ACS Surgery News

MADRID – Evidence is mounting that lung transplantation is feasible in highly select patients positive for human immunodeficiency virus.

A retrospective analysis of three patients revealed no long-term resurgence of HIV viremia or profound complications of overt immune suppression. CD4 counts decreased initially in one patient, but recovered after about 1 year with antiretroviral therapy (ART). All patients were adequately controlled on combination ART, had no HIV viremia for 2 years prior to surgery, and had no resistance to standard antiretrovirals.

"Not all HIV-positive patients would be candidates," Dr. Harish Seethamraju said during a late-breaking abstract session at the world congress of the American College of Chest Physicians. "You want to ensure compliance; and an ability to manage complex medication regimens would be the challenge for any person. So, people who have an in-depth knowledge about their disease and are able to manage their HIV well for a prolonged period of time would be ideal candidates."

As with other solid-organ transplants, acute rejection remains a concern and was reported in patient 1, who underwent bilateral transplant for HIV-associated pulmonary arterial hypertension. The patient experienced three episodes of rejection, including bronchiolitis obliterans syndrome and rejection with respiratory syncytial virus pneumonia requiring admission at 15 months, which tipped her course dramatically and resulted in loss of most of her lung function by post-transplant 43 months, he said.

Mild acute rejection occurred in patients 2 and 3, who were transplanted for idiopathic pulmonary fibrosis, but they remain free of acute rejection and are actively employed 15 months and 41 months after transplant.

Surgeons at Houston Methodist Hospital and the University of California, San Francisco, where the transplants were performed, also learned that ART has to be initiated very early on post-transplant, said Dr. Seethamraju, now medical director of the lung transplant program, University of Kentucky, Lexington.

"In patient 2, we found a resurgence of HIV viremia within 10 days, but we just stopped the medication for the first 4 days and that’s all it took for the virus to come back," he said.

The study findings should provide guidance for clinicians considering transplantation in the wake of the recently approved HIV Organ Policy Equity (HOPE) Act, which made it legal in the United States now to transplant HIV-positive organs in HIV-positive patients. HIV patients are often referred for lung transplant because of an increased incidence of pulmonary hypertension and infections, but their HIV status has traditionally been taken as a contraindication due to the potential risks of added immunosuppression, said Dr. Seethamraju. Only one case report has been published of an HIV and hepatitis B virus coinfected patient with cystic fibrosis who underwent successful double lung transplant, he said.

During a discussion of the study, CHEST Congress cochair Dr. Joan Soriano, of Hospital Universitari Son Espases, Palma de Mallorca, Spain, asked whether any of the centers would consider lung transplantation in HIV-positive patients with chronic obstructive pulmonary disease (COPD).

Dr. Seethamraju replied that COPD is the second-most-common indication for transplant after idiopathic pulmonary fibrosis and interstitial lung disease, but that the United Network for Organ Sharing 2005 lung allocation scores are very low for COPD patients, and thus organs would be hard to obtain for this specific group of HIV patients. "But it would be a great candidate for us," he added. "We would definitely do a transplant in that group of patients, irrespective of their HIV status."

Dr. Seethamraju and his coauthors reported no relevant disclosures.

[email protected]

MADRID – Evidence is mounting that lung transplantation is feasible in highly select patients positive for human immunodeficiency virus.

A retrospective analysis of three patients revealed no long-term resurgence of HIV viremia or profound complications of overt immune suppression. CD4 counts decreased initially in one patient, but recovered after about 1 year with antiretroviral therapy (ART). All patients were adequately controlled on combination ART, had no HIV viremia for 2 years prior to surgery, and had no resistance to standard antiretrovirals.

"Not all HIV-positive patients would be candidates," Dr. Harish Seethamraju said during a late-breaking abstract session at the world congress of the American College of Chest Physicians. "You want to ensure compliance; and an ability to manage complex medication regimens would be the challenge for any person. So, people who have an in-depth knowledge about their disease and are able to manage their HIV well for a prolonged period of time would be ideal candidates."

As with other solid-organ transplants, acute rejection remains a concern and was reported in patient 1, who underwent bilateral transplant for HIV-associated pulmonary arterial hypertension. The patient experienced three episodes of rejection, including bronchiolitis obliterans syndrome and rejection with respiratory syncytial virus pneumonia requiring admission at 15 months, which tipped her course dramatically and resulted in loss of most of her lung function by post-transplant 43 months, he said.

Mild acute rejection occurred in patients 2 and 3, who were transplanted for idiopathic pulmonary fibrosis, but they remain free of acute rejection and are actively employed 15 months and 41 months after transplant.

Surgeons at Houston Methodist Hospital and the University of California, San Francisco, where the transplants were performed, also learned that ART has to be initiated very early on post-transplant, said Dr. Seethamraju, now medical director of the lung transplant program, University of Kentucky, Lexington.

"In patient 2, we found a resurgence of HIV viremia within 10 days, but we just stopped the medication for the first 4 days and that’s all it took for the virus to come back," he said.

The study findings should provide guidance for clinicians considering transplantation in the wake of the recently approved HIV Organ Policy Equity (HOPE) Act, which made it legal in the United States now to transplant HIV-positive organs in HIV-positive patients. HIV patients are often referred for lung transplant because of an increased incidence of pulmonary hypertension and infections, but their HIV status has traditionally been taken as a contraindication due to the potential risks of added immunosuppression, said Dr. Seethamraju. Only one case report has been published of an HIV and hepatitis B virus coinfected patient with cystic fibrosis who underwent successful double lung transplant, he said.

During a discussion of the study, CHEST Congress cochair Dr. Joan Soriano, of Hospital Universitari Son Espases, Palma de Mallorca, Spain, asked whether any of the centers would consider lung transplantation in HIV-positive patients with chronic obstructive pulmonary disease (COPD).

Dr. Seethamraju replied that COPD is the second-most-common indication for transplant after idiopathic pulmonary fibrosis and interstitial lung disease, but that the United Network for Organ Sharing 2005 lung allocation scores are very low for COPD patients, and thus organs would be hard to obtain for this specific group of HIV patients. "But it would be a great candidate for us," he added. "We would definitely do a transplant in that group of patients, irrespective of their HIV status."

Dr. Seethamraju and his coauthors reported no relevant disclosures.

[email protected]

MADRID – Evidence is mounting that lung transplantation is feasible in highly select patients positive for human immunodeficiency virus.

A retrospective analysis of three patients revealed no long-term resurgence of HIV viremia or profound complications of overt immune suppression. CD4 counts decreased initially in one patient, but recovered after about 1 year with antiretroviral therapy (ART). All patients were adequately controlled on combination ART, had no HIV viremia for 2 years prior to surgery, and had no resistance to standard antiretrovirals.

"Not all HIV-positive patients would be candidates," Dr. Harish Seethamraju said during a late-breaking abstract session at the world congress of the American College of Chest Physicians. "You want to ensure compliance; and an ability to manage complex medication regimens would be the challenge for any person. So, people who have an in-depth knowledge about their disease and are able to manage their HIV well for a prolonged period of time would be ideal candidates."

As with other solid-organ transplants, acute rejection remains a concern and was reported in patient 1, who underwent bilateral transplant for HIV-associated pulmonary arterial hypertension. The patient experienced three episodes of rejection, including bronchiolitis obliterans syndrome and rejection with respiratory syncytial virus pneumonia requiring admission at 15 months, which tipped her course dramatically and resulted in loss of most of her lung function by post-transplant 43 months, he said.

Mild acute rejection occurred in patients 2 and 3, who were transplanted for idiopathic pulmonary fibrosis, but they remain free of acute rejection and are actively employed 15 months and 41 months after transplant.

Surgeons at Houston Methodist Hospital and the University of California, San Francisco, where the transplants were performed, also learned that ART has to be initiated very early on post-transplant, said Dr. Seethamraju, now medical director of the lung transplant program, University of Kentucky, Lexington.

"In patient 2, we found a resurgence of HIV viremia within 10 days, but we just stopped the medication for the first 4 days and that’s all it took for the virus to come back," he said.

The study findings should provide guidance for clinicians considering transplantation in the wake of the recently approved HIV Organ Policy Equity (HOPE) Act, which made it legal in the United States now to transplant HIV-positive organs in HIV-positive patients. HIV patients are often referred for lung transplant because of an increased incidence of pulmonary hypertension and infections, but their HIV status has traditionally been taken as a contraindication due to the potential risks of added immunosuppression, said Dr. Seethamraju. Only one case report has been published of an HIV and hepatitis B virus coinfected patient with cystic fibrosis who underwent successful double lung transplant, he said.

During a discussion of the study, CHEST Congress cochair Dr. Joan Soriano, of Hospital Universitari Son Espases, Palma de Mallorca, Spain, asked whether any of the centers would consider lung transplantation in HIV-positive patients with chronic obstructive pulmonary disease (COPD).

Dr. Seethamraju replied that COPD is the second-most-common indication for transplant after idiopathic pulmonary fibrosis and interstitial lung disease, but that the United Network for Organ Sharing 2005 lung allocation scores are very low for COPD patients, and thus organs would be hard to obtain for this specific group of HIV patients. "But it would be a great candidate for us," he added. "We would definitely do a transplant in that group of patients, irrespective of their HIV status."

Dr. Seethamraju and his coauthors reported no relevant disclosures.

[email protected]

PHOENIX, ARIZ. – Induction therapy does not appear to significantly increase the risk of postoperative complications in patients who undergo minimally invasive esophagectomy for esophageal adenocarcinoma, according to results of a study reported at the annual Society of Surgical Oncology Cancer Symposium.

"After balancing pretreatment variables that can potentially influence treatment decisions, we found that induction therapy does not significantly impact on perioperative outcomes compared with patients who are treated with minimally invasive esophagectomy as primary therapy," said Dr. Katie Sue Nason, of the department of cardiothoracic surgery at the University of Pittsburgh.

That conclusion comes from a propensity-matched analysis in which patients with similar pretreatment predictor variables were paired in an attempt to reduce comparison biases.

The investigators found no significant differences in mortality, major adverse events, readmissions, reoperations, or length of stay between 197 patients who received induction therapy and minimally invasive esophagectomy and 178 who had esophagectomy alone.

Although induction chemoradiation therapy may reduce the incidence of local and distant treatment failures in patients with esophageal cancer, it has the potential to increase the risk of postoperative adverse outcomes.

"What’s often not considered is that these factors that influence postoperative outcomes may also be influencing treatment allocation," Dr. Nason said.

In observational studies, for example, there may be larger differences in observed covariates between treatment groups that could lead to biased estimates of treatment effects.

"This could be adjusted for using propensity score matching, where you generate the conditional probability of one individual being treated with a particular treatment approach given multiple pretreatment covariates. By doing propensity score matching, you can then balance these covariates such as age and various comorbid illnesses between the two groups, and perhaps eliminate this treatment allocation bias that impacts on the relationship between the treatment and the postoperative outcomes," Dr. Nason explained.

She and her colleagues applied the technique to an analysis of outcomes from 375 patients with clinical stage II or greater esophageal adenocarcinoma treated with minimally invasive esophagectomy. They assessed tumor variables, comorbidities, treatments, and outcomes, and created propensity matching scores to match surgery-only patients one-on-one with no repeats to a patient who also underwent induction therapy and had a propensity score within 0.05 of that for the surgery-only patient.

Patients without suitable matches were excluded from the data set.

The extensive list of variables included age, smoking status, alcohol use, history of Barrett’s esophagus, myriad comorbidities, cancer location, pretreatment clinical stage, and many others.

Among the 375 patients, the investigators were able to generate propensity-matching scores for 82 pairs for the comparison of treatments and outcome.

They found that there were no significant differences between induction and surgery-only patients in the primary outcome of adverse events within 30 days of surgery, including in-hospital and 30-day mortality, major adverse events or at least 1 postoperative adverse event, readmission within 30 days, reoperation in-hospital or within 30 days, or length of stay greater than 10 days.

Dr. Nason noted that although unmatched patients differed in age, presentation with alarm symptoms, daily alcohol use, clinical stage and comorbid illnesses, the pretreatment variables were all well balanced in the propensity-matched analysis.

Mortality after minimally invasive esophagectomy was 1.8% among all 375 patients, 1.5% among patients who underwent induction, and 2.3% among patients who underwent surgery alone; these differences were not significant.

Major adverse events occurred in 28% of patients overall, 27% of those who received induction, and 30% of those who had surgery alone, also not significant.

The study was internally funded. Dr. Nason reported having no financial disclosures.

PHOENIX, ARIZ. – Induction therapy does not appear to significantly increase the risk of postoperative complications in patients who undergo minimally invasive esophagectomy for esophageal adenocarcinoma, according to results of a study reported at the annual Society of Surgical Oncology Cancer Symposium.

"After balancing pretreatment variables that can potentially influence treatment decisions, we found that induction therapy does not significantly impact on perioperative outcomes compared with patients who are treated with minimally invasive esophagectomy as primary therapy," said Dr. Katie Sue Nason, of the department of cardiothoracic surgery at the University of Pittsburgh.

That conclusion comes from a propensity-matched analysis in which patients with similar pretreatment predictor variables were paired in an attempt to reduce comparison biases.

The investigators found no significant differences in mortality, major adverse events, readmissions, reoperations, or length of stay between 197 patients who received induction therapy and minimally invasive esophagectomy and 178 who had esophagectomy alone.

Although induction chemoradiation therapy may reduce the incidence of local and distant treatment failures in patients with esophageal cancer, it has the potential to increase the risk of postoperative adverse outcomes.

"What’s often not considered is that these factors that influence postoperative outcomes may also be influencing treatment allocation," Dr. Nason said.

In observational studies, for example, there may be larger differences in observed covariates between treatment groups that could lead to biased estimates of treatment effects.

"This could be adjusted for using propensity score matching, where you generate the conditional probability of one individual being treated with a particular treatment approach given multiple pretreatment covariates. By doing propensity score matching, you can then balance these covariates such as age and various comorbid illnesses between the two groups, and perhaps eliminate this treatment allocation bias that impacts on the relationship between the treatment and the postoperative outcomes," Dr. Nason explained.

She and her colleagues applied the technique to an analysis of outcomes from 375 patients with clinical stage II or greater esophageal adenocarcinoma treated with minimally invasive esophagectomy. They assessed tumor variables, comorbidities, treatments, and outcomes, and created propensity matching scores to match surgery-only patients one-on-one with no repeats to a patient who also underwent induction therapy and had a propensity score within 0.05 of that for the surgery-only patient.

Patients without suitable matches were excluded from the data set.

The extensive list of variables included age, smoking status, alcohol use, history of Barrett’s esophagus, myriad comorbidities, cancer location, pretreatment clinical stage, and many others.

Among the 375 patients, the investigators were able to generate propensity-matching scores for 82 pairs for the comparison of treatments and outcome.

They found that there were no significant differences between induction and surgery-only patients in the primary outcome of adverse events within 30 days of surgery, including in-hospital and 30-day mortality, major adverse events or at least 1 postoperative adverse event, readmission within 30 days, reoperation in-hospital or within 30 days, or length of stay greater than 10 days.

Dr. Nason noted that although unmatched patients differed in age, presentation with alarm symptoms, daily alcohol use, clinical stage and comorbid illnesses, the pretreatment variables were all well balanced in the propensity-matched analysis.

Mortality after minimally invasive esophagectomy was 1.8% among all 375 patients, 1.5% among patients who underwent induction, and 2.3% among patients who underwent surgery alone; these differences were not significant.

Major adverse events occurred in 28% of patients overall, 27% of those who received induction, and 30% of those who had surgery alone, also not significant.

The study was internally funded. Dr. Nason reported having no financial disclosures.

PHOENIX, ARIZ. – Induction therapy does not appear to significantly increase the risk of postoperative complications in patients who undergo minimally invasive esophagectomy for esophageal adenocarcinoma, according to results of a study reported at the annual Society of Surgical Oncology Cancer Symposium.

"After balancing pretreatment variables that can potentially influence treatment decisions, we found that induction therapy does not significantly impact on perioperative outcomes compared with patients who are treated with minimally invasive esophagectomy as primary therapy," said Dr. Katie Sue Nason, of the department of cardiothoracic surgery at the University of Pittsburgh.

That conclusion comes from a propensity-matched analysis in which patients with similar pretreatment predictor variables were paired in an attempt to reduce comparison biases.

The investigators found no significant differences in mortality, major adverse events, readmissions, reoperations, or length of stay between 197 patients who received induction therapy and minimally invasive esophagectomy and 178 who had esophagectomy alone.

Although induction chemoradiation therapy may reduce the incidence of local and distant treatment failures in patients with esophageal cancer, it has the potential to increase the risk of postoperative adverse outcomes.

"What’s often not considered is that these factors that influence postoperative outcomes may also be influencing treatment allocation," Dr. Nason said.

In observational studies, for example, there may be larger differences in observed covariates between treatment groups that could lead to biased estimates of treatment effects.

"This could be adjusted for using propensity score matching, where you generate the conditional probability of one individual being treated with a particular treatment approach given multiple pretreatment covariates. By doing propensity score matching, you can then balance these covariates such as age and various comorbid illnesses between the two groups, and perhaps eliminate this treatment allocation bias that impacts on the relationship between the treatment and the postoperative outcomes," Dr. Nason explained.

She and her colleagues applied the technique to an analysis of outcomes from 375 patients with clinical stage II or greater esophageal adenocarcinoma treated with minimally invasive esophagectomy. They assessed tumor variables, comorbidities, treatments, and outcomes, and created propensity matching scores to match surgery-only patients one-on-one with no repeats to a patient who also underwent induction therapy and had a propensity score within 0.05 of that for the surgery-only patient.

Patients without suitable matches were excluded from the data set.

The extensive list of variables included age, smoking status, alcohol use, history of Barrett’s esophagus, myriad comorbidities, cancer location, pretreatment clinical stage, and many others.

Among the 375 patients, the investigators were able to generate propensity-matching scores for 82 pairs for the comparison of treatments and outcome.

They found that there were no significant differences between induction and surgery-only patients in the primary outcome of adverse events within 30 days of surgery, including in-hospital and 30-day mortality, major adverse events or at least 1 postoperative adverse event, readmission within 30 days, reoperation in-hospital or within 30 days, or length of stay greater than 10 days.

Dr. Nason noted that although unmatched patients differed in age, presentation with alarm symptoms, daily alcohol use, clinical stage and comorbid illnesses, the pretreatment variables were all well balanced in the propensity-matched analysis.

Mortality after minimally invasive esophagectomy was 1.8% among all 375 patients, 1.5% among patients who underwent induction, and 2.3% among patients who underwent surgery alone; these differences were not significant.

Major adverse events occurred in 28% of patients overall, 27% of those who received induction, and 30% of those who had surgery alone, also not significant.

The study was internally funded. Dr. Nason reported having no financial disclosures.

SCOTTSDALE, ARIZ. – When it comes to holding or continuing with ACE inhibitors before surgery, all bets are off, a perioperative medicine consultant suggested.

Patients on angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) have about a 50% risk of developing hypotension during surgery, and a significant proportion of those episodes could be severe, said Dr. Paul Grant, of the University of Michigan Health System in Ann Arbor.

"I recommend having some sort of standard approach [to perioperative ACE inhibitor use] at your institution if that’s at all possible, either for a certain surgery type or across the board," he said at a meeting on perioperative medicine sponsored by the University of Miami.

Evidence from a small number of randomized trials and observational studies suggests that continuing ACE inhibitors during cardiac surgery may result in less cardiac enzyme release, less kidney injury, and a lower incidence of atrial fibrillation. In vascular surgery, evidence suggests that patients on ACE inhibitors who are undergoing surgery have less of a drop in cardiac output and may have improved creatinine clearance.

On the other hand, patients who remain on ACE inhibitors during surgery can experience a "profound" drop in blood pressure requiring immediate intervention, he said.

Data to support the continue vs. hold debate are sparse, but include a trial of 51 patients randomized to continue ACE inhibitors on the day of surgery or to have the drugs held for 12-24 hours before surgery. In all, 33 of the patients were on captopril (Capoten), and 18 were on enalapril (Vasotec).

The investigators found that among patients randomized to continue ACE inhibitor therapy, 7 of 7 on captopril and 9 of 14 on enalapril developed hypotension, defined as a systolic blood pressure (SBP) less than 90 mm Hg. In contrast, among patients assigned to the ACE-inhibitor hold protocol, only 2 of 11 on captopril and 4 of 19 on enalapril developed hypotension during surgery.

In a second randomized trial, investigators looked at 37 patients on an ARB who were randomly assigned to either discontinue ARB on the day before surgery (18 patients), or to receive their ARB 1 hour before anesthesia induction (19 patients).

The authors defined hypotension for their study as an SBP less than 80 mm Hg for more than 1 minute. They found that all 19 patients who continued on ARB had hypotension during surgery, compared with 12 of 18 who discontinued their ARB the day before. Patients who received their ARB on the day of surgery used significantly more vasoactive drugs. Despite the discontinuation of the ARB, there were no differences in hypertension between the groups in the recovery period. Postoperative cardiac complications occurred in 1 patient in each group.

In the final randomized study that Dr. Grant cited, 40 patients on an ACE inhibitor with good left-ventricular function were scheduled to undergo coronary artery bypass graft (CABG). They were randomly assigned to hold or continue on ACE inhibitors on the day of surgery.

Patients in whom the ACE inhibitors were held before CABG had higher mean blood pressures than patients who continued on the drugs, and they used less vasopressor during the surgery. In contrast, patients who continued on ACE inhibitors needed more vasodilators after CABG and in the recovery period. The authors of this trial did not study other clinical endpoints, Dr. Grant noted.

Evidence from two observational studies was more equivocal, however.

In a retrospective observational study, investigators studied the relationship between the timing of discontinuing ACE inhibitors and angiotensin II receptor subtype 1 antagonists (ARA) and the onset of hypotension in 267 patients scheduled for general surgery.

They found that patients exposed to an ACE inhibitor or ARA within 10 hours of anesthesia had an adjusted odds ratio of 1.74 for moderate hypotension (SBP 85 mm Hg or less; P = .04), but there was no difference in severe hypotension between these patients and those who discontinued the drugs more than 10 hours before surgery. There were no differences in either vasopressor use or postoperative complications, including unplanned intensive care unit stay, myocardial infarction, stroke, renal impairment, or death.

A second, smaller study compared 12 vascular surgery patients on ARB the day of surgery with matched cohorts of patients taking beta-blockers and/or calcium channel blockers the day of surgery, or ACE inhibitors held on the day of surgery.

Hypotension (SBP less than 90 mm Hg in this study) occurred in all of the patients on ARB but in only 60% (27 of 45) patients on the beta-blocker/calcium channel blockers, and in 67% (18 of 27) in the ACE-inhibitor hold cohort. The ARB patients were also less responsive to ephedrine and phenylephrine than other patients, and in some cases responded only to a vasopressin system agonist, Dr. Grant noted.

Finally, the authors of a random-effects meta-analysis of five studies with a total of 434 patients reported that patients receiving an immediate preoperative ACE inhibitor or ARA dose had a relative risk of 1.50 for developing hypotension requiring vasopressors at or shortly after induction of anesthesia, compared with patients who did not receive the drugs.

Dr. Grant noted that the American College of Physicians’ Smart Medicine guidelines on perioperative management of hypertensive patients recommend continuing ACE inhibitors "with caution," and they advise clinicians to avoid hypovolemia in patients maintained on ACE inhibitors during surgery. He said that in certain cases, it may be appropriate to continue surgical patients on ACE inhibitors or ARB, as in patients with hypertension that is difficult to control with multiple medications, or in those with severe heart disease who have adequate blood pressure.

Dr. Grant reported having no financial disclosures.

SCOTTSDALE, ARIZ. – When it comes to holding or continuing with ACE inhibitors before surgery, all bets are off, a perioperative medicine consultant suggested.

Patients on angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) have about a 50% risk of developing hypotension during surgery, and a significant proportion of those episodes could be severe, said Dr. Paul Grant, of the University of Michigan Health System in Ann Arbor.

"I recommend having some sort of standard approach [to perioperative ACE inhibitor use] at your institution if that’s at all possible, either for a certain surgery type or across the board," he said at a meeting on perioperative medicine sponsored by the University of Miami.

Evidence from a small number of randomized trials and observational studies suggests that continuing ACE inhibitors during cardiac surgery may result in less cardiac enzyme release, less kidney injury, and a lower incidence of atrial fibrillation. In vascular surgery, evidence suggests that patients on ACE inhibitors who are undergoing surgery have less of a drop in cardiac output and may have improved creatinine clearance.

On the other hand, patients who remain on ACE inhibitors during surgery can experience a "profound" drop in blood pressure requiring immediate intervention, he said.

Data to support the continue vs. hold debate are sparse, but include a trial of 51 patients randomized to continue ACE inhibitors on the day of surgery or to have the drugs held for 12-24 hours before surgery. In all, 33 of the patients were on captopril (Capoten), and 18 were on enalapril (Vasotec).

The investigators found that among patients randomized to continue ACE inhibitor therapy, 7 of 7 on captopril and 9 of 14 on enalapril developed hypotension, defined as a systolic blood pressure (SBP) less than 90 mm Hg. In contrast, among patients assigned to the ACE-inhibitor hold protocol, only 2 of 11 on captopril and 4 of 19 on enalapril developed hypotension during surgery.

In a second randomized trial, investigators looked at 37 patients on an ARB who were randomly assigned to either discontinue ARB on the day before surgery (18 patients), or to receive their ARB 1 hour before anesthesia induction (19 patients).

The authors defined hypotension for their study as an SBP less than 80 mm Hg for more than 1 minute. They found that all 19 patients who continued on ARB had hypotension during surgery, compared with 12 of 18 who discontinued their ARB the day before. Patients who received their ARB on the day of surgery used significantly more vasoactive drugs. Despite the discontinuation of the ARB, there were no differences in hypertension between the groups in the recovery period. Postoperative cardiac complications occurred in 1 patient in each group.

In the final randomized study that Dr. Grant cited, 40 patients on an ACE inhibitor with good left-ventricular function were scheduled to undergo coronary artery bypass graft (CABG). They were randomly assigned to hold or continue on ACE inhibitors on the day of surgery.

Patients in whom the ACE inhibitors were held before CABG had higher mean blood pressures than patients who continued on the drugs, and they used less vasopressor during the surgery. In contrast, patients who continued on ACE inhibitors needed more vasodilators after CABG and in the recovery period. The authors of this trial did not study other clinical endpoints, Dr. Grant noted.

Evidence from two observational studies was more equivocal, however.

In a retrospective observational study, investigators studied the relationship between the timing of discontinuing ACE inhibitors and angiotensin II receptor subtype 1 antagonists (ARA) and the onset of hypotension in 267 patients scheduled for general surgery.

They found that patients exposed to an ACE inhibitor or ARA within 10 hours of anesthesia had an adjusted odds ratio of 1.74 for moderate hypotension (SBP 85 mm Hg or less; P = .04), but there was no difference in severe hypotension between these patients and those who discontinued the drugs more than 10 hours before surgery. There were no differences in either vasopressor use or postoperative complications, including unplanned intensive care unit stay, myocardial infarction, stroke, renal impairment, or death.

A second, smaller study compared 12 vascular surgery patients on ARB the day of surgery with matched cohorts of patients taking beta-blockers and/or calcium channel blockers the day of surgery, or ACE inhibitors held on the day of surgery.

Hypotension (SBP less than 90 mm Hg in this study) occurred in all of the patients on ARB but in only 60% (27 of 45) patients on the beta-blocker/calcium channel blockers, and in 67% (18 of 27) in the ACE-inhibitor hold cohort. The ARB patients were also less responsive to ephedrine and phenylephrine than other patients, and in some cases responded only to a vasopressin system agonist, Dr. Grant noted.

Finally, the authors of a random-effects meta-analysis of five studies with a total of 434 patients reported that patients receiving an immediate preoperative ACE inhibitor or ARA dose had a relative risk of 1.50 for developing hypotension requiring vasopressors at or shortly after induction of anesthesia, compared with patients who did not receive the drugs.

Dr. Grant noted that the American College of Physicians’ Smart Medicine guidelines on perioperative management of hypertensive patients recommend continuing ACE inhibitors "with caution," and they advise clinicians to avoid hypovolemia in patients maintained on ACE inhibitors during surgery. He said that in certain cases, it may be appropriate to continue surgical patients on ACE inhibitors or ARB, as in patients with hypertension that is difficult to control with multiple medications, or in those with severe heart disease who have adequate blood pressure.

Dr. Grant reported having no financial disclosures.

SCOTTSDALE, ARIZ. – When it comes to holding or continuing with ACE inhibitors before surgery, all bets are off, a perioperative medicine consultant suggested.

Patients on angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) have about a 50% risk of developing hypotension during surgery, and a significant proportion of those episodes could be severe, said Dr. Paul Grant, of the University of Michigan Health System in Ann Arbor.

"I recommend having some sort of standard approach [to perioperative ACE inhibitor use] at your institution if that’s at all possible, either for a certain surgery type or across the board," he said at a meeting on perioperative medicine sponsored by the University of Miami.

Evidence from a small number of randomized trials and observational studies suggests that continuing ACE inhibitors during cardiac surgery may result in less cardiac enzyme release, less kidney injury, and a lower incidence of atrial fibrillation. In vascular surgery, evidence suggests that patients on ACE inhibitors who are undergoing surgery have less of a drop in cardiac output and may have improved creatinine clearance.

On the other hand, patients who remain on ACE inhibitors during surgery can experience a "profound" drop in blood pressure requiring immediate intervention, he said.

Data to support the continue vs. hold debate are sparse, but include a trial of 51 patients randomized to continue ACE inhibitors on the day of surgery or to have the drugs held for 12-24 hours before surgery. In all, 33 of the patients were on captopril (Capoten), and 18 were on enalapril (Vasotec).

The investigators found that among patients randomized to continue ACE inhibitor therapy, 7 of 7 on captopril and 9 of 14 on enalapril developed hypotension, defined as a systolic blood pressure (SBP) less than 90 mm Hg. In contrast, among patients assigned to the ACE-inhibitor hold protocol, only 2 of 11 on captopril and 4 of 19 on enalapril developed hypotension during surgery.

In a second randomized trial, investigators looked at 37 patients on an ARB who were randomly assigned to either discontinue ARB on the day before surgery (18 patients), or to receive their ARB 1 hour before anesthesia induction (19 patients).

The authors defined hypotension for their study as an SBP less than 80 mm Hg for more than 1 minute. They found that all 19 patients who continued on ARB had hypotension during surgery, compared with 12 of 18 who discontinued their ARB the day before. Patients who received their ARB on the day of surgery used significantly more vasoactive drugs. Despite the discontinuation of the ARB, there were no differences in hypertension between the groups in the recovery period. Postoperative cardiac complications occurred in 1 patient in each group.

In the final randomized study that Dr. Grant cited, 40 patients on an ACE inhibitor with good left-ventricular function were scheduled to undergo coronary artery bypass graft (CABG). They were randomly assigned to hold or continue on ACE inhibitors on the day of surgery.

Patients in whom the ACE inhibitors were held before CABG had higher mean blood pressures than patients who continued on the drugs, and they used less vasopressor during the surgery. In contrast, patients who continued on ACE inhibitors needed more vasodilators after CABG and in the recovery period. The authors of this trial did not study other clinical endpoints, Dr. Grant noted.

Evidence from two observational studies was more equivocal, however.

In a retrospective observational study, investigators studied the relationship between the timing of discontinuing ACE inhibitors and angiotensin II receptor subtype 1 antagonists (ARA) and the onset of hypotension in 267 patients scheduled for general surgery.

They found that patients exposed to an ACE inhibitor or ARA within 10 hours of anesthesia had an adjusted odds ratio of 1.74 for moderate hypotension (SBP 85 mm Hg or less; P = .04), but there was no difference in severe hypotension between these patients and those who discontinued the drugs more than 10 hours before surgery. There were no differences in either vasopressor use or postoperative complications, including unplanned intensive care unit stay, myocardial infarction, stroke, renal impairment, or death.

A second, smaller study compared 12 vascular surgery patients on ARB the day of surgery with matched cohorts of patients taking beta-blockers and/or calcium channel blockers the day of surgery, or ACE inhibitors held on the day of surgery.

Hypotension (SBP less than 90 mm Hg in this study) occurred in all of the patients on ARB but in only 60% (27 of 45) patients on the beta-blocker/calcium channel blockers, and in 67% (18 of 27) in the ACE-inhibitor hold cohort. The ARB patients were also less responsive to ephedrine and phenylephrine than other patients, and in some cases responded only to a vasopressin system agonist, Dr. Grant noted.

Finally, the authors of a random-effects meta-analysis of five studies with a total of 434 patients reported that patients receiving an immediate preoperative ACE inhibitor or ARA dose had a relative risk of 1.50 for developing hypotension requiring vasopressors at or shortly after induction of anesthesia, compared with patients who did not receive the drugs.

Dr. Grant noted that the American College of Physicians’ Smart Medicine guidelines on perioperative management of hypertensive patients recommend continuing ACE inhibitors "with caution," and they advise clinicians to avoid hypovolemia in patients maintained on ACE inhibitors during surgery. He said that in certain cases, it may be appropriate to continue surgical patients on ACE inhibitors or ARB, as in patients with hypertension that is difficult to control with multiple medications, or in those with severe heart disease who have adequate blood pressure.

Dr. Grant reported having no financial disclosures.

Just over 7 million Americans signed up for private health insurance plans through federal and state insurance marketplaces during the Affordable Care Act’s first open enrollment period, according to preliminary figures released by the White House April 1.

The number is a bit of a surprise since only 4.2 million individuals had signed up for health plans as of March 1. A last minute surge helped the administration meet enrollment projections that were made before the technical glitches plagued the start of healthcare.gov in October and November.

Complete enrollment numbers, as well information on how many people have actually paid their premiums, will not be available for a few more weeks, administration officials said.

In the meantime, President Obama pointed to the enrollment number as proof that the health care law is working. And he blasted opponents who have spent the last several months trying to repeal or undermine the law.

"I will always work with anyone who is willing to make this law work even better," President Obama said from the Rose Garden. "But the debate over repealing this law is over. The Affordable Care Act is here to stay."

[email protected]

On Twitter @maryellenny

Just over 7 million Americans signed up for private health insurance plans through federal and state insurance marketplaces during the Affordable Care Act’s first open enrollment period, according to preliminary figures released by the White House April 1.

The number is a bit of a surprise since only 4.2 million individuals had signed up for health plans as of March 1. A last minute surge helped the administration meet enrollment projections that were made before the technical glitches plagued the start of healthcare.gov in October and November.

Complete enrollment numbers, as well information on how many people have actually paid their premiums, will not be available for a few more weeks, administration officials said.

In the meantime, President Obama pointed to the enrollment number as proof that the health care law is working. And he blasted opponents who have spent the last several months trying to repeal or undermine the law.

"I will always work with anyone who is willing to make this law work even better," President Obama said from the Rose Garden. "But the debate over repealing this law is over. The Affordable Care Act is here to stay."

[email protected]

On Twitter @maryellenny

Just over 7 million Americans signed up for private health insurance plans through federal and state insurance marketplaces during the Affordable Care Act’s first open enrollment period, according to preliminary figures released by the White House April 1.

The number is a bit of a surprise since only 4.2 million individuals had signed up for health plans as of March 1. A last minute surge helped the administration meet enrollment projections that were made before the technical glitches plagued the start of healthcare.gov in October and November.

Complete enrollment numbers, as well information on how many people have actually paid their premiums, will not be available for a few more weeks, administration officials said.

In the meantime, President Obama pointed to the enrollment number as proof that the health care law is working. And he blasted opponents who have spent the last several months trying to repeal or undermine the law.

"I will always work with anyone who is willing to make this law work even better," President Obama said from the Rose Garden. "But the debate over repealing this law is over. The Affordable Care Act is here to stay."

[email protected]

On Twitter @maryellenny

CHICAGO – Clopidogrel use after endovascular lower-extremity revascularization was significantly associated with 1-year freedom from amputation and survival, but only 38% of the Medicare population was on the drug post intervention in a large retrospective analysis.

Patients with the most severe peripheral vascular disease, ulceration, or gangrene benefited the most from post revascularization clopidogrel (Plavix), but were the least likely to be using the drug, Dr. Mark L. Janzen said at the annual meeting of the Midwestern Vascular Surgical Society.

Patrice Wendling/Frontline Medical News

The analysis involved 14,353 patients, 65 years and older, who underwent lower-extremity revascularization in 2007 and 2008 and were identified from the Medicare Provider Analysis and Review files using ICD-9 codes. Of these, 5,697 had claudication (50%), 1,467 rest pain (10%), and 7,189 ulceration or gangrene (50%).

Overall amputation rates for patients started on clopidogrel right after the procedure were significantly lower than for nonusers at 30 days (10.34% vs. 14.1%), 90 days (14.1% vs. 18.7%), and 1 year (19.7% vs. 24.1%; all P values less than .0001), said Dr. Janzen of the University of Missouri Hospitals and Clinics, Columbia.

Among patients with ulceration or gangrene, limb loss was 21.2% and 26.6% with and without clopidogrel at 30 days, 28.5% and 34.8% at 90 days (P less than .0001), and 38.2% and 43.5% at 1 year.

Only 35.7% of patients with ulceration or gangrene were on post-procedure clopidogrel, compared with 37.4% with rest pain and 40.4% with claudication, according to National Drug Code Directory and Medicare Part D files. Combination therapy with aspirin and clopidogrel or other antiplatelet therapies was not evaluated.

Interestingly, clopidogrel did not significantly affect amputation rates in patients with claudication or rest pain, Dr. Janzen said.

Multivariate logistic regression analyses adjusted for patient demographics, comorbidities, and disease severity, confirmed that clopidogrel nonusers were more likely than users to undergo amputation at 30 days (odds ratio, 1.28), 90 days (OR, 1.29), and 1 year (OR, 1.16).

In the ulceration/gangrene subgroup, failure to use clopidogrel increased the odds of amputation (OR, 1.2) "to levels approaching renal failure (OR, 1.24) and diabetes (OR, 1.6), two known risk factors for below-the-knee amputation," he observed.

Cox regression analyses revealed a 20% higher hazard of death at 1 year among all patients for nonusers than for clopidogrel users (hazard ratio 1.2; P less than .0001).

During a discussion of the study, Dr. Sean Patrick Lyden of the Cleveland Clinic, questioned the impact of end-stage renal disease (ESRD) on the results, remarking that ESRD is probably the strongest predictor of limb loss in patients with ulceration or gangrene and that clopidogrel is typically not given to ESRD patients because the pharmacodynamics are unknown.

Dr. Janzen said it was a valid point, but that the study did not look specifically at ESRD.

This line of questioning was picked up by another attendee, who asked whether amputation rates were calculated for patients with ESRD and diabetes. Although the analysis did not look at outcomes for this lethal combination of comorbidities, Dr. Janzen said a prior study reported a 5-year amputation rate of about 27% in patients with peripheral vascular disease and diabetes (Diabetes Care 2003;26:491-4).

Dr. Iraklis Pipinos, professor of surgery at the University of Nebraska Medical Center in Omaha, commented that "This is a fantastic study and a tremendously important question."

He went on to ask whether the patients with ulceration or gangrene underwent additional lower extremity revascularization procedures, observing that the 1-year amputation rates were quite high in this subgroup.

Dr. Janzen said the study was not designed to determine rates of procedure repetition, although it was noted that overall clopidogrel users were less likely to convert to open bypass early in their post-procedure course.

Finally, the audience asked about the optimal duration of post-procedure clopidogrel, with one attendee observing that it’s not unusual for patients to discontinue clopidogrel 6 weeks after an endovascular revascularization procedure. Dr. Janzen said new cardiology trends recommend that patients with both bare metal and drug-eluting stents remain on clopidogrel for a full year after stent placement and that the optimal duration for patients undergoing endovascular lower limb revascularization is unknown and hopefully will be answered in properly powered randomized trials.

Dr. Janzen and his coauthors reported having no financial disclosures.

[email protected]

CHICAGO – Clopidogrel use after endovascular lower-extremity revascularization was significantly associated with 1-year freedom from amputation and survival, but only 38% of the Medicare population was on the drug post intervention in a large retrospective analysis.

Patients with the most severe peripheral vascular disease, ulceration, or gangrene benefited the most from post revascularization clopidogrel (Plavix), but were the least likely to be using the drug, Dr. Mark L. Janzen said at the annual meeting of the Midwestern Vascular Surgical Society.

Patrice Wendling/Frontline Medical News

The analysis involved 14,353 patients, 65 years and older, who underwent lower-extremity revascularization in 2007 and 2008 and were identified from the Medicare Provider Analysis and Review files using ICD-9 codes. Of these, 5,697 had claudication (50%), 1,467 rest pain (10%), and 7,189 ulceration or gangrene (50%).

Overall amputation rates for patients started on clopidogrel right after the procedure were significantly lower than for nonusers at 30 days (10.34% vs. 14.1%), 90 days (14.1% vs. 18.7%), and 1 year (19.7% vs. 24.1%; all P values less than .0001), said Dr. Janzen of the University of Missouri Hospitals and Clinics, Columbia.

Among patients with ulceration or gangrene, limb loss was 21.2% and 26.6% with and without clopidogrel at 30 days, 28.5% and 34.8% at 90 days (P less than .0001), and 38.2% and 43.5% at 1 year.

Only 35.7% of patients with ulceration or gangrene were on post-procedure clopidogrel, compared with 37.4% with rest pain and 40.4% with claudication, according to National Drug Code Directory and Medicare Part D files. Combination therapy with aspirin and clopidogrel or other antiplatelet therapies was not evaluated.

Interestingly, clopidogrel did not significantly affect amputation rates in patients with claudication or rest pain, Dr. Janzen said.

Multivariate logistic regression analyses adjusted for patient demographics, comorbidities, and disease severity, confirmed that clopidogrel nonusers were more likely than users to undergo amputation at 30 days (odds ratio, 1.28), 90 days (OR, 1.29), and 1 year (OR, 1.16).

In the ulceration/gangrene subgroup, failure to use clopidogrel increased the odds of amputation (OR, 1.2) "to levels approaching renal failure (OR, 1.24) and diabetes (OR, 1.6), two known risk factors for below-the-knee amputation," he observed.

Cox regression analyses revealed a 20% higher hazard of death at 1 year among all patients for nonusers than for clopidogrel users (hazard ratio 1.2; P less than .0001).

During a discussion of the study, Dr. Sean Patrick Lyden of the Cleveland Clinic, questioned the impact of end-stage renal disease (ESRD) on the results, remarking that ESRD is probably the strongest predictor of limb loss in patients with ulceration or gangrene and that clopidogrel is typically not given to ESRD patients because the pharmacodynamics are unknown.

Dr. Janzen said it was a valid point, but that the study did not look specifically at ESRD.

This line of questioning was picked up by another attendee, who asked whether amputation rates were calculated for patients with ESRD and diabetes. Although the analysis did not look at outcomes for this lethal combination of comorbidities, Dr. Janzen said a prior study reported a 5-year amputation rate of about 27% in patients with peripheral vascular disease and diabetes (Diabetes Care 2003;26:491-4).

Dr. Iraklis Pipinos, professor of surgery at the University of Nebraska Medical Center in Omaha, commented that "This is a fantastic study and a tremendously important question."

He went on to ask whether the patients with ulceration or gangrene underwent additional lower extremity revascularization procedures, observing that the 1-year amputation rates were quite high in this subgroup.

Dr. Janzen said the study was not designed to determine rates of procedure repetition, although it was noted that overall clopidogrel users were less likely to convert to open bypass early in their post-procedure course.

Finally, the audience asked about the optimal duration of post-procedure clopidogrel, with one attendee observing that it’s not unusual for patients to discontinue clopidogrel 6 weeks after an endovascular revascularization procedure. Dr. Janzen said new cardiology trends recommend that patients with both bare metal and drug-eluting stents remain on clopidogrel for a full year after stent placement and that the optimal duration for patients undergoing endovascular lower limb revascularization is unknown and hopefully will be answered in properly powered randomized trials.

Dr. Janzen and his coauthors reported having no financial disclosures.

[email protected]

CHICAGO – Clopidogrel use after endovascular lower-extremity revascularization was significantly associated with 1-year freedom from amputation and survival, but only 38% of the Medicare population was on the drug post intervention in a large retrospective analysis.

Patients with the most severe peripheral vascular disease, ulceration, or gangrene benefited the most from post revascularization clopidogrel (Plavix), but were the least likely to be using the drug, Dr. Mark L. Janzen said at the annual meeting of the Midwestern Vascular Surgical Society.

Patrice Wendling/Frontline Medical News

The analysis involved 14,353 patients, 65 years and older, who underwent lower-extremity revascularization in 2007 and 2008 and were identified from the Medicare Provider Analysis and Review files using ICD-9 codes. Of these, 5,697 had claudication (50%), 1,467 rest pain (10%), and 7,189 ulceration or gangrene (50%).

Overall amputation rates for patients started on clopidogrel right after the procedure were significantly lower than for nonusers at 30 days (10.34% vs. 14.1%), 90 days (14.1% vs. 18.7%), and 1 year (19.7% vs. 24.1%; all P values less than .0001), said Dr. Janzen of the University of Missouri Hospitals and Clinics, Columbia.

Among patients with ulceration or gangrene, limb loss was 21.2% and 26.6% with and without clopidogrel at 30 days, 28.5% and 34.8% at 90 days (P less than .0001), and 38.2% and 43.5% at 1 year.

Only 35.7% of patients with ulceration or gangrene were on post-procedure clopidogrel, compared with 37.4% with rest pain and 40.4% with claudication, according to National Drug Code Directory and Medicare Part D files. Combination therapy with aspirin and clopidogrel or other antiplatelet therapies was not evaluated.

Interestingly, clopidogrel did not significantly affect amputation rates in patients with claudication or rest pain, Dr. Janzen said.

Multivariate logistic regression analyses adjusted for patient demographics, comorbidities, and disease severity, confirmed that clopidogrel nonusers were more likely than users to undergo amputation at 30 days (odds ratio, 1.28), 90 days (OR, 1.29), and 1 year (OR, 1.16).

In the ulceration/gangrene subgroup, failure to use clopidogrel increased the odds of amputation (OR, 1.2) "to levels approaching renal failure (OR, 1.24) and diabetes (OR, 1.6), two known risk factors for below-the-knee amputation," he observed.

Cox regression analyses revealed a 20% higher hazard of death at 1 year among all patients for nonusers than for clopidogrel users (hazard ratio 1.2; P less than .0001).

During a discussion of the study, Dr. Sean Patrick Lyden of the Cleveland Clinic, questioned the impact of end-stage renal disease (ESRD) on the results, remarking that ESRD is probably the strongest predictor of limb loss in patients with ulceration or gangrene and that clopidogrel is typically not given to ESRD patients because the pharmacodynamics are unknown.

Dr. Janzen said it was a valid point, but that the study did not look specifically at ESRD.

This line of questioning was picked up by another attendee, who asked whether amputation rates were calculated for patients with ESRD and diabetes. Although the analysis did not look at outcomes for this lethal combination of comorbidities, Dr. Janzen said a prior study reported a 5-year amputation rate of about 27% in patients with peripheral vascular disease and diabetes (Diabetes Care 2003;26:491-4).

Dr. Iraklis Pipinos, professor of surgery at the University of Nebraska Medical Center in Omaha, commented that "This is a fantastic study and a tremendously important question."

He went on to ask whether the patients with ulceration or gangrene underwent additional lower extremity revascularization procedures, observing that the 1-year amputation rates were quite high in this subgroup.

Dr. Janzen said the study was not designed to determine rates of procedure repetition, although it was noted that overall clopidogrel users were less likely to convert to open bypass early in their post-procedure course.

Finally, the audience asked about the optimal duration of post-procedure clopidogrel, with one attendee observing that it’s not unusual for patients to discontinue clopidogrel 6 weeks after an endovascular revascularization procedure. Dr. Janzen said new cardiology trends recommend that patients with both bare metal and drug-eluting stents remain on clopidogrel for a full year after stent placement and that the optimal duration for patients undergoing endovascular lower limb revascularization is unknown and hopefully will be answered in properly powered randomized trials.

Dr. Janzen and his coauthors reported having no financial disclosures.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously to support the approval of the antibacterial drug dalbavancin for the treatment of acute bacterial skin and skin structure infections.

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 12-0 that dalbavancin (Dalvance), manufactured by Durata Therapeutics, is safe and effective for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Because of its long elimination half-life, the firm is proposing a dosing regimen of 1,000 mg on day 1 and 500 mg on day 8, administered intravenously.

Durata is seeking a proposed indication for the lipoglycopeptide antibacterial drug to treat adult patients with ABSSSI caused by the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius,and S. constellatus).

The firm’s phase III data was composed of five studies: one uncomplicated skin infection study comparing dalbavancin to cefazolin/cephalexin; two complicated skin infection studies (one comparing skin infection caused by MRSA, dalbavancin to vancomycin/cephalexin; one comparing dalbavancin to linezolid) and two ABSSSI studies (DUR001-301/-302) – both comparing dalbavancin to vancomycin/linezolid.

The DUR001-301 and DUR001-302 studies were identical in design; noninferiority, double-blind, double-dummy, randomized trials comparing two weekly doses of dalbavancin (on day 1 and day 8) to vancomycin IV with the option to switch to oral linezolid in patients with ABSSSI known or suspected to be caused by gram-positive bacteria. Treatment duration lasted 10-14 days.

The primary endpoints for DUR001-301/-302 were early response (defined as cessation of spread of the lesion and absence of fever) at 48-72 hours post initiation of therapy. The noninferiority margin was 10%.

Both studies showed dalbavancin to be noninferior to the regimen of vancomycin/linezolid. Since the lower bound of the 95% confidence interval for the treatment difference was above –10% (–4.6% in DUR001-301 and –7.4% in DUR001-302), both trials met their primary endpoints.

Both studies also met the key secondary endpoint, in which clinical response is defined as a greater than or equal to 20% reduction in lesion area from baseline (no fever component).

The FDA also analyzed the sensitivity studies of additional secondary efficacy outcome measures of clinical status at the end of treatment in the intent-to-treat and clinically evaluable populations. There were inconsistencies between the two trials, with lower success rates for dalbavancin vs. the comparator in DUR001-301 and slightly higher success rates for dalbavancin in DUR001-302.

"Overall, in these sensitivity analyses success rates at [end of treatment/short-term follow-up] tended to be less favorable in both treatment arms in both trials as stricter requirements were placed on the degree of erythema necessary to be evaluated as a success," the FDA wrote in its pre–committee executive summary.

The panel members concluded that the drug was generally both safe and effective, and welcomed it as another treatment option for patients.

"This just gives that clinician who is trying to personalize medicine more tools in their toolbox," said Dr. Alan Magill, a director on malaria policy at the Bill and Melinda Gates Foundation. "I think that’s a very important consideration going forward."

Additionally, panelists suggested that the drug labeling address the major safety finding of possible dalbavancin-associated liver injury, particularly in patients with liver disease.

"I have some issues with liver function tests," said Dr. Paul G. Auwaerter, clinical director of the division of infectious diseases at the Johns Hopkins University, Baltimore. "The labeling might consider something such as preexisting liver disease, or if liver function tests are rising during the hospitalization, there could be consideration whether the second drug administration should be given."

Dr. James M. Steckelberg, professor of medicine in the Mayo Clinic’s division of infectious diseases, Rochester, Minn., noted, "If you’re going to give the second dose on day 8, I’d particularly want to check those [liver function] levels before you do that dose, and probably have the result back, rather than do that later. I would give some thought to that, especially in the labeling, about what should be done about safety monitoring for a drug that’s dosed totally differently from anything we’re doing now."

Furthermore, panelists advised the FDA and the sponsor to develop additional postmarket studies.

"I recommend that the agency work closely with the sponsor to develop some cogent and clear guidelines for follow-up and monitoring for safety before clinicians are using this drug. It’s going to be used a lot, probably in the outpatient setting, and the whole paradigm is very different from what’s currently done," Dr. Steckelberg said.

Dr. Magill also recommended that a postmarket study address pediatric patient populations.

"There are several unanswered questions about other patient populations, like pediatrics, and potential for other indications. I think what happens next is very important, whether it’s a postmarketing surveillance of some kind, required phase IV studies, or the sponsor seeking new indications with new data and a new trial," Dr. Magill said. "I’d be looking forward to see how that evolves."

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously to support the approval of the antibacterial drug dalbavancin for the treatment of acute bacterial skin and skin structure infections.

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 12-0 that dalbavancin (Dalvance), manufactured by Durata Therapeutics, is safe and effective for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Because of its long elimination half-life, the firm is proposing a dosing regimen of 1,000 mg on day 1 and 500 mg on day 8, administered intravenously.

Durata is seeking a proposed indication for the lipoglycopeptide antibacterial drug to treat adult patients with ABSSSI caused by the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius,and S. constellatus).

The firm’s phase III data was composed of five studies: one uncomplicated skin infection study comparing dalbavancin to cefazolin/cephalexin; two complicated skin infection studies (one comparing skin infection caused by MRSA, dalbavancin to vancomycin/cephalexin; one comparing dalbavancin to linezolid) and two ABSSSI studies (DUR001-301/-302) – both comparing dalbavancin to vancomycin/linezolid.

The DUR001-301 and DUR001-302 studies were identical in design; noninferiority, double-blind, double-dummy, randomized trials comparing two weekly doses of dalbavancin (on day 1 and day 8) to vancomycin IV with the option to switch to oral linezolid in patients with ABSSSI known or suspected to be caused by gram-positive bacteria. Treatment duration lasted 10-14 days.

The primary endpoints for DUR001-301/-302 were early response (defined as cessation of spread of the lesion and absence of fever) at 48-72 hours post initiation of therapy. The noninferiority margin was 10%.

Both studies showed dalbavancin to be noninferior to the regimen of vancomycin/linezolid. Since the lower bound of the 95% confidence interval for the treatment difference was above –10% (–4.6% in DUR001-301 and –7.4% in DUR001-302), both trials met their primary endpoints.

Both studies also met the key secondary endpoint, in which clinical response is defined as a greater than or equal to 20% reduction in lesion area from baseline (no fever component).

The FDA also analyzed the sensitivity studies of additional secondary efficacy outcome measures of clinical status at the end of treatment in the intent-to-treat and clinically evaluable populations. There were inconsistencies between the two trials, with lower success rates for dalbavancin vs. the comparator in DUR001-301 and slightly higher success rates for dalbavancin in DUR001-302.

"Overall, in these sensitivity analyses success rates at [end of treatment/short-term follow-up] tended to be less favorable in both treatment arms in both trials as stricter requirements were placed on the degree of erythema necessary to be evaluated as a success," the FDA wrote in its pre–committee executive summary.

The panel members concluded that the drug was generally both safe and effective, and welcomed it as another treatment option for patients.

"This just gives that clinician who is trying to personalize medicine more tools in their toolbox," said Dr. Alan Magill, a director on malaria policy at the Bill and Melinda Gates Foundation. "I think that’s a very important consideration going forward."

Additionally, panelists suggested that the drug labeling address the major safety finding of possible dalbavancin-associated liver injury, particularly in patients with liver disease.

"I have some issues with liver function tests," said Dr. Paul G. Auwaerter, clinical director of the division of infectious diseases at the Johns Hopkins University, Baltimore. "The labeling might consider something such as preexisting liver disease, or if liver function tests are rising during the hospitalization, there could be consideration whether the second drug administration should be given."

Dr. James M. Steckelberg, professor of medicine in the Mayo Clinic’s division of infectious diseases, Rochester, Minn., noted, "If you’re going to give the second dose on day 8, I’d particularly want to check those [liver function] levels before you do that dose, and probably have the result back, rather than do that later. I would give some thought to that, especially in the labeling, about what should be done about safety monitoring for a drug that’s dosed totally differently from anything we’re doing now."

Furthermore, panelists advised the FDA and the sponsor to develop additional postmarket studies.

"I recommend that the agency work closely with the sponsor to develop some cogent and clear guidelines for follow-up and monitoring for safety before clinicians are using this drug. It’s going to be used a lot, probably in the outpatient setting, and the whole paradigm is very different from what’s currently done," Dr. Steckelberg said.

Dr. Magill also recommended that a postmarket study address pediatric patient populations.

"There are several unanswered questions about other patient populations, like pediatrics, and potential for other indications. I think what happens next is very important, whether it’s a postmarketing surveillance of some kind, required phase IV studies, or the sponsor seeking new indications with new data and a new trial," Dr. Magill said. "I’d be looking forward to see how that evolves."

SILVER SPRING, MD. – A Food and Drug Administration advisory committee voted unanimously to support the approval of the antibacterial drug dalbavancin for the treatment of acute bacterial skin and skin structure infections.

At a March 31 meeting, the FDA Anti-Infective Drugs Advisory Committee voted 12-0 that dalbavancin (Dalvance), manufactured by Durata Therapeutics, is safe and effective for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Because of its long elimination half-life, the firm is proposing a dosing regimen of 1,000 mg on day 1 and 500 mg on day 8, administered intravenously.

Durata is seeking a proposed indication for the lipoglycopeptide antibacterial drug to treat adult patients with ABSSSI caused by the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-resistant isolates [MRSA]), Streptococcus pyogenes, Streptococcus agalactiae, and the Streptococcus anginosus group (including S. anginosus, S. intermedius,and S. constellatus).

The firm’s phase III data was composed of five studies: one uncomplicated skin infection study comparing dalbavancin to cefazolin/cephalexin; two complicated skin infection studies (one comparing skin infection caused by MRSA, dalbavancin to vancomycin/cephalexin; one comparing dalbavancin to linezolid) and two ABSSSI studies (DUR001-301/-302) – both comparing dalbavancin to vancomycin/linezolid.

The DUR001-301 and DUR001-302 studies were identical in design; noninferiority, double-blind, double-dummy, randomized trials comparing two weekly doses of dalbavancin (on day 1 and day 8) to vancomycin IV with the option to switch to oral linezolid in patients with ABSSSI known or suspected to be caused by gram-positive bacteria. Treatment duration lasted 10-14 days.

The primary endpoints for DUR001-301/-302 were early response (defined as cessation of spread of the lesion and absence of fever) at 48-72 hours post initiation of therapy. The noninferiority margin was 10%.

Both studies showed dalbavancin to be noninferior to the regimen of vancomycin/linezolid. Since the lower bound of the 95% confidence interval for the treatment difference was above –10% (–4.6% in DUR001-301 and –7.4% in DUR001-302), both trials met their primary endpoints.

Both studies also met the key secondary endpoint, in which clinical response is defined as a greater than or equal to 20% reduction in lesion area from baseline (no fever component).

The FDA also analyzed the sensitivity studies of additional secondary efficacy outcome measures of clinical status at the end of treatment in the intent-to-treat and clinically evaluable populations. There were inconsistencies between the two trials, with lower success rates for dalbavancin vs. the comparator in DUR001-301 and slightly higher success rates for dalbavancin in DUR001-302.

"Overall, in these sensitivity analyses success rates at [end of treatment/short-term follow-up] tended to be less favorable in both treatment arms in both trials as stricter requirements were placed on the degree of erythema necessary to be evaluated as a success," the FDA wrote in its pre–committee executive summary.

The panel members concluded that the drug was generally both safe and effective, and welcomed it as another treatment option for patients.

"This just gives that clinician who is trying to personalize medicine more tools in their toolbox," said Dr. Alan Magill, a director on malaria policy at the Bill and Melinda Gates Foundation. "I think that’s a very important consideration going forward."

Additionally, panelists suggested that the drug labeling address the major safety finding of possible dalbavancin-associated liver injury, particularly in patients with liver disease.

"I have some issues with liver function tests," said Dr. Paul G. Auwaerter, clinical director of the division of infectious diseases at the Johns Hopkins University, Baltimore. "The labeling might consider something such as preexisting liver disease, or if liver function tests are rising during the hospitalization, there could be consideration whether the second drug administration should be given."

Dr. James M. Steckelberg, professor of medicine in the Mayo Clinic’s division of infectious diseases, Rochester, Minn., noted, "If you’re going to give the second dose on day 8, I’d particularly want to check those [liver function] levels before you do that dose, and probably have the result back, rather than do that later. I would give some thought to that, especially in the labeling, about what should be done about safety monitoring for a drug that’s dosed totally differently from anything we’re doing now."

Furthermore, panelists advised the FDA and the sponsor to develop additional postmarket studies.

"I recommend that the agency work closely with the sponsor to develop some cogent and clear guidelines for follow-up and monitoring for safety before clinicians are using this drug. It’s going to be used a lot, probably in the outpatient setting, and the whole paradigm is very different from what’s currently done," Dr. Steckelberg said.

Dr. Magill also recommended that a postmarket study address pediatric patient populations.

"There are several unanswered questions about other patient populations, like pediatrics, and potential for other indications. I think what happens next is very important, whether it’s a postmarketing surveillance of some kind, required phase IV studies, or the sponsor seeking new indications with new data and a new trial," Dr. Magill said. "I’d be looking forward to see how that evolves."

A DNA methylation marker panel from urine sediments was superior to gold standard tests for predicting recurrence of bladder cancer, investigators reported April 1 in Clinical Cancer Research.

Eighty percent of patients with positive scores on the three-marker panel developed recurrent, biopsy-proven urothelial carcinoma after complete resection of the visible primary tumor (95% confidence interval, 62%-98%), reported Dr. Sheng-Fang Su of University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and his associates.

The panel’s positive predictive value far exceeded the values for cytology (35%; 95% CI, 14%-56%) and cytoscopy (15%; 95% CI, 0-31%), the investigators reported (Clin. Cancer Res. 2014 [doi:10.1158/1078-0432.CCR-13-2637]).

©Sebastian Kaulitzki/thinkstockphotos.com

The prospective study enrolled 90 patients who had undergone transurethral resection of noninvasive urothelial carcinomas (Tis, Ta, T1; grade low high). Median age of patients was 69 years (range, 41-96). Patients with high-grade Ta/T1 tumors had received intravesical Bacillus Calmette-Guerin vaccine or mitomycin C at their physicians’ discretion.

The investigators performed cytology and extracted DNA from 368 urine and bladder wash specimens collected from patients over a seven-year period. Patients also underwent cytoscopy. The investigators used logistic regression to assess the sensitivity and specificity of various combinations of DNA methylation markers.

The optimal panel included a tumor-specific hypermethylated marker (SOX1), an epigenetic marker (IRAK3), and a field defect-associated hypomethylated marker (L1-MET), the researchers said. The panel’s sensitivity was 80% (95% CI, 60%-96%) and specificity was 97% (95% CI, 91%-100%), they reported. The negative predictive value of the panel (74%) resembled that of cytoscopy (80%) and cytology (76%), they said.

Dr. Su and his associates noted that previous marker tests were more sensitive than cytology, including the FDA-approved NMP-22, ImmunoCyst, and UroVysion tests. But these are expensive, labor-intensive, less specific, and benign urinary conditions can compromise their reliability, they added.

A panel like the one used in the study could help clinicians determine the appropriate frequency of follow-up cytology after bladder cancer resection, the investigators said. But they noted that the validation sets were not ideal and that the urine markers should be further explored in a larger, independent cohort.

The National Cancer Institute funded the research. One of the researchers, Dr. Jones, reported having been a consultant and advisory board member of Astex, Lilly, and Zymo. The other authors reported no conflicts of interest.

A DNA methylation marker panel from urine sediments was superior to gold standard tests for predicting recurrence of bladder cancer, investigators reported April 1 in Clinical Cancer Research.

Eighty percent of patients with positive scores on the three-marker panel developed recurrent, biopsy-proven urothelial carcinoma after complete resection of the visible primary tumor (95% confidence interval, 62%-98%), reported Dr. Sheng-Fang Su of University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and his associates.

The panel’s positive predictive value far exceeded the values for cytology (35%; 95% CI, 14%-56%) and cytoscopy (15%; 95% CI, 0-31%), the investigators reported (Clin. Cancer Res. 2014 [doi:10.1158/1078-0432.CCR-13-2637]).

©Sebastian Kaulitzki/thinkstockphotos.com

The prospective study enrolled 90 patients who had undergone transurethral resection of noninvasive urothelial carcinomas (Tis, Ta, T1; grade low high). Median age of patients was 69 years (range, 41-96). Patients with high-grade Ta/T1 tumors had received intravesical Bacillus Calmette-Guerin vaccine or mitomycin C at their physicians’ discretion.

The investigators performed cytology and extracted DNA from 368 urine and bladder wash specimens collected from patients over a seven-year period. Patients also underwent cytoscopy. The investigators used logistic regression to assess the sensitivity and specificity of various combinations of DNA methylation markers.

The optimal panel included a tumor-specific hypermethylated marker (SOX1), an epigenetic marker (IRAK3), and a field defect-associated hypomethylated marker (L1-MET), the researchers said. The panel’s sensitivity was 80% (95% CI, 60%-96%) and specificity was 97% (95% CI, 91%-100%), they reported. The negative predictive value of the panel (74%) resembled that of cytoscopy (80%) and cytology (76%), they said.

Dr. Su and his associates noted that previous marker tests were more sensitive than cytology, including the FDA-approved NMP-22, ImmunoCyst, and UroVysion tests. But these are expensive, labor-intensive, less specific, and benign urinary conditions can compromise their reliability, they added.

A panel like the one used in the study could help clinicians determine the appropriate frequency of follow-up cytology after bladder cancer resection, the investigators said. But they noted that the validation sets were not ideal and that the urine markers should be further explored in a larger, independent cohort.

The National Cancer Institute funded the research. One of the researchers, Dr. Jones, reported having been a consultant and advisory board member of Astex, Lilly, and Zymo. The other authors reported no conflicts of interest.

A DNA methylation marker panel from urine sediments was superior to gold standard tests for predicting recurrence of bladder cancer, investigators reported April 1 in Clinical Cancer Research.

Eighty percent of patients with positive scores on the three-marker panel developed recurrent, biopsy-proven urothelial carcinoma after complete resection of the visible primary tumor (95% confidence interval, 62%-98%), reported Dr. Sheng-Fang Su of University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and his associates.

The panel’s positive predictive value far exceeded the values for cytology (35%; 95% CI, 14%-56%) and cytoscopy (15%; 95% CI, 0-31%), the investigators reported (Clin. Cancer Res. 2014 [doi:10.1158/1078-0432.CCR-13-2637]).

©Sebastian Kaulitzki/thinkstockphotos.com

The prospective study enrolled 90 patients who had undergone transurethral resection of noninvasive urothelial carcinomas (Tis, Ta, T1; grade low high). Median age of patients was 69 years (range, 41-96). Patients with high-grade Ta/T1 tumors had received intravesical Bacillus Calmette-Guerin vaccine or mitomycin C at their physicians’ discretion.

The investigators performed cytology and extracted DNA from 368 urine and bladder wash specimens collected from patients over a seven-year period. Patients also underwent cytoscopy. The investigators used logistic regression to assess the sensitivity and specificity of various combinations of DNA methylation markers.

The optimal panel included a tumor-specific hypermethylated marker (SOX1), an epigenetic marker (IRAK3), and a field defect-associated hypomethylated marker (L1-MET), the researchers said. The panel’s sensitivity was 80% (95% CI, 60%-96%) and specificity was 97% (95% CI, 91%-100%), they reported. The negative predictive value of the panel (74%) resembled that of cytoscopy (80%) and cytology (76%), they said.

Dr. Su and his associates noted that previous marker tests were more sensitive than cytology, including the FDA-approved NMP-22, ImmunoCyst, and UroVysion tests. But these are expensive, labor-intensive, less specific, and benign urinary conditions can compromise their reliability, they added.

A panel like the one used in the study could help clinicians determine the appropriate frequency of follow-up cytology after bladder cancer resection, the investigators said. But they noted that the validation sets were not ideal and that the urine markers should be further explored in a larger, independent cohort.

The National Cancer Institute funded the research. One of the researchers, Dr. Jones, reported having been a consultant and advisory board member of Astex, Lilly, and Zymo. The other authors reported no conflicts of interest.

In a last-minute move, Congress averted a scheduled 24% cut to Medicare physician fees slated to start on April 1, while simultaneously delaying the move to the ICD-10 coding sets.

On March 31, the Senate voted 64 to 35 to approve H.R. 4302, a bill that replaces the scheduled cut called for by the Medicare Sustainable Growth Rate formula with a 0.5% fee increase through the end of 2014 and a pay freeze from Jan. 1, 2015 through March 15, 2015. The bill also bars the Health and Human Services (HHS) department from implementing ICD-10 until Oct. 1, 2015.

Alicia Ault/Frontline Medical News

The House passed the same legislation on March 27. It now heads to the White House for President Obama’s signature.

At first glance, the bill looks like good news for physicians, who will get relief from both a hefty Medicare fee cut and a costly new regulatory requirement. But many physician organizations, led by the American Medical Association, have campaigned against the temporary patch, saying that it essentially stops the work to permanently repeal the SGR.

"It appears that an unprecedented, bipartisan agreement on Medicare reform is on the verge of being cast aside because elected leaders are unwilling to make tough choices to strengthen programs serving 50 million Americans," the AMA and more than 50 other medical societies wrote to congressional leaders before the House vote.

Several physician groups had endorsed a bipartisan legislative package that would have eliminated the SGR and replaced it with a combination of small fee increases and delivery system reforms. The hurdle to passing the legislation was finding a way to pay for it that would appeal to both Democrats and Republicans.

Recently, the House passed H.R. 4015, which would have funded the permanent SGR repeal package with a 5-year delay of the Affordable Care Act’s individual insurance mandate. But that bill is unlikely to be considered in the Democratic-controlled Senate. And an attempt by Sen. Ron Wyden (D.-Ore.) to move the permanent SGR repeal forward and pay for it using the savings from the end of the wars in Iraq and Afghanistan failed to gain enough votes in the Senate.

Before the March 31 vote, Sen. Wyden chided fellow lawmakers for continuing to pass temporary fixes to the SGR problem rather than replacing it and moving to a payment system that incentivizes quality improvement. "It can’t be ducked much longer," he said.

But Sen. Orrin Hatch (R.-Utah), who worked on the bipartisan bill to replace the SGR, said he objects to the funding mechanism that Sen. Wyden proposed. He said the 12-month SGR patch will give lawmakers more time to agree on how to pay for a permanent fix. "I’m not going to make the perfect the enemy of the good," he said on the Senate floor.

[email protected]

On Twitter @maryellenny

In a last-minute move, Congress averted a scheduled 24% cut to Medicare physician fees slated to start on April 1, while simultaneously delaying the move to the ICD-10 coding sets.

On March 31, the Senate voted 64 to 35 to approve H.R. 4302, a bill that replaces the scheduled cut called for by the Medicare Sustainable Growth Rate formula with a 0.5% fee increase through the end of 2014 and a pay freeze from Jan. 1, 2015 through March 15, 2015. The bill also bars the Health and Human Services (HHS) department from implementing ICD-10 until Oct. 1, 2015.

Alicia Ault/Frontline Medical News

The House passed the same legislation on March 27. It now heads to the White House for President Obama’s signature.

At first glance, the bill looks like good news for physicians, who will get relief from both a hefty Medicare fee cut and a costly new regulatory requirement. But many physician organizations, led by the American Medical Association, have campaigned against the temporary patch, saying that it essentially stops the work to permanently repeal the SGR.

"It appears that an unprecedented, bipartisan agreement on Medicare reform is on the verge of being cast aside because elected leaders are unwilling to make tough choices to strengthen programs serving 50 million Americans," the AMA and more than 50 other medical societies wrote to congressional leaders before the House vote.

Several physician groups had endorsed a bipartisan legislative package that would have eliminated the SGR and replaced it with a combination of small fee increases and delivery system reforms. The hurdle to passing the legislation was finding a way to pay for it that would appeal to both Democrats and Republicans.

Recently, the House passed H.R. 4015, which would have funded the permanent SGR repeal package with a 5-year delay of the Affordable Care Act’s individual insurance mandate. But that bill is unlikely to be considered in the Democratic-controlled Senate. And an attempt by Sen. Ron Wyden (D.-Ore.) to move the permanent SGR repeal forward and pay for it using the savings from the end of the wars in Iraq and Afghanistan failed to gain enough votes in the Senate.

Before the March 31 vote, Sen. Wyden chided fellow lawmakers for continuing to pass temporary fixes to the SGR problem rather than replacing it and moving to a payment system that incentivizes quality improvement. "It can’t be ducked much longer," he said.

But Sen. Orrin Hatch (R.-Utah), who worked on the bipartisan bill to replace the SGR, said he objects to the funding mechanism that Sen. Wyden proposed. He said the 12-month SGR patch will give lawmakers more time to agree on how to pay for a permanent fix. "I’m not going to make the perfect the enemy of the good," he said on the Senate floor.

[email protected]

On Twitter @maryellenny

In a last-minute move, Congress averted a scheduled 24% cut to Medicare physician fees slated to start on April 1, while simultaneously delaying the move to the ICD-10 coding sets.

On March 31, the Senate voted 64 to 35 to approve H.R. 4302, a bill that replaces the scheduled cut called for by the Medicare Sustainable Growth Rate formula with a 0.5% fee increase through the end of 2014 and a pay freeze from Jan. 1, 2015 through March 15, 2015. The bill also bars the Health and Human Services (HHS) department from implementing ICD-10 until Oct. 1, 2015.

Alicia Ault/Frontline Medical News

The House passed the same legislation on March 27. It now heads to the White House for President Obama’s signature.

At first glance, the bill looks like good news for physicians, who will get relief from both a hefty Medicare fee cut and a costly new regulatory requirement. But many physician organizations, led by the American Medical Association, have campaigned against the temporary patch, saying that it essentially stops the work to permanently repeal the SGR.

"It appears that an unprecedented, bipartisan agreement on Medicare reform is on the verge of being cast aside because elected leaders are unwilling to make tough choices to strengthen programs serving 50 million Americans," the AMA and more than 50 other medical societies wrote to congressional leaders before the House vote.

Several physician groups had endorsed a bipartisan legislative package that would have eliminated the SGR and replaced it with a combination of small fee increases and delivery system reforms. The hurdle to passing the legislation was finding a way to pay for it that would appeal to both Democrats and Republicans.

Recently, the House passed H.R. 4015, which would have funded the permanent SGR repeal package with a 5-year delay of the Affordable Care Act’s individual insurance mandate. But that bill is unlikely to be considered in the Democratic-controlled Senate. And an attempt by Sen. Ron Wyden (D.-Ore.) to move the permanent SGR repeal forward and pay for it using the savings from the end of the wars in Iraq and Afghanistan failed to gain enough votes in the Senate.

Before the March 31 vote, Sen. Wyden chided fellow lawmakers for continuing to pass temporary fixes to the SGR problem rather than replacing it and moving to a payment system that incentivizes quality improvement. "It can’t be ducked much longer," he said.

But Sen. Orrin Hatch (R.-Utah), who worked on the bipartisan bill to replace the SGR, said he objects to the funding mechanism that Sen. Wyden proposed. He said the 12-month SGR patch will give lawmakers more time to agree on how to pay for a permanent fix. "I’m not going to make the perfect the enemy of the good," he said on the Senate floor.

[email protected]

On Twitter @maryellenny

LAS VEGAS – Lengths of hospital stay were nearly halved in elderly hip fracture patients started on enteral nutrition within 24 hours of surgery, according to a retrospective cohort study of 100 sequential hip fracture patients at Salem (Ore.) Hospital.

The 89 patients fed by nasogastric tube within 24 hours stayed in the hospital an average of 4.43 days. The 11 fed an average of 4.36 days later stayed an average of 7.80 days.

The risk of hospital stays 5 days or longer quadrupled when enteral nutrition was delayed (RR, 4.14). Two patients (18%) died in the delayed-feeding group; eight (9%) died in the early-feeding group.

The average age in the study was 83 years old. Patients who went for more than a day without being fed – the range was 2-7 days – were a bit older with an average age of 86 years, "meaning that they were unlikely to have much in the way of reserves and were very likely to have some malnutrition at baseline," said Dr. Cynthia Wallace, medical director of Vibra Specialty Hospital in Portland, Ore., as well as a palliative care consultant at Salem Hospital.

"Association doesn’t prove causality," she said. It’s possible that those who went longer without nutrition were sicker and more confused.

Alex Otto/Frontline Medical News

Even so, "the correlation was pretty compelling." The findings argue strongly for early nutrition "whether or not it’s known absolutely" that it improves outcomes. Nutrition is essential for recovery: "If you are going to treat a patient aggressively, you need to give them nutrition. It’s just the right thing to do." It may also save a lot of money. A day in the hospital costs more than $4,000, while feedings cost about $35 a day, Dr. Wallace said at the Society of Hospital Medicine annual meeting.

"Given an ALOS [average length of stay] of 7 days without intervention, an early 3-day trial of enteral nutrition could save the hospital between $2,939 and $12,065 for an ALOS reduction of 1-4 days, respectively," she reported in the accompanying abstract. "Assuming a utility of 100%, the cost per outpatient day gained for the patient varies from $25 to $100 for a range of 4 to 1 days gained. If early enteral nutrition is responsible for the reduction in ALOS, less than 10% of 1 cent is spent to garner $1 in reduced inpatient costs."

Days go by

It’s not uncommon for elderly patients to go days without being fed. One of the reasons, Dr. Wallace said, is because there’s been an overextrapolation from studies showing that percutaneous gastrostomy tubes don’t improve quality of life or survival in end-stage dementia.

Those findings "have unintentionally influenced use of temporary feeding tubes in patients with acute issues who are otherwise receiving full medical treatment" and have resulted "in inappropriate withholding of enteral nutrition" in the elderly, she said.

"We’ve morphed the data into saying, ‘Oh, if I’ve got a patient who has some underlying dementia, I shouldn’t give them tube feeds. But the data about not doing [gastrostomy] tubes in advanced dementia has to do with people who are not undergoing acute medical treatment. That’s a very different situation from hip fractures and other acute problems in the elderly. Unfortunately, the evidence for one situation has been transposed onto a different situation, so a lot of hospitalists hesitate to initiate tube feeds," she said.

In patients who waited more than a day to get fed, "there was a lag time to even getting a nutrition consult. Nobody really quite noticed that they weren’t getting nutrition." That’s consistent "with what I’ve seen throughout my hospitalist career, and not just in hip fractures. As hospitalist doctors, we get very worked up about the medical issues, and we simply don’t attend to nutrition. We sometimes think somebody else is taking care of it," she said.

"The ages were [statistically] the same between the two groups, and there was a pretty [even] distribution of comorbidities," she noted.

Dr. Wallace said she had no relevant financial disclosures. The work received no outside funding.

[email protected]

LAS VEGAS – Lengths of hospital stay were nearly halved in elderly hip fracture patients started on enteral nutrition within 24 hours of surgery, according to a retrospective cohort study of 100 sequential hip fracture patients at Salem (Ore.) Hospital.

The 89 patients fed by nasogastric tube within 24 hours stayed in the hospital an average of 4.43 days. The 11 fed an average of 4.36 days later stayed an average of 7.80 days.

The risk of hospital stays 5 days or longer quadrupled when enteral nutrition was delayed (RR, 4.14). Two patients (18%) died in the delayed-feeding group; eight (9%) died in the early-feeding group.

The average age in the study was 83 years old. Patients who went for more than a day without being fed – the range was 2-7 days – were a bit older with an average age of 86 years, "meaning that they were unlikely to have much in the way of reserves and were very likely to have some malnutrition at baseline," said Dr. Cynthia Wallace, medical director of Vibra Specialty Hospital in Portland, Ore., as well as a palliative care consultant at Salem Hospital.

"Association doesn’t prove causality," she said. It’s possible that those who went longer without nutrition were sicker and more confused.

Alex Otto/Frontline Medical News

Even so, "the correlation was pretty compelling." The findings argue strongly for early nutrition "whether or not it’s known absolutely" that it improves outcomes. Nutrition is essential for recovery: "If you are going to treat a patient aggressively, you need to give them nutrition. It’s just the right thing to do." It may also save a lot of money. A day in the hospital costs more than $4,000, while feedings cost about $35 a day, Dr. Wallace said at the Society of Hospital Medicine annual meeting.

"Given an ALOS [average length of stay] of 7 days without intervention, an early 3-day trial of enteral nutrition could save the hospital between $2,939 and $12,065 for an ALOS reduction of 1-4 days, respectively," she reported in the accompanying abstract. "Assuming a utility of 100%, the cost per outpatient day gained for the patient varies from $25 to $100 for a range of 4 to 1 days gained. If early enteral nutrition is responsible for the reduction in ALOS, less than 10% of 1 cent is spent to garner $1 in reduced inpatient costs."

Days go by

It’s not uncommon for elderly patients to go days without being fed. One of the reasons, Dr. Wallace said, is because there’s been an overextrapolation from studies showing that percutaneous gastrostomy tubes don’t improve quality of life or survival in end-stage dementia.

Those findings "have unintentionally influenced use of temporary feeding tubes in patients with acute issues who are otherwise receiving full medical treatment" and have resulted "in inappropriate withholding of enteral nutrition" in the elderly, she said.

"We’ve morphed the data into saying, ‘Oh, if I’ve got a patient who has some underlying dementia, I shouldn’t give them tube feeds. But the data about not doing [gastrostomy] tubes in advanced dementia has to do with people who are not undergoing acute medical treatment. That’s a very different situation from hip fractures and other acute problems in the elderly. Unfortunately, the evidence for one situation has been transposed onto a different situation, so a lot of hospitalists hesitate to initiate tube feeds," she said.

In patients who waited more than a day to get fed, "there was a lag time to even getting a nutrition consult. Nobody really quite noticed that they weren’t getting nutrition." That’s consistent "with what I’ve seen throughout my hospitalist career, and not just in hip fractures. As hospitalist doctors, we get very worked up about the medical issues, and we simply don’t attend to nutrition. We sometimes think somebody else is taking care of it," she said.

"The ages were [statistically] the same between the two groups, and there was a pretty [even] distribution of comorbidities," she noted.

Dr. Wallace said she had no relevant financial disclosures. The work received no outside funding.

[email protected]

LAS VEGAS – Lengths of hospital stay were nearly halved in elderly hip fracture patients started on enteral nutrition within 24 hours of surgery, according to a retrospective cohort study of 100 sequential hip fracture patients at Salem (Ore.) Hospital.

The 89 patients fed by nasogastric tube within 24 hours stayed in the hospital an average of 4.43 days. The 11 fed an average of 4.36 days later stayed an average of 7.80 days.

The risk of hospital stays 5 days or longer quadrupled when enteral nutrition was delayed (RR, 4.14). Two patients (18%) died in the delayed-feeding group; eight (9%) died in the early-feeding group.

The average age in the study was 83 years old. Patients who went for more than a day without being fed – the range was 2-7 days – were a bit older with an average age of 86 years, "meaning that they were unlikely to have much in the way of reserves and were very likely to have some malnutrition at baseline," said Dr. Cynthia Wallace, medical director of Vibra Specialty Hospital in Portland, Ore., as well as a palliative care consultant at Salem Hospital.

"Association doesn’t prove causality," she said. It’s possible that those who went longer without nutrition were sicker and more confused.

Alex Otto/Frontline Medical News

Even so, "the correlation was pretty compelling." The findings argue strongly for early nutrition "whether or not it’s known absolutely" that it improves outcomes. Nutrition is essential for recovery: "If you are going to treat a patient aggressively, you need to give them nutrition. It’s just the right thing to do." It may also save a lot of money. A day in the hospital costs more than $4,000, while feedings cost about $35 a day, Dr. Wallace said at the Society of Hospital Medicine annual meeting.

"Given an ALOS [average length of stay] of 7 days without intervention, an early 3-day trial of enteral nutrition could save the hospital between $2,939 and $12,065 for an ALOS reduction of 1-4 days, respectively," she reported in the accompanying abstract. "Assuming a utility of 100%, the cost per outpatient day gained for the patient varies from $25 to $100 for a range of 4 to 1 days gained. If early enteral nutrition is responsible for the reduction in ALOS, less than 10% of 1 cent is spent to garner $1 in reduced inpatient costs."

Days go by

It’s not uncommon for elderly patients to go days without being fed. One of the reasons, Dr. Wallace said, is because there’s been an overextrapolation from studies showing that percutaneous gastrostomy tubes don’t improve quality of life or survival in end-stage dementia.

Those findings "have unintentionally influenced use of temporary feeding tubes in patients with acute issues who are otherwise receiving full medical treatment" and have resulted "in inappropriate withholding of enteral nutrition" in the elderly, she said.

"We’ve morphed the data into saying, ‘Oh, if I’ve got a patient who has some underlying dementia, I shouldn’t give them tube feeds. But the data about not doing [gastrostomy] tubes in advanced dementia has to do with people who are not undergoing acute medical treatment. That’s a very different situation from hip fractures and other acute problems in the elderly. Unfortunately, the evidence for one situation has been transposed onto a different situation, so a lot of hospitalists hesitate to initiate tube feeds," she said.

In patients who waited more than a day to get fed, "there was a lag time to even getting a nutrition consult. Nobody really quite noticed that they weren’t getting nutrition." That’s consistent "with what I’ve seen throughout my hospitalist career, and not just in hip fractures. As hospitalist doctors, we get very worked up about the medical issues, and we simply don’t attend to nutrition. We sometimes think somebody else is taking care of it," she said.

"The ages were [statistically] the same between the two groups, and there was a pretty [even] distribution of comorbidities," she noted.

Dr. Wallace said she had no relevant financial disclosures. The work received no outside funding.

[email protected]

Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.

Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.

The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).

© Darren Hester/Fotolia.com

MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.

Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha₂ adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.

The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.

A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.

The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.

The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.

Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.

These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.

Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).

These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.

POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.

Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.

Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.

The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.

Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.

Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.

The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).

© Darren Hester/Fotolia.com

MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.

Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha₂ adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.

The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.

A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.

The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.

The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.

Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.

These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.

Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).

These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.

POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.

Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.

Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.

The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.

Neither perioperative aspirin therapy nor perioperative clonidine prevented death or MI in patients undergoing noncardiac surgery who were at risk for major vascular complications, according to data reported at the annual meeting of the American College of Cardiology.

Far from being protective, both preventive strategies exerted harmful effects: Aspirin raised the risk of major bleeding, and clonidine increased the risks of clinically important hypotension, bradycardia, and nonfatal MI, said Dr. P. J. Devereaux of the Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton (Ont.) General Hospital, and his associates in the POISE-2 (Perioperative Ischemic Evaluation 2) clinical trial.

The POISE-2 findings were simultaneously reported online in the New England Journal of Medicine 2014 March 31 [doi:10/1056.
NEJMoa1401105] and [doi:10/1056.
NEJMoa1401106]).

© Darren Hester/Fotolia.com

MI is the most common major vascular complication related to noncardiac surgery, and perioperative aspirin is thought to prevent it by inhibiting thrombus formation. At present, one-third of patients at risk for vascular complications receive perioperative aspirin even though the risks and benefits of this preventive strategy are uncertain.

Similarly, small trials have indicated that the antihypertensive agent clonidine, an alpha₂ adrenergic agonist, reduces the risk of myocardial ischemia without inducing hemodynamic instability when given to at-risk patients undergoing noncardiac surgery, which in turn may prevent MI and death. Clonidine has additional analgesic, anxiolytic, antishivering, and anti-inflammatory effects that may be helpful.

The POISE-2 trial was designed to determine whether either of these approaches was more effective than placebo at preventing the composite endpoint of MI or death within 30 days of surgery.

A total of 10,010 patients were enrolled at 135 hospitals in 23 countries, stratified by whether they were already taking daily aspirin prophylaxis, and randomly assigned in a double-blind fashion to receive either perioperative aspirin (4,998 subjects) or placebo (5,012 subjects), and to receive either perioperative clonidine (5,009 subjects) or placebo (5,001 subjects). The mean age of these participants was 68.6 years, and 52.8% were men. Most were at risk because of their history of vascular disease; advanced age; need for dialysis; smoking status; or comorbid diabetes, heart failure, transient ischemic attack, or hypertension.

The types of surgery they underwent included general, orthopedic, urologic, gynecologic, vascular, and thoracic procedures.

The primary outcome of death or MI occurred in 7% of the aspirin group and 7.1% of the placebo group, a nonsignificant difference. The risks of other adverse outcomes, including stroke, cardiac revascularization, pulmonary embolism, acute kidney injury, and deep vein thrombosis, also were not significantly different between the two groups.

Median length of hospital stay and length of ICU and CCU stays also were not significantly different between patients who received aspirin and those who received placebo. However, aspirin raised the risk of major bleeding (4.6%), compared with placebo (3.8%), for a hazard ratio of 1.23. The most common sites of bleeding were the surgical site and the GI tract.

These effects were consistent across all subgroups of patients. In particular, they were the same whether the patients were already taking daily prophylactic aspirin therapy.

Clonidine also did not prevent death or MI within 30 days, compared with placebo; the rates were 7.3% and 6.8%, respectively. The risks of other adverse outcomes also were not significantly different between the two groups, nor were lengths of hospital, ICU, or CCU stays. However, clonidine raised the risk of clinically important hypotension (47.6% vs. 37.1%), clinically important bradycardia (12% vs. 8.1%), and nonfatal cardiac arrest (0.3% vs. 0.1%).

These effects were consistent across all subgroups of patients. In particular, clonidine was no more beneficial than was placebo in patients who underwent vascular surgery, a subgroup in whom previous, smaller studies found the drug to protect against both MI and mortality.

POISE-2 was not designed to determine why aspirin wasn’t effective at preventing perioperative MI, but Dr. Devereaux and his associates offered three possible explanations. First, MI was associated with major bleeding, and aspirin raises the risk of this complication. "It is possible that aspirin prevented some perioperative MI through thrombus inhibition [but] caused some MIs through bleeding and the subsequent mismatch between the supply of and the demand for myocardial oxygen, thus resulting in the overall neutral effect in our study," they said.

Second, the heart rate findings couldn’t statistically rule out a possible moderate beneficial effect of aspirin therapy. And third, it is possible that coronary-artery thrombus isn’t the dominant mechanism of perioperative MI, and aspirin’s antithrombotic effect didn’t address this unknown dominant mechanism.

Similarly, it is not known why clonidine failed to be protective, but the investigators offered two possible reasons. First, the drug induced hypotension, which raises the risk of perioperative MI. And second, it also induced bradycardia, which may be a proxy for an overall adverse effect on heart rate control; this also can increase the risk of perioperative MI, they said.

The POISE-2 trial was supported by the Canadian Institutes of Health Research, the National Health and Medical Research Council of Australia, and the Spanish Ministry of Health and Social Policy. Bayer Pharma provided the aspirin used in the study, and Boehringer Ingelheim provided the clonidine and some funding. Dr. Devereaux reported ties to Abbott, Bayer Pharma, Boehringer Ingelheim, Covidien, Roche, and Stryker and; some of his associates reported ties to several industry sources.