–57).

But I agree with Dr. Wenzel's suggestion in the editorial (N. Engl. J. Med. 2010;362:75–7) that real-time PCR screening and decolonization is probably appropriate for surgical patients where the stakes are especially high (e.g., cardiothoracic procedures and total joint replacements).

JAMES PILE, M.D., a hospitalist and infectious diseases specialist, is the acting director of the Division of Hospital Medicine for the MetroHealth campus of Case Western Reserve University, Cleveland, Ohio. He reported no conflicts of interest.

Two unrelated preoperative treatments sharply reduced the number of surgical site infections in patients at facilities in the United States and the Netherlands, according to the results of two randomized trials.

In one study, preoperative cleansing of patients' skin with chlorhexidine-alcohol instead of standard povidone-iodine cut the risk of surgical site infection (SSI) by any organism by 41% and the risk of surgical site staph infection by 50%.

In the other study, rapid identification of surgical patients who are nasal carriers of Staphylococcus aureus, followed by immediate treatment with nasal mupirocin ointment, reduced the risk of hospital-acquired S. aureus infections by nearly 60%.

Dr. Rabih O. Darouiche of Baylor College of Medicine,´Houston, and his associates performed what they described as the first prospective, randomized trial that directly compared the efficacy of two skin antiseptics in preventing SSIs.

The study included 813 patients treated at six university-affiliated U.S. hospitals who were undergoing clean-contaminated surgery—colorectal, small intestinal, gastroesophageal, biliary, thoracic, gynecologic, or urologic procedures—performed under controlled conditions without substantial spillage or unusual contamination.

The patients were randomly assigned to undergo either the standard preoperative scrubbing followed by painting with an aqueous solution of 10% povidone-iodine (422 patients) or preoperative scrubbing with applicators containing 2% chlorhexidine gluconate and 70% isopropyl alcohol (391 patients). All subjects also received systemic prophylactic antibiotics preoperatively.

The overall rate of SSI was markedly lower with chlorhexidine (9.5%) than with povidone-iodine (16.1%). The chlorhexidine preparation reduced the rates of both superficial and deep incisional infections, regardless of the type of surgery.

Dr. Darouiche and his colleagues estimated that the number of patients who needed to undergo skin preparation with chlorhexidine-alcohol instead of povidone-iodine in order to prevent one case of SSI was 17.

The proportion of patients infected with an identifiable microorganism was similar between the two groups. There also were no significant differences in the types of microorganisms causing the infections, except that streptococcal infections were less common in patients who received chlorhexidine-alcohol than in those who received povidone-iodine.

The number of adverse events and serious adverse events also was similar between the two groups. Three patients in each group developed pruritus, erythema, or both around the surgical wound, outcomes that were considered to be possibly related to the antiseptic preparations.

“The superior clinical protection provided by chlorhexidine-alcohol is probably related to its more rapid action, persistent activity despite exposure to bodily fluids, and residual effect,” Dr. Darouiche and his associates wrote (N. Engl. J. Med. 2010;362:18–26).

Mupirocin nasal ointment had previously been shown to reduce hospital-associated staph infection, but the authors of the second study said that final proof would be needed from a prospective, randomized clinical trial.

In the study by Dr. Lonneke G.M. Bode of Erasmus University Medical Center, Rotterdam, the Netherlands, and her associates, more than 6,000 surgical patients at three academic and two general hospitals in the Netherlands initially were screened for nasal carriage of S. aureus at hospital admission using a real-time polymerase chain reaction assay. The 917 patients who tested positive were randomly assigned to receive mupirocin nasal ointment plus chlorhexidine gluconate soap for their skin (504 study subjects) or placebo ointment plus placebo soap (413 subjects) before undergoing surgery. The skin treatment was added because nasal carriers of the organism often have both skin and nasal colonization.

The patients, who underwent cardiothoracic, vascular, orthopedic, gastrointestinal, or general procedures, were treated for 5 days regardless of the timing of any interventions, and were followed for staphylococcal SSI for 6 weeks.

A total of 49 patients developed S. aureus infections at the surgical site. The rate was more than twice as high among placebo patients (7.7%) as among those who received active treatment (3.4%).

The treatment benefit was most pronounced in reducing the risk that patients would develop deep SSIs. The rate of such staph infections was 0.9% in patients who received mupirocin vs. 4.4% in those who received placebo.

Mean hospital stay also was significantly reduced—by nearly 2 days—with active treatment, compared with placebo. The only adverse effect of active treatment was local irritation, which resolved after mupirocin treatment was discontinued.

“The results of our trial provide solid evidence of the preventive effect of S. aureus decolonization and a good estimate of the size of this effect: The risk of hospital-associated S. aureus infections was reduced by nearly 60%,” Dr. Bode and her colleagues wrote (N. Engl. J. Med. 2010;362:9–17´. “It is plausible that this strategy would also be effective in carriers of methicillin-resistant strains of S. aureus that are susceptible to mupirocin.”

Disclosures: Dr. Darouiche reported receiving research and educational grants from Cardinal Health. Dr. Bode's study was supported by grants from ZonMw, Mölnlycke Health Care, GlaxoSmithKline, Roche, bioMérieux, and 3M.

My Take

Chlorhexidine Prep Clearly Superior

These are both high-quality studies, but I believe that the findings reported by Dr. Darouiche and colleagues will have more immediate impact. They convincingly demonstrate that a chlorhexidine-alcohol prep is superior to the traditional povidone-iodine solution. Chlorhexidine previously has been shown to be clearly superior to povidone-iodine when used as a skin prep for central venous catheter insertion.

The authors found that the chlorhexidine-alcohol product showed relatively greater superiority in the prevention of superficial incisional surgical site infections and relatively less in preventing more serious infections. Still, the overall benefit associated with the chlorhexidine solution suggests that hospitals not already using it as a surgical prep should begin doing so.

The study by Dr. Bode and colleagues is intriguing, showing that real-time PCR screening of primarily surgical patients on or before admission, coupled with a 5-day course of intranasal mupirocin and chlorhexidine baths, significantly decreased the incidence of nosocomial Staphylococcus aureus infections. This was particularly true of deep surgical site infections, a sometimes devastating complication.

However, the study has limitations that I believe will prevent the results from being immediately embraced in this country. None of the S. aureus isolates in the study were methicillin resistant, yet in the United States, a high percentage of colonizing isolates are community-associated MRSA, and an increasing percentage of those are mupirocin resistant. Also, a recent large Swiss study employing a similar “search and destroy” strategy for MRSA colonization before surgery failed to show benefit (JAMA 2008;299:1149–57).

But I agree with Dr. Wenzel's suggestion in the editorial (N. Engl. J. Med. 2010;362:75–7) that real-time PCR screening and decolonization is probably appropriate for surgical patients where the stakes are especially high (e.g., cardiothoracic procedures and total joint replacements).

JAMES PILE, M.D., a hospitalist and infectious diseases specialist, is the acting director of the Division of Hospital Medicine for the MetroHealth campus of Case Western Reserve University, Cleveland, Ohio. He reported no conflicts of interest.

Two unrelated preoperative treatments sharply reduced the number of surgical site infections in patients at facilities in the United States and the Netherlands, according to the results of two randomized trials.

In one study, preoperative cleansing of patients' skin with chlorhexidine-alcohol instead of standard povidone-iodine cut the risk of surgical site infection (SSI) by any organism by 41% and the risk of surgical site staph infection by 50%.

In the other study, rapid identification of surgical patients who are nasal carriers of Staphylococcus aureus, followed by immediate treatment with nasal mupirocin ointment, reduced the risk of hospital-acquired S. aureus infections by nearly 60%.

Dr. Rabih O. Darouiche of Baylor College of Medicine,´Houston, and his associates performed what they described as the first prospective, randomized trial that directly compared the efficacy of two skin antiseptics in preventing SSIs.

The study included 813 patients treated at six university-affiliated U.S. hospitals who were undergoing clean-contaminated surgery—colorectal, small intestinal, gastroesophageal, biliary, thoracic, gynecologic, or urologic procedures—performed under controlled conditions without substantial spillage or unusual contamination.

The patients were randomly assigned to undergo either the standard preoperative scrubbing followed by painting with an aqueous solution of 10% povidone-iodine (422 patients) or preoperative scrubbing with applicators containing 2% chlorhexidine gluconate and 70% isopropyl alcohol (391 patients). All subjects also received systemic prophylactic antibiotics preoperatively.

The overall rate of SSI was markedly lower with chlorhexidine (9.5%) than with povidone-iodine (16.1%). The chlorhexidine preparation reduced the rates of both superficial and deep incisional infections, regardless of the type of surgery.

Dr. Darouiche and his colleagues estimated that the number of patients who needed to undergo skin preparation with chlorhexidine-alcohol instead of povidone-iodine in order to prevent one case of SSI was 17.

The proportion of patients infected with an identifiable microorganism was similar between the two groups. There also were no significant differences in the types of microorganisms causing the infections, except that streptococcal infections were less common in patients who received chlorhexidine-alcohol than in those who received povidone-iodine.

The number of adverse events and serious adverse events also was similar between the two groups. Three patients in each group developed pruritus, erythema, or both around the surgical wound, outcomes that were considered to be possibly related to the antiseptic preparations.

“The superior clinical protection provided by chlorhexidine-alcohol is probably related to its more rapid action, persistent activity despite exposure to bodily fluids, and residual effect,” Dr. Darouiche and his associates wrote (N. Engl. J. Med. 2010;362:18–26).

Mupirocin nasal ointment had previously been shown to reduce hospital-associated staph infection, but the authors of the second study said that final proof would be needed from a prospective, randomized clinical trial.

In the study by Dr. Lonneke G.M. Bode of Erasmus University Medical Center, Rotterdam, the Netherlands, and her associates, more than 6,000 surgical patients at three academic and two general hospitals in the Netherlands initially were screened for nasal carriage of S. aureus at hospital admission using a real-time polymerase chain reaction assay. The 917 patients who tested positive were randomly assigned to receive mupirocin nasal ointment plus chlorhexidine gluconate soap for their skin (504 study subjects) or placebo ointment plus placebo soap (413 subjects) before undergoing surgery. The skin treatment was added because nasal carriers of the organism often have both skin and nasal colonization.

The patients, who underwent cardiothoracic, vascular, orthopedic, gastrointestinal, or general procedures, were treated for 5 days regardless of the timing of any interventions, and were followed for staphylococcal SSI for 6 weeks.

A total of 49 patients developed S. aureus infections at the surgical site. The rate was more than twice as high among placebo patients (7.7%) as among those who received active treatment (3.4%).

The treatment benefit was most pronounced in reducing the risk that patients would develop deep SSIs. The rate of such staph infections was 0.9% in patients who received mupirocin vs. 4.4% in those who received placebo.

Mean hospital stay also was significantly reduced—by nearly 2 days—with active treatment, compared with placebo. The only adverse effect of active treatment was local irritation, which resolved after mupirocin treatment was discontinued.

“The results of our trial provide solid evidence of the preventive effect of S. aureus decolonization and a good estimate of the size of this effect: The risk of hospital-associated S. aureus infections was reduced by nearly 60%,” Dr. Bode and her colleagues wrote (N. Engl. J. Med. 2010;362:9–17´. “It is plausible that this strategy would also be effective in carriers of methicillin-resistant strains of S. aureus that are susceptible to mupirocin.”

Disclosures: Dr. Darouiche reported receiving research and educational grants from Cardinal Health. Dr. Bode's study was supported by grants from ZonMw, Mölnlycke Health Care, GlaxoSmithKline, Roche, bioMérieux, and 3M.

My Take

Chlorhexidine Prep Clearly Superior

These are both high-quality studies, but I believe that the findings reported by Dr. Darouiche and colleagues will have more immediate impact. They convincingly demonstrate that a chlorhexidine-alcohol prep is superior to the traditional povidone-iodine solution. Chlorhexidine previously has been shown to be clearly superior to povidone-iodine when used as a skin prep for central venous catheter insertion.

The authors found that the chlorhexidine-alcohol product showed relatively greater superiority in the prevention of superficial incisional surgical site infections and relatively less in preventing more serious infections. Still, the overall benefit associated with the chlorhexidine solution suggests that hospitals not already using it as a surgical prep should begin doing so.

The study by Dr. Bode and colleagues is intriguing, showing that real-time PCR screening of primarily surgical patients on or before admission, coupled with a 5-day course of intranasal mupirocin and chlorhexidine baths, significantly decreased the incidence of nosocomial Staphylococcus aureus infections. This was particularly true of deep surgical site infections, a sometimes devastating complication.

However, the study has limitations that I believe will prevent the results from being immediately embraced in this country. None of the S. aureus isolates in the study were methicillin resistant, yet in the United States, a high percentage of colonizing isolates are community-associated MRSA, and an increasing percentage of those are mupirocin resistant. Also, a recent large Swiss study employing a similar “search and destroy” strategy for MRSA colonization before surgery failed to show benefit (JAMA 2008;299:1149–57).

But I agree with Dr. Wenzel's suggestion in the editorial (N. Engl. J. Med. 2010;362:75–7) that real-time PCR screening and decolonization is probably appropriate for surgical patients where the stakes are especially high (e.g., cardiothoracic procedures and total joint replacements).

JAMES PILE, M.D., a hospitalist and infectious diseases specialist, is the acting director of the Division of Hospital Medicine for the MetroHealth campus of Case Western Reserve University, Cleveland, Ohio. He reported no conflicts of interest.

Premarketing approval of cardiovascular devices by the Food and Drug Administration often rests on a shaky foundation, according to a review.

Most of the clinical studies the FDA has relied on to approve CV devices are neither blinded nor randomized. About half are not controlled or use only historical controls, which produces biased results favoring the devices, the study investigators reported. In addition, most of the studies use surrogate instead of clinically meaningful end points, use composite instead of individual outcome measures, exclude data on patients who have unfavorable outcomes, and are performed in subjects not representative of the patient populations that will be using the devices.

Moreover, the majority of such FDA approvals have rested on the results of a single study, reported Dr. Sanket S. Dhruva and associates at the University of California, San Francisco

The public assumes that the FDA has a “rigorous device approval process, and strict standards for cardiovascular devices.” Yet the type and quality of the evidence on which the FDA bases its approval have never been systematically examined until now, the investigators noted.

They reviewed the 123 clinical studies underlying FDA approval of 78 cardiovascular devices between 2000 and 2007.

The mean number of studies supporting each approval was only 1.6; fully 65%of the device approvals were supported by only a single study. Most approvals did not cite even one blinded or randomized study. Overall, only 27% of the supporting studies were randomized and only 14% were blinded.

Nearly half of the studies supporting FDA approval failed to include a control group for comparison. Of those that did include a control group, retrospectively selected controls were commonly used, which biases the results in favor of the device, the authors wrote.

Of the supporting studies, 14% did not even state a primary end point. Moreover, “the vast majority of end points were surrogates, which may not be reliable predictors of actual patient benefits,” Dr. Dhruva and colleagues said.

Most studies assessed composite rather than individual outcomes, which in cardiovascular trials “have been shown to compromise individual end points that often vary in clinical significance and do not contribute equally to the composite measure,” the researchers added.

Many studies excluded data from lead-in periods, which effectively excludes subjects who have immediate unfavorable outcomes. Most also showed large discrepancies between the number of subjects enrolled and the number included in final analyses.

In all, data on 10,352 subjects were excluded, which constitutes nearly a third of the total study population; 20% of the studies did not even report the number of participants.

In more than one-third of the device approvals, “we were not able to ascertain that even one study had been conducted in the United States. This results in uncertain generalizability of approved medical devices to the U.S. population,” Dr. Dhruva and associates said (JAMA 2009;302:2679-85).

In addition, many devices were approved “using a post hoc analysis of data,” which can bias the results in favor of the device, they said. In one notable example, a cardiovascular device was approved by the FDA based “wholly on a post hoc analysis for a single subgroup” assessed in a single study.

“The importance of the 'seal of FDA approval' cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the investigators noted.

Such devices also are commonly used for nonapproved indications. “For example, Medicare data show that 69% of current drug-eluting stent use is 'off-label,'” Dr. Dhruva and colleagues noted.

The study findings are particularly disturbing given that FDA device approval effectively preempts consumers from bringing lawsuits related to problems with device safety or effectiveness. Moreover, manufacturers are not required to seek out and report device malfunctions, “so device-related adverse events are substantially underreported,” the researchers said.

“The bar for evidence of benefit should be higher for devices [than for drugs] because they are implanted and cannot simply be discontinued, as drugs can be,” they added.

Disclosures: Dr. Dhruva's associate in this study, Dr. Rita Redberg, reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other conflicts of interest were reported.

Premarketing approval of cardiovascular devices by the Food and Drug Administration often rests on a shaky foundation, according to a review.

Most of the clinical studies the FDA has relied on to approve CV devices are neither blinded nor randomized. About half are not controlled or use only historical controls, which produces biased results favoring the devices, the study investigators reported. In addition, most of the studies use surrogate instead of clinically meaningful end points, use composite instead of individual outcome measures, exclude data on patients who have unfavorable outcomes, and are performed in subjects not representative of the patient populations that will be using the devices.

Moreover, the majority of such FDA approvals have rested on the results of a single study, reported Dr. Sanket S. Dhruva and associates at the University of California, San Francisco

The public assumes that the FDA has a “rigorous device approval process, and strict standards for cardiovascular devices.” Yet the type and quality of the evidence on which the FDA bases its approval have never been systematically examined until now, the investigators noted.

They reviewed the 123 clinical studies underlying FDA approval of 78 cardiovascular devices between 2000 and 2007.

The mean number of studies supporting each approval was only 1.6; fully 65%of the device approvals were supported by only a single study. Most approvals did not cite even one blinded or randomized study. Overall, only 27% of the supporting studies were randomized and only 14% were blinded.

Nearly half of the studies supporting FDA approval failed to include a control group for comparison. Of those that did include a control group, retrospectively selected controls were commonly used, which biases the results in favor of the device, the authors wrote.

Of the supporting studies, 14% did not even state a primary end point. Moreover, “the vast majority of end points were surrogates, which may not be reliable predictors of actual patient benefits,” Dr. Dhruva and colleagues said.

Most studies assessed composite rather than individual outcomes, which in cardiovascular trials “have been shown to compromise individual end points that often vary in clinical significance and do not contribute equally to the composite measure,” the researchers added.

Many studies excluded data from lead-in periods, which effectively excludes subjects who have immediate unfavorable outcomes. Most also showed large discrepancies between the number of subjects enrolled and the number included in final analyses.

In all, data on 10,352 subjects were excluded, which constitutes nearly a third of the total study population; 20% of the studies did not even report the number of participants.

In more than one-third of the device approvals, “we were not able to ascertain that even one study had been conducted in the United States. This results in uncertain generalizability of approved medical devices to the U.S. population,” Dr. Dhruva and associates said (JAMA 2009;302:2679-85).

In addition, many devices were approved “using a post hoc analysis of data,” which can bias the results in favor of the device, they said. In one notable example, a cardiovascular device was approved by the FDA based “wholly on a post hoc analysis for a single subgroup” assessed in a single study.

“The importance of the 'seal of FDA approval' cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the investigators noted.

Such devices also are commonly used for nonapproved indications. “For example, Medicare data show that 69% of current drug-eluting stent use is 'off-label,'” Dr. Dhruva and colleagues noted.

The study findings are particularly disturbing given that FDA device approval effectively preempts consumers from bringing lawsuits related to problems with device safety or effectiveness. Moreover, manufacturers are not required to seek out and report device malfunctions, “so device-related adverse events are substantially underreported,” the researchers said.

“The bar for evidence of benefit should be higher for devices [than for drugs] because they are implanted and cannot simply be discontinued, as drugs can be,” they added.

Disclosures: Dr. Dhruva's associate in this study, Dr. Rita Redberg, reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other conflicts of interest were reported.

Premarketing approval of cardiovascular devices by the Food and Drug Administration often rests on a shaky foundation, according to a review.

Most of the clinical studies the FDA has relied on to approve CV devices are neither blinded nor randomized. About half are not controlled or use only historical controls, which produces biased results favoring the devices, the study investigators reported. In addition, most of the studies use surrogate instead of clinically meaningful end points, use composite instead of individual outcome measures, exclude data on patients who have unfavorable outcomes, and are performed in subjects not representative of the patient populations that will be using the devices.

Moreover, the majority of such FDA approvals have rested on the results of a single study, reported Dr. Sanket S. Dhruva and associates at the University of California, San Francisco

The public assumes that the FDA has a “rigorous device approval process, and strict standards for cardiovascular devices.” Yet the type and quality of the evidence on which the FDA bases its approval have never been systematically examined until now, the investigators noted.

They reviewed the 123 clinical studies underlying FDA approval of 78 cardiovascular devices between 2000 and 2007.

The mean number of studies supporting each approval was only 1.6; fully 65%of the device approvals were supported by only a single study. Most approvals did not cite even one blinded or randomized study. Overall, only 27% of the supporting studies were randomized and only 14% were blinded.

Nearly half of the studies supporting FDA approval failed to include a control group for comparison. Of those that did include a control group, retrospectively selected controls were commonly used, which biases the results in favor of the device, the authors wrote.

Of the supporting studies, 14% did not even state a primary end point. Moreover, “the vast majority of end points were surrogates, which may not be reliable predictors of actual patient benefits,” Dr. Dhruva and colleagues said.

Most studies assessed composite rather than individual outcomes, which in cardiovascular trials “have been shown to compromise individual end points that often vary in clinical significance and do not contribute equally to the composite measure,” the researchers added.

Many studies excluded data from lead-in periods, which effectively excludes subjects who have immediate unfavorable outcomes. Most also showed large discrepancies between the number of subjects enrolled and the number included in final analyses.

In all, data on 10,352 subjects were excluded, which constitutes nearly a third of the total study population; 20% of the studies did not even report the number of participants.

In more than one-third of the device approvals, “we were not able to ascertain that even one study had been conducted in the United States. This results in uncertain generalizability of approved medical devices to the U.S. population,” Dr. Dhruva and associates said (JAMA 2009;302:2679-85).

In addition, many devices were approved “using a post hoc analysis of data,” which can bias the results in favor of the device, they said. In one notable example, a cardiovascular device was approved by the FDA based “wholly on a post hoc analysis for a single subgroup” assessed in a single study.

“The importance of the 'seal of FDA approval' cannot be overstated. Many manufacturers immediately encourage widespread use of their devices based on FDA approval through direct-to-consumer advertising, detailing to physicians, and continuing medical education venues,” the investigators noted.

Such devices also are commonly used for nonapproved indications. “For example, Medicare data show that 69% of current drug-eluting stent use is 'off-label,'” Dr. Dhruva and colleagues noted.

The study findings are particularly disturbing given that FDA device approval effectively preempts consumers from bringing lawsuits related to problems with device safety or effectiveness. Moreover, manufacturers are not required to seek out and report device malfunctions, “so device-related adverse events are substantially underreported,” the researchers said.

“The bar for evidence of benefit should be higher for devices [than for drugs] because they are implanted and cannot simply be discontinued, as drugs can be,” they added.

Disclosures: Dr. Dhruva's associate in this study, Dr. Rita Redberg, reported being a member of the FDA Circulatory System Devices Panel and a member of the California Technology Assessment Forum. No other conflicts of interest were reported.

Two common variants in the lipoprotein(a) gene have been found to correlate with both plasma lipoprotein levels and the risk of coronary disease, according to Dr. Robert Clarke of the University of Oxford (England) and his associates.

The finding supports the hypothesis that lipoprotein plays a causal role in coronary disease.

The investigators examined genetic associations in coronary artery disease using data from the Precocious Coronary Artery Disease (PROCARDIS) Consortium multicenter case-control study. The study cohort included 3,145 patients from the United Kingdom, Italy, Sweden, and Germany who developed coronary artery disease before age 66 years and also had a similarly affected sibling, and 3,352 control subjects.

Genotyping was performed on participants' blood samples using a novel gene chip that was specifically designed to screen more than 48,000 single-nucleotide polymorphisms (SNPs) for 2,100 candidate genes thought to be potentially relevant to heart disease. “With this gene chip, we confirmed the previous identification of three chromosomal regions that were correlated with the risk of coronary disease: 6q26-27, 9p21, and 1p13,” Dr. Clarke and his colleagues noted.

The 6q26-27 region showed the strongest association with coronary disease, and that region is known to include the gene for lipoprotein(a) (LPA).

“We then used comprehensive SNP typing to characterize the spectrum of variation at the LPA locus and showed the independent relevance of several variants … for both the Lp(a) lipoprotein level and the risk of coronary disease,” the investigators wrote (N. Engl. J. Med. 2009;361:2518-28).

Two variants in particular (rs3798220 and rs10455872) together accounted for 36% of the variation in plasma lipoprotein levels among study subjects.

The investigators replicated these findings in separate cohorts from three other clinical trials of coronary disease, which included 4,846 cases and 4,594 control subjects.

“The linear dose-response relationship of the LPA variants with both the Lp(a) lipoprotein level and the risk of coronary disease provided compelling support for a causal role of an elevated plasma level of Lp(a) lipoprotein and the risk of coronary disease,” the researchers said.

“One in six persons carries a variant LPA allele and thus has a risk of coronary disease that is increased by a factor of 1.5,” they added.

Disclosures: This study was supported in part by AstraZeneca. The investigators' financial disclosures are available at NEJM.org

Two common variants in the lipoprotein(a) gene have been found to correlate with both plasma lipoprotein levels and the risk of coronary disease, according to Dr. Robert Clarke of the University of Oxford (England) and his associates.

The finding supports the hypothesis that lipoprotein plays a causal role in coronary disease.

The investigators examined genetic associations in coronary artery disease using data from the Precocious Coronary Artery Disease (PROCARDIS) Consortium multicenter case-control study. The study cohort included 3,145 patients from the United Kingdom, Italy, Sweden, and Germany who developed coronary artery disease before age 66 years and also had a similarly affected sibling, and 3,352 control subjects.

Genotyping was performed on participants' blood samples using a novel gene chip that was specifically designed to screen more than 48,000 single-nucleotide polymorphisms (SNPs) for 2,100 candidate genes thought to be potentially relevant to heart disease. “With this gene chip, we confirmed the previous identification of three chromosomal regions that were correlated with the risk of coronary disease: 6q26-27, 9p21, and 1p13,” Dr. Clarke and his colleagues noted.

The 6q26-27 region showed the strongest association with coronary disease, and that region is known to include the gene for lipoprotein(a) (LPA).

“We then used comprehensive SNP typing to characterize the spectrum of variation at the LPA locus and showed the independent relevance of several variants … for both the Lp(a) lipoprotein level and the risk of coronary disease,” the investigators wrote (N. Engl. J. Med. 2009;361:2518-28).

Two variants in particular (rs3798220 and rs10455872) together accounted for 36% of the variation in plasma lipoprotein levels among study subjects.

The investigators replicated these findings in separate cohorts from three other clinical trials of coronary disease, which included 4,846 cases and 4,594 control subjects.

“The linear dose-response relationship of the LPA variants with both the Lp(a) lipoprotein level and the risk of coronary disease provided compelling support for a causal role of an elevated plasma level of Lp(a) lipoprotein and the risk of coronary disease,” the researchers said.

“One in six persons carries a variant LPA allele and thus has a risk of coronary disease that is increased by a factor of 1.5,” they added.

Disclosures: This study was supported in part by AstraZeneca. The investigators' financial disclosures are available at NEJM.org

Two common variants in the lipoprotein(a) gene have been found to correlate with both plasma lipoprotein levels and the risk of coronary disease, according to Dr. Robert Clarke of the University of Oxford (England) and his associates.

The finding supports the hypothesis that lipoprotein plays a causal role in coronary disease.

The investigators examined genetic associations in coronary artery disease using data from the Precocious Coronary Artery Disease (PROCARDIS) Consortium multicenter case-control study. The study cohort included 3,145 patients from the United Kingdom, Italy, Sweden, and Germany who developed coronary artery disease before age 66 years and also had a similarly affected sibling, and 3,352 control subjects.

Genotyping was performed on participants' blood samples using a novel gene chip that was specifically designed to screen more than 48,000 single-nucleotide polymorphisms (SNPs) for 2,100 candidate genes thought to be potentially relevant to heart disease. “With this gene chip, we confirmed the previous identification of three chromosomal regions that were correlated with the risk of coronary disease: 6q26-27, 9p21, and 1p13,” Dr. Clarke and his colleagues noted.

The 6q26-27 region showed the strongest association with coronary disease, and that region is known to include the gene for lipoprotein(a) (LPA).

“We then used comprehensive SNP typing to characterize the spectrum of variation at the LPA locus and showed the independent relevance of several variants … for both the Lp(a) lipoprotein level and the risk of coronary disease,” the investigators wrote (N. Engl. J. Med. 2009;361:2518-28).

Two variants in particular (rs3798220 and rs10455872) together accounted for 36% of the variation in plasma lipoprotein levels among study subjects.

The investigators replicated these findings in separate cohorts from three other clinical trials of coronary disease, which included 4,846 cases and 4,594 control subjects.

“The linear dose-response relationship of the LPA variants with both the Lp(a) lipoprotein level and the risk of coronary disease provided compelling support for a causal role of an elevated plasma level of Lp(a) lipoprotein and the risk of coronary disease,” the researchers said.

“One in six persons carries a variant LPA allele and thus has a risk of coronary disease that is increased by a factor of 1.5,” they added.

Disclosures: This study was supported in part by AstraZeneca. The investigators' financial disclosures are available at NEJM.org

The cost of systemic therapies for psoriasis increased so fast in recent years that it outpaced the inflation rates for all items and for prescription drugs overall, according to a report in the January issue of the Archives of Dermatology.

The costs for brand name psoriasis drugs increased an average of 66% from 2000 to 2008. In comparison, the cost of other consumer items rose by 26% and that of prescription drugs overall rose by 30% during the same interval.

Much of this increase in the cost of psoriasis therapies can be attributed to the high cost of newer biologic therapies relative to that of more traditional systemic treatments. The advent of brand name versions of older drugs also has hiked treatment costs, wrote Dr. Vivianne Beyer and Dr. Stephen E. Wolverton, both of Indiana University, Indianapolis.

The investigators devised a cost model for each systemic psoriasis therapy based on continuous, yearlong outpatient treatment, including the expenses for medications, office visits, and recommended laboratory tests and monitoring procedures. They did not include the costs of treatment for adverse effects, or indirect costs such as time missed from work.

The researchers then compared the direct annual costs of phototherapy, systemic agents, and biologics from 2000 through 2008. In general, “traditional therapies remain much more affordable than biologic therapies,” they said.

It has been reported that prescription drug costs in general are outpacing the inflation rate, and “this trend also applies to therapies for psoriasis,” the investigators wrote. “Costs for all psoriasis medications except methotrexate, cyclosporine, alefacept, and infliximab have increased at a substantially greater rate” than inflation.

The annual change in the price of systemic drugs varied widely during the study period, from a net decrease of 24% in the cost of methotrexate to a net increase of 316% in the cost of Oxsoralen-Ultra, a brand name version of methoxsalen.

Acitretin showed the second-largest rise in price, an increase of 158% between 2000 and 2008.

In contrast, the cost of one brand name version of cyclosporine, Neoral, did not increase at all and the cost of another, Gengraf, dropped by 4%.

“Therapies such as acitretin, adalimumab, efalizumab, and etanercept have increased in cost steadily every year, whereas methotrexate, cyclosporine, and alefacept have seen minor, if any, increases in price since 2000,” the authors said (Arch. Derm. 2010;146:46-54).

For drugs and biologics, the annual cost of treatment in 2008 ranged from a low of $1,197 for methotrexate to a high of $27,577 for alefacept. Phototherapy costs ranged from a low of $3,083 per year for UVB to a high of $7,288 for PUVA, including induction and maintenance costs.

Dr. Beyer reported no financial conflicts of interest. Dr. Wolverton reported that he is a consultant for Eli Lilly & Co. regarding psoriasis therapy, is a consultant for Amgen Inc. regarding etanercept, and received royalties from Elsevier Publishing for a textbook on dermatology drugs.

The cost of systemic therapies for psoriasis increased so fast in recent years that it outpaced the inflation rates for all items and for prescription drugs overall, according to a report in the January issue of the Archives of Dermatology.

The costs for brand name psoriasis drugs increased an average of 66% from 2000 to 2008. In comparison, the cost of other consumer items rose by 26% and that of prescription drugs overall rose by 30% during the same interval.

Much of this increase in the cost of psoriasis therapies can be attributed to the high cost of newer biologic therapies relative to that of more traditional systemic treatments. The advent of brand name versions of older drugs also has hiked treatment costs, wrote Dr. Vivianne Beyer and Dr. Stephen E. Wolverton, both of Indiana University, Indianapolis.

The investigators devised a cost model for each systemic psoriasis therapy based on continuous, yearlong outpatient treatment, including the expenses for medications, office visits, and recommended laboratory tests and monitoring procedures. They did not include the costs of treatment for adverse effects, or indirect costs such as time missed from work.

The researchers then compared the direct annual costs of phototherapy, systemic agents, and biologics from 2000 through 2008. In general, “traditional therapies remain much more affordable than biologic therapies,” they said.

It has been reported that prescription drug costs in general are outpacing the inflation rate, and “this trend also applies to therapies for psoriasis,” the investigators wrote. “Costs for all psoriasis medications except methotrexate, cyclosporine, alefacept, and infliximab have increased at a substantially greater rate” than inflation.

The annual change in the price of systemic drugs varied widely during the study period, from a net decrease of 24% in the cost of methotrexate to a net increase of 316% in the cost of Oxsoralen-Ultra, a brand name version of methoxsalen.

Acitretin showed the second-largest rise in price, an increase of 158% between 2000 and 2008.

In contrast, the cost of one brand name version of cyclosporine, Neoral, did not increase at all and the cost of another, Gengraf, dropped by 4%.

“Therapies such as acitretin, adalimumab, efalizumab, and etanercept have increased in cost steadily every year, whereas methotrexate, cyclosporine, and alefacept have seen minor, if any, increases in price since 2000,” the authors said (Arch. Derm. 2010;146:46-54).

For drugs and biologics, the annual cost of treatment in 2008 ranged from a low of $1,197 for methotrexate to a high of $27,577 for alefacept. Phototherapy costs ranged from a low of $3,083 per year for UVB to a high of $7,288 for PUVA, including induction and maintenance costs.

Dr. Beyer reported no financial conflicts of interest. Dr. Wolverton reported that he is a consultant for Eli Lilly & Co. regarding psoriasis therapy, is a consultant for Amgen Inc. regarding etanercept, and received royalties from Elsevier Publishing for a textbook on dermatology drugs.

The cost of systemic therapies for psoriasis increased so fast in recent years that it outpaced the inflation rates for all items and for prescription drugs overall, according to a report in the January issue of the Archives of Dermatology.

The costs for brand name psoriasis drugs increased an average of 66% from 2000 to 2008. In comparison, the cost of other consumer items rose by 26% and that of prescription drugs overall rose by 30% during the same interval.

Much of this increase in the cost of psoriasis therapies can be attributed to the high cost of newer biologic therapies relative to that of more traditional systemic treatments. The advent of brand name versions of older drugs also has hiked treatment costs, wrote Dr. Vivianne Beyer and Dr. Stephen E. Wolverton, both of Indiana University, Indianapolis.

The investigators devised a cost model for each systemic psoriasis therapy based on continuous, yearlong outpatient treatment, including the expenses for medications, office visits, and recommended laboratory tests and monitoring procedures. They did not include the costs of treatment for adverse effects, or indirect costs such as time missed from work.

The researchers then compared the direct annual costs of phototherapy, systemic agents, and biologics from 2000 through 2008. In general, “traditional therapies remain much more affordable than biologic therapies,” they said.

It has been reported that prescription drug costs in general are outpacing the inflation rate, and “this trend also applies to therapies for psoriasis,” the investigators wrote. “Costs for all psoriasis medications except methotrexate, cyclosporine, alefacept, and infliximab have increased at a substantially greater rate” than inflation.

The annual change in the price of systemic drugs varied widely during the study period, from a net decrease of 24% in the cost of methotrexate to a net increase of 316% in the cost of Oxsoralen-Ultra, a brand name version of methoxsalen.

Acitretin showed the second-largest rise in price, an increase of 158% between 2000 and 2008.

In contrast, the cost of one brand name version of cyclosporine, Neoral, did not increase at all and the cost of another, Gengraf, dropped by 4%.

“Therapies such as acitretin, adalimumab, efalizumab, and etanercept have increased in cost steadily every year, whereas methotrexate, cyclosporine, and alefacept have seen minor, if any, increases in price since 2000,” the authors said (Arch. Derm. 2010;146:46-54).

For drugs and biologics, the annual cost of treatment in 2008 ranged from a low of $1,197 for methotrexate to a high of $27,577 for alefacept. Phototherapy costs ranged from a low of $3,083 per year for UVB to a high of $7,288 for PUVA, including induction and maintenance costs.

Dr. Beyer reported no financial conflicts of interest. Dr. Wolverton reported that he is a consultant for Eli Lilly & Co. regarding psoriasis therapy, is a consultant for Amgen Inc. regarding etanercept, and received royalties from Elsevier Publishing for a textbook on dermatology drugs.

Voriconazole, approved for use against serious fungal infections in 2002, has been linked to five more cases of melanoma in situ in two patients, according to a report published online Jan. 18 in the Archives of Dermatology.

Both patients, aged 20 and 39 years, first exhibited photosensitivity followed by extensive photodamage before the lesions were identified in affected areas.

These cases, even added to the four already reported in the literature, are not enough to establish that the drug plays “a definitive causal role” in skin malignancy. However, “we believe that the presence of accelerated photodamage in [two relatively young] patients, coupled with the recent reports supporting an association between voriconazole use and [aggressive] squamous cell carcinoma, warrant further exploration of the role of the drug in skin cancer formation,” said Dr. Daniel D. Miller of the University of California, San Francisco, and his associates (Arch Dermatol. 2010 [doi:10.1001/archdermatol.2009.362]).

“Until such studies further define the skin cancer risk associated with voriconazole, we recommend surveillance for skin cancer formation in all patients who require long-term voriconazole treatment, particularly those who manifest signs or symptoms of photosensitivity or chronic photodamage,” the investigators noted.

They described the two most recent patients in case reports.

The first patient was a 39-year-old woman who was first referred for severe photosensitivity and extensive lentigines on the photoexposed surfaces of the face, upper trunk, and extensor extremities. There was no personal or family history of photosensitivity or skin cancer.

The woman lived in an area endemic for coccidioidomycosis and had been receiving oral voriconazole for 3 years to treat coccidioidomycosis meningitis. Severe erythema with eruptive pigmented macules had developed 1 year after starting treatment.

Histopathology of a specimen taken from an erythematous macule on the right helix showed melanoma in situ.

Five months later, Dr. Miller and his colleagues discovered another ill-defined lesion on the patient —“a brownish blue patch within a field of solar lentigines on severely sun-damaged skin on the mid-upper chest”— that proved to be another melanoma in situ.

One year later, two additional in situ melanomas were identified on the right forearm and the dorsal surface of the left hand. Voriconazole therapy was discontinued, and the patient continues to be monitored for suspicious skin lesions every 3-6 months.

In the second case, an adolescent male with chronic granulomatous disease had been taking long-term voriconazole to treat pulmonary Aspergillus infection. After 2 years of the therapy, he had begun to develop lentigines on sun-exposed areas of his body, including the face, forearms, and dorsal surfaces of his hands.

At age 20 years, after 55 months of treatment, an irregular, darkly pigmented macule on his left forearm was found to be melanoma in situ. His therapy was switched from voriconazole to posaconazole. No subsequent lesions have been identified, and the patient reports fading of his extensive lentigines since discontinuing voriconazole.

The courses of these two patients are clinically similar to what happens in patients who undergo long-term PUVA therapy and in those with xeroderma pigmentosum. However, in the two case reports, "the rapid onset of extensive lentigines, as well as the short interval of voriconazole therapy before melanoma developed (relative to that seen due to PUVA), suggest perhaps an even more accelerated process of carcinogenesis," Dr. Miller and his colleagues said.

“Future comparisons between xeroderma pigmentosum-associated melanomas and those occurring in the setting of voriconazole-associated phototoxic effects may provide valuable insight into the contribution of UV light to melanoma genesis,” they added.

Dr. Miller reported no relevant conflicts of interest.

Voriconazole, approved for use against serious fungal infections in 2002, has been linked to five more cases of melanoma in situ in two patients, according to a report published online Jan. 18 in the Archives of Dermatology.

Both patients, aged 20 and 39 years, first exhibited photosensitivity followed by extensive photodamage before the lesions were identified in affected areas.

These cases, even added to the four already reported in the literature, are not enough to establish that the drug plays “a definitive causal role” in skin malignancy. However, “we believe that the presence of accelerated photodamage in [two relatively young] patients, coupled with the recent reports supporting an association between voriconazole use and [aggressive] squamous cell carcinoma, warrant further exploration of the role of the drug in skin cancer formation,” said Dr. Daniel D. Miller of the University of California, San Francisco, and his associates (Arch Dermatol. 2010 [doi:10.1001/archdermatol.2009.362]).

“Until such studies further define the skin cancer risk associated with voriconazole, we recommend surveillance for skin cancer formation in all patients who require long-term voriconazole treatment, particularly those who manifest signs or symptoms of photosensitivity or chronic photodamage,” the investigators noted.

They described the two most recent patients in case reports.

The first patient was a 39-year-old woman who was first referred for severe photosensitivity and extensive lentigines on the photoexposed surfaces of the face, upper trunk, and extensor extremities. There was no personal or family history of photosensitivity or skin cancer.

The woman lived in an area endemic for coccidioidomycosis and had been receiving oral voriconazole for 3 years to treat coccidioidomycosis meningitis. Severe erythema with eruptive pigmented macules had developed 1 year after starting treatment.

Histopathology of a specimen taken from an erythematous macule on the right helix showed melanoma in situ.

Five months later, Dr. Miller and his colleagues discovered another ill-defined lesion on the patient —“a brownish blue patch within a field of solar lentigines on severely sun-damaged skin on the mid-upper chest”— that proved to be another melanoma in situ.

One year later, two additional in situ melanomas were identified on the right forearm and the dorsal surface of the left hand. Voriconazole therapy was discontinued, and the patient continues to be monitored for suspicious skin lesions every 3-6 months.

In the second case, an adolescent male with chronic granulomatous disease had been taking long-term voriconazole to treat pulmonary Aspergillus infection. After 2 years of the therapy, he had begun to develop lentigines on sun-exposed areas of his body, including the face, forearms, and dorsal surfaces of his hands.

At age 20 years, after 55 months of treatment, an irregular, darkly pigmented macule on his left forearm was found to be melanoma in situ. His therapy was switched from voriconazole to posaconazole. No subsequent lesions have been identified, and the patient reports fading of his extensive lentigines since discontinuing voriconazole.

The courses of these two patients are clinically similar to what happens in patients who undergo long-term PUVA therapy and in those with xeroderma pigmentosum. However, in the two case reports, "the rapid onset of extensive lentigines, as well as the short interval of voriconazole therapy before melanoma developed (relative to that seen due to PUVA), suggest perhaps an even more accelerated process of carcinogenesis," Dr. Miller and his colleagues said.

“Future comparisons between xeroderma pigmentosum-associated melanomas and those occurring in the setting of voriconazole-associated phototoxic effects may provide valuable insight into the contribution of UV light to melanoma genesis,” they added.

Dr. Miller reported no relevant conflicts of interest.

Voriconazole, approved for use against serious fungal infections in 2002, has been linked to five more cases of melanoma in situ in two patients, according to a report published online Jan. 18 in the Archives of Dermatology.

Both patients, aged 20 and 39 years, first exhibited photosensitivity followed by extensive photodamage before the lesions were identified in affected areas.

These cases, even added to the four already reported in the literature, are not enough to establish that the drug plays “a definitive causal role” in skin malignancy. However, “we believe that the presence of accelerated photodamage in [two relatively young] patients, coupled with the recent reports supporting an association between voriconazole use and [aggressive] squamous cell carcinoma, warrant further exploration of the role of the drug in skin cancer formation,” said Dr. Daniel D. Miller of the University of California, San Francisco, and his associates (Arch Dermatol. 2010 [doi:10.1001/archdermatol.2009.362]).

“Until such studies further define the skin cancer risk associated with voriconazole, we recommend surveillance for skin cancer formation in all patients who require long-term voriconazole treatment, particularly those who manifest signs or symptoms of photosensitivity or chronic photodamage,” the investigators noted.

They described the two most recent patients in case reports.

The first patient was a 39-year-old woman who was first referred for severe photosensitivity and extensive lentigines on the photoexposed surfaces of the face, upper trunk, and extensor extremities. There was no personal or family history of photosensitivity or skin cancer.

The woman lived in an area endemic for coccidioidomycosis and had been receiving oral voriconazole for 3 years to treat coccidioidomycosis meningitis. Severe erythema with eruptive pigmented macules had developed 1 year after starting treatment.

Histopathology of a specimen taken from an erythematous macule on the right helix showed melanoma in situ.

Five months later, Dr. Miller and his colleagues discovered another ill-defined lesion on the patient —“a brownish blue patch within a field of solar lentigines on severely sun-damaged skin on the mid-upper chest”— that proved to be another melanoma in situ.

One year later, two additional in situ melanomas were identified on the right forearm and the dorsal surface of the left hand. Voriconazole therapy was discontinued, and the patient continues to be monitored for suspicious skin lesions every 3-6 months.

In the second case, an adolescent male with chronic granulomatous disease had been taking long-term voriconazole to treat pulmonary Aspergillus infection. After 2 years of the therapy, he had begun to develop lentigines on sun-exposed areas of his body, including the face, forearms, and dorsal surfaces of his hands.

At age 20 years, after 55 months of treatment, an irregular, darkly pigmented macule on his left forearm was found to be melanoma in situ. His therapy was switched from voriconazole to posaconazole. No subsequent lesions have been identified, and the patient reports fading of his extensive lentigines since discontinuing voriconazole.

The courses of these two patients are clinically similar to what happens in patients who undergo long-term PUVA therapy and in those with xeroderma pigmentosum. However, in the two case reports, "the rapid onset of extensive lentigines, as well as the short interval of voriconazole therapy before melanoma developed (relative to that seen due to PUVA), suggest perhaps an even more accelerated process of carcinogenesis," Dr. Miller and his colleagues said.

“Future comparisons between xeroderma pigmentosum-associated melanomas and those occurring in the setting of voriconazole-associated phototoxic effects may provide valuable insight into the contribution of UV light to melanoma genesis,” they added.

Dr. Miller reported no relevant conflicts of interest.

Disclosures: No financial conflicts of interest were reported by the authors.

Breast density on mammography is a significant risk factor for local cancer recurrence, based on a study of more than 300 women.

In a study of 335 women with breast cancer, the actuarial risk of local disease recurrence at 10 years was 5% for women with the lowest breast density, 13% for those with intermediate breast density, and 21% for women with the highest breast density, said Dr. Tulin Cil of the University Health Network, Toronto, and associates.

None of the 34 women who had low breast density and who did not receive adjuvant radiotherapy developed a recurrence, suggesting that they were not harmed by foregoing radiotherapy. If larger studies confirm that women with less dense breasts can safely avoid radiotherapy, that could result in “considerable savings, reduced morbidity, and improved quality of life,” the researchers said. If women with dense breasts are found in larger studies to be at higher risk for local recurrence, radiotherapy would indeed be beneficial for these patients, they added.

Several recent studies have suggested that high breast density corresponds with a higher risk of local recurrence, but the biologic basis for this association is unknown. Dr. Cil and colleagues assessed breast density on pretreatment mammograms taken in 335 women who underwent breast-conserving surgery for invasive cancer at Women's College Hospital in Toronto between 1987 and 1998.

The patients were categorized as having low (less than 25%) density, intermediate (25%-50%) density, or high (greater than 50%) density according to a variation of the Wolfe classification system. The study population was fairly equally distributed among these three classifications. Patients in these three groups had similar tumor characteristics, received similar adjuvant therapies, and had similar estrogen receptor status.

Sixteen percent of the women with high breast density developed a local recurrence, compared with 10% of the women with intermediate breast density and 3% of those with low breast density. After age, menopausal status, and radiotherapy status were controlled for, women with high breast density were found to have a hazard ratio of 5.7 for developing local cancer recurrence, compared with the low-density group (Cancer 2009;115:5780-7). Women with intermediate breast density had a hazard ratio of 3.6, compared with the low-density group (see box). There were no differences in rates of distant cancer recurrence among the three groups.

Among women who received adjuvant radiotherapy, “the prognostic effect of mammographic density was found to be minimal and nonsignificant.” However, among women who did not receive radiotherapy—who constituted 29% of this study population—the difference in prognostic effect was marked.

It is not yet known whether attempting to reduce breast density through dietary or lifestyle alterations might influence recurrence risk, they said.

Elsevier Global Medical News

Disclosures: No financial conflicts of interest were reported by the authors.

Breast density on mammography is a significant risk factor for local cancer recurrence, based on a study of more than 300 women.

In a study of 335 women with breast cancer, the actuarial risk of local disease recurrence at 10 years was 5% for women with the lowest breast density, 13% for those with intermediate breast density, and 21% for women with the highest breast density, said Dr. Tulin Cil of the University Health Network, Toronto, and associates.

None of the 34 women who had low breast density and who did not receive adjuvant radiotherapy developed a recurrence, suggesting that they were not harmed by foregoing radiotherapy. If larger studies confirm that women with less dense breasts can safely avoid radiotherapy, that could result in “considerable savings, reduced morbidity, and improved quality of life,” the researchers said. If women with dense breasts are found in larger studies to be at higher risk for local recurrence, radiotherapy would indeed be beneficial for these patients, they added.

Several recent studies have suggested that high breast density corresponds with a higher risk of local recurrence, but the biologic basis for this association is unknown. Dr. Cil and colleagues assessed breast density on pretreatment mammograms taken in 335 women who underwent breast-conserving surgery for invasive cancer at Women's College Hospital in Toronto between 1987 and 1998.

The patients were categorized as having low (less than 25%) density, intermediate (25%-50%) density, or high (greater than 50%) density according to a variation of the Wolfe classification system. The study population was fairly equally distributed among these three classifications. Patients in these three groups had similar tumor characteristics, received similar adjuvant therapies, and had similar estrogen receptor status.

Sixteen percent of the women with high breast density developed a local recurrence, compared with 10% of the women with intermediate breast density and 3% of those with low breast density. After age, menopausal status, and radiotherapy status were controlled for, women with high breast density were found to have a hazard ratio of 5.7 for developing local cancer recurrence, compared with the low-density group (Cancer 2009;115:5780-7). Women with intermediate breast density had a hazard ratio of 3.6, compared with the low-density group (see box). There were no differences in rates of distant cancer recurrence among the three groups.

Among women who received adjuvant radiotherapy, “the prognostic effect of mammographic density was found to be minimal and nonsignificant.” However, among women who did not receive radiotherapy—who constituted 29% of this study population—the difference in prognostic effect was marked.

It is not yet known whether attempting to reduce breast density through dietary or lifestyle alterations might influence recurrence risk, they said.

Elsevier Global Medical News

Disclosures: No financial conflicts of interest were reported by the authors.

Breast density on mammography is a significant risk factor for local cancer recurrence, based on a study of more than 300 women.

In a study of 335 women with breast cancer, the actuarial risk of local disease recurrence at 10 years was 5% for women with the lowest breast density, 13% for those with intermediate breast density, and 21% for women with the highest breast density, said Dr. Tulin Cil of the University Health Network, Toronto, and associates.

None of the 34 women who had low breast density and who did not receive adjuvant radiotherapy developed a recurrence, suggesting that they were not harmed by foregoing radiotherapy. If larger studies confirm that women with less dense breasts can safely avoid radiotherapy, that could result in “considerable savings, reduced morbidity, and improved quality of life,” the researchers said. If women with dense breasts are found in larger studies to be at higher risk for local recurrence, radiotherapy would indeed be beneficial for these patients, they added.

Several recent studies have suggested that high breast density corresponds with a higher risk of local recurrence, but the biologic basis for this association is unknown. Dr. Cil and colleagues assessed breast density on pretreatment mammograms taken in 335 women who underwent breast-conserving surgery for invasive cancer at Women's College Hospital in Toronto between 1987 and 1998.

The patients were categorized as having low (less than 25%) density, intermediate (25%-50%) density, or high (greater than 50%) density according to a variation of the Wolfe classification system. The study population was fairly equally distributed among these three classifications. Patients in these three groups had similar tumor characteristics, received similar adjuvant therapies, and had similar estrogen receptor status.

Sixteen percent of the women with high breast density developed a local recurrence, compared with 10% of the women with intermediate breast density and 3% of those with low breast density. After age, menopausal status, and radiotherapy status were controlled for, women with high breast density were found to have a hazard ratio of 5.7 for developing local cancer recurrence, compared with the low-density group (Cancer 2009;115:5780-7). Women with intermediate breast density had a hazard ratio of 3.6, compared with the low-density group (see box). There were no differences in rates of distant cancer recurrence among the three groups.

Among women who received adjuvant radiotherapy, “the prognostic effect of mammographic density was found to be minimal and nonsignificant.” However, among women who did not receive radiotherapy—who constituted 29% of this study population—the difference in prognostic effect was marked.

It is not yet known whether attempting to reduce breast density through dietary or lifestyle alterations might influence recurrence risk, they said.

Elsevier Global Medical News

Chronic musculoskeletal pain raises elderly people's risk of falling, independent of their underlying pathologies or the medications they may be taking for the pain, according to a study of more than 700 elders living independently.

The finding that pain is “an overlooked and potentially important risk factor for falls” suggests that “the common complaint of aches and pains of old age is related to a greater hazard than previously thought,” Suzanne G. Leveille, Ph.D., R.N., of the University of Massachusetts, Boston, and her associates wrote (JAMA 2009;302:2214-21).

“Daily discomfort may accompany not only difficulties in performing daily activities but equally as important may be a risk for falls and possibly fall-related injuries in the older population,” the authors wrote.

Dr. Leveille and her colleagues used data from the MOBILIZE Boston study to identify new strategies for preventing falls. (The study's title stands for Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly.) The researchers assessed data on 749 men and women aged 70 and older who were living in a variety of urban and suburban settings.

The study participants were evaluated during home and clinic visits at the beginning of the study. The researchers noted the severity and location of musculoskeletal pain, as well as its interference with daily activities. Monthly for up to 18 months thereafter, the participants reported pain symptoms and all falls on postcards.

This study design enabled the researchers to track the risk of falls over time in relation to baseline chronic pain and pain reported periodically.

Overall, 40% of the study subjects reported chronic polyarticular pain, and another 24% reported chronic pain in just one joint area. A total of 1,029 falls occurred during follow-up, with 405 subjects (54%) falling at least once during the study.

Compared with participants who did not report chronic pain, those who did had a significantly higher rate of falls, regardless of whether their pain was measured by location, severity, or degree of interference with daily life, Dr. Leveille and her colleagues said.

Chronic pain was persistently associated with fall risk after the data were adjusted to account for coexisting chronic conditions, other risk factors for falling, baseline balance and mobility, the use of psychotherapeutic medications, and the use of analgesics.

There also was a strong, graded relationship between monthly pain-severity ratings and the risk for falling during the subsequent month.

“For example, among persons who reported severe or very severe pain for any given month on their calendar postcard, there was a 77% increased likelihood for a fall in the subsequent month, compared with those who reported no pain,” the investigators said.

“Persons reporting even very mild pain also had an elevated risk of falling in any given month,” they added.

There are three possible mechanisms underlying the link between pain and falling, according to the researchers. First, joint pathology may cause both pain and the instability that can lead to falling.

However, Dr. Leveille and her colleagues deemed that explanation unlikely because the association in this study was independent of hand and knee osteoarthritis and of mobility.

Second, the neuromuscular effects of pain could cause muscle weakness, slowed responses to an impending fall, or gait alterations, all of which can lead to falling. Third, said the researchers, chronic pain may distract patients or otherwise interfere with the cognitive activity needed to prevent falling.

Other studies have shown that patients with chronic pain show decreased executive function and attention. Moreover, avoiding or interrupting a fall “typically requires a cognitively mediated physical maneuver,” Dr. Leveille and her associates noted.

A randomized controlled trial might determine whether improved pain control could reduce the risk for falling in elderly patients, the researchers said.

Disclosures: Dr. Leveille reported no financial conflict of interest. The MOBILIZE Boston study was supported in part by a grant from Pfizer Inc.

Chronic musculoskeletal pain raises elderly people's risk of falling, independent of their underlying pathologies or the medications they may be taking for the pain, according to a study of more than 700 elders living independently.

The finding that pain is “an overlooked and potentially important risk factor for falls” suggests that “the common complaint of aches and pains of old age is related to a greater hazard than previously thought,” Suzanne G. Leveille, Ph.D., R.N., of the University of Massachusetts, Boston, and her associates wrote (JAMA 2009;302:2214-21).

“Daily discomfort may accompany not only difficulties in performing daily activities but equally as important may be a risk for falls and possibly fall-related injuries in the older population,” the authors wrote.

Dr. Leveille and her colleagues used data from the MOBILIZE Boston study to identify new strategies for preventing falls. (The study's title stands for Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly.) The researchers assessed data on 749 men and women aged 70 and older who were living in a variety of urban and suburban settings.

The study participants were evaluated during home and clinic visits at the beginning of the study. The researchers noted the severity and location of musculoskeletal pain, as well as its interference with daily activities. Monthly for up to 18 months thereafter, the participants reported pain symptoms and all falls on postcards.

This study design enabled the researchers to track the risk of falls over time in relation to baseline chronic pain and pain reported periodically.

Overall, 40% of the study subjects reported chronic polyarticular pain, and another 24% reported chronic pain in just one joint area. A total of 1,029 falls occurred during follow-up, with 405 subjects (54%) falling at least once during the study.

Compared with participants who did not report chronic pain, those who did had a significantly higher rate of falls, regardless of whether their pain was measured by location, severity, or degree of interference with daily life, Dr. Leveille and her colleagues said.

Chronic pain was persistently associated with fall risk after the data were adjusted to account for coexisting chronic conditions, other risk factors for falling, baseline balance and mobility, the use of psychotherapeutic medications, and the use of analgesics.

There also was a strong, graded relationship between monthly pain-severity ratings and the risk for falling during the subsequent month.

“For example, among persons who reported severe or very severe pain for any given month on their calendar postcard, there was a 77% increased likelihood for a fall in the subsequent month, compared with those who reported no pain,” the investigators said.

“Persons reporting even very mild pain also had an elevated risk of falling in any given month,” they added.

There are three possible mechanisms underlying the link between pain and falling, according to the researchers. First, joint pathology may cause both pain and the instability that can lead to falling.

However, Dr. Leveille and her colleagues deemed that explanation unlikely because the association in this study was independent of hand and knee osteoarthritis and of mobility.

Second, the neuromuscular effects of pain could cause muscle weakness, slowed responses to an impending fall, or gait alterations, all of which can lead to falling. Third, said the researchers, chronic pain may distract patients or otherwise interfere with the cognitive activity needed to prevent falling.

Other studies have shown that patients with chronic pain show decreased executive function and attention. Moreover, avoiding or interrupting a fall “typically requires a cognitively mediated physical maneuver,” Dr. Leveille and her associates noted.

A randomized controlled trial might determine whether improved pain control could reduce the risk for falling in elderly patients, the researchers said.

Disclosures: Dr. Leveille reported no financial conflict of interest. The MOBILIZE Boston study was supported in part by a grant from Pfizer Inc.

Chronic musculoskeletal pain raises elderly people's risk of falling, independent of their underlying pathologies or the medications they may be taking for the pain, according to a study of more than 700 elders living independently.

The finding that pain is “an overlooked and potentially important risk factor for falls” suggests that “the common complaint of aches and pains of old age is related to a greater hazard than previously thought,” Suzanne G. Leveille, Ph.D., R.N., of the University of Massachusetts, Boston, and her associates wrote (JAMA 2009;302:2214-21).

“Daily discomfort may accompany not only difficulties in performing daily activities but equally as important may be a risk for falls and possibly fall-related injuries in the older population,” the authors wrote.

Dr. Leveille and her colleagues used data from the MOBILIZE Boston study to identify new strategies for preventing falls. (The study's title stands for Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly.) The researchers assessed data on 749 men and women aged 70 and older who were living in a variety of urban and suburban settings.

The study participants were evaluated during home and clinic visits at the beginning of the study. The researchers noted the severity and location of musculoskeletal pain, as well as its interference with daily activities. Monthly for up to 18 months thereafter, the participants reported pain symptoms and all falls on postcards.

This study design enabled the researchers to track the risk of falls over time in relation to baseline chronic pain and pain reported periodically.

Overall, 40% of the study subjects reported chronic polyarticular pain, and another 24% reported chronic pain in just one joint area. A total of 1,029 falls occurred during follow-up, with 405 subjects (54%) falling at least once during the study.

Compared with participants who did not report chronic pain, those who did had a significantly higher rate of falls, regardless of whether their pain was measured by location, severity, or degree of interference with daily life, Dr. Leveille and her colleagues said.

Chronic pain was persistently associated with fall risk after the data were adjusted to account for coexisting chronic conditions, other risk factors for falling, baseline balance and mobility, the use of psychotherapeutic medications, and the use of analgesics.

There also was a strong, graded relationship between monthly pain-severity ratings and the risk for falling during the subsequent month.

“For example, among persons who reported severe or very severe pain for any given month on their calendar postcard, there was a 77% increased likelihood for a fall in the subsequent month, compared with those who reported no pain,” the investigators said.

“Persons reporting even very mild pain also had an elevated risk of falling in any given month,” they added.

There are three possible mechanisms underlying the link between pain and falling, according to the researchers. First, joint pathology may cause both pain and the instability that can lead to falling.

However, Dr. Leveille and her colleagues deemed that explanation unlikely because the association in this study was independent of hand and knee osteoarthritis and of mobility.

Second, the neuromuscular effects of pain could cause muscle weakness, slowed responses to an impending fall, or gait alterations, all of which can lead to falling. Third, said the researchers, chronic pain may distract patients or otherwise interfere with the cognitive activity needed to prevent falling.

Other studies have shown that patients with chronic pain show decreased executive function and attention. Moreover, avoiding or interrupting a fall “typically requires a cognitively mediated physical maneuver,” Dr. Leveille and her associates noted.

A randomized controlled trial might determine whether improved pain control could reduce the risk for falling in elderly patients, the researchers said.

Disclosures: Dr. Leveille reported no financial conflict of interest. The MOBILIZE Boston study was supported in part by a grant from Pfizer Inc.

Most primary care practices are not large enough for significant differences in performance to be assessed using national quality and cost benchmarks, according to a report.

Nationally, fewer than 2% of all primary care practices were able to be reliably assessed because their caseloads were too small. Even when their case loads were pooled with those of other physicians in the practice, and even if 2–3 years' worth of cases were included, the numbers were too small to reliably assess quality, according to David J. Nyweide, Ph.D., of the Centers for Medicare and Medicaid Services and his associates.

The CMS has “been overseeing a series of value-based purchasing initiatives,” including pay-for-performance projects and the Physician Quality Reporting Initiative. Dr. Nyweide and his colleagues questioned whether individual physicians see a sufficient number of patients with various disorders such that their performance can be judged against commonly used quality and cost measures.

Using national mean ambulatory Medicare spending data, the researchers calculated the caseloads that would be necessary to detect meaningful differences on each commonly used performance measure, including rates at which 66- to 69-year-old women received mammography, rates of hemoglobin A_1c testing for diabetics aged 65–75 years, rates of preventable hospitalizations associated with 13 specific adult conditions, and rates of hospital readmission for heart failure patients.

In all, 71,980 primary care physicians who were affiliated with 30,794 practices were included in the study. Most of the practices (61%) were solo. Caseloads ranged from a median of 170 patients for solo practitioners to 13,400 for practices with more than 50 primary care physicians.

The investigators found that “only the largest primary care physician practices, which are also the most uncommon, can be expected to have sufficient caseloads to measure significant differences in performance.”

A year-long caseload of 328 women aged 66–69 years old would be needed to detect a 10% difference in the rate of mammography for that age group, and 19,069 patients would be needed to reliably detect a 10% difference in the rate of preventable hospitalizations.

Overall, fewer than 2% of the practices could be reliably compared on any of the performance measures.

Even grouping caseloads by 2-year and 3-year periods failed to amass sufficient sample sizes for reliable comparisons among practices.

“The results from this study call into question the wisdom of pay-for-performance programs and quality reporting initiatives that focus on differentiating the value of care delivered to the Medicare population by primary care physicians,” Dr. Nyweide and his colleagues wrote (JAMA 2009;302:2444–50).

In an accompanying editorial, Dr. Donald M. Berwick, president of the Institute for Healthcare Improvement, pointed out that by focusing on quality metrics one at a time, Dr. Nyweide and associates were “viewing care through a tiny keyhole. … If valid quality metrics could be constructed that cross conditions, more patients could contribute relevant data.”

In addition, “more could be known if data could be aggregated from all payers, not just Medicare. Creating shared pools of transparent performance information for Medicare, Medicaid, and private insurers would be a step toward maturation in the ability to improve U.S. health care.”

At the very least, Dr. Berwick advised that patients be asked directly about their experiences of care. “Attributes of care like 'patient-centeredness,' 'timeliness,' and overall responsiveness … are important qualities in their own right, and each physician's entire patient panel can contribute to sample size for these qualities” (JAMA 2009;302:2485–6).

Dr. Nyweide and Dr. Berwick reported having no conflicts of interest.

Most primary care practices are not large enough for significant differences in performance to be assessed using national quality and cost benchmarks, according to a report.

Nationally, fewer than 2% of all primary care practices were able to be reliably assessed because their caseloads were too small. Even when their case loads were pooled with those of other physicians in the practice, and even if 2–3 years' worth of cases were included, the numbers were too small to reliably assess quality, according to David J. Nyweide, Ph.D., of the Centers for Medicare and Medicaid Services and his associates.

The CMS has “been overseeing a series of value-based purchasing initiatives,” including pay-for-performance projects and the Physician Quality Reporting Initiative. Dr. Nyweide and his colleagues questioned whether individual physicians see a sufficient number of patients with various disorders such that their performance can be judged against commonly used quality and cost measures.

Using national mean ambulatory Medicare spending data, the researchers calculated the caseloads that would be necessary to detect meaningful differences on each commonly used performance measure, including rates at which 66- to 69-year-old women received mammography, rates of hemoglobin A_1c testing for diabetics aged 65–75 years, rates of preventable hospitalizations associated with 13 specific adult conditions, and rates of hospital readmission for heart failure patients.

In all, 71,980 primary care physicians who were affiliated with 30,794 practices were included in the study. Most of the practices (61%) were solo. Caseloads ranged from a median of 170 patients for solo practitioners to 13,400 for practices with more than 50 primary care physicians.

The investigators found that “only the largest primary care physician practices, which are also the most uncommon, can be expected to have sufficient caseloads to measure significant differences in performance.”

A year-long caseload of 328 women aged 66–69 years old would be needed to detect a 10% difference in the rate of mammography for that age group, and 19,069 patients would be needed to reliably detect a 10% difference in the rate of preventable hospitalizations.

Overall, fewer than 2% of the practices could be reliably compared on any of the performance measures.

Even grouping caseloads by 2-year and 3-year periods failed to amass sufficient sample sizes for reliable comparisons among practices.

“The results from this study call into question the wisdom of pay-for-performance programs and quality reporting initiatives that focus on differentiating the value of care delivered to the Medicare population by primary care physicians,” Dr. Nyweide and his colleagues wrote (JAMA 2009;302:2444–50).

In an accompanying editorial, Dr. Donald M. Berwick, president of the Institute for Healthcare Improvement, pointed out that by focusing on quality metrics one at a time, Dr. Nyweide and associates were “viewing care through a tiny keyhole. … If valid quality metrics could be constructed that cross conditions, more patients could contribute relevant data.”

In addition, “more could be known if data could be aggregated from all payers, not just Medicare. Creating shared pools of transparent performance information for Medicare, Medicaid, and private insurers would be a step toward maturation in the ability to improve U.S. health care.”

At the very least, Dr. Berwick advised that patients be asked directly about their experiences of care. “Attributes of care like 'patient-centeredness,' 'timeliness,' and overall responsiveness … are important qualities in their own right, and each physician's entire patient panel can contribute to sample size for these qualities” (JAMA 2009;302:2485–6).

Dr. Nyweide and Dr. Berwick reported having no conflicts of interest.

Most primary care practices are not large enough for significant differences in performance to be assessed using national quality and cost benchmarks, according to a report.

Nationally, fewer than 2% of all primary care practices were able to be reliably assessed because their caseloads were too small. Even when their case loads were pooled with those of other physicians in the practice, and even if 2–3 years' worth of cases were included, the numbers were too small to reliably assess quality, according to David J. Nyweide, Ph.D., of the Centers for Medicare and Medicaid Services and his associates.

The CMS has “been overseeing a series of value-based purchasing initiatives,” including pay-for-performance projects and the Physician Quality Reporting Initiative. Dr. Nyweide and his colleagues questioned whether individual physicians see a sufficient number of patients with various disorders such that their performance can be judged against commonly used quality and cost measures.

Using national mean ambulatory Medicare spending data, the researchers calculated the caseloads that would be necessary to detect meaningful differences on each commonly used performance measure, including rates at which 66- to 69-year-old women received mammography, rates of hemoglobin A_1c testing for diabetics aged 65–75 years, rates of preventable hospitalizations associated with 13 specific adult conditions, and rates of hospital readmission for heart failure patients.

In all, 71,980 primary care physicians who were affiliated with 30,794 practices were included in the study. Most of the practices (61%) were solo. Caseloads ranged from a median of 170 patients for solo practitioners to 13,400 for practices with more than 50 primary care physicians.

The investigators found that “only the largest primary care physician practices, which are also the most uncommon, can be expected to have sufficient caseloads to measure significant differences in performance.”

A year-long caseload of 328 women aged 66–69 years old would be needed to detect a 10% difference in the rate of mammography for that age group, and 19,069 patients would be needed to reliably detect a 10% difference in the rate of preventable hospitalizations.

Overall, fewer than 2% of the practices could be reliably compared on any of the performance measures.

Even grouping caseloads by 2-year and 3-year periods failed to amass sufficient sample sizes for reliable comparisons among practices.

“The results from this study call into question the wisdom of pay-for-performance programs and quality reporting initiatives that focus on differentiating the value of care delivered to the Medicare population by primary care physicians,” Dr. Nyweide and his colleagues wrote (JAMA 2009;302:2444–50).

In an accompanying editorial, Dr. Donald M. Berwick, president of the Institute for Healthcare Improvement, pointed out that by focusing on quality metrics one at a time, Dr. Nyweide and associates were “viewing care through a tiny keyhole. … If valid quality metrics could be constructed that cross conditions, more patients could contribute relevant data.”

In addition, “more could be known if data could be aggregated from all payers, not just Medicare. Creating shared pools of transparent performance information for Medicare, Medicaid, and private insurers would be a step toward maturation in the ability to improve U.S. health care.”

At the very least, Dr. Berwick advised that patients be asked directly about their experiences of care. “Attributes of care like 'patient-centeredness,' 'timeliness,' and overall responsiveness … are important qualities in their own right, and each physician's entire patient panel can contribute to sample size for these qualities” (JAMA 2009;302:2485–6).

Dr. Nyweide and Dr. Berwick reported having no conflicts of interest.

A variation in the MMP12 gene appears to be associated with beneficial pulmonary effects in children who have asthma and in adults who smoke, particularly smokers with chronic obstructive pulmonary disease, according to a study.

“Our results suggest that variants of MMP12 are determinants of the level of lung function in subjects who are at risk for airflow obstruction,” said Dr. Gary M. Hunninghake and Dr. Michael H. Cho of Brigham and Women's Hospital, Boston, and their associates.

The investigators tested for an association between single-nucleotide polymorphisms (SNPs) in the MMP12 gene and lung function as assessed by forced expiratory volume in 1 second (FEV₁) in cohorts participating in seven clinical trials. The MMP12 gene encodes matrix metalloproteinase 12, which is produced by macrophages, “the predominant cell type that patrols the lower airspaces under normal conditions and the main inflammatory cell type that is recruited with smoking,” the investigators noted.

Matrix metalloproteinases degrade extracellular matrix molecules such as collagen and elastin and are also involved in epithelial repair and the regulation of cytokine and chemokine activity.

The researchers first found that the minor allele of SNP rs2276109 in the MMP12 gene was significantly associated with increased FEV₁ in children with asthma (but not nonasthmatic children) who were subjects in the Genetics of Asthma in Costa Rica Study. They then found the same link between the SNP and increased FEV₁ among children taking budesonide—but not among those who were not taking budesonide—in the Childhood Asthma Management Program. The same link between the SNP and increased FEV₁ existed among children with asthma (but not nonasthmatic children) in the BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) study.

Dr. Hunninghake and his colleagues then tested for the same association in adults who were subjects in the Boston Early-Onset COPD Study, the Lovelace Smokers Cohort, and the Normative Aging Study. The researchers found that the same SNP variation was associated with improved lung function in adults who were current or former smokers, but not in nonsmokers.

Finally, the investigators found that the same MMP12 variant appeared to protect patients at risk for COPD against the disease in those same three adult cohorts. The absence of the SNP rs2276109 was associated with a 54% increase in the risk of the onset of COPD and a population attributable risk of COPD of 28%.

The findings support the so-called “Dutch hypothesis,” which states that asthma and COPD are different manifestations of a single disease entity and suggests that as-yet unknown genetic variants may underlie both asthma and COPD, the investigators said (N. Engl. J. Med. 2009;361[doi:10.1056/NEJMoa0904006]).

Most previous studies of genetic associations in pulmonary function have relied on a single cohort, the study's authors noted. “A strength of our study is that it included the analysis of multiple measurements of pulmonary function in a large number of subjects—more than 20,000 FEV₁ measurements in more than 8,300 subjects,” they added.

“Evidence is accumulating that asthma and COPD share common pathogenetic pathways,” noted Dr. Guy G. Brusselle of Ghent (Belgium) University Hospital, in an accompanying editorial. “This study … adds to the accumulating evidence that several mechanisms may lead to the development of COPD” (N. Engl. J. Med. 2009;361[doi:10.1056/NEJMe0919626]).

The study's strengths include the inclusion of seven cohorts with more than 8,300 subjects; the replication of an association between the SNP and FEV₁ both in adult smokers and children with asthma; and the researchers' ability to repeat the analyses after stratification for asthma status and smoking status.

Dr. Hunninghake and Dr. Cho reported no conflicts of interest. Their associates reported receiving support from a several pharmaceutical companies.

A variation in the MMP12 gene appears to be associated with beneficial pulmonary effects in children who have asthma and in adults who smoke, particularly smokers with chronic obstructive pulmonary disease, according to a study.

“Our results suggest that variants of MMP12 are determinants of the level of lung function in subjects who are at risk for airflow obstruction,” said Dr. Gary M. Hunninghake and Dr. Michael H. Cho of Brigham and Women's Hospital, Boston, and their associates.

The investigators tested for an association between single-nucleotide polymorphisms (SNPs) in the MMP12 gene and lung function as assessed by forced expiratory volume in 1 second (FEV₁) in cohorts participating in seven clinical trials. The MMP12 gene encodes matrix metalloproteinase 12, which is produced by macrophages, “the predominant cell type that patrols the lower airspaces under normal conditions and the main inflammatory cell type that is recruited with smoking,” the investigators noted.

Matrix metalloproteinases degrade extracellular matrix molecules such as collagen and elastin and are also involved in epithelial repair and the regulation of cytokine and chemokine activity.

The researchers first found that the minor allele of SNP rs2276109 in the MMP12 gene was significantly associated with increased FEV₁ in children with asthma (but not nonasthmatic children) who were subjects in the Genetics of Asthma in Costa Rica Study. They then found the same link between the SNP and increased FEV₁ among children taking budesonide—but not among those who were not taking budesonide—in the Childhood Asthma Management Program. The same link between the SNP and increased FEV₁ existed among children with asthma (but not nonasthmatic children) in the BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) study.

Dr. Hunninghake and his colleagues then tested for the same association in adults who were subjects in the Boston Early-Onset COPD Study, the Lovelace Smokers Cohort, and the Normative Aging Study. The researchers found that the same SNP variation was associated with improved lung function in adults who were current or former smokers, but not in nonsmokers.

Finally, the investigators found that the same MMP12 variant appeared to protect patients at risk for COPD against the disease in those same three adult cohorts. The absence of the SNP rs2276109 was associated with a 54% increase in the risk of the onset of COPD and a population attributable risk of COPD of 28%.

The findings support the so-called “Dutch hypothesis,” which states that asthma and COPD are different manifestations of a single disease entity and suggests that as-yet unknown genetic variants may underlie both asthma and COPD, the investigators said (N. Engl. J. Med. 2009;361[doi:10.1056/NEJMoa0904006]).

Most previous studies of genetic associations in pulmonary function have relied on a single cohort, the study's authors noted. “A strength of our study is that it included the analysis of multiple measurements of pulmonary function in a large number of subjects—more than 20,000 FEV₁ measurements in more than 8,300 subjects,” they added.

“Evidence is accumulating that asthma and COPD share common pathogenetic pathways,” noted Dr. Guy G. Brusselle of Ghent (Belgium) University Hospital, in an accompanying editorial. “This study … adds to the accumulating evidence that several mechanisms may lead to the development of COPD” (N. Engl. J. Med. 2009;361[doi:10.1056/NEJMe0919626]).

The study's strengths include the inclusion of seven cohorts with more than 8,300 subjects; the replication of an association between the SNP and FEV₁ both in adult smokers and children with asthma; and the researchers' ability to repeat the analyses after stratification for asthma status and smoking status.

Dr. Hunninghake and Dr. Cho reported no conflicts of interest. Their associates reported receiving support from a several pharmaceutical companies.

A variation in the MMP12 gene appears to be associated with beneficial pulmonary effects in children who have asthma and in adults who smoke, particularly smokers with chronic obstructive pulmonary disease, according to a study.

“Our results suggest that variants of MMP12 are determinants of the level of lung function in subjects who are at risk for airflow obstruction,” said Dr. Gary M. Hunninghake and Dr. Michael H. Cho of Brigham and Women's Hospital, Boston, and their associates.

The investigators tested for an association between single-nucleotide polymorphisms (SNPs) in the MMP12 gene and lung function as assessed by forced expiratory volume in 1 second (FEV₁) in cohorts participating in seven clinical trials. The MMP12 gene encodes matrix metalloproteinase 12, which is produced by macrophages, “the predominant cell type that patrols the lower airspaces under normal conditions and the main inflammatory cell type that is recruited with smoking,” the investigators noted.

Matrix metalloproteinases degrade extracellular matrix molecules such as collagen and elastin and are also involved in epithelial repair and the regulation of cytokine and chemokine activity.

The researchers first found that the minor allele of SNP rs2276109 in the MMP12 gene was significantly associated with increased FEV₁ in children with asthma (but not nonasthmatic children) who were subjects in the Genetics of Asthma in Costa Rica Study. They then found the same link between the SNP and increased FEV₁ among children taking budesonide—but not among those who were not taking budesonide—in the Childhood Asthma Management Program. The same link between the SNP and increased FEV₁ existed among children with asthma (but not nonasthmatic children) in the BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological Survey) study.

Dr. Hunninghake and his colleagues then tested for the same association in adults who were subjects in the Boston Early-Onset COPD Study, the Lovelace Smokers Cohort, and the Normative Aging Study. The researchers found that the same SNP variation was associated with improved lung function in adults who were current or former smokers, but not in nonsmokers.

Finally, the investigators found that the same MMP12 variant appeared to protect patients at risk for COPD against the disease in those same three adult cohorts. The absence of the SNP rs2276109 was associated with a 54% increase in the risk of the onset of COPD and a population attributable risk of COPD of 28%.

The findings support the so-called “Dutch hypothesis,” which states that asthma and COPD are different manifestations of a single disease entity and suggests that as-yet unknown genetic variants may underlie both asthma and COPD, the investigators said (N. Engl. J. Med. 2009;361[doi:10.1056/NEJMoa0904006]).

Most previous studies of genetic associations in pulmonary function have relied on a single cohort, the study's authors noted. “A strength of our study is that it included the analysis of multiple measurements of pulmonary function in a large number of subjects—more than 20,000 FEV₁ measurements in more than 8,300 subjects,” they added.

“Evidence is accumulating that asthma and COPD share common pathogenetic pathways,” noted Dr. Guy G. Brusselle of Ghent (Belgium) University Hospital, in an accompanying editorial. “This study … adds to the accumulating evidence that several mechanisms may lead to the development of COPD” (N. Engl. J. Med. 2009;361[doi:10.1056/NEJMe0919626]).

The study's strengths include the inclusion of seven cohorts with more than 8,300 subjects; the replication of an association between the SNP and FEV₁ both in adult smokers and children with asthma; and the researchers' ability to repeat the analyses after stratification for asthma status and smoking status.

Dr. Hunninghake and Dr. Cho reported no conflicts of interest. Their associates reported receiving support from a several pharmaceutical companies.